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1.	Ahmad, Abrar, et al. (author) Alpha 2-macroglobulin 5 bp insertion/deletion polymorphism increases the risk of recurrent venous thromboembolism 2018 In: Gene Reports. - : Elsevier BV. - 2452-0144. ; 13, s. 104-109 Journal article (peer-reviewed)abstract Alpha 2-macroglobulin (A2M) is a protease inhibitor that has been reported to neutralize thrombin, which may decrease the risk of thrombosis. A 5-base pairs (bp) insertion/deletion polymorphism (rs3832852) at the splice acceptor site of exon 18 has been shown to affect the binding of A2M with proteases. However, the role of this important variant in A2M in recurrent VTE is unknown. We investigated the role of 5 bp insertion/deletion polymorphism in VTE recurrence in a follow up study. A2M 5 bp insertion/deletion polymorphism was genotyped in Malmö Thrombophilia Study (MATS, n = 1465, with follow up of ~10 years) by TaqMan Allelic Discrimination assay. Univariate Cox regression analysis showed that A2M polymorphism was significantly associated with higher risk of VTE recurrence (hazard ratio [HR] = 2.61, 95% confidence interval [CI] = 1.06–6.45, P = 0.037). This association remained significant (HR = 2.61, 95% CI = 1.06–6.47, P = 0.038) even after adjusting for sex, family history of VTE, thrombophilia and acquired risk factors for VTE. In conclusion, our results indicate that patients with A2M 5 bp insertion/deletion polymorphism are at significantly higher risk of VTE recurrence and this may predict VTE recurrence.
2.	Ahmad, Abrar, et al. (author) Association between TLR9 rs5743836 polymorphism and risk of recurrent venous thromboembolism 2017 In: Journal of Thrombosis and Thrombolysis. - : Springer Science and Business Media LLC. - 1573-742X .- 0929-5305. ; 44:1, s. 130-138 Journal article (peer-reviewed)abstract Recent gene knockout studies on mice have shown the role of toll-like receptor 9 (TLR9) in resolution of venous thromboembolism (VTE) through sterile inflammation. However, the role of a putative functional TLR9 polymorphism (rs5743836) in risk assessment of VTE recurrence remains unknown. The aim of our study was to investigate the TLR9 rs5743836 polymorphism in VTE patients and its association with the risk of VTE recurrence. We analyzed TLR9 rs5743836 polymorphism in Malmö thrombophilia study patients; a prospective follow-up study of 1465 VTE patients by Taqman PCR. From a total of 1465 VTE patients, those who had VTE before inclusion and those who died or had VTE recurrence during anticoagulant treatment were excluded (n = 415). Cox regression analyses were performed on the remaining 1050 VTE patients, including 126 (12.5%) patients that had recurrent VTE during follow-up period. TLR9 polymorphism was significantly associated with higher risk of VTE recurrence in female patients (HR 3.46, 95% CI 1.06-11.33) independent of acquired risk factors for VTE, family history, risk of thrombophilia and deep vein thrombosis (DVT) location. Similarly, in unprovoked VTE patients, TLR9 polymorphism was significantly associated with higher risk of VTE recurrence in female patients (HR 5.94, 95% CI 1.25-28.13) after adjusting for family history, risk of thrombophilia and DVT location. No association between TLR9 polymorphism and risk of VTE recurrence was found in male patients. Our results suggest that TLR9 rs5743836 polymorphism is an independent risk factor for VTE recurrence in female patients but not in males.
3.	Ahmad, Abrar, et al. (author) Evaluation of Expression Level of Apolipoprotein M as a Diagnostic Marker for Primary Venous Thromboembolism 2018 In: Clinical and Applied Thrombosis/Hemostasis. - : SAGE Publications. - 1938-2723 .- 1076-0296. ; 24:3, s. 416-422 Journal article (peer-reviewed)abstract Recently, decreased levels of apolipoprotein M (ApoM) were shown to be associated with higher risk of recurrent venous thromboembolism (VTE) in male patients. However, the role of ApoM in primary VTE is unknown. We aimed in our study to analyze the plasma levels of ApoM in patients with VTE in order to evaluate the diagnostic importance of ApoM in primary VTE. A total of 357 patients with suspected first episode of VTE were recruited prospectively in the SCORE study. Plasma samples from 307 patients were available for quantifying the plasma levels of ApoM in patients with VTE using sandwich enzyme-linked immunosorbent assay method. Among the whole population, plasma levels (mean [standard deviation]) of ApoM were not significantly different between patients with VTE (0.72 [0.20]) and non-VTE patients (0.72 [0.16]), P = .99. Similarly, in regression analyses, no significant association of ApoM plasma levels with the risk of VTE was found on univariate (odds ratio [OR] =1.0, 95% confidence interval [CI] 0.21-4.84, P = .99) and multivariate analysis (OR = 1.25, 95% CI = 0.19-8.34, P = .819) after adjusting for age, body mass index, and smoking. Moreover, results did not differ significantly after stratification of data according to sex ( P > .05). In this study, our results do not suggest a diagnostic role for ApoM plasma levels in patients with primary VTE. Moreover, the current study suggests that role of ApoM as a risk factor may differ for primary VTE and recurrent VTE in male patients.
4.	Ahmad, Abrar, et al. (author) Fat mass and obesity-associated gene rs9939609 polymorphism is a potential biomarker of recurrent venous thromboembolism in male but not in female patients 2018 In: Gene. - : Elsevier BV. - 0378-1119. ; 647, s. 136-142 Journal article (peer-reviewed)abstract Multiple genetic variations have been identified in FTO (fat mass and obesity-associated) gene. Among them, FTO rs9939609 polymorphism is shown to be associated with the risk of primary venous thromboembolism (VTE). However, its role in recurrent VTE is not known. The aim of our study was to investigate the association between FTO rs9939609 polymorphism and the risk of VTE recurrence in a prospective follow-up study in both male and female patients. FTO rs9939609 polymorphism (T/A) was analyzed in the Malmö thrombophilia study (MATS, followed for ~10 years) by using TaqMan PCR. MATS patients (n = 1050) were followed from the discontinuation of anticoagulant treatment until diagnosis of VTE recurrence or the end of follow-up. A total of 126 patients (12%) had VTE recurrence during follow-up. Cox regression analyses showed that sex modified the potential effect of FTO rs9939609 polymorphism on VTE recurrence. Male patients with the AA genotype for the FTO rs9939609 polymorphism had significantly higher risk of VTE recurrence as compared to the TT or AT genotypes (univariate hazard ratio [HR] = 2.05, 95% confidence interval [CI] = 1.2-3.5, P = 0.009 and adjusted HR = 2.03, 95% CI 1.2-3.6, P = 0.013). There was no association between FTO rs9939609 polymorphism and VTE recurrence in female patients. In conclusion, our results show that FTO rs9939609 polymorphism in recurrent VTE may differ according to gender and FTO polymorphism may predict VTE recurrence in male patients.
5.	Ahmad, Abrar, et al. (author) Identification of Genetic Aberrations in Thrombomodulin Gene in Patients with Recurrent Venous Thromboembolism 2017 In: Clinical and Applied Thrombosis/Hemostasis. - : SAGE Publications. - 1076-0296 .- 1938-2723. ; 23:4, s. 319-328 Journal article (peer-reviewed)abstract Thrombomodulin (THBD) serves as a cofactor for thrombin-mediated activation of anticoagulant protein C pathway. Genetic aberrations in THBD have been studied in arterial and venous thrombosis. However, genetic changes in THBD and their role in the risk assessment of recurrent venous thromboembolism (VTE) are not well understood. The aim of the present study was to identify the genetic aberrations in THBD and their association with the risk of VTE recurrence in a prospective population-based study. We sequenced the entire THBD gene, first in selected patients with VTE (n = 95) by Sanger sequencing and later validated those polymorphisms with minor allele frequency (MAF) ≥5% in the whole study population (n = 1465 with the follow-up period of 1998-2008) by Taqman polymerase chain reaction. In total, we identified 8 polymorphisms in THBD, and 3 polymorphisms with MAF ≥5% were further validated. No significant association between THBD polymorphisms and risk of VTE recurrence on univariate or multivariate Cox regression analysis was found (hazard ratio [HR] = 0.89, 95% confidence interval [CI] = 0.62-1.28, HR = 1.27, 95% CI = 0.88-1.85, and HR = 1.15, 95% CI = 0.80-1.66 for THBD rs1962, rs1042580, and rs3176123 polymorphisms, respectively), adjusted for family history, acquired risk factors for VTE, location of deep vein thrombosis, and risk of thrombophilia. Subanalysis of patients with unprovoked first VTE also showed no significant association of identified THBD polymorphisms with the risk of VTE recurrence. Our results show that aberrations in the THBD gene may not be useful for the assessment of VTE recurrence; however, further studies with large sample size are needed to confirm these findings.
6.	Ahmad, Abrar, et al. (author) Identification of polymorphisms in Apolipoprotein M gene and their relationship with risk of recurrent venous thromboembolism 2016 In: Thrombosis and Haemostasis. - 0340-6245. ; 116:3, s. 41-432 Journal article (peer-reviewed)abstract Apolipoprotein M (ApoM) plasma levels have been reported to be associated with risk of venous thromboembolism (VTE) recurrence. However, the role of genetic alterations in the ApoM gene in VTE recurrence remains unknown. The aim of this study was to identify genetic aberrations in ApoM gene in VTE recurrence and their role in prediction of VTE recurrence in a prospective follow-up study of 1465 VTE patients. During follow-up, 156 (10.6 %) patients had VTE recurrence. First screening of whole ApoM gene was performed by Sanger's sequencing in selected age and sex matched non-recurrent and recurrent patients (n=95). In total six polymorphisms were identified and two polymorphisms (rs805297 and rs9404941) with minor allele frequency (MAF) ≥5 % were further genotyped in the whole cohort by Taqman PCR. ApoM rs805297 polymorphism was significantly associated with higher risk of VTE recurrence in males but not in females on both univariate (p= 0.038, hazard ratio = 1.72, confidence interval = 1.03-2.88) and on multivariate analysis adjusted with mild and severe thrombophilia, family history, location and acquired risk factors for VTE. However, ApoM rs9404941 polymorphism showed no significant association with risk of VTE recurrence in all patients as well as in different gender groups. Moreover, ApoM rs805297 and rs9404941 polymorphisms were not associated with the ApoM plasma levels. In conclusion, for the first time we have sequenced whole ApoM gene in VTE and identified six polymorphisms. ApoM rs805297 was significantly associated with higher risk of VTE recurrence in male but not in female patients.
