Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People With Type 2 Diabetes.

OBJECTIVE: To identify genetic risk factors for incident cardiovascular disease (CVD) among people with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: We conducted a multiancestry time-to-event genome-wide association study for incident CVD among people with T2D. We also tested 204 known coronary artery disease (CAD) variants for association with incident CVD. RESULTS: Among 49,230 participants with T2D, 8,956 had incident CVD events (event rate 18.2%). We identified three novel genetic loci for incident CVD: rs147138607 (near CACNA1E/ZNF648, hazard ratio [HR] 1.23, P = 3.6 × 10-9), rs11444867 (near HS3ST1, HR 1.89, P = 9.9 × 10-9), and rs335407 (near TFB1M/NOX3, HR 1.25, P = 1.5 × 10-8). Among 204 known CAD loci, 5 were associated with incident CVD in T2D (multiple comparison-adjusted P < 0.00024, 0.05/204). A standardized polygenic score of these 204 variants was associated with incident CVD with HR 1.14 (P = 1.0 × 10-16). CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.

Metabolic disorders mediate the relation of miscarriage with cardiovascular diseases.

AIMS: The extent to which the contribution of pregnancy loss to cardiovascular diseases (CVDs) can be explained by metabolic disorders is poorly elucidated but holds insights for reducing long-term cardiovascular risk. The aim of this study is to investigate the mediating effects of hypertension, diabetes mellitus (DM), and lipoprotein metabolism disorders on the association of miscarriage and stillbirth with coronary heart disease (CHD), stroke, heart failure, atrial fibrillation, and composite outcomes. METHODS AND RESULTS: A total of 163 283 ever-gravid women (age 55.3 ± 7.9 years) from the UK Biobank cohort without established metabolic disorders and CVDs were included and followed from 2007 to 2010 baseline until December 2020. Causal mediation analyses were used to estimate the proportion mediated. Hypertension mediated 11.1% (95% confidence interval, 3.7-18.5%) of the association between a history of miscarriage and incident CHD. Approximately, 9.5% (4.1-14.8%) of the effect of recurrent miscarriages on incident CHD was via hypertension, 8.4% (2.5-14.3%) of the effect was via lipoprotein metabolism disorders, 1.7% (0.5-2.9%) of the effect was via DM, and 10.7% (0.2-21.1%) of the effect of recurrent miscarriages on incident stroke was via hypertension. Hypertension mediated the largest proportion of effect for the atherosclerotic cardiovascular event (15.5% for a history of miscarriage and 9.4% for recurrent miscarriages), followed by lipoprotein metabolism disorders and DM. CONCLUSION: Hypertension, DM, and lipoprotein metabolism disorders mediated the association between miscarriage and various cardiovascular outcomes in later life. In particular, hypertension mediated a large proportion of the relationship between miscarriage and atherosclerotic CVD.

Hypertension, diabetes, and lipoprotein metabolism disorders mediated the association between miscarriage and various cardiovascular outcomes in later life. Hypertension mediated the largest proportion of effect for the atherosclerotic cardiovascular event (15.5% for a history of miscarriage and 9.4% for recurrent miscarriages). Women who have experienced miscarriage should be regularly monitored for possible required interventions on blood pressure, blood lipids, and glucose to reduce their long-term cardiovascular risk. Our findings contribute to ongoing research efforts to better understand the pathogenesis of pregnancy loss leading to CVD. In particular, we identified metabolic disorders processes as potential mediators. Implications: Our findings warrant early monitoring and intensive (preventive) treatment of hypertension and lipoprotein metabolism disorders among women who experience miscarriage(s) to lower their burden of later-life clinical cardiovascular events.

Integrative single-cell meta-analysis reveals disease-relevant vascular cell states and markers in human atherosclerosis.

