| 1. |
- Bennet, Anna M., et al.
(author)
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Decreased risk for myocardial infarction and lower tumor necrosis factor-alpha levels in carriers of variants of the PDCD1 gene
- 2006
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In: Human Immunology. - : Elsevier BV. - 0198-8859 .- 1879-1166. ; 67:9, s. 700-705
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Journal article (peer-reviewed)abstract
- Increasing interest has been directed toward the inflammatory mechanisms involved in the pathogenesis of myocardial infarction (MI). In the search for genetic mechanisms underlying these inflammatory components, we studied variants of programmed cell death-1 (PDCD1), an immunoinhibitory receptor that inhibits lymphocyte activation and cytokine production, previously shown to be associated with several autoimmune disorders. The PD1.1, PD1.3, and PD1.6 polymorphisms of the PDCD1 gene were typed in the Stockholm Heart Epidemiology Program, a population-based clinical material consisting of 1179 first-time MI case patients and 1528 unaffected control subjects. Individual alleles and haplotypes were studied for association with levels of the inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-6, and C-reactive protein and risk for MI. We observed a weak protective effect of PD1.3A allele for MI (odds ratio: 0.78, 95% confidence interval: 0.61-0.98). We also observed decreased levels of TNF-alpha in carriers of the PD1.1A/PD1.3G/PD1.6A haplotype, which is consistent with our previous observation that this haplotype may be protective from autoimmune conditions. Carriers of variants of the PDCD1 gene exhibit a decreased risk for nonfatal myocardial infarction, and PDCD1 mediates variation in TNF-alpha levels.
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| 2. |
- Bennet, Anna M, et al.
(author)
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Genetic association of sequence variants near AGER/NOTCH4 and dementia.
- 2011
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In: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 24:3, s. 475-84
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Journal article (peer-reviewed)abstract
- We performed a survey of sequence variation in a series of 20 genes involved in inflammation-related pathways for association with dementia risk in twin and unrelated case-control samples consisting in total of 1462 Swedish dementia casesand 1929 controls. For a total of 218 tested genetic markers, strong evidence was obtained implicating a region near AGER and NOTCH4 on chromosome 6p with replication across both samples and maximum combined significance at marker rs1800625 (OR = 1.37, 95% CI 1.19–1.56, p = 1.36×10(–6)). Imputation of the associated genomic interval provided an improved signal atrs8365, near the 3UTR of AGER (p = 7.34×10(–7)). The associated region extends 120 kb encompassing 11 candidate genes.While AGER encodes a key receptor for amyloid-β protein, an analysis of network context based upon genes now confirmed to contribute to dementia risk (AβPP, PSEN1, PSEN2, CR1, CLU, PICALM, and APOE) suggested strong functional coupling to NOTCH4, with no significant coupling to the remaining candidates. The implicated region occurs in the broad HLA locus on chromosome 6p, but associated markers were not in strong LD with known variants that regulate HLA gene function, suggesting that this may represent a signal distinct from immune-system pathways.
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| 3. |
- Bennet, Anna M, et al.
(author)
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Pleiotropy in the Presence of Allelic Heterogeneity: Alternative Genetic Models for the Influence of APOE on Serum LDL, CSF Amyloid-β42, and Dementia.
- 2010
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In: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 22:1, s. 129-134
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Journal article (peer-reviewed)abstract
- The two genetic polymorphisms, rs7412 and rs429358, that collectively form the ε2, ε3, and ε4 alleles of apolipoprotein E (APOE) are among the most widely studied sequence variants in the genome. The predominant model for testing APOE involves the haplotype combinations of ε2, ε3, and ε4 and has been basis of associations with dementia, atherosclerosis, and serum lipid levels. Here, we demonstrate the functional independence of these two component sites, with rs7412 contributing to the majority of variance in serum LDL (p=10-20), whereas rs429358 alone influences variance in CSF amyloid-β42 (Aβ42) (p=10-17). This latter relationship is also reflected in the association of APOE with dementia, where rs429358 strongly influences disease (p=10-67), but rs7412 does not. Models based upon ε2, ε3, and ε4 explained less variance for both dementia risk and CSF Aβ42 than did rs429358 alone. When adjusted for CSF Aβ42, the association of rs429358 with dementia is greatly reduced but remains significant indicating that APOE polymorphism influences disease by additional mechanisms distinct from Aβ42 metabolism. We reach four principal conclusion from this study: 1) rs429358 alone is responsible for the association of APOE with dementia; 2) The association of APOE with dementia is substantially mediated by its effect on CNS Aβ42 levels; 3) The association of APOE with dementia is not mediated by its impact on peripheral lipid metabolism; and 4) The dichotomy of effects of rs429358 and rs7412 represents one of the best examples of genetic pleiotropy for complex traits known and illustrates the importance of allelic heterogeneity in APOE.