7.	Ahmad, Abrar, et al. (author) Risk prediction of recurrent venous thromboembolism : a multiple genetic risk model 2019 In: Journal of Thrombosis and Thrombolysis. - : Springer Science and Business Media LLC. - 0929-5305 .- 1573-742X. ; 47:2, s. 216-226 Journal article (peer-reviewed)abstract A single genetic biomarker is unable to accurately predict the risk for venous thromboembolism (VTE) recurrence. We aimed to: (a) develop a multiple single nucleotide polymorphisms (SNPs) model to predict the risk of VTE recurrence and (b) validate a previously described genetic risk score (GRS) and compare its performance with the model developed in this study. Twenty-two SNPs, including established and putative SNPs associated with VTE risk, were genotyped in the Malmö thrombophilia study cohort (MATS; n = 1465, follow-up ~ 10 years) by using TaqMan PCR. Out of 22-SNPs, 12 had an association with the risk of VTE recurrence and were included for calculating GRSs. The risk of VTE recurrence was calculated by stratifying patients according to number of risk alleles. In 12-SNP GRS, patients with ≥ 7 risk alleles were associated with higher risk of VTE recurrence compared to patients having ≤ 6 risk alleles. In a simplified model (8-SNP GRS), the discriminative power of 8-SNP GRS was similar to that of 12-SNP GRS based on post-test probabilities (PP). Furthermore, 8-SNP GRS further improved the risk prediction of VTE recurrence in unprovoked VTE and male patients (PP% = 15.4 vs 8.3, 17.1 vs 7.2 and 19.0 vs 7.1 for high risk groups vs low risk groups in whole population, males and unprovoked VTE patients respectively). In addition, we also validated previously described 5-SNP GRS in our cohort and found that the 8-SNP GRS performed better than the 5-SNP GRS in terms of higher PP. Our results show that a multiple SNP GRS consisting of 8-SNPs may be an effective model for prediction of VTE recurrence, particularly in unprovoked VTE and male patients.
8.	Ahmad, Abrar, et al. (author) Thrombomodulin gene c.1418C>T polymorphism and risk of recurrent venous thromboembolism. 2016 In: Journal of Thrombosis and Thrombolysis. - : Springer Science and Business Media LLC. - 1573-742X .- 0929-5305. ; 42:1, s. 135-141 Journal article (peer-reviewed)abstract Thrombomodulin gene (THBD) is a critical cofactor in protein C anticoagulant system. THBD c.1418C>T polymorphism is reported to be associated with higher risk of primary venous thromboembolism (VTE) but its role in VTE recurrence is unknown. The aim of this study was to investigate the role of THBD polymorphism in VTE recurrence. THBD c.1418C>T polymorphism was genotyped by using Taqman polymerase chain reaction in a prospective population based study of 1465 consecutive objectively verified VTE patients. Uni- and multivariate Cox regression were performed for the risk assessment of VTE recurrence. Patients who had VTE before inclusion or had recurrence or died during anticoagulant treatment were excluded. Among the remaining (N = 1046) patients, 126 (12.05 %) had VTE recurrence during the follow up period (from 1998 to 2008). THBD polymorphism was not significantly associated with risk of VTE recurrence in the univariate [Hazard ratio (HR) 1.11, 95 % confidence interval (CI) 0.78-1.59, p = 0.55] as well as the multivariate analysis adjusted for age, sex and thrombophilia (HR 1.11, 95 % CI 0.78-1.59, p = 0.54). Similarly, in unprovoked first VTE (n = 614), no association was observed between THBD polymorphism and risk of VTE recurrence (HR 1.22 and 95 % CI 0.78-1.89, p = 0.38). In this prospective study, our results do not suggest a predictive role for THBD c.1418C>T polymorphism in VTE recurrence.
9.	Ahrén, Jonatan, et al. (author) A hypothesis - generating Swedish extended national cross-sectional family study of multimorbidity severity and venous thromboembolism 2023 In: BMJ Open. - 2044-6055. ; 13:6, s. 1-8 Journal article (peer-reviewed)abstract OBJECTIVES: Venous thromboembolism (VTE) is a common worldwide disease. The burden of multimorbidity, that is, two or more chronic diseases, has increased. Whether multimorbidity is associated with VTE risk remains to be studied. Our aim was to determine any association between multimorbidity and VTE and any possible shared familial susceptibility.DESIGN: A nationwide extended cross-sectional hypothesis - generating family study between 1997 and 2015.SETTING: The Swedish Multigeneration Register, the National Patient Register, the Total Population Register and the Swedish cause of death register were linked.PARTICIPANTS: 2 694 442 unique individuals were analysed for VTE and multimorbidity.MAIN OUTCOMES AND MEASURES: Multimorbidity was determined by a counting method using 45 non-communicable diseases. Multimorbidity was defined by the occurrence of ≥2 diseases. A multimorbidity score was constructed defined by 0, 1, 2, 3, 4 or 5 or more diseases.RESULTS: Sixteen percent (n=440 742) of the study population was multimorbid. Of the multimorbid patients, 58% were females. There was an association between multimorbidity and VTE. The adjusted odds ratio (OR) for VTE in individuals with multimorbidity (2 ≥ diagnoses) was 3.16 (95% CI: 3.06 to 3.27) compared with individuals without multimorbidity. There was an association between number of diseases and VTE. The adjusted OR was 1.94 (95% CI: 1.86 to 2.02) for one disease, 2.93 (95% CI: 2.80 to 3.08) for two diseases, 4.07 (95% CI: 3.85 to 4.31) for three diseases, 5.46 (95% CI: 5.10 to 5.85) for four diseases and 9.08 (95% CI: 8.56 to 9.64) for 5 ≥ diseases. The association between multimorbidity and VTE was stronger in males OR 3.45 (3.29 to 3.62) than in females OR 2.91 (2.77 to 3.04). There were significant but mostly weak familial associations between multimorbidity in relatives and VTE.CONCLUSIONS: Increasing multimorbidity exhibits a strong and increasing association with VTE. Familial associations suggest a weak shared familial susceptibility. The association between multimorbidity and VTE suggests that future cohort studies where multimorbidity is used to predict VTE might be worthwhile.
10.	Ahrén, Jonatan, et al. (author) Multimorbidity disease clusters are associated with venous thromboembolism : an extended cross-sectional national study In: Journal of Thrombosis and Thrombolysis. - 0929-5305. Journal article (peer-reviewed)abstract Multimorbidity, i.e., two or more non-communicable diseases (NCDs), is an escalating challenge for society. Venous thromboembolism (VTE) is a common cardiovascular disease and it is unknown which multimorbidity clusters associates with VTE. Our aim was to examine the association between different common disease clusters of multimorbidity and VTE. The study is an extended (1997–2015) cross-sectional Swedish study using the National Patient Register and the Multigeneration Register. A total of 2,694,442 Swedish-born individuals were included in the study. Multimorbidity was defined by 45 NCDs. A principal component analysis (PCA) identified multimorbidity disease clusters. Odds ratios (OR) for VTE were calculated for the different multimorbidity disease clusters. There were 16% (n = 440,742) of multimorbid individuals in the study population. Forty-four of the individual 45 NCDs were associated with VTE. The PCA analysis identified nine multimorbidity disease clusters, F1-F9. Seven of these multimorbidity clusters were associated with VTE. The adjusted OR for VTE in the multimorbid patients was for the first three clusters: F1 (cardiometabolic diseases) 3.44 (95%CI 3.24–3.65), F2 (mental disorders) 2.25 (95%CI 2.14–2.37) and F3 (digestive system diseases) 4.35 (95%CI 3.63–5.22). There was an association between multimorbidity severity and OR for VTE. For instance, the occurrence of at least five diseases was in F1 and F2 associated with ORs for VTE: 8.17 (95%CI 6.32–10.55) and 6.31 (95%CI 4.34–9.17), respectively. In this nationwide study we have shown a strong association between VTE and different multimorbidity disease clusters that might be useful for VTE prediction. Graphical abstract: (Figure presented.)
11.	Akrawi, Delshad, et al. (author) End stage renal disease risk and neighbourhood deprivation: A nationwide cohort study in Sweden. 2014 In: European Journal of Internal Medicine. - : Elsevier BV. - 1879-0828 .- 0953-6205. ; 25:9, s. 853-859 Journal article (peer-reviewed)abstract Chronic kidney disease has been associated with socioeconomic disparities and neighbourhood deprivation. We aimed to determine whether there is an association between neighbourhood deprivation and end stage renal disease (ESRD), and whether this association is independent of individual-level sociodemographic factors and comorbidities.
12.	Akrawi, Delshad, et al. (author) Familial risks of kidney failure in sweden: a nationwide family study. 2014 In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:11 Journal article (peer-reviewed)abstract The value of family history as a risk factor for kidney failure has not been determined in a nationwide setting.
13.	Akrawi, Delshad Saleh, et al. (author) Familial risks of glomerulonephritis : a nationwide family study in Sweden 2016 In: Annals of Medicine. - : Informa UK Limited. - 0785-3890 .- 1365-2060. ; 48:5, s. 313-322 Journal article (peer-reviewed)abstract Objective: Familial risks of glomerulonephritis (acute, chronic and unspecified glomerulonephritis) have not been studied. This study aims to determine the familial risks of glomerulonephritis. Methods: Individuals born from1932 onwards diagnosed with glomerulonephritis (acute [n = 7011], chronic [n = 10,242] and unspecified glomerulonephritis [n = 5762]) were included. The familial risk (Standardized incidence ratio = SIR) was calculated for individuals whose parents/full-siblings were diagnosed with glomerulonephritis compared to those whose parents/full-siblings were not. The procedure was repeated for spouses. Familial concordant risk (same disease in proband and exposed relative) and discordant risk (different disease in proband and exposed relative) of glomerulonephritis were determined. Results: Familial concordant risks (parents/full-sibling history) were: SIR = 3.57 (95% confidence interval, 2.77–4.53) for acute glomerulonephritis, SIR = 3.84 (3.37–4.36) for chronic glomerulonephritis and SIR = 3.75 (2.85–4.83) for unspecified glomerulonephritis. High familial risks were observed if two or more relatives were affected; the SIR was 209.83 (150.51–284.87) in individuals with at least one affected parent as well as one full-sibling. The spouse risk was only moderately increased (SIR = 1.53, 1.33–1.75). Conclusions: Family history of glomerulonephritis is a strong predictor for glomerulonephritis, and is a potentially useful tool in clinical risk assessment. Our data emphasize the contribution of familial factors to the glomerulonephritis burden in the community.Key messagesThe familial risks (full-sibling/parent history) of glomerulonephritis (acute, chronic and unspecified glomerulonephritis) have not been determined previously.The familial risks of glomerulonephritis were increased among individuals with family history of acute, chronic or unspecified glomerulonephritis.The familial risks of glomerulonephritis were slightly increased among spouses indicating a modest non-genetic contribution.Very high familial risks were observed in multiplex families, i.e. with one or more affected first-degree relatives.
