| 1. |
- Svensson, Thomas, et al.
(författare)
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Plasma concentration of Caspase-8 is associated with short sleep duration and the risk of incident diabetes mellitus
- 2018
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 103:4, s. 1592-1600
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Tidskriftsartikel (refereegranskat)abstract
- Context: The biological mechanism for the association between sleep duration and incident diabetes mellitus (DM) is unclear. Sleep duration and Caspase-8, a marker of apoptotic activity, have both been implicated in beta cell function.Objective: To investigate the associations between sleep duration and plasma Caspase-8, and incident DM, respectively.Design: Prospective cohort study.Setting: The Malmö Diet and Cancer (MDC) Study is a population-based, prospective study run in the city of Malmö, Sweden.Participants: 4023 individuals from the MDC Study aged 45-68 years at baseline without a history of prevalent DM, and with information on habitual sleep duration.Main outcomes: Incident DM.Results: Mean follow-up time was 17.8 years. Sleep duration was the only behavioural variable significantly associated with plasma Caspase-8. Plasma Caspase-8 was significantly associated with incident DM per standard deviation of its transformed continuous form (hazard ratio [HR]= 1.24, 95% confidence interval [CI] 1.13-1.36), and when dichotomized into high (quartile 4) (HR=1.44, 95%CI: 1.19-1.74) compared to low (quartiles 1-3) concentrations. Caspase-8 interacted with sleep duration; compared to 7-8 hours of sleep and low plasma Caspase-8, individuals with high plasma Caspase-8 and sleep duration <6 hours (HR=3.54, 95%CI: 2.12-5.90), 6-7 hours (HR=1.81, 95%CI: 1.24-2.65), and 8-9 hours (HR=1.54, 95%CI: 1.09-2.18) were at significantly increased risks of incident DM.Conclusions: Sleep duration is associated with plasma Caspase-8. Caspase-8 independently predicts DM years before disease onset and modifies the effect of sleep duration on incident DM. Future studies should investigate if change of sleep duration modifies plasma concentrations of Caspase-8.
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| 2. |
- Svensson, Thomas, et al.
(författare)
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Very short sleep duration reveals a proteomic fingerprint that is selectively associated with incident diabetes mellitus but not with incident coronary heart disease : a cohort study
- 2024
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Ingår i: BMC Medicine. - 1741-7015. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The molecular pathways linking short and long sleep duration with incident diabetes mellitus (iDM) and incident coronary heart disease (iCHD) are not known. We aimed to identify circulating protein patterns associated with sleep duration and test their impact on incident cardiometabolic disease. Methods: We assessed sleep duration and measured 78 plasma proteins among 3336 participants aged 46–68 years, free from DM and CHD at baseline, and identified cases of iDM and iCHD using national registers. Incident events occurring in the first 3 years of follow-up were excluded from analyses. Tenfold cross-fit partialing-out lasso logistic regression adjusted for age and sex was used to identify proteins that significantly predicted sleep duration quintiles when compared with the referent quintile 3 (Q3). Predictive proteins were weighted and combined into proteomic scores (PS) for sleep duration Q1, Q2, Q4, and Q5. Combinations of PS were included in a linear regression model to identify the best predictors of habitual sleep duration. Cox proportional hazards regression models with sleep duration quintiles and sleep-predictive PS as the main exposures were related to iDM and iCHD after adjustment for known covariates. Results: Sixteen unique proteomic markers, predominantly reflecting inflammation and apoptosis, predicted sleep duration quintiles. The combination of PSQ1 and PSQ5 best predicted sleep duration. Mean follow-up times for iDM (n = 522) and iCHD (n = 411) were 21.8 and 22.4 years, respectively. Compared with sleep duration Q3, all sleep duration quintiles were positively and significantly associated with iDM. Only sleep duration Q1 was positively and significantly associated with iCHD. Inclusion of PSQ1 and PSQ5 abrogated the association between sleep duration Q1 and iDM. Moreover, PSQ1 was significantly associated with iDM (HR = 1.27, 95% CI: 1.06–1.53). PSQ1 and PSQ5 were not associated with iCHD and did not markedly attenuate the association between sleep duration Q1 with iCHD. Conclusions: We here identify plasma proteomic fingerprints of sleep duration and suggest that PSQ1 could explain the association between very short sleep duration and incident DM.