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| 4. |
- Bennet, Anna M, et al.
(author)
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The risk of myocardial infarction is enhanced by a synergistic interaction between serum insulin and smoking.
- 2002
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In: European Journal of Endocrinology. - : Oxford University Press (OUP). - 0804-4643 .- 1479-683X. ; 147:5, s. 641-7
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Journal article (peer-reviewed)abstract
- OBJECTIVES: To evaluate the relationship between levels of serum insulin, the homeostasis model assessment (HOMA) and IGF-binding protein-1 (IGFBP-1) as factors related to myocardial infarction (MI) risk, and their interaction with lifestyle-related risk factors. DESIGN: The Stockholm epidemiology programme (SHEEP), a case-control study, consisting of 749 first-time MI cases (510 men, 239 women) and 1101 healthy controls (705 men, 396 women) was used. METHODS: The risk of developing MI was assessed by calculating odds ratios (OR) and synergistic interactions (SI) between serum insulin, IGFBP-1, HOMA and other variables related to MI risk (including smoking) in men and women. RESULTS: Subjects with elevated levels of insulin and HOMA (>75th percentile) had increased MI risks when compared with individuals with low levels. ORs for elevated insulin and HOMA (adjusted for age and residential area) for men: insulin 1.6 (95% confidence interval (CI) 1.3-2.1) and HOMA 1.5 (95% CI 1.1-1.9) and for women: insulin 2.1 (95% CI 1.5-2.9) and HOMA 1.9 (95% CI 1.3-2.8). Women with low levels of IGFBP-1 (<10th percentile) showed a tendency towards elevated MI risk even if this was not statistically significant (OR 1.5 (95% CI 0.9-2.6)). Smokers with high levels of serum insulin had greatly increased MI risk (OR for men: 4.7 (95% CI 3.0-7.2) and OR for women: 8.1 (95% CI 4.5-14.8)). SI scores based upon these interactions were statistically significant. CONCLUSIONS: These results might have preventive cardiovascular implications as they clearly suggest that subjects with insulin resistance are particularly susceptible to the hazards of smoking.
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| 5. |
- Janszky, Imre, et al.
(author)
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Alcohol and long-term prognosis after a first acute myocardial infarction : the SHEEP study
- 2008
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In: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 29:1, s. 45-53
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Journal article (peer-reviewed)abstract
- CONTEXTFew studies have investigated the relation between alcohol consumption, former drinking, and prognosis after an acute myocardial infarction (AMI), particularly for non-fatal outcomes.OBJECTIVETo investigate the prognostic importance of drinking habits among patients surviving a first AMI.DESIGN, SETTINGS, AND PATIENTSA total of 1346 consecutive patients between 45-70 years with a first non-fatal AMI underwent a standardized clinical examination and were followed for over 8 years.MAIN OUTCOME MEASURESTotal and cardiac mortality and hospitalization for non-fatal cardiovascular disease in relation to individual alcoholic beverage consumption at the time of AMI and 5 years before inclusion, assessed by a standardized questionnaire administered during hospitalization.RESULTSWe recorded 267 deaths, and 145 deaths from cardiac causes, during the follow-up period. After adjustment for several potential confounders, hazard ratios for total and cardiac mortality were 0.77 (0.51-1.15) and 0.61 (0.36-1.02) for those drinking >0-<5 g per day, 0.77 (0.50-1.18) and 0.62 (0.36-1.07) for those drinking 5-20 g per day, and 0.89 (0.56-1.40) and 0.69 (0.38-1.25) for those drinking over 20 g per day. Risk of hospitalization for recurrent non-fatal AMI, stroke, or heart failure generally showed a similar pattern to that of total and cardiac mortality. Recent quitters at the time of AMI had a hazard ratio of 4.55 (2.03-10.20) for total mortality. Measures of insulin sensitivity appeared to be the strongest mediators of this association.CONCLUSIONSModerate alcohol drinking might have beneficial effects on several aspects of long-term prognosis after an AMI. Our findings also highlight that former drinkers should be examined separately from long-term abstainers. The potential mechanisms that underlie this association still need to be elucidated.