14.	Akrawi, Delshad Saleh, et al. (author) Heritability of End-Stage Renal Disease : A Swedish Adoption Study 2018 In: Nephron. - : S. Karger AG. - 1660-8151 .- 2235-3186. ; 138:2, s. 157-165 Journal article (peer-reviewed)abstract Background/Aims: The heritability of end-stage renal disease (ESRD) among adoptees has not been examined so far. By studying adoptees and their biological and adoptive parents, it is possible to differentiate between the genetic causes and environmental causes of familial aggregation. This nationwide study aimed to disentangle the genetic and shared environmental contribution to the familial transmission of ESRD. Methods: We performed a family study for Swedish-born adoptees (born between 1945 until 1995) and their biological and adoptive parents. The Swedish Multi-Generation Register was linked to the National Patient Registry for the period 1964–2012. ESRD was defined as patients in active uremic care, that is, chronic dialysis or kidney transplantation. OR for ESRD was determined for adoptees with an affected biological parent with ESRD compared with adoptees without a biological parent with ESRD. The OR for ESRD was also calculated in adoptees with an adoptive parent with ESRD compared with adoptees with an adoptive parent without ESRD. Moreover, heritability for ESRD was estimated with Falconer’s regression. Results: A total of 111 adoptees, 463 adoptive parents, and 397 biological parents were affected by ESRD. The OR for ESRD was 6.41 in adoptees (95% CI 2.96–13.89) of biological parents diagnosed with ESRD. The OR for ESRD was 2.40 in adoptees (95% CI 0.76–7.60) of adoptive parents diagnosed with ESRD. The heritability of ESRD was 59.5 ± 18.2%. Conclusion: The family history of ESRD in a biological parent is an important risk factor for ESRD. The high heritability indicates that genetic factors play an important role in understanding the etiology of ESRD.
15.	Akrawi, Delshad Saleh, et al. (author) Heritability of glomerulonephritis : A Swedish adoption study 2019 In: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 49:8 Journal article (peer-reviewed)abstract Background: Glomerulonephritis clusters in families. However, infections are common inducers of glomerulonephritis and may also cluster in families. Studies of adoptees and their biological and adoptive parents may disentangle genetic from environmental causes of familial clustering. This is the first adoption study aimed to estimate the genetic contribution to the familial transmission of glomerulonephritis. Materials and methods: We performed a family study for Swedish-born adoptees (born 1945–2000) and their biological and adoptive parents. The Swedish Multi-Generation Register was linked to the Hospital Inpatient Register for the period 1964–2012 and the Hospital Outpatient Register for 2001–2012. Odds ratio (OR) for glomerulonephritis was determined for adoptees with a biological parent with glomerulonephritis compared with adoptees without an affected biological parent. Similarly, the OR for glomerulonephritis was also determined in adoptees with an affected adoptive parent compared with adoptees without an affected adoptive parent. Heritability was estimated to be twice the observed tetrachoric correlation among adoptees and biological parents, under the assumption that only additive genetic factors contribute to the similarity between biological parents and adoptees. Results: The OR for glomerulonephritis was 4.08 in adoptees (95% confidence interval [CI] 1.79-9.27, P-value = 0.001) of biological parents diagnosed with glomerulonephritis. The OR for glomerulonephritis was 1.67 in adoptees (95% CI 0.53-5.26, P-value = 0.380) of adoptive parents diagnosed with glomerulonephritis. The heritability was 48%. Conclusion: Family history of glomerulonephritis in a biological parent is a risk factor for glomerulonephritis. The present study indicates that genetic factors play an important role in the aetiology of glomerulonephritis.
16.	Ali Khan, Uzair, et al. (author) Personal History of Diabetes as Important as Family History of Colorectal Cancer for Risk of Colorectal Cancer : A Nationwide Cohort Study 2020 In: The American journal of gastroenterology. - : Ovid Technologies (Wolters Kluwer Health). - 1572-0241 .- 0002-9270. ; 115:7, s. 1103-1109 Journal article (peer-reviewed)abstract INTRODUCTION: Diabetes mellitus (DM) and colorectal cancer (CRC) share some risk factors, including lifestyle and metabolic disturbances. We aimed to provide in-depth information on the association of CRC risk, especially early-onset CRC, with DM, family history of CRC, and age at DM diagnosis. METHODS: A nationwide cohort study was conducted using Swedish family cancer data sets, inpatient, and outpatient registers (follow-up: 1964-2015), including all individuals born after 1931 and their parents (12,614,256 individuals; 559,375 diabetic patients; 162,226 CRC patients). RESULTS: DM diagnosis before the age of 50 years was associated with a 1.9-fold increased risk of CRC before the age of 50 years (95% CI for standardized incidence ratio: 1.6-2.3) vs 1.3-fold risk of CRC at/after the age of 50 years (1.2-1.4). DM diagnosis before the age of 50 years in those with a family history of CRC was associated with 6.9-fold risk of CRC before the age of 50 years (4.1-12) and 1.9-fold risk of CRC at/after the age of 50 years (1.4-2.5). Diabetic patients had a similar lifetime risk of CRC before the age of 50 years (0.4%, 95% CI: 0.3%-0.4%) to those with only a family history of CRC (0.5%, 0.5%-0.5%), double that of the population (0.2%, 0.2%-0.2%). DISCUSSION: Our large cohort with valid information on DM and family history of cancer showed that DM is associated with increased risk of CRC in a magnitude close to having family history of CRC. Associations of DM and CRC family history with increased CRC risk were most prominent in young adults. These findings warrant further studies on harms, benefits, and cost-effectiveness of CRC screening in patients with diabetes, especially type 2, at earlier ages than in the general population.
17.	Ali Khan, Uzair, et al. (author) Risk of colorectal cancer in patients with diabetes mellitus : A Swedish nationwide cohort study 2020 In: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1676. ; 17:11 Journal article (peer-reviewed)abstract BACKGROUND: Colorectal cancer (CRC) incidence is increasing among young adults below screening age, despite the effectiveness of screening in older populations. Individuals with diabetes mellitus are at increased risk of early-onset CRC. We aimed to determine how many years earlier than the general population patients with diabetes with/without family history of CRC reach the threshold risk at which CRC screening is recommended to the general population. METHODS AND FINDINGS: A nationwide cohort study (follow-up:1964-2015) involving all Swedish residents born after 1931 and their parents was carried out using record linkage of Swedish Population Register, Cancer Registry, National Patient Register, and Multi-Generation Register. Of 12,614,256 individuals who were followed between 1964 and 2015 (51% men; age range at baseline 0-107 years), 162,226 developed CRC, and 559,375 developed diabetes. Age-specific 10-year cumulative risk curves were used to draw conclusions about how many years earlier patients with diabetes reach the 10-year cumulative risks of CRC in 50-year-old men and women (most common age of first screening), which were 0.44% and 0.41%, respectively. Diabetic patients attained the screening level of CRC risk earlier than the general Swedish population. Men with diabetes reached 0.44% risk at age 45 (5 years earlier than the recommended age of screening). In women with diabetes, the risk advancement was 4 years. Risk was more pronounced for those with additional family history of CRC (12-21 years earlier depending on sex and benchmark starting age of screening). The study limitations include lack of detailed information on diabetes type, lifestyle factors, and colonoscopy data. CONCLUSIONS: Using high-quality registers, this study is, to our knowledge, the first one that provides novel evidence-based information for risk-adapted starting ages of CRC screening for patients with diabetes, who are at higher risk of early-onset CRC than the general population.
18.	Amstadter, Ananda B., et al. (author) Post-traumatic stress disorder and drug use disorder : examination of aetiological models in a Swedish population-based cohort 2023 In: European Journal of Psychotraumatology. - 2000-8066. ; 14:2 Journal article (peer-reviewed)abstract Background: There are two primary phenotypic models of comorbidity between post-traumatic stress disorder (PTSD) and drug use disorder (DUD), i.e. self-medication (PTSD precedes and causes DUD) and susceptibility (DUD precedes and causes PTSD). We sought to clarify the longitudinal relationship between PTSD and DUD, while examining sex differences. Method: We used approximately 23 years of longitudinal data from Swedish population registries to conduct two complementary statistical models: Cox proportional hazard models (N ≈ 1.5 million) and a cross-lagged panel model (N ≈ 3.8 million). Results: Cox proportional hazards models, adjusting for cohort and socioeconomic status, found strong evidence for the self-medication hypothesis, as PTSD predicted increased risk for DUD among both women [hazard ratio (HR) = 5.34, 95% confidence interval (CI) 5.18, 5.51] and men (HR = 3.65, 95% CI 3.54, 3.77), and moreover, that the PTSD to DUD association was significantly higher among women (interaction term 0.68, 95% CI 0.65, 0.71). The results of the susceptibility model were significant, but not as strong as the self-medication model. DUD predicted risk for PTSD among both women (HR = 2.43, 95% CI 2.38, 2.50) and men (HR = 2.55, 95% CI 2.50, 2.60), and HR was significantly higher in men (interaction term 1.05, 95% CI 1.02, 1.08). Investigating the pathways simultaneously in the cross-lagged model yielded support for both pathways of risk. The cross-paths instantiating the susceptibility model (0.10–0.22 in females, 0.12–0.19 in males) were mostly larger than those capturing the self-medication model (0.01–0.16 in females, 0.04–0.22 in males). Conclusions: We demonstrate that the relationship between PTSD and DUD is bidirectional, with evidence that future research should prioritize examining specific pathways of risk that may differ between men and women.
19.	Amstadter, Ananda B., et al. (author) Testing Phenotypic Models of Posttraumatic Stress Disorder and Alcohol Use Disorder Comorbidity Using Longitudinal Registry Data 2023 In: Journal of Studies on Alcohol and Drugs. - : Alcohol Research Documentation, Inc.. - 1937-1888 .- 1938-4114. ; 84:3, s. 378-388 Journal article (peer-reviewed)abstract Objective: Two predominant phenotypic models of causality exist to explain the high co-occurrence of posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD): the self-medication and susceptibility models. Population-based longitudinal studies that simultaneously examine both models are needed. Thus, the goal of the pres-ent study is to test these models using the Swedish National Registries. Method: Registries were used to conduct longitudinal Cox proportional hazard models (n ≈ 1.5 million) and cross-lagged panel models (N ≈ 3.8 million) with follow-up periods of ~23 years. Results: Covarying for cohort and socioeconomic status, Cox proportional hazards model results found strong support for the self-medication model. Results showed that PTSD predicted increased risk for AUD among both men (HR = 4.58 [4.42, 4.74]) and women (HR = 4.14 [3.99, 4.30]), significantly more so for men (interaction HR = 1.11 [1.05, 1.16]). Support was also found for the susceptibility model, although the effects were lower in magnitude than those for the self-medication model. AUD increased risk for PTSD among men (HR = 2.53 [2.47, 2.60]) and women (HR = 2.06 [2.01, 2.12]), and significantly more so for men (interaction term HR = 1.23 [1.18, 1.28]). Cross-lagged model results of simultaneously testing both models found support for bidirectionality. The PTSD-to-AUD paths and the AUD-to-PTSD paths were of modest effect for men and women. Conclusions: The results from both complementary statistical approaches demonstrate that the models of comorbidity are not mutually exclusive. Although the Cox model results evidenced more support for the self-medication pathway, the cross-lagged model results suggest that the prospective relationships between these disorders are nuanced across development. (J. Stud. Alcohol Drugs, 84, 378–388, 2023).