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| 3. |
- Brink, Annie, et al.
(författare)
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Sex-Specific Risk Factors for Deep Venous Thrombosis and Pulmonary Embolism in a Population-Based Historical Cohort Study of Middle-Aged and Older Individuals
- 2023
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Ingår i: Journal of the American Heart Association. - 2047-9980. ; 12:5, s. 1-13
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Whether sex-specific differences exist for risk factors for pulmonary embolism (PE) and deep venous thrombosis (DVT), with the exception of pregnancy and estrogen therapy, has been sparsely studied. We aimed to study whether sex-specific differences of risk factors exist for noncancer-related DVT and PE in middle-aged and older individuals without cardiovascular history or previous diagnosis in a population-based historical (retrospective) cohort. METHODS AND RESULTS: Potential venous thromboembolism (VTE) risk factors were registered at baseline in 15 807 women and 9996 men aged 44 to 74 years, who participated in the Malmö Diet and Cancer study (1991–1996). We excluded subjects with a previous history of VTE, cancer, a diagnosis of cardiovascular disease, or a diagnosis of cancer-associated VTE during follow-up. Patients were followed up from baseline until the first event of PE or DVT, death, or December 31, 2018. During the follow-up period, 365 (2.3%) women and 168 (1.7%) men were affected by first DVT, and 309 (2.0%) women and 154 (1.5%) men were affected by first PE. In the multivariable Cox regression models, the anthropometric obesity markers of weight, body mass index, waist and hip circumference, fat percentage, and muscle weight were in a dose-dependent way associated with DVT and PE among women but not men. In an analysis that included patients with cardiovascular disease and cancer-related VTE, the results were similar for women. For men, several obesity measures became significantly associated with PE or DVT but were weaker than in women, especially for DVT. CONCLUSIONS: Anthropometric obesity measures are more important risk factors for both DVT and PE among women than men, especially for individuals without cardiovascular history or previous diagnosis or cancer-related VTE.
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| 4. |
- Chen, X., et al.
(författare)
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A genome-wide association study of IgM antibody against phosphorylcholine: shared genetics and phenotypic relationship to chronic lymphocytic leukemia
- 2018
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 27:10, s. 1809-1818
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Tidskriftsartikel (refereegranskat)abstract
- Phosphorylcholine (PC) is an epitope on oxidized low-density lipoprotein (oxLDL), apoptotic cells and several pathogens like Streptococcus pneumoniae. Immunoglobulin M against PC (IgM anti-PC) has the ability to inhibit uptake of oxLDL by macrophages and increase clearance of apoptotic cells. From our genome-wide association studies (GWASs) in four European-ancestry cohorts, six single nucleotide polymorphisms (SNPs) in 11q24.1 were discovered (in 3002 individuals) and replicated (in 646 individuals) to be associated with serum level of IgM anti-PC (the leading SNP rs35923643-G, combined beta = 0.19, 95% confidence interval 0.13-0.24, P = 4.3 x 10-11). The haplotype tagged by rs35923643-G (or its proxy SNP rs735665-A) is also known as the top risk allele for chronic lymphocytic leukemia (CLL), and a main increasing allele for general IgM. By using summary GWAS results of IgM anti-PC and CLL in the polygenic risk score (PRS) analysis, PRS on the basis of IgM anti-PC risk alleles positively associated with CLL risk (explained 0.6% of CLL variance, P = 1.2 x 10-15). Functional prediction suggested that rs35923643-G might impede the binding of Runt-related transcription factor 3, a tumor suppressor playing a central role in the immune regulation of cancers. Contrary to the expectations from the shared genetics between IgM anti-PC and CLL, an inverse relationship at the phenotypic level was found in a nested case-control study (30 CLL cases with 90 age- and sex-matched controls), potentially reflecting reverse causation. The suggested function of the top variant as well as the phenotypic association between IgM anti-PC and CLL risk needs replication and motivates further studies.
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| 5. |
- Engström, Gunnar, et al.