Coronary artery disease (CAD) is characterized by atherosclerotic plaque formation in the arterial wall. CAD progression involves complex interactions and phenotypic plasticity among vascular and immune cell lineages. Single-cell RNA-seq (scRNA-seq) studies have highlighted lineage-specific transcriptomic signatures, but human cell phenotypes remain controversial. Here, we perform an integrated meta-analysis of 22 scRNA-seq libraries to generate a comprehensive map of human atherosclerosis with 118,578 cells. Besides characterizing granular cell-type diversity and communication, we leverage this atlas to provide insights into smooth muscle cell (SMC) modulation. We integrate genome-wide association study data and uncover a critical role for modulated SMC phenotypes in CAD, myocardial infarction, and coronary calcification. Finally, we identify fibromyocyte/fibrochondrogenic SMC markers (LTBP1 and CRTAC1) as proxies of atherosclerosis progression and validate these through omics and spatial imaging analyses. Altogether, we create a unified atlas of human atherosclerosis informing cell state-specific mechanistic and translational studies of cardiovascular diseases.

Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification.

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.

Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2D) confers a two- to three-fold increased risk of cardiovascular disease (CVD). However, the mechanisms underlying increased CVD risk among people with T2D are only partially understood. We hypothesized that a genetic association study among people with T2D at risk for developing incident cardiovascular complications could provide insights into molecular genetic aspects underlying CVD. METHODS: From 16 studies of the Cohorts for Heart & Aging Research in Genomic Epidemiology (CHARGE) Consortium, we conducted a multi-ancestry time-to-event genome-wide association study (GWAS) for incident CVD among people with T2D using Cox proportional hazards models. Incident CVD was defined based on a composite of coronary artery disease (CAD), stroke, and cardiovascular death that occurred at least one year after the diagnosis of T2D. Cohort-level estimated effect sizes were combined using inverse variance weighted fixed effects meta-analysis. We also tested 204 known CAD variants for association with incident CVD among patients with T2D. RESULTS: A total of 49,230 participants with T2D were included in the analyses (31,118 European ancestries and 18,112 non-European ancestries) which consisted of 8,956 incident CVD cases over a range of mean follow-up duration between 3.2 and 33.7 years (event rate 18.2%). We identified three novel, distinct genetic loci for incident CVD among individuals with T2D that reached the threshold for genome-wide significance (P<5.0×10-8): rs147138607 (intergenic variant between CACNA1E and ZNF648) with a hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.15 - 1.32, P=3.6×10-9, rs11444867 (intergenic variant near HS3ST1) with HR 1.89, 95% CI 1.52 - 2.35, P=9.9×10-9, and rs335407 (intergenic variant between TFB1M and NOX3) HR 1.25, 95% CI 1.16 - 1.35, P=1.5×10-8. Among 204 known CAD loci, 32 were associated with incident CVD in people with T2D with P<0.05, and 5 were significant after Bonferroni correction (P<0.00024, 0.05/204). A polygenic score of these 204 variants was significantly associated with incident CVD with HR 1.14 (95% CI 1.12 - 1.16) per 1 standard deviation increase (P=1.0×10-16). CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.

Coronary Artery Calcium Score and Polygenic Risk Score for the Prediction of Coronary Heart Disease Events.

Importance: Coronary artery calcium score and polygenic risk score have each separately been proposed as novel markers to identify risk of coronary heart disease (CHD), but no prior studies have directly compared these markers in the same cohorts. Objective: To evaluate change in CHD risk prediction when a coronary artery calcium score, a polygenic risk score, or both are added to a traditional risk factor-based model. Design, Setting, and Participants: Two observational population-based studies involving individuals aged 45 years through 79 years of European ancestry and free of clinical CHD at baseline: the Multi-Ethnic Study of Atherosclerosis (MESA) study involved 1991 participants at 6 US centers and the Rotterdam Study (RS) involved 1217 in Rotterdam, the Netherlands. Exposure: Traditional risk factors were used to calculate CHD risk (eg, pooled cohort equations [PCEs]), computed tomography for the coronary artery calcium score, and genotyped samples for a validated polygenic risk score. Main Outcomes and Measures: Model discrimination, calibration, and net reclassification improvement (at the recommended risk threshold of 7.5%) for prediction of incident CHD events were assessed. Results: The median age was 61 years in MESA and 67 years in RS. Both log (coronary artery calcium+1) and polygenic risk score were significantly associated with 10-year risk of incident CHD (hazards ratio per SD, 2.60; 95% CI, 2.08-3.26 and 1.43; 95% CI, 1.20-1.71, respectively), in MESA. The C statistic for the coronary artery calcium score was 0.76 (95% CI, 0.71-0.79) and for the polygenic risk score, 0.69 (95% CI, 0.63-0.71). The change in the C statistic when each was added to the PCEs was 0.09 (95% CI, 0.06-0.13) for the coronary artery calcium score, 0.02 (95% CI, 0.00-0.04) for the polygenic risk score, and 0.10 (95% CI, 0.07-0.14) for both. Overall categorical net reclassification improvement was significant when the coronary artery calcium score (0.19; 95% CI, 0.06-0.28) but was not significant when the polygenic risk score (0.04; 95% CI, -0.05 to 0.10) was added to the PCEs. Calibration of the PCEs and models with coronary artery calcium and/or polygenic risk scores was adequate (all χ2<20). Subgroup analysis stratified by the median age demonstrated similar findings. Similar findings were observed for 10-year risk in RS and in longer-term follow-up in MESA (median, 16.0 years). Conclusions and Relevance: In 2 cohorts of middle-aged to older adults from the US and the Netherlands, the coronary artery calcium score had better discrimination than the polygenic risk score for risk prediction of CHD. In addition, the coronary artery calcium score but not the polygenic risk score significantly improved risk discrimination and risk reclassification for CHD when added to traditional risk factors.