20.	Anker-Hansen, Christian, et al. (author) Mitochondria-DNA copy-number in osteoporosis and osteoarthritis among middle-aged women - A population-based cohort study 2024 In: Osteoarthritis and Cartilage Open. - 2665-9131. ; 6:3 Journal article (peer-reviewed)abstract Background: Mitochondrial DNA copy number (mtDNA-CN) is associated with aging. A relationship between mtDNA-CN and degenerative disorders, e.g. osteoarthritis (OA) and osteoporosis (OP), has been suggested. We aimed to investigate the relationship of mtDNA-CN and incident OA and OP. Materials and methods: MtDNA-CN was studied in relationship to incident OA and OP in a population-based cohort study of 6916 middle-aged women (52–63 years). Totally 2521 women with sufficient quality of mtDNA were analyzed. After exclusions, 1978 women remained in the study population. Four different endpoints obtained from the National Patient register were studied: 1) OA, 2) OP 3) OA surgery, and 4) OP fracture. In the multivariate model adjustments were made for potential OA and OP risk factors. Results: Women with low mtDNA-CN were older and had more activity at work. 125 women (6.32%) were affected by incident OP and 254 women (12.84%) had an OP fracture. Incident OA affected 451 women (22.80%) and 175 women (8.85%) had OA surgery. There were no associations between mtDNA-CN and incident risk of OA (Hazard ratio = 1.00, 95% confidence interval 0.83–1.20), OA surgery (0.79, 0.58–1.07), OP (0.89, 0.62–1.27), or OP fracture (1.00, 0.78–1.29). However, incident OP was significantly associated with T-score (bone density), smoking, diabetes mellitus, and chronic obstructive bronchitis (COPD). OA was associated with body mass index and COPD. Conclusions: The present study suggests that mtDNA-CN, reflecting mitochondrial dysfunction, is not a major predictor for incident OA or OP. However, due to the limited study size minor associations cannot be excluded.
21.	Antonson, Carl, et al. (author) Stress-Related Symptoms in Swedish Adolescents: : A Study in Two Upper Secondary Schools 2014 In: Journal of Educational and Developmental Psychology. - : Canadian Center of Science and Education. - 1927-0526 .- 1927-0534. ; 4:2, s. 65-73 Journal article (peer-reviewed)
22.	Antonson, Carl, et al. (author) Upper secondary school students’ compliance with two Internet-based self-help programmes : a randomised controlled trial 2017 In: European Child and Adolescent Psychiatry. - : Springer Science and Business Media LLC. - 1018-8827 .- 1435-165X. ; , s. 1-10 Journal article (peer-reviewed)abstract Psychiatric symptoms and stress are on the increase among Swedish adolescents. We aimed to study the potential effect and feasibility of two Internet-based self-help programmes, one mindfulness based (iMBI) and the other music based in a randomised controlled trial that targeted adolescents. A total of 283 upper secondary school students in two Swedish schools were randomised to either a waiting list or one of the two programmes, on their own incentive, on schooltime. General psychiatric health (Symptoms Checklist 90), sleep quality (Pittsburgh Sleep Quality Index), and perceived stress (Perceived Stress Scale) were assessed before and after the interventions. In total, 202 participants answered the questionnaires. Less than 20 logged into each intervention and only 1 performed a full intervention (iMBI). No significant differences in any of the scales were found between those who logged in and those who did not. The potential effect of Internet-based self-help programmes was not possible to examine due to low compliance rates. Adolescents seem to have a very low compliance with Internet-based self-help programmes if left to their own incentive. There were no associations between the psychiatric and stress-related symptoms at baseline and compliance in any of the intervention groups, and no evidence for differences in compliance in relation to the type of programme. Additional studies are needed to examine how compliance rates can be increased in Internet-based self-help mindfulness programmes in adolescents, as the potentially positive effects of mindfulness are partly related to compliance rates.
23.	Arvidsson, Daniel, et al. (author) Cross-cultural validation of a simple self-report instrument of physical activity in immigrants from the Middle East and native Swedes. 2014 In: Scandinavian Journal of Public Health. - : SAGE Publications. - 1403-4948 .- 1651-1905. ; 42:3, s. 255-262 Journal article (peer-reviewed)abstract AIM: To investigate cross-cultural validity of a simple self-report instrument of physical activity intended to be used in Swedish health care. Methods: A validation study performed in 599 Iraqis (58% men) and 553 Swedes (53% men) aged 30-75 years living in the city of Malmö, Sweden. The self-report instrument by the Swedish National Board of Health and Welfare was compared to corresponding measures assessed from accelerometry as reference. Results: The agreement between the methods in assessing the participants as sufficiently/insufficiently physically active (cut-point 150 min/week) was 65% in the Iraqis and 52% in the Swedes (p<0.001). The proportion disagreement where the self-reported physical activity was sufficient but insufficient according to the accelerometry was 26% and 45% in Iraqis and Swedes, respectively. Physical activity time (min/week) was overestimated by self-report compared to accelerometry by 71% in the Iraqis and 115% in the Swedes (p<0.001). The smallest and largest overestimation was seen in Iraqi (57%) and Swedish (139%) women, respectively. The deviation of the self-report instrument compared to accelerometry was related to the physical activity level, as the overestimation mainly occurred at lower physical activity. Conclusions: The self-report instrument proposed by the Swedish National Board of Health and Welfare may overestimate the proportion sufficiently physically active, but to an extent depending on cultural background and gender.
24.	Arvidsson, Daniel, et al. (author) Vigorous Physical Activity may be Important for the Insulin Sensitivity in Immigrants From the Middle East and Native Swedes 2015 In: Journal of Physical Activity & Health. - : Human Kinetics. - 1543-3080 .- 1543-5474. ; 12:2, s. 273-281 Journal article (peer-reviewed)abstract Purpose: To compare physical activity measures and their associations with insulin sensitivity, beta-cell function and body mass index (BMI) between Iraqi immigrants and native Swedes. Methods: A cross-sectional study of 493 Iraqis (58% men) and 469 Swedes (54% men) aged 30 to 75 years living in the city of Malmo, Sweden. Accelerometry was used for physical activity measures (sedentary time, breaks in sedentary time, moderate and vigorous physical activity, total counts). Insulin sensitivity index and oral disposal index were determined from an oral glucose tolerance test and BMI by body weight and height. Results: Iraqi men were less physically active than Swedish men, while the physical activity was more similar in the women. BMI was a strong predictor of insulin sensitivity and beta-cell function and frequently associated with the physical activity measures. BMI modified the associations of insulin sensitivity and beta-cell function with the physical activity measures to such extent that only VPA and total counts show direct associations with insulin sensitivity in addition to the indirect associations via BMI. Iraqi women demonstrated weaker associations compared with Swedish women. Conclusions: Physical activity and performed at vigorous intensity may be important mainly for the insulin sensitivity in Iraqi immigrants and native Swedes.
25.	Bennet, Louise, et al. (author) High prevalence of type 2 diabetes in Iraqi and Swedish residents in a deprived Swedish neighbourhood - a population based study 2011 In: BMC Public Health. - : Springer Science and Business Media LLC. - 1471-2458. ; 11 Journal article (peer-reviewed)abstract Background: Immigrants from the Middle-East are at high risk of developing type 2 diabetes (T2D). The aim of the present survey was to measure, in a single deprived neighbourhood, the prevalence rates of impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and T2D in residents originating from Iraq and to compare them to those in residents born in Sweden. An additional aim was to identify metabolic, lifestyle and socioeconomic risk factors associated with IFG/IGT and T2D in these residents. Methods: The study was conducted February 1'st to March 31'st 2010. Men and women aged 45 to 65 years of Swedish or Iraqi origin, living in the neighbourhood of Rosengard, Malmo, Sweden, were randomly selected from the census register. Each participant signed a written informed consent form, underwent a physical examination and an oral glucose tolerance test (OGTT), provided blood samples and filled in a questionnaire. A total of 175 subjects participated (Swedish origin n = 79, Iraqi origin n = 96), reflecting an overall response rate of almost 60%. Results: In total, 21.9% and 19.0% of the Iraqi and Swedish participants, respectively, suffered from T2D, while 24.0% of the Iraqi participants and 25.3% of the Swedish participants had IFG/IGT. There were no significant differences in prevalence rates relating to country of origin. Obesity (BMI >= 30 kg/m(2)) and sedentary leisure time physical activity were highly prevalent in both groups, while a family history of diabetes was more prevalent in participants from Iraq (49.2%) than in those from Sweden (22.8%) (p = 0.001). Being obese or having a sedentary leisure time were, independently associated with T2D (OR 5.43 (95% CI 2.10-14.02) and 2.89 (95% CI 1.03-8.10) respectively), while economic difficulties were independently associated with IFG/IGT (OR 2.55 (95% CI 1.06-6.15)) after adjustment for the confounding effects of other common risk factors for T2D. Conclusions: This study reveals a high prevalence of T2D, independently of country of origin (Iraq or Sweden), in a socially vulnerable area and additionally presents a risk factor profile that is markedly different from that of Sweden in general.
26.	Blunk, Inga, et al. (author) Genomic imprinting analyses identify maternal effects as a cause of phenotypic variability in type 1 diabetes and rheumatoid arthritis 2020 In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1 Journal article (peer-reviewed)abstract Imprinted genes, giving rise to parent-of-origin effects (POEs), have been hypothesised to affect type 1 diabetes (T1D) and rheumatoid arthritis (RA). However, maternal effects may also play a role. By using a mixed model that is able to simultaneously consider all kinds of POEs, the importance of POEs for the development of T1D and RA was investigated in a variance components analysis. The analysis was based on Swedish population-scale pedigree data. With P = 0.18 (T1D) and P = 0.26 (RA) imprinting variances were not significant. Explaining up to 19.00% (± 2.00%) and 15.00% (± 6.00%) of the phenotypic variance, the maternal environmental variance was significant for T1D (P = 1.60 × 10−24) and for RA (P = 0.02). For the first time, the existence of maternal genetic effects on RA was indicated, contributing up to 16.00% (± 3.00%) of the total variance. Environmental factors such as the social economic index, the number of offspring, birth year as well as their interactions with sex showed large effects.
27.	Calling, Susanna, et al. (author) Coronary heart disease in mothers and fathers of adult children with alcohol use disorders 2021 In: Addiction. - : Wiley. - 0965-2140 .- 1360-0443. ; 116:12, s. 3390-3397 Journal article (peer-reviewed)abstract Background and aim: Having a family member with an alcohol use disorder (AUD) may negatively affect a person's health. Our aim was to study the long-term risk of coronary heart disease (CHD) in parents who have an offspring with AUD. Design: Cohort study with Cox regression models and co-sibling analyses. Setting: Sweden. Participants: From population registers, we selected all parent-offspring pairs in which the parent was born in Sweden between 1945 and 1965. Measurements: Baseline was set when the offspring was 15 years old and AUD was assessed from medical and criminal registers. The parents were followed for CHD during a mean follow-up of 18 years. Hazard ratios (HRs) in mothers and fathers were calculated and adjusted for potential confounders (year of birth, age at childbirth, sex of the child, parent' AUD, educational level, and marital status). Findings: In mothers, the adjusted HR for CHD was 1.24 (95% CI = 1.19–1.28) in relation to having a child with AUD. In fathers, the HR for CHD was lower than in mothers but still increased; the adjusted HR was 1.08 (95% CI = 1.05–1.12). In the co-sibling analyses, the HRs for mothers were similar to the HRs estimated from the population-based sample, but in fathers the association did not remain significant (HR = 0.98 [0.90–1.06]). Conclusions: In Sweden, there appears to be an association between having an offspring with alcohol use disorder and increased risk of developing coronary heart disease. For fathers, the association did not remain in co-sibling analyses.