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| 6. |
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| 7. |
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| 8. |
- Lundgren, Markus, et al.
(author)
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Analgesic antipyretic use among young children in the TEDDY study : No association with islet autoimmunity
- 2017
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In: BMC Pediatrics. - : Springer Science and Business Media LLC. - 1471-2431. ; 17:1
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Journal article (peer-reviewed)abstract
- Background: The use of analgesic antipyretics (ANAP) in children have long been a matter of controversy. Data on their practical use on an individual level has, however, been scarce. There are indications of possible effects on glucose homeostasis and immune function related to the use of ANAP. The aim of this study was to analyze patterns of analgesic antipyretic use across the clinical centers of The Environmental Determinants of Diabetes in the Young (TEDDY) prospective cohort study and test if ANAP use was a risk factor for islet autoimmunity. Methods: Data were collected for 8542 children in the first 2.5 years of life. Incidence was analyzed using logistic regression with country and first child status as independent variables. Holm's procedure was used to adjust for multiplicity of intercountry comparisons. Time to autoantibody seroconversion was analyzed using a Cox proportional hazards model with cumulative analgesic use as primary time dependent covariate of interest. For each categorization, a generalized estimating equation (GEE) approach was used. Results: Higher prevalence of ANAP use was found in the U.S. (95.7%) and Sweden (94.8%) compared to Finland (78.1%) and Germany (80.2%). First-born children were more commonly given acetaminophen (OR 1.26; 95% CI 1.07, 1.49; p = 0.007) but less commonly Non-Steroidal Anti-inflammatory Drugs (NSAID) (OR 0.86; 95% CI 0.78, 0.95; p = 0.002). Acetaminophen and NSAID use in the absence of fever and infection was more prevalent in the U.S. (40.4%; 26.3% of doses) compared to Sweden, Finland and Germany (p < 0.001). Acetaminophen or NSAID use before age 2.5 years did not predict development of islet autoimmunity by age 6 years (HR 1.02, 95% CI 0.99-1.09; p = 0.27). In a sub-analysis, acetaminophen use in children with fever weakly predicted development of islet autoimmunity by age 3 years (HR 1.05; 95% CI 1.01-1.09; p = 0.024). Conclusions: ANAP use in young children is not a risk factor for seroconversion by age 6 years. Use of ANAP is widespread in young children, and significantly higher in the U.S. compared to other study sites, where use is common also in absence of fever and infection.
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| 9. |
- McGale, Paul, et al.
(author)
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Incidence of heart disease in 35,000 women treated with radiotherapy for breast cancer in Denmark and Sweden
- 2011
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In: Radiotherapy and Oncology. - Amsterdam : Elsevier. - 0167-8140 .- 1879-0887. ; 100:2, s. 167-175
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Journal article (peer-reviewed)abstract
- Purpose: To study incidence of radiation-related heart disease in a large population of breast cancer patients followed for up to 30 years. Material and methods: 72,134 women diagnosed with breast cancer in Denmark or Sweden during 1976-2006 and followed prospectively. Radiation-related risk was studied by comparing women with left-sided and right-sided tumours. Results: 34,825 women (48%) received radiotherapy. Among unirradiated women tumour laterality had little relevance to heart disease. Among irradiated women mean dose to the whole heart was 6.3 Gy for left-sided tumours and 2.7 Gy for right-sided tumours. Mortality was similar in irradiated women with left-sided and right-sided tumours, but incidence ratios, left-sided versus right-sided, were raised: acute myocardial infarction 1.22 (95% CI 1.06-1.42), angina 1.25 (1.05-1.49), pericarditis 1.61 (1.06-2.43), valvular heart disease 1.54 (1.11-2.13). Incidence ratios for all heart disease were as high for women irradiated since 1990 (1.09 [1.00-1.19]) as for women irradiated during 1976-1989 (1.08 [0.99-1.17]), and were higher for women diagnosed with ischaemic heart disease prior to breast cancer than for other women (1.58 [1.19-2.10] versus 1.08 [1.01-1.15], p for difference = 0.01). Conclusions: Breast cancer radiotherapy has, at least until recently, increased the risk of developing ischaemic heart disease, pericarditis and valvular disease. Women with ischaemic heart disease before breast cancer diagnosis may have incurred higher risks than others. (C) 2011 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 100 (2011) 167-175
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| 10. |
- Reynolds, Chandra A, et al.