Lowering of Circulating Sclerostin May Increase Risk of Atherosclerosis and Its Risk Factors: Evidence From a Genome-Wide Association Meta-Analysis Followed by Mendelian Randomization.

OBJECTIVE: In this study, we aimed to establish the causal effects of lowering sclerostin, target of the antiosteoporosis drug romosozumab, on atherosclerosis and its risk factors. METHODS: A genome-wide association study meta-analysis was performed of circulating sclerostin levels in 33,961 European individuals. Mendelian randomization (MR) was used to predict the causal effects of sclerostin lowering on 15 atherosclerosis-related diseases and risk factors. RESULTS: We found that 18 conditionally independent variants were associated with circulating sclerostin. Of these, 1 cis signal in SOST and 3 trans signals in B4GALNT3, RIN3, and SERPINA1 regions showed directionally opposite signals for sclerostin levels and estimated bone mineral density. Variants with these 4 regions were selected as genetic instruments. MR using 5 correlated cis-SNPs suggested that lower sclerostin increased the risk of type 2 diabetes mellitus (DM) (odds ratio [OR] 1.32 [95% confidence interval (95% CI) 1.03-1.69]) and myocardial infarction (MI) (OR 1.35 [95% CI 1.01-1.79]); sclerostin lowering was also suggested to increase the extent of coronary artery calcification (CAC) (ß = 0.24 [95% CI 0.02-0.45]). MR using both cis and trans instruments suggested that lower sclerostin increased hypertension risk (OR 1.09 [95% CI 1.04-1.15]), but otherwise had attenuated effects. CONCLUSION: This study provides genetic evidence to suggest that lower levels of sclerostin may increase the risk of hypertension, type 2 DM, MI, and the extent of CAC. Taken together, these findings underscore the requirement for strategies to mitigate potential adverse effects of romosozumab treatment on atherosclerosis and its related risk factors.

Female Reproductive Factors and Risk of New-Onset Heart Failure: Findings From UK Biobank.

BACKGROUND: A comprehensive evaluation of woman-specific risk factors in relation to incident heart failure (HF) is limited. OBJECTIVES: This study sought to investigate the association of multiple female reproductive factors with the risk of HF. METHODS: Between 2007 and 2010, 229,026 women (mean age: 56.5 years) without prevalent HF from the UK Biobank cohort were included and followed until December 2020. The relation between (self-reported) reproductive factors and HF was analyzed using Cox proportional hazards models with adjustment for potential confounding. RESULTS: Menarche at age <12 years, compared to age 12-13 years, carried a 9% larger risk of HF (HR: 1.09 [95% CI: 1.01-1.18]). Younger age at menopause was associated with a higher risk of HF (HRage <45 y vs 50-51 y: 1.15 [95% CI: 1.03-1.28]; HRage 45-49 y vs 50-51 y: 1.11 [95% CI: 1.01-1.23]). Younger maternal age at first live birth (HRage <21 y vs 24-26 y: 1.42 [95% CI: 1.28-1.59]; HRage 21-23 y vs 24-26 y: 1.14 [95% CI: 1.03-1.26]) and at last live birth (HRage <26 y vs 29-31 y: 1.19 [95% CI: 1.07-1.33]) were associated with higher risk of HF. Compared to women with 1 or 2 children, having 3 or 4 children (HR: 1.09 [95% CI: 1.02-1.17]) or >4 children (HR: 1.24 [95% CI: 1.05-1.47]) was associated with higher HF risk. Experiencing miscarriages or abortions was not significantly associated with incident HF, whereas experiencing 1 stillbirth and recurrent stillbirths conferred a 20% and 43% larger risk of HF, respectively, compared to no stillbirth. CONCLUSIONS: The findings emphasize the importance of female reproductive history in the assessment of HF risk.