28.	Calling, Susanna, et al. (author) Longitudinal trends in self-reported anxiety. Effects of age and birth cohort during 25 years 2017 In: BMC Psychiatry. - : Springer Science and Business Media LLC. - 1471-244X. ; 17:1 Journal article (peer-reviewed)abstract Background: Anxiety has been suggested to increase among young individuals, but previous studies on longitudinal trends are inconclusive. The aim of this study was to analyze longitudinally, the changes over time of prevalence of self-reported anxiety in the Swedish population between 1980/1981 and 2004/2005, in different birth cohorts and age groups. Methods: A random sample of non-institutionalized persons aged 16-71years was interviewed every eighth year. Self-reported anxiety was assessed using the question" Do you suffer from nervousness, uneasiness, or anxiety?" (no; yes, mild; yes, severe). Mixed models with random intercepts were used to estimate changes in rates of anxiety (mild or severe) within different age groups and birth cohorts and in males and females separately. In addition to three time-related variables - year of interview, age at the time of the interview, and year of birth -the following explanatory variables were included: education, urbanization, marital status, smoking, leisure time physical activity and body mass index. Results: Overall prevalence of self-reported anxiety increased from 8.0 to 12.4% in males and from 17.8% to 23.6% in females, during the 25-year follow-up period. The increasing trend was found in all age groups except in the oldest age groups, and the highest increase was found in young adults 16-23years, with more than a three-fold increase in females, and a 2.5-fold increase in males, after adjustments for covariates. Conclusions: Between 1980/81 and 2004/05, there was an increasing prevalence of self-reported anxiety in all age groups except in the oldest, which indicates increased suffering for a large part of the population, and probably an increased burden on the health care system. Clinical efforts should focus particularly on young females (16-23years), where the increase was particularly large; almost one third experienced anxiety at the end of the 25-year follow-up.
29.	Calling, Susanna, et al. (author) Preterm birth and unintentional injuries: risks to children, adolescents and young adults show no consistent pattern. 2012 In: Acta paediatrica. - : Wiley. - 1651-2227 .- 0803-5253. Journal article (peer-reviewed)abstract AIM: Preterm birth is associated with a number of physical and mental health issues. The aim of this study was to find out if there was also any association between individuals born preterm in Sweden between 1984 and 2006 and the risk of unintentional injuries during childhood, adolescence and young adulthood METHODS: The study followed 2,297,134 individuals, including 5.9% born preterm, from 1985 to 2007 for unintentional injuries leading to hospitalisation or death (n=244,021). The males and females were divided into four age groups: 1-5 years, 6-12 years, 13-18 years and 19-23 years. Hazard ratios were calculated for falls, transport injuries and other injuries RESULTS: After adjusting for a comprehensive set of covariates, some of the preterm subgroups demonstrated slightly increased risks of unintentional injuries, while others showed slightly decreased risks. However, most of the estimates were borderline or non-significant in both males and females. In addition, the absolute risk differences between individuals born preterm and full term were small CONCLUSION: Despite the association between preterm birth and a variety of physical and mental health consequences, this study shows that there is no consistent risk pattern between preterm birth and unintentional injuries in childhood, adolescence and young adulthood. ©2012 The Author(s)/Acta Paediatrica ©2012 Foundation Acta Paediatrica©2012 The Author(s)/Acta Paediatrica ©2012 Foundation Acta Paediatrica.
30.	Calling, Susanna, et al. (author) Shared and non-shared familial susceptibility of coronary heart disease, ischemic stroke, peripheral artery disease and aortic disease. 2013 In: International Journal of Cardiology. - : Elsevier BV. - 0167-5273. ; 168:3, s. 2844-2850 Journal article (peer-reviewed)abstract BACKGROUND: Little is known about whether the four main manifestations of arterial vascular disease (coronary heart disease=CHD, ischemic stroke, peripheral artery disease=PAD, and aortic (i.e. atherosclerosis/aneurysm) disease=AD) share familial susceptibility. The aim of this nationwide study was to determine the familial risks of concordant (same disease in proband and exposed relative) and discordant (different disease in proband and exposed relative) cardiovascular disease (CVD). METHODS: Data from the Swedish Multigeneration Register on individuals aged 0-76years were linked to Swedish Hospital Discharge Register data for the period 1964-2008. Standardized incidence ratios (SIRs) for CHD (n=140,708 cases), ischemic stroke (n=73,771), PAD (n=18,982) and AD (n=7879) were calculated for siblings of individuals hospitalized due to CHD, stroke, PAD or AD compared to those of unaffected siblings. The procedure was repeated for parent-offspring and spouses. RESULTS: All concordant and discordant sibling risks were increased for both males and females. Concordant risks were generally higher than discordant risks. The highest sibling risks were observed for premature concordant disease (<55years for males and <65years for females): SIR for CHD=1.93 (95% CI: 1.90-1.96), SIR for ischemic stroke=1.45 (1.39-1.50), SIR for PAD=2.76 (2.54-3.00), and SIR for AD=6.36 (5.28-7.59). Premature parent-offspring transmission followed the same pattern. The disease risk was modestly increased in spouses, highest for AD (SIR=1.48 (1.28-1.69)) and PAD (SIR=1.27 (1.21-1.32)). CONCLUSIONS: The four main manifestations of CVD share familial susceptibility, but unique site-specific familial factors may exist.
31.	Calling, Susanna, et al. (author) Socioeconomic inequalities and infant mortality of 46 470 preterm infants born in Sweden between 1992 and 2006 2011 In: Paediatric and Perinatal Epidemiology. - : Wiley. - 0269-5022. ; 25:4, s. 357-365 Journal article (peer-reviewed)abstract Socioeconomic inequalities and infant mortality of 46 470 preterm infants born in Sweden between 1992 and 2006. Paediatric and Perinatal Epidemiology 2011; 25: 357-365. Studies on possible sociodemographic inequities in the survival of preterm infants are scarce. Individual and neighbourhood sociodemographic factors are related to preterm birth and to infant mortality in full-term infants. The aim here was to examine whether infant mortality in Swedish preterm infants is related to individual and neighbourhood sociodemographic factors, and to study whether the hypothesised association between neighbourhood deprivation and infant mortality persists after accounting for individual sociodemographic factors. The study included 46 470 infants with a gestational length of < 37 weeks, born in Sweden between 1992 and 2006. Neighbourhood deprivation was assessed by an index (education, income, unemployment, welfare assistance) in small geographical units, and categorised into low, moderate and high deprivation. Adjusted odds ratios for infant mortality were examined in relation to individual and neighbourhood sociodemographic factors. After adjusting for maternal age, infant mortality was associated with the following sociodemographic variables: maternal non-married/non-cohabiting status, low family income, low maternal education and rural status. After full adjustment, the odds ratio [95% confidence interval] was 2.98 [2.42, 3.67] for low family income compared with high family income. An increase in infant mortality was also associated with high neighbourhood deprivation; however, this increased risk no longer remained statistically significant after adjusting for individual sociodemographic factors. In conclusion, this study showed an increased infant mortality in preterm infants born to women with a less favourable sociodemographic profile.
32.	Calling, Susanna, et al. (author) Socioeconomic status and alcohol use disorders across the lifespan : A co-relative control study 2019 In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 14:10, s. 0224127-0224127 Journal article (peer-reviewed)abstract OBJECTIVES: Alcohol use disorders (AUD) is well known to aggregate in families and is associated with socioeconomic status (SES). The objective was to study the effect of education, income and neighborhood SES in adulthood on AUD, and to explore whether the potential associations were confounded by shared familial factors, by using a co-relative control design. METHODS: Data on AUD was drawn from the Swedish inpatient and outpatient care registers; prescription drug register; and crime data. Through national population registers we collected information on income, education and neighborhood SES at age 25, 30, 35 and 40 years in all individuals born in Sweden between 1950 and 1980. Each sex-specific stratum consisted of approximately 750,000-1,200,000 individuals, who were followed for AUD for a mean follow-up time ranging between 10 and 15 years until the end of 2013. Cox proportional hazards models were used to investigate the risk of AUD as a function of income, education and neighborhood SES in the general population and in pairs of first cousins and full siblings within the same sex, who differed in their exposure to the SES measure. RESULTS: Higher educational level, higher income and higher neighborhood SES were all associated with a reduced risk for AUD for both males and females in all ages. The potentially protective effect remained but was attenuated when comparing pairs of first cousins and full siblings. CONCLUSIONS: High educational level and income in adulthood, as well as high neighborhood socioeconomic status, may represent protective factors against alcohol use disorders, even when shared familial factors, e.g. childhood socioeconomic status and genetic factors, have been taken into account.
33.	Calling, Susanna, et al. (author) The ratio of total cholesterol to high density lipoprotein cholesterol and myocardial infarction in Women's health in the Lund area (WHILA) : a 17-year follow-up cohort study 2019 In: BMC Cardiovascular Disorders. - : Springer Science and Business Media LLC. - 1471-2261. ; 19:1 Journal article (peer-reviewed)abstract BACKGROUND: Identifying variables predictive of acute myocardial infarction (AMI) in women is important. The use of the ratio of total cholesterol-to-high density lipoprotein cholesterol (TC/HDL-C) is often overlooked. The aim was to study TC/HDL-C in relation to later AMI, in a large sample of women, adjusted for age, educational status, smoking, waist-hip ratio, blood pressure, and neighbourhood socioeconomic status. The hypothesis was that increasing TC/HDL-C is associated with an increased risk of later AMI.METHODS: From December 1995 to February 2000, 6147 women aged 50-59 years from the Womens' Health in Lund area (WHILA) study in southern Sweden underwent a physical examination, laboratory tests and filled in a questionnaire. The women were followed through national registers for incidence of AMI during a mean follow up of 17 years.RESULTS: An increasing TC/HDL-C showed a strong relationship with AMI, with the lowest hazard ratio (HR = 1) in women with a ratio of ≤3.5. The HR for AMI was 1.14 (95% CI: 0.73-1.78) for those with a ratio between 3.5 and 4.0; in those with a ratio between 4.0 and 5.0 the HR for AMI was 1.46 (95% CI: 1.00-2.13) and in those with a ratio > 5.0 the HR was 1.89 (95% CI 1.26-2.82), after adjusting for potential confounding factors.CONCLUSIONS: TC/HDL-C ratio is a powerful predictor of AMI in middle-aged women. The results indicate that this variable should be used in clinical practice and is important for early identification of individuals at risk of AMI.