(author)
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A survey of ABCA1 sequence variation confirms association with dementia.
- 2009
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In: Human mutation. - : Hindawi Limited. - 1098-1004 .- 1059-7794. ; 30:9, s. 1348-54
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Journal article (peer-reviewed)abstract
- We and others have conducted targeted genetic association analyses of ABCA1 in relation to Alzheimer disease risk with a resultant mixture of both support and refutation, but all previous studies have been based upon only a few markers. Here, a detailed survey of genetic variation in the ABCA1 region has been performed in a total of 1,567 Swedish dementia cases (including 1,275 with Alzheimer disease) and 2,203 controls, providing evidence of association with maximum significance at marker rs2230805 (odds ratio [OR]=1.39; 95% confidence interval [CI] 1.23-1.57, p=7.7x10(-8)). Haplotype-based tests confirmed association of this genomic region after excluding rs2230805, and imputation did not reveal additional markers with greater support. Significantly associating markers reside in two distinct linkage disequilibrium blocks with maxima near the promoter and in the terminal exon of a truncated ABCA1 splice form. The putative risk allele of rs2230805 was also found to be associated with reduced cerebrospinal fluid levels of beta-amyloid. The strongest evidence of association was obtained when all forms of dementia were considered together, but effect sizes were similar when only confirmed Alzheimer disease cases were assessed. Results further implicate ABCA1 in dementia, reinforcing the putative involvement of lipid transport in neurodegenerative disease.
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| 11. |
- Reynolds, Chandra A, et al.
(author)
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Sequence variation in SORL1 and dementia risk in Swedes.
- 2010
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In: Neurogenetics. - : Springer Science and Business Media LLC. - 1364-6753 .- 1364-6745. ; 11:1, s. 139-42
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Journal article (peer-reviewed)abstract
- The gene encoding the neuronal sortilin-related receptor SORL1 has been claimed to be associated with Alzheimer's disease (AD) by independent groups and across various human populations. We evaluated six genetic markers in SORL1 in a sample of 1,558 Swedish dementia cases (including 1,270 AD cases) and 2,179 controls. For both single-marker-based and haplotype-based analyses, we found no strong support for SORL1 as a dementia or AD risk-modifying gene in our sample in isolation nor did we observe association with AD/dementia-related traits, including cerebrospinal fluid beta-amyloid(1-42), tau levels, or age at onset. However, meta-analyses of markers in this study together with previously published studies on SORL1 encompassing in excess of 13,000 individuals does suggest significant association with AD (best odds ratio = 1.097; 95% confidence interval = 1.038-1.158, p = 0.001). All six markers were significant in meta-analyses and it is notable that they occur in two distinct linkage disequilibrium blocks. These data are consistent with either allelic heterogeneity or the existence of as yet untested functional variants and these will be important considerations in further attempts to evaluate the importance of sequence variation in SORL1 with AD risk.
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| 12. |
- Strålin, Kristoffer, et al.
(author)
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Mortality in hospitalized COVID-19 patients was associated with the COVID-19 admission rate during the first year of the pandemic in Sweden
- 2022
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In: Infectious Diseases. - : Taylor & Francis Ltd. - 2374-4235 .- 2374-4243. ; 54:2, s. 145-151
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Journal article (peer-reviewed)abstract
- Introduction Studies from the first pandemic wave found associations between COVID-19 hospital load and mortality. Here, we aimed to study if mortality of hospitalized COVID-19 patients was associated with the COVID-19 admission rate during a full year of the pandemic in Sweden. Method Observational review of all patients admitted to hospital with COVID-19 in Sweden between March 2020 and February 2021 (n = 42,017). Primary outcome was 60-day all-cause mortality related to number of COVID-19 hospital admissions per month/100,000 inhabitants. Poisson regression was used to estimate the relative risk for death by month of admission, adjusting for pre-existing factors. Results The overall mortality was 17.4%. Excluding March 2020, mortality was clearly correlated to the number of COVID-19 admissions per month (coefficient of correlation rho=.96; p<.0001). After adjustment for pre-existing factors, the correlation remained significant (rho=.75, p=.02). Patients admitted in December (high admission rate and high mortality) had more comorbidities and longer hospital stays, and patients treated in intensive care units (ICU) had longer pre-ICU hospital stays and worse respiratory status on ICU admission than those admitted in July to September (low admission rate and low mortality). Conclusion Mortality in hospitalized COVID-19 patients was clearly associated with the COVID-19 admission rate. Admission of healthier patients between pandemic waves and delayed ICU care during wave peaks could contribute to this pattern. The study supports measures to flatten-the-curve to reduce the number of COVID-19 patients admitted to hospital.