(författare)
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Soluble urokinase plasminogen activator receptor and incidence of venous thromboembolism.
- 2015
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Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 115:3, s. 657-662
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Tidskriftsartikel (refereegranskat)abstract
- Raised plasma levels of the soluble urokinase plasminogen activator receptor (suPAR) have been associated with increased incidence of cardiovascular diseases. Whether suPAR is associated with venous thromboembolism (VTE) is largely unknown. The purpose of the present study was to investigate the relationship between suPAR and incidence of VTE in a cohort study. suPAR was measured in 5,203 subjects (aged 46-68 years, 58 % women) from the general population, who participated in the Malmö Diet and Cancer (MDC) study between 1991 and 1994. Incident cases of VTE were identified from the Swedish patient register during a mean follow-up of 15.7 years. Of 5,203 subjects with measurements of suPAR, 239 had VTE during follow-up (127 venous thrombosis, 86 lung embolism, 26 both). Incidence of VTE was significantly higher in subjects with suPAR levels in the top quartile. Adjusted for age and sex, the HR (4th vs 1st quartile) was 1.74 (95 %CI: 1.2-2.6, p for trend=0.003). After adjustments for risk factors, the HR was 1.66 (95 %CI: 1.1-2.5, p for trend=0.016). High level of suPAR was a risk indicator for incidence of VTE in this population-based cohort study. The causal relationships between suPAR and VTE remain to be explored.
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| 6. |
- Hallengren, Erik, et al.
(författare)
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Genetic determinants of growth hormone and GH-related phenotypes
- 2017
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 18, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Higher fasting Growth Hormone (GH) has been associated with increased cardiovascular morbidity and mortality. Our objective was to find genetic determinants of fasting GH in order to facilitate future efforts of analyzing the association between fasting growth hormone and cardiovascular disease. A genome-wide association study (GWAS) was performed in a discovery cohort of 4134 persons (58% females; age 46-68 yrs), linking SNPs to fasting hs-GH. Fifteen SNPs were replicated in an independent cohort of 5262 persons (28.9% females; age 56-85 yrs). The best performing SNP was analyzed vs GH-related variables in a third independent cohort (n = 24,047; 61% females; age 44-73 yrs). A candidate gene approach searched for significant SNPs in the genes GH1 and GHR in the discovery cohort and was replicated as previously described.RESULTS: In the GWAS, the minor allele of rs7208736 was associated with lower GH in the discovery cohort (p = 5.15*10^-6) and the replication cohort (p = 0.005). The GH reducing allele was associated with lower BMI (P = 0.026) and waist (P = 0.021) in males only. In the candidate gene approach rs13153388 in the GHR-gene was associated with elevated GH-levels (P = 0.003) in the discovery cohort only and reduced height (P = 0.003).CONCLUSION: In the first GWAS ever for GH, we identify a novel locus on chromosome 17 associated with fasting GH levels, suggesting novel biological mechanisms behind GH secretion and GH-related traits. The candidate gene approach identified a genetic variant in the GHR, which was associated with an elevation of fasting hs-GH and lower height suggesting reduced GHR ligand sensitivity. Our findings need further replication.
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| 7. |
- Lumbers, R. T., et al.
(författare)
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The genomics of heart failure: design and rationale of the HERMES consortium
- 2021
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Ingår i: Esc Heart Failure. - : Wiley. - 2055-5822. ; 8:6, s. 5531-5541
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Tidskriftsartikel (refereegranskat)abstract
- Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 x 10(-8) under an additive genetic model. Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.
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| 8. |
- Magnusson, Martin, et al.