34.	Calling, Susanna, et al. (author) Total cholesterol/HDL-C ratio versus non-HDL-C as predictors for ischemic heart disease : a 17-year follow-up study of women in southern Sweden 2021 In: BMC Cardiovascular Disorders. - : Springer Science and Business Media LLC. - 1471-2261. ; 21:1 Journal article (peer-reviewed)abstract Background: A distorted blood lipid profile is an important risk factor for ischemic heart disease (IHD) but the predictive ability of the different lipid measures has rarely been studied. Our aim was to examine and compare, in a large sample of women, the predictive ability of total cholesterol/HDL cholesterol ratio (TC/HDL-C) and non-HDL-C in relation to IHD, adjusted for age, exercise, smoking, waist-hip ratio, blood pressure, and diabetes mellitus. Methods: Between 1995 and 2000, a total of 6537 women aged 50–59 years from the Women’s Health in Lund area (WHILA) study in southern Sweden were included and underwent a baseline examination. The women were followed through national registers for incidence of IHD during a mean follow-up of 17 years. The prediction accuracy was estimated through Harrell’s C and Akaike Information Criterion (AIC). Results: Increasing TC/HDL-C as well as non-HDL-C showed strong associations with IHD, with the highest risk in the 5th quintile, where the HR was 2.30 (95% CI: 1.70–3.11) for TC/HDL-C and 1.67 (95% CI: 1.25–2.24) for non-HDL-C, after adjustments. Comparisons using Harrell’s C and AIC indicated that TC/HDL-C has a slightly higher predictive ability than that of non-HDL-C (Harrell’s C 0.62 and 0.59 respectively, p = 0.003 for difference, age-adjusted model; AIC for TC/HDL-C < AIC for non-HDL-C). Conclusions: TC/HDL-C ratio and non-HDL-C are both clinical predictors for IHD in middle-aged women. The results indicate that the predictive ability of TC/HDL-C was higher than that of non-HDL-C; however, non-HDL-C was linearly related to IHD (p = 0.58) and may be easier to calculate and interpret in clinical practice, for early identification of future IHD in women.
35.	Calling, Susanna, et al. (author) Trajectories of body mass index and risk for coronary heart disease : A 38-year follow-up study 2021 In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 16:10 October 2021 Journal article (peer-reviewed)abstract Objective Obesity is a well-known risk factor for coronary heart disease (CHD), but there is little evidence on the effect of long-term trajectories of body mass index (BMI) over the life course. By using repeated assessments, the aim was to study the risk of CHD in adults during 38 years in different trajectories of BMI. Methods A sample of 2129 men and women, aged 20-59 years at baseline, took part in four repeated interviews between 1980 and 2005. Data on BMI, medical history, lifestyle and socioeconomy were collected. Based on the World Health Organization categories of BMI, life course trajectories of stable normal weight, stable overweight, stable obesity, increasing BMI and fluctuating BMI were created. The individuals were followed through national registers for first hospitalization of CHD (389 events) until the end of 2017, and Hazard Ratios (HRs) were calculated, adjusted for age, sex, socioeconomic factors, lifestyle factors and metabolic comorbidities. Results Stable normal weight in all assessments was the reference group. Those who had an increase in BMI from normal weight in the first assessment to overweight or obesity in later assessments had no increased risk of CHD, HR 1.04 (95% CI: 0.70-1.53). The HR for individuals with fluctuating BMI was 1.25 (0.97-1.61), for stable overweight 1.43 (1.03-1.98), for stable obesity 1.50 (0.92-2.55), and for stable overweight or obesity 1.45 (1.07-1.97), after full adjustments. Conclusion Having a stable overweight or obesity throughout adult life was associated with increased CHD risk but changing from normal weight at baseline to overweight or obesity was not associated with increased CHD risk. Prevention of obesity early in life may be particularly important to reduce CHD risk.
36.	Calling, Susanna, et al. (author) Women's Health in the Lund Area (WHILA) study. Health problems and acute myocardial infarction in women – A 17-year follow-up study 2018 In: Maturitas. - : Elsevier BV. - 0378-5122. ; 115, s. 45-50 Journal article (peer-reviewed)abstract Objectives: The literature has highlighted the importance of identifying symptoms predictive of acute myocardial infarction (AMI) in women, in addition to traditional cardiovascular risk factors. The objective was to study subjective health problems, in relation to later AMI, in a large sample of women, adjusted for age, educational status, smoking, waist/hip ratio, blood pressure, total cholesterol/HDL ratio, diabetes and neighbourhood socioeconomic status. Study design: From December 1995 to February 2000 a cohort of 6711 women aged 50–59 years in southern Sweden underwent a physical examination and answered a questionnaire that had 18 items on health problems such as stress symptoms, tiredness and pain. Main outcome measures: Incidence of AMI during a mean follow-up of 17 years, drawn from national registers. Results: The number of health problems showed a J-shaped relationship with AMI, with the lowest hazard ratio (HR) in women with a median of 4 health problems. The HR for AMI in women with 0 health problems was 1.58 (95% CI: 0.95–2.63) and in those with 13 problems HR 1.65 (95% CI 1.16–2.36), after adjusting for potential confounding factors. Conclusions: The presence of several health problems, including pain and stress symptoms, is associated with an increased risk of later AMI in middle-aged women. Awareness among clinicians of predictive risk factors for AMI is important for the early identification of individuals at higher risk.
37.	Cardoso, Rafael, et al. (author) Colorectal cancer incidence, mortality, and stage distribution in European countries in the colorectal cancer screening era: an international population-based study 2021 In: The Lancet Oncology. - 1474-5488. ; 22:7, s. 1002-1013 Journal article (peer-reviewed)abstract Background: Colorectal cancer screening programmes and uptake vary substantially across Europe. We aimed to compare changes over time in colorectal cancer incidence, mortality, and stage distribution in relation to colorectal cancer screening implementation in European countries. Methods: Data from nearly 3·1 million patients with colorectal cancer diagnosed from 2000 onwards (up to 2016 for most countries) were obtained from 21 European countries, and were used to analyse changes over time in age-standardised colorectal cancer incidence and stage distribution. The WHO mortality database was used to analyse changes over time in age-standardised colorectal cancer mortality over the same period for the 16 countries with nationwide data. Incidence rates were calculated for all sites of the colon and rectum combined, as well as the subsites proximal colon, distal colon, and rectum. Average annual percentage changes (AAPCs) in incidence and mortality were estimated and relevant patterns were descriptively analysed. Findings: In countries with long-standing programmes of screening colonoscopy and faecal tests (ie, Austria, the Czech Republic, and Germany), colorectal cancer incidence decreased substantially over time, with AAPCs ranging from −2·5% (95% CI −2·8 to −2·2) to −1·6% (−2·0 to −1·2) in men and from −2·4% (−2·7 to −2·1) to −1·3% (−1·7 to −0·9) in women. In countries where screening programmes were implemented during the study period, age-standardised colorectal cancer incidence either remained stable or increased up to the year screening was implemented. AAPCs for these countries ranged from −0·2% (95% CI −1·4 to 1·0) to 1·5% (1·1 to 1·8) in men and from −0·5% (−1·7 to 0·6) to 1·2% (0·8 to 1·5) in women. Where high screening coverage and uptake were rapidly achieved (ie, Denmark, the Netherlands, and Slovenia), age-standardised incidence rates initially increased but then subsequently decreased. Conversely, colorectal cancer incidence increased in most countries where no large-scale screening programmes were available (eg, Bulgaria, Estonia, Norway, and Ukraine), with AAPCs ranging from 0·3% (95% CI 0·1 to 0·5) to 1·9% (1·2 to 2·6) in men and from 0·6% (0·4 to 0·8) to 1·1% (0·8 to 1·4) in women. The largest decreases in colorectal cancer mortality were seen in countries with long-standing screening programmes. Interpretation: We observed divergent trends in colorectal cancer incidence, mortality, and stage distribution across European countries, which appear to be largely explained by different levels of colorectal cancer screening implementation. Funding: German Cancer Aid (Deutsche Krebshilfe) and the German Federal Ministry of Education and Research. © 2021 Elsevier Ltd
38.	Carlsson, Axel C., et al. (author) Differences and time trends in drug treatment of atrial fibrillation in men and women and doctors' adherence to warfarin therapy recommendations 2013 In: European Journal of Clinical Pharmacology. - : Springer Science and Business Media LLC. - 0031-6970 .- 1432-1041. ; 69:2, s. 245-253 Journal article (peer-reviewed)abstract Little is known about prescription trends in atrial fibrillation (AF) in primary health care in Sweden. The aim was to study time trends in pharmacotherapy, in men and women with AF. We also aimed at studying doctors' adherence to CHADS2 for prescribing warfarin. CHADS2 assesses stroke risk by presence of known risk factors, i.e., congestive heart failure, hypertension, age > 75 years, diabetes, previous stroke and transient ischemic attack. Data were obtained from primary health care records that contained individual clinical data. In total, 371,036 patients were included in the sample from 2002, and 424,329 patients were included in the sample from 2007. The study population consisted of individuals aged 45+ years who were diagnosed with AF in 2002 (1,330 men and 1,096 women) and 2007 (2,748 men and 2,234 women). The pharmacotherapies prescribed in 2002 and 2007 were analyzed separately in men and women. Logistic regression was used to calculate the association between the CHADS2 score and prescribed warfarin treatment. Selective beta-blockers, anti-coagulant therapy and lipid-lowering drugs were prescribed more frequently in 2007 than in 2002. In 2007, antithrombotic and RAS-blocking agents were prescribed more frequently to men, whereas beta-1 selective beta-blockers were prescribed more frequently to women. There was no consistent association between the CHADS2 score and prescribed warfarin treatment. Pharmacotherapy of AF has improved over time, though CHADS2 guidelines need to be implemented systematically in primary health care in Sweden to decrease the risk of stroke and improve quality of life in patients with AF.
39.	Carlsson, Axel C., et al. (author) Effects of prescribed antihypertensives and other cardiovascular drugs on mortality in patients with atrial fibrillation and hypertension : a cohort study from Sweden 2014 In: Hypertension Research. - : Springer Science and Business Media LLC. - 0916-9636 .- 1348-4214. ; 37:6, s. 553-559 Journal article (peer-reviewed)abstract Although antihypertensive drugs are known to reduce mortality in individuals with hypertension, the effects of different cardiovascular pharmacotherapies on mortality among patients with hypertension and atrial fibrillation (AF) have been less thoroughly explored. To study mortality rates in men and women separately with hypertension and AF prescribed different cardiovascular pharmacotherapies. A cohort of men (n = 2809) and women (n = 2793) aged > 45 years diagnosed with hypertension and AF were selected using patient records. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using Cox regression, with all-cause mortality as the outcome. Analysis was performed on the whole population and after stratification by age and sex. Independent factors were prescribed pharmacotherapies. Adjustments were made for a propensity score comprising age, comorbidities, education and marital status. The higher the number of antihypertensive drugs prescribed, the lower the mortality rate (P-value for trend 0.005). Individuals prescribed 4-5 antihypertensive drugs had a lower risk of mortality than those prescribed 0-1 drugs (HR: 0.62; 95% CI: 0.45-0.86). The HRs for the following drug classes were: loop diuretics 1.39 (95% CI: 1.08-1.78), non-selective beta-blockers 0.68 (95% CI: 0.53-0.88), angiotensin receptor blockers 0.75 (95% CI: 0.56-0.99) and statins 0.68 (95% CI: 0.53-0.88). AF patients with hypertension prescribed statins, non-selective b-blockers and angiotensin receptor blockers had low relative mortality risks, suggesting that these prescribed pharmacotherapies were beneficial. This needs to be further explored in other clinical settings.