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| 13. |
- Strålin, Kristoffer, et al.
(author)
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Mortality trends among hospitalised COVID-19 patients in Sweden : A nationwide observational cohort study
- 2021
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In: The Lancet Regional Health. - : Elsevier. - 2666-7762. ; 4
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Journal article (peer-reviewed)abstract
- Background: It is important to know if mortality among hospitalised COVID-19 patients has changed as the pandemic has progressed. The aim of this study was to describe the dynamics over time of mortality among patients hospitalised for COVID-19 in Sweden, using nationwide data compiled by the Swedish National Board of Health and Welfare. Methods: Observational cohort study where all patients hospitalised in Sweden between March 1 and September 30, 2020, with SARS-CoV-2 RNA positivity 14 days before to 5 days after admission and a discharge code for COVID-19 were included. Outcome was 60-day all-cause mortality. Patients were categorised according to month of hospital admission. Poisson regression was used to estimate the relative risk of death by month of admission, adjusting for, age, sex, comorbidities, care dependency, country of birth, healthcare region, and Simplified Acute Physiology, version 3 (patients in intensive care units; ICU). Findings: A total of 17,140 patients were included, of which 2943 died within 60 days of admission. The overall 60-day mortality was thus 17.2% (95% CI, 16.6%-17.7%), and it decreased from 24.7% (95% CI, 23.0%-26.5%) in March to 10.4% (95% CI, 8.9%-12.1%) post-wave (July-September). Adjusted relative risk (RR) of death was 0.46 (95% CI, 0.39-0.54) post-wave, using March as reference. Corresponding RR for patients not admitted to ICU and those admitted to ICU were 0.49 (95% CI, 0.42-0.59) and 0.49 (95% CI, 0.33-0.72), respectively. The proportion of patients admitted to ICU decreased from 19.4% (95% CI, 17.9%-21.1%) in the March cohort to 8.9% (95% CI, 7.5%-10.6%) post-wave. Interpretation: There was a gradual decline in mortality during the spring of 2020 in Swedish hospitalised COVID-19 patients, independent of baseline patient characteristics. Future research is needed to explain the reasons for this decline. The changing COVID-19 mortality should be taken into account when management and results of studies from the first pandemic wave are evaluated. (C) 2021 The Authors. Published by Elsevier Ltd.
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| 14. |
- Wiklund, Fredrik E, et al.
(author)
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Macrophage inhibitory cytokine-1 (MIC-1/GDF15) : a new marker of all-cause mortality
- 2010
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In: Aging Cell. - : Wiley. - 1474-9718 .- 1474-9726. ; 9:6, s. 1057-1064
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Journal article (peer-reviewed)abstract
- Macrophage inhibitory cytokine-1 (MIC-1/GDF15) is a member of the TGF-b superfamily, previously studied in cancer and inflammation. In addition to regulating body weight, MIC-1/GDF15 may be used to predict mortality and/or disease course in cancer, cardiovascular disease (CVD), chronic renal and heart failure, as well as pulmonary embolism. These data suggested that MIC-1/GDF15 may be a marker of all-cause mortality. To determine whether serum MIC-1/GDF15 estimation is a predictor of all-cause mortality, we examined a cohort of 876 male subjects aged 35-80 years, selected from the Swedish Population Registry, and followed them for overall mortality. Serum MIC-1/GDF15 levels were determined for all subjects from samples taken at study entry. A second (independent) cohort of 324 same-sex twins (69% female) from the Swedish Twin Registry was similarly examined. All the twins had telomere length measured and 183 had serum levels of interleukin 6 (IL-6) and C-reactive protein (CRP) available. Patients were followed for up to 14 years and had cause-specific and all-cause mortality determined. Serum MIC-1/GDF15 levels predicted mortality in the all-male cohort with an adjusted odds ratio (OR) of death of 3.38 (95%CI 1.38-8.26). This finding was validated in the twin cohort. Serum MIC-1/GDF15 remained an independent predictor of mortality when further adjusted for telomere length, IL-6 and CRP. Additionally, serum MIC-1/GDF15 levels were directly correlated with survival time independently of genetic background. Serum MIC-1/GDF15 is a novel predictor of all-cause mortality.
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