(författare)
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Cystatin C and risk of diabetes and the metabolic syndrome - Biomarker and genotype association analyses
- 2016
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:5
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Tidskriftsartikel (refereegranskat)abstract
- Background We recently reported a relationship between plasma levels of cystatin C and incidence of the metabolic syndrome (MetS) among the first 2,369 subjects who participated in the reexamination study of the population-based Malmö and Diet Cancer Cardiovascular cohort (MDC-CC-re-exam). In this study we aimed to replicate these results and also investigate if cystatin C was causally associated with MetS and diabetes. Methods We estimated the effect size of the strongest GWAS derived cystatin C SNP (major allele of rs13038305) on plasma cystatin C in the now completed MDC-CC-re-exam (n = 3,734) and thereafter examined the association between plasma cystatin C (403 cases of diabetes and2665 controls) as well as rs13038305 (235 cases and 2425 controls) with incident diabetes. The association of rs13038305 and incident MetS (511 cases of MetS and 1980 controls) was similarly investigated in the whole MDC-CC-re-exam. We also attempted to replicate our previously shown association of cystatin C with incident MetS in subjects from the MDC-CC-re-exam (147 cases and 711 controls) that were not included in our previous report. Results In the entire MDC-CC-re-exam, each copy of the major allele of rs13038305 was associated with approximately 0.30 standard deviation (SD) higher plasma concentration of cystatin C (β = 0.33, p = 4.2E-28 ) in age and sex adjusted analysis. Cystatin C in plasma was not associated with incident diabetes after adjustment for known diabetes risk factors (OR per 1 SD increment 0.99 (0.86-1.13), p = 0.842). In the replication cohort of MDC-CC-re-exam, the OR (95% CI) for incident MetS in subjects belonging to quartiles 1, 2, 3 and 4 of plasma cystatin C levels was 1.00 (reference), 1.21 (0.70-2.07), 1.62 (0.95-2.78) and 1.72 (1.01-2.93) (ptrend = 0.026) in age and sex adjusted analysis. In the entire MDC-CC-re-exam the odds ratio for incident MetS and diabetes per copy of the major rs13038305 allele was 1.13, (0.95-1.34), p = 0.160 and 1.07, 95% CI 0.89-1.30, p = 0.478, respectively. Conclusion We were able to replicate our previously shown association between high levels of cystatin C and increased risk of future development of MetS. However, a causal involvement of cystatin C in the etiology of MetS or diabetes seems unlikely since genetic elevation of plasma cystatin C was not significantly related to incidence of these diseases.
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| 9. |
- Manderstedt, Eric, et al.
(författare)
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Classic Thrombophilias and Thrombotic Risk Among Middle-Aged and Older Adults : A Population-Based Cohort Study
- 2022
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Ingår i: Journal of the American Heart Association. - : Wiley-Blackwell Publishing Ltd. - 2047-9980. ; 11:4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Five classic thrombophilias have been recognized: factor V Leiden (rs6025), the prothrombin G20210A variant (rs1799963), and protein C, protein S, and antithrombin deficiencies. This study aimed to determine the thrombotic risk of classic thrombophilias in a cohort of middle-aged and older adults. METHODS AND RESULTS: Factor V Leiden, prothrombin G20210A and protein-coding variants in the PROC (protein C), PROS1 (protein S), and SERPINC1 (antithrombin) anticoagulant genes were determined in 29 387 subjects (born 1923–1950, 60% women) who participated in the Malmö Diet and Cancer study (1991–1996). The Human Gene Mutation Database was used to define 68 disease-causing mutations. Patients were followed up from baseline until the first event of venous thromboembolism (VTE), death, or Dec 31, 2018. Carriership (n=908, 3.1%) for disease-causing mutations in the PROC, PROS1, and SERPINC1 genes was associated with incident VTE: Hazard ratio (HR) was 1.6 (95% CI, 1.3–1.9). Variants not in Human Gene Mutation Database were not linked to VTE (HR, 1.1; 95% CI, 0.8–1.5). Heterozygosity for rs6025 and rs1799963 was associated with incident VTE: HR, 1.8 (95% CI, 1.6–2.0) and HR, 1.6 (95% CI, 1.3–2.0), respectively. The HR for carrying 1 classical thrombophilia variant was 1.7 (95% CI, 1.6–1.9). HR was 3.9 (95% CI, 3.1–5.0) for carriers of ≥2 thrombophilia variants. CONCLUSIONS: The 5 classic thrombophilias are associated with a dose-graded risk of VTE in middle-aged and older adults. Disease-causing variants in the PROC, PROS1, and SERPINC1 genes were more common than the rs1799963 variant but the conferred genetic risk was comparable with the rs6025 and rs1799963 variants.
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