40.	Carlsson, Axel C., et al. (author) Neighborhood deprivation and warfarin, aspirin and statin prescription - A cohort study of men and women treated for atrial fibrillation in Swedish primary care 2015 In: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 187, s. 547-552 Journal article (peer-reviewed)abstract Background: Weaimed to study differences in the prescribing of warfarin, aspirin and statins to patients with atrial fibrillation (AF) in socio-economically diverse neighborhoods. We also aimed to explore the effects of neighborhood deprivation on the relationship between CHADS2 risk score and warfarin prescription. Methods: Data were obtained from primary health care records that contained individual clinical data that were linked to national data on neighborhood of residence and a deprivation index for different neighborhoods. Logistic regression was used to estimate the potential neighborhood differences in prescribed warfarin, aspirin and statins, and the association between the CHADS2 score and prescribed warfarin treatment, in neighborhoods with high, middle (referent) and low socio-economic (SES). Results: After adjustment for age, socio-economic factors, co-morbidities and moves to neighborhoods with different SES during follow-up, adults with AF living in high SES neighborhoods were more often prescribed warfarin (men odds ratio (OR) (95% confidence interval (CI): 1.44 (1.27-1.62); and women OR (95% CI): 1.19 (1.05-1.36)) and statins (men OR (95% CI): 1.23 (1.07-1.41); women OR (95% CI): 1.23 (1.05-1.44)) compared to their counterparts residing in middle SES. Prescription of aspirin was lower in men from high SES neighborhoods (OR (95% CI): 0.75 (0.65-0.86)) than in those from middle SES neighborhoods. Higher CHADS2 risk scores were associated with higher warfarin prescription which remained after adjustment for neighborhood SES. Conclusions: The apparent inequalities in pharmacotherapy seen in the present study call for resource allocation to primary care in neighborhoods with low and middle socio-economic status.
41.	Carlsson, Axel C, et al. (author) Neighborhood socioeconomic status at the age of 40 years and ischemic stroke before the age of 50 years : A nationwide cohort study from Sweden 2017 In: International Journal of Stroke. - : SAGE PUBLICATIONS LTD. - 1747-4930 .- 1747-4949. ; 12:8, s. 815-826 Journal article (peer-reviewed)abstract Objective: We aimed to study the association between neighborhood socioeconomic status at the age of 40 years and risk of ischemic stroke before the age of 50 years.Methods: All individuals in Sweden were included if their 40th birthday occurred between 1998 and 2010. National registers were used to categorize neighborhood socioeconomic status into high, middle, and low and to retrieve information on incident ischemic strokes. Hazard ratios and their 95% confidence intervals were estimated.Results: A total of 1,153,451 adults (women 48.9%) were followed for a mean of 5.5 years (SD 3.5 years), during which 1777 (0.30%) strokes among men and 1374 (0.24%) strokes among women were recorded. After adjustment for sex, marital status, education level, immigrant status, region of residence, and neighborhood services, there was a lower risk of stroke in residents from high-socioeconomic status neighborhoods (hazard ratio 0.87, 95% confidence interval 0.78-0.96), and an increased risk of stroke in adults from low-socioeconomic status neighborhoods (hazard ratio 1.16, 95% confidence interval 1.06-1.27), compared to their counterparts living in middle-socioeconomic status neighborhoods. After further adjustment for hospital diagnoses of hypertension, diabetes, heart failure, and atrial fibrillation prior to the age of 40, the higher risk in neighborhoods with low socioeconomic status was attenuated, but remained significant (hazard ratio 1.12, 95% confidence interval 1.02-1.23).Conclusions: In a nationwide study of individuals between 40 and 50 years, we found that the risk of ischemic stroke differed depending on neighborhood socioeconomic status, which calls for increased efforts to prevent cardiovascular diseases in low socioeconomic status neighborhoods.
42.	Carlsson, Axel C., et al. (author) Neighbourhood socioeconomic status and coronary heart disease in individuals between 40 and 50 years. 2016 In: Heart. - : BMJ. - 1355-6037 .- 1468-201X. ; 102:10 Journal article (peer-reviewed)abstract OBJECTIVE: The incidence of myocardial infarction (MI) has decreased in general but not among younger middle-aged adults. We performed a cohort study of the association between neighbourhood socioeconomic status (SES) at the age of 40 and risk of MI before the age of 50 years. METHODS: All individuals in Sweden were included in the year of their 40th birthday, if it occurred between 1998 and 2010. National registers were used to categorise neighbourhood SES into high, middle and low, and to retrieve information on incident MI and coronary heart disease (CHD). Cox regression models, adjusted for marital status, education level, immigrant status and region of residence, provided an estimate of the HRs and 95% CIs for MI or CHD. RESULTS: Out of 587 933 men and 563 719 women, incident MI occurred in 2877 (0.48%) men and 932 (0.17%) women; and CHD occurred in 4400 (0.74%) men and 1756 (0.31%) women during a mean follow-up of 5.5 years. Using individuals living in middle-SES neighbourhoods as referents, living in high-SES neighbourhoods was associated with lower risk of MI in both sexes (HR (95% CI): men: 0.72 (0.64 to 0.82), women: 0.66 (0.53 to 0.81)); living in low-SES neighbourhoods was associated with a higher risk of MI (HR (95% CI): men: 1.31 (1.20 to 1.44), women: 1.28 (1.08 to 1.50)). Similar risk estimates for CHD were found. CONCLUSIONS: The results of our study suggest an increased risk of MI and CHD among residents from low-SES neighbourhoods and a lower risk in those from high-SES neighbourhoods compared with residents in middle-SES neighbourhoods.
43.	Castro, Felipe A., et al. (author) Increased Risk of Hepatobiliary Cancers After Hospitalization for Autoimmune Disease 2014 In: Clinical Gastroenterology and Hepatology. - : Elsevier BV. - 1542-7714 .- 1542-3565. ; 12:6, s. 1038-1045 Journal article (peer-reviewed)abstract BACKGROUND & AIMS: Some autoimmune diseases are associated with increased risk of liver cancer. However, there has been no comprehensive evaluation of autoimmune diseases among patients who develop different subtypes of hepatobiliary cancer. We examined the association between autoimmune diseases and cancers of the liver and biliary tract in the Swedish population. METHODS: We analyzed data from national datasets at the Center for Primary Health Care Research (Lund University, Sweden). Data on patients with autoimmune disorders were retrieved from the Swedish Hospital Discharge Register, from 1964 through 2008; 33 diseases were evaluated. Hepatobiliary cancer cases were retrieved from the Swedish Cancer Registry. We calculated standardized incidence ratios (SIRs) and hazard ratios for incident cancers and deaths from hepatobiliary cancers. RESULTS: Among 402,462 patients with autoimmune disorders, 582 were diagnosed with primary liver cancer, 330 with gallbladder cancer, 115 with extrahepatic bile duct cancer, and 43 with ampulla of Vater cancers. We identified 14 autoimmune conditions that were significantly associated with increased risk of primary liver cancer (overall SIR [any autoimmune disease], 2.1; 95% confidence interval [CI], 2.0-2.3), 5 conditions associated with gallbladder cancer (overall SIR, 1.3; 95% CI, 1.1-1.4), and 3 associated with extrahepatic bile duct cancer (overall SIR, 1.6; 95% CI, 1.3-1.9). The autoimmune disorders with the strongest association with primary liver cancer were primary biliary cirrhosis (SIR, 39.5; 95% CI, 28.2-53.8) and autoimmune hepatitis (SIR, 29.0; 95% CI, 9.1-68.2); ulcerative colitis was strongly associated with extrahepatic bile duct cancer (SIR, 5.6; 95% CI, 3.6-8.4). Celiac disease, Crohn's disease, systemic sclerosis, and ulcerative colitis were associated with at least 2 types of cancer. Increased hazard ratios were observed only for patients with biliary tract cancer who had been hospitalized for autoimmune conditions. CONCLUSIONS: In a study of the Swedish population, we identified an increased risk of hepatobiliary cancers among individuals diagnosed with autoimmune disease. Associations among different cancer types indicate that shared immunomodulatory mechanisms determine susceptibility to hepatobiliary cancer.
44.	Cederroth, Christopher R., et al. (author) Association of Genetic vs Environmental Factors in Swedish Adoptees with Clinically Significant Tinnitus 2019 In: JAMA Otolaryngology - Head and Neck Surgery. - : American Medical Association (AMA). - 2168-6181 .- 2168-619X. ; 145:3, s. 222-229 Journal article (peer-reviewed)abstract Importance: No effective treatments are currently available for severe tinnitus, which affects 1% of the population and lowers the quality of life. The factors that contribute to the transition from mild to severe tinnitus are poorly known. Before performing genetic analyses and determining the mechanisms involved in the development of severe tinnitus, its heritability needs to be determined. Objectives: To examine whether clinically significant tinnitus is associated with genetic factors and to evaluate the genetic risk in the transmission of tinnitus using adoptees. Design, Setting, and Participants: Data from adoptees and their biological and adoptive parents from Swedish nationwide registers were collected from January 1, 1964, to December 31, 2015, and used to separate genetic from environmental factors in familial clustering. In all, 11 060 adoptees, 19 015 adoptive parents, and 17 025 biological parents were investigated. The study used a cohort design and a case-control approach to study genetic and nongenetic factors in tinnitus among adoptees. Main Outcomes and Measures: The primary outcome was odds ratio (OR) of tinnitus in adoptees with at least 1 affected biological parent compared with adoptees without any affected biological parent using logistic regression. The secondary outcome was OR in adoptees with at least 1 affected adoptive parent compared with adoptees without any affected adoptive parent. Results: A total of 1029 patients (440 [42.8%] male; mean [SD] age, 62 [14] years) with tinnitus were identified. The prevalence of diagnosed tinnitus was 2.2%. The OR for tinnitus was 2.22 for adoptees (95% CI, 1.03-4.81) of biological parents diagnosed with tinnitus, whereas the OR was 1.00 (95% CI, 0.43-2.32) for adoptees from adoptive parents diagnosed with tinnitus. Mean (SE) heritability determined using tetrachoric correlations was 31% (14%). Conclusions and Relevance: The findings suggest that genetic factors are associated with the familial clustering of clinically significant tinnitus with no shared-environment association, revealing that the transition from negligible to severe tinnitus may be associated with genetic factors. These findings may provide insight for future genetic analyses that focus on severe tinnitus..