DNA repair in cardiomyocytes is critical for maintaining cardiac function in mice.

Heart failure has reached epidemic proportions in a progressively ageing population. The molecular mechanisms underlying heart failure remain elusive, but evidence indicates that DNA damage is enhanced in failing hearts. Here, we tested the hypothesis that endogenous DNA repair in cardiomyocytes is critical for maintaining normal cardiac function, so that perturbed repair of spontaneous DNA damage drives early onset of heart failure. To increase the burden of spontaneous DNA damage, we knocked out the DNA repair endonucleases xeroderma pigmentosum complementation group G (XPG) and excision repair cross-complementation group 1 (ERCC1), either systemically or cardiomyocyte-restricted, and studied the effects on cardiac function and structure. Loss of DNA repair permitted normal heart development but subsequently caused progressive deterioration of cardiac function, resulting in overt congestive heart failure and premature death within 6 months. Cardiac biopsies revealed increased oxidative stress associated with increased fibrosis and apoptosis. Moreover, gene set enrichment analysis showed enrichment of pathways associated with impaired DNA repair and apoptosis, and identified TP53 as one of the top active upstream transcription regulators. In support of the observed cardiac phenotype in mutant mice, several genetic variants in the ERCC1 and XPG gene in human GWAS data were found to be associated with cardiac remodelling and dysfunction. In conclusion, unrepaired spontaneous DNA damage in differentiated cardiomyocytes drives early onset of cardiac failure. These observations implicate DNA damage as a potential novel therapeutic target and highlight systemic and cardiomyocyte-restricted DNA repair-deficient mouse mutants as bona fide models of heart failure.

Association between arterial stiffness/remodeling and new-onset type 2 diabetes mellitus in general population.

OBJECTIVE: We studied if large artery stiffness is involved in type 2 diabetes pathogenesis. We also investigated the effect of genetic risk for type 2 diabetes in these associations and the causality. RESEARCH DESIGN AND METHODS: In the prospective population-based Rotterdam Study (n = 3,055; mean age, 67.2 years), markers of aortic and carotid stiffnesses and measures of arterial remodeling were assessed. Cox proportional hazard regression analysis estimated the associations between arterial stiffness measures with incident type 2 diabetes. We used 403 single nucleotide polymorphisms to calculate the genetic risk score (GRS) for type 2 diabetes. We adopted Mendelian randomization (MR) analysis to evaluate the causal associations. RESULTS: Over a median follow-up of 14.0 years, higher carotid-femoral pulse wave velocity (hazard ratio,1.18; 95 %CI: 1.04-1.35), carotid distensibility coefficient (1.17; 1.04-1.32), and carotid intima-media thickness (1.15; 1.01-1.32) were independently associated with incident diabetes. The associations were stronger among individuals with a higher GRS for type 2 diabetes. MR analysis did not support the causality of the observed associations. CONCLUSIONS: Elevated arterial stiffness is independently associated with incident type 2 diabetes. For most arterial stiffness markers, the associations with incident type 2 diabetes were more robust in individuals with a higher GRS for diabetes.

Autoimmune diseases and new-onset atrial fibrillation: a UK Biobank study.