45.	Chartier, Karen G., et al. (author) Triangulation of evidence on immigration and rates of alcohol use disorder in Sweden : Evidence of acculturation effects 2023 In: Alcoholism: Clinical and Experimental Research. - : Wiley. - 0145-6008 .- 1530-0277. ; 47:1, s. 104-115 Journal article (peer-reviewed)abstract Background: This study aimed to determine the robustness of the impact of immigration on risk for alcohol use disorder (AUD) using different measures, designs, and immigrant regional cohorts. Methods: The analytic sample included all individuals born between 1950 and 1990 and registered in Sweden from 1973 to 2017. Using Cox regression models, we examined the risk for AUD from Swedish nationwide registries in immigrants to Sweden from seven geographical regions: Africa, Asia and Oceania, Eastern Europe, Finland, Latin America and the Caribbean, Middle East/North Africa, and Western countries. We assessed greater exposure to Swedish culture, which we interpreted as increasing acculturation, by (i) comparing first-generation immigrants and their children with no and one native Swedish parent and (ii) examining age at immigration. The baseline comparison group was the native Swedish population. We also examined AUD risk in first-generation sibling pairs discordant for their age at immigration. Results: In nearly all immigrant cohorts in Sweden, increasing degrees of acculturation, as assessed by both our variables, were associated with rates of AUD that approached those of the Swedish population. These findings occurred in both men and women and both regional cohorts whose first-generation immigrants had lower and higher levels of AUD than native-born Swedes. For most cohorts, the rates of change with acculturation were greater in women than in men. In sibling pairs from most regions, the sibling who was younger at immigration had a higher rate of AUD. Conclusions: An examination of both sexes and two different proxies for acculturation provides consistent support for socio-cultural influences on AUD risk. Our co-sibling analyses suggest that a meaningful proportion of this effect is likely to be causal in nature.
46.	Chattopadhyay, Subhayan, et al. (author) Impact of family history of cancer on risk and mortality of second cancers in patients with prostate cancer 2019 In: Prostate Cancer and Prostatic Diseases. - : Springer Science and Business Media LLC. - 1365-7852 .- 1476-5608. ; 22:1, s. 143-149 Journal article (peer-reviewed)abstract Background: Survival rates are increasing in patients with prostate cancer, and second primary cancers (SPCs) are becoming more common in these patients. However, the etiology and clinical consequences of SPCs are not well-known. We define the impact of family history on SPC and causes of mortality in these patients. Patients and methods: A nation-wide cohort study based on the Swedish Family-Cancer Database covering 4.4 million men and 80,449 prostate cancers diagnosed between 1990 and 2015. Relative risks (RRs) and cumulative incidence for SPCs and for familial SPC were calculated for prostate cancer patients. Results: SPC was diagnosed in 6,396 men and more than a third of these patients had a first-degree family history of any cancer; the familial risk was 1.37 (95% CI: 1.27–1.40), compared to 1.10 (1.08–1.16), without a family history. Cumulative incidence by the age of 83 years reached 21% for prostate cancer alone, 28% in those with SPC, and 35% in patients with SPC and family history. Family history was associated with the risk of seven specific SPCs, including colorectal, lung, kidney, bladder and skin (both melanoma and squamous cell) cancers, and leukemia. Colorectal and lung cancers were common SPCs, and family history doubled the risk of these SPCs. In patients with SPC, half of all causes of death were due to SPC and only 12.77% were due to prostate cancer. Most deaths in SPC were caused by lung and colorectal cancers. Conclusions: SPCs were an important cause of death in patients with prostate cancer and family history was an important risk factor for SPCs. Prevention of SPC should be essential when prostate cancer survival rates are being improved and this could start by conducting a thorough assessment of family history at the time of prostate cancer diagnosis.
47.	Chattopadhyay, Subhayan, et al. (author) Risk of second primary cancer following myeloid neoplasia and risk of myeloid neoplasia as second primary cancer : a nationwide, observational follow up study in Sweden 2018 In: The Lancet Haematology. - 2352-3026. ; 5:8, s. 368-377 Journal article (peer-reviewed)abstract Background: Although advances in the treatment of myeloid neoplasms have led to improved patient survival, this improvement has been accompanied by an increased risk of second primary cancer (ie, the risk of another cancer after myeloid neoplasia). We aimed to assess bi-directional associations between myeloid cancers and other cancers—ie, development of second primary cancer in patients who have previously had myeloid cancer, and risks of myeloid neoplasia in patients who have previously had another cancer—to provide insight into possible mechanisms beyond side-effects of treatment and shared risk factors. Methods: Using the Swedish Family-Cancer Database, we identified 35 928 individuals with primary myeloid cancer, including myeloproliferative neoplasms, acute myeloid leukaemia, chronic myeloid leukaemia, and myelodysplastic syndrome diagnosed between 1958 and 2015. The Swedish Family-Cancer Database includes every individual registered as a resident in Sweden starting in 1932, with full parental history. The primary endpoint was the assessment of relative risks (RRs) for second primary cancer, which we performed using means of incidence rate ratios, regressed over a generalised Poisson model. Findings: Between 1958 and 2015, overall relative risk of second primary cancers was significantly increased after acute myeloid leukaemia (RR 1·29, 95% CI 1·17–1·41), chronic myeloid leukaemia (1·52, 1·35–1·69), myelodysplastic syndrome (1·42, 1·26–1·59), and all myeloproliferative neoplasms (1·37, 1·30–1·43) relative to the incidence of these cancers as first primary cancer. With myeloid neoplasia as a second primary cancer, risks were significantly increased for acute myeloid leukaemia (1·57, 1·48–1·65), chronic myeloid leukaemia (1·26, 1·13–1·40), and myelodysplastic syndrome (1·54, 1·42–1·67) relative to the incidence of these myeloid neoplasms as first primary cancers. Relative risk of upper aerodigestive tract cancer, squamous cell skin cancer, and non-Hodgkin lymphoma as second primary cancers were increased after all four types of myeloid neoplasia relative to their incidence as first primary cancers. High risks of myelodysplastic syndrome and acute myeloid leukaemia as second primary cancers were found after haematological cancers (RRs between 5·08 and 10·04). Interpretation: The relative risks of second primary cancer are important for the long-term management of patients with myeloid cancers. The bi-directional associations of myeloid cancers with many other cancers suggest a number of candidate mechanisms that might contribute to the development and aetiology of a second primary cancer. These mechanisms might include immune dysfunction or the effects of treatment, and these should be assessed in future investigations. Funding: Deutsche Krebshilfe, Jane and Aatos Erkko Foundation, Sigrid Juselius Foundation, Finnish Cancer Organizations, Swedish Research Council, ALF from Region Skåne, and Bloodwise.
48.	Chattopadhyay, Subhayan, et al. (author) Second primary cancers in non-Hodgkin lymphoma : Bidirectional analyses suggesting role for immune dysfunction 2018 In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 143:10, s. 2449-2457 Journal article (peer-reviewed)abstract Second primary cancers (SPCs) account for an increasing proportion of all cancer diagnoses. It is unlikely that prior therapy is solely responsible for SPC risk. To investigate risk of SPC after diagnosis of non-Hodgkin lymphoma (NHL) and 10 of its subtypes we conducted a novel bidirectional analysis, SPCs after NHL and NHL as SPC. Using the Swedish Family-Cancer Database, we identified 19,833 individuals with primary NHL diagnosed between 1993 and 2015. We calculated relative risks (RRs) of SPCs in NHL survivors and, for bi-directional analysis, risk of NHL as SPC. The overall RRs were significantly bidirectionally increased for NHL and 7 cancers. After diagnosis of NHL risks were increased for upper aerodigestive tract (RR = 1.96), colorectal (1.35), kidney (3.10), bladder (1.54) and squamous cell skin cancer (SCC) (4.12), melanoma (1.98) and Hodgkin lymphoma (9.38). The concordance between RRs for each bidirectional association between NHL and 31 different cancers was highly significant (r = 0.86, p < 0.0001). Melanoma was bidirectionally associated with all 10 subtypes of NHL. The observed bidirectional associations between NHL and cancer suggest that therapy-related carcinogenic mechanisms cannot solely explain the findings. Considering that skin SCC and melanoma are usually treated by surgery and that these cancers and NHL are most responsive of any cancer to immune suppression, the consistent bidirectional results provide population-level evidence that immune suppressed state is a key underlying mechanism in the context of SPCs. Furthermore, the quantified risks for NHL subtypes have direct clinical application in the management of NHL patients.
49.	Chattopadhyay, Subhayan, et al. (author) Second primary cancers in non-Hodgkin lymphoma : Family history and survival 2020 In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 146:4, s. 970-976 Journal article (peer-reviewed)abstract Second primary cancers (SPCs) account for an increasing proportion of all cancer diagnoses and family history of cancer may be a risk factor for SPCs. Using the Swedish Family-Cancer Database on non-Hodgkin lymphoma (NHL), we assessed the influence of family history on risk of SPCs and of SPCs on survival. NHL patients were identified from the years 1958 to 2015 and generalized Poisson models were used to calculate relative risks (RRs) for SPCs and familial SPCs. Among 14,393 NHL patients, a total of 1,866 (13.0%) were diagnosed with SPC. Familial risk of nine particular cancers was associated with risks of these cancers as SPCs, with twofold to fivefold increase in RRs. At the end of a 25-year follow-up period, the survival probability for persons with SPC was only 20% of that for patients without SPC; the hazard ratio for SPC was 1.59 (95% CI: 1.46–1.72). Survival could be predicted by the prognostic groups based on first cancers and HRs increase systematically with worse prognosis yielding a trend of p = 4.6 × 10 −5 . SPCs had deleterious consequences for survival in NHL patients. Family history was associated with increasing numbers of SPCs. Prevention of SPCs and their early detection is an important target in the overall strategy to improve survival in NHL patients. Counseling for avoidance of risk factors and targeted screening based on family history are feasible steps in risk reduction.
50.	Chattopadhyay, Subhayan, et al. (author) Second Primary Cancers in Patients with Invasive and In Situ Squamous Cell Skin Carcinoma, Kaposi Sarcoma, and Merkel Cell Carcinoma : Role for Immune Mechanisms? 2020 In: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X. ; 140:1, s. 48-55 Journal article (peer-reviewed)abstract Second primary cancers (SPCs) are becoming a common cancer entity, which may interfere with survival in relatively benign first primary cancers. We examined the hypothesis that immune dysfunction may contribute to SPCs by assessing SPCs associated with known immune responsive skin cancers, invasive and in situ squamous cell carcinoma, Kaposi sarcoma, and Merkel cell carcinoma. Cancers were identified from the Swedish Cancer Registry from the year 1958 to 2015. Standardized relative risks were calculated bidirectionally for any SPC after skin cancer and for skin cancer as SPC. Over 80,000 first primary cancers were identified for each invasive and in situ squamous cell carcinoma of the skin. Bidirectional increased risks were observed for 26 cancers associated with invasive skin cancer; the Spearman rank correlation was 0.72 (P = 4.6 × 10–5). The highest bidirectional relative risks were for invasive and in situ skin cancer as SPCs (14.59 and 16.71, respectively). Remarkably high risks for second in situ squamous cell carcinoma of the skin were found after Kaposi sarcoma (685.68) and Merkel cell carcinoma (117.23). The high systematic bidirectional risks between immune responsive skin cancers and most other cancers suggest that immune suppression is a key mechanism contributing to an increased risk of SPCs.

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