AIMS: The underlying mechanisms of atrial fibrillation (AF) are largely unknown. Inflammation may underlie atrial remodelling. Autoimmune diseases, related to increased systemic inflammation, may therefore be associated with new-onset AF. METHODS AND RESULTS: Participants from the population-based UK Biobank were screened for rheumatic fever, gastrointestinal autoimmune diseases, autoimmune diseases targeting the musculoskeletal system and connective tissues, and neurological autoimmune diseases. Between 2006 and 2022, participants were followed for incident AF. Cox proportional hazards regression analyses were performed to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) to quantify associations. 494 072 participants free from AF were included (median age 58.0 years, 54.8% women). After a median of 12.8 years, 27 194 (5.5%) participants were diagnosed with new-onset AF. Rheumatic fever without heart involvement (HR, 95% CI: 1.47, 1.26-1.72), Crohn's disease (1.23, 1.05-1.45), ulcerative colitis (1.17, 1.06-1.31), rheumatoid arthritis (1.39, 1.28-1.51), polyarteritis nodosa (1.82, 1.04-3.09), systemic lupus erythematosus (1.82, 1.41-2.35), and systemic sclerosis (2.32, 1.57-3.44) were associated with a larger AF risk. In sex-stratified analyses, rheumatic fever without heart involvement, multiple sclerosis, Crohn's disease, seropositive rheumatoid arthritis, psoriatic and enteropathic arthropathies, systemic sclerosis and ankylosing spondylitis were associated with larger AF risk in women, whereas only men showed a larger AF risk associated with ulcerative colitis. CONCLUSIONS: Various autoimmune diseases are associated with new-onset AF, more distinct in women. Our findings elaborate on the pathophysiological differences in autoimmunity and AF risk between men and women.

Association Between Sex-Specific Risk Factors and Risk of New-Onset Atrial Fibrillation Among Women.

Importance: Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide, with different epidemiological and pathophysiological processes for women vs men and a poorer prognosis for women. Further investigation of sex-specific risk factors associated with AF development in women is warranted. Objective: To investigate the linear and potential nonlinear associations between sex-specific risk factors and the risk of new-onset AF in women. Design, Setting, and Participants: This population-based cohort study obtained data from the 2006 to 2010 UK Biobank study, a cohort of more than 500 000 participants aged 40 to 69 years. Participants were women without AF and history of hysterectomy and/or bilateral oophorectomy at baseline. Median follow-up period for AF onset was 11.6 years, and follow-up ended on October 3, 2020. Exposures: Self-reported, sex-specific risk factors, including age at menarche, history of irregular menstrual cycle, menopause status, age at menopause, years after menopause, age at first live birth, years after last birth, history of spontaneous miscarriages, history of stillbirths, number of live births, and total reproductive years. Main Outcomes and Measures: The primary outcome was new-onset AF, which was defined by the use of International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code I48. Results: A total of 235 191 women (mean [SD] age, 55.7 [8.1] years) were included in the present study. During follow-up, 4629 (2.0%) women experienced new-onset AF. In multivariable-adjusted models, history of irregular menstrual cycle was associated with higher AF risk (hazard ratio [HR], 1.34; 95% CI, 1.01-1.79). Both early menarche (age 7-11 years; HR, 1.10 [95% CI, 1.00-1.21]) and late menarche (age 13-18 years; HR, 1.08 [95% CI, 1.00-1.17]) were associated with AF incidence. Early menopause (age 35-44 years; HR, 1.24 [95% CI, 1.10-1.39]) and delayed menopause (age ≥60 years; HR, 1.34 [95% CI, 1.10-1.78]) were associated with higher risk of AF. Compared with women with 1 to 2 live births, those with 0 live births (HR, 1.13; 95% CI, 1.04-1.24) or 7 or more live births (HR, 1.67; 95% CI, 1.03-2.70) both had significantly higher AF risk. Conclusions and Relevance: Results of this study suggest that irregular menstrual cycles, nulliparity, and multiparity were associated with higher risk of new-onset AF among women. The results highlight the importance of taking into account the reproductive history of women in devising screening strategies for AF prevention.

Disentangling the association between kidney function and atrial fibrillation: a bidirectional Mendelian randomization study.

BACKGROUND: The potential bidirectional causal association between kidney function and atrial fibrillation (AF) remains unclear. METHODS: We conducted a bidirectional two-sample Mendelian randomization (MR) analysis. From multiple genome-wide association studies (GWAS), we retrieved genetic variants associated with kidney function (estimated glomerular filtration rate based on creatinine (eGFRcreat), blood urea nitrogen (BUN), chronic kidney disease (CKD stage ≥G3): n = 1,045,620, eGFR based on cystatin C: n = 24,063-32,861, urine albumin-to-creatinine ratio (UACR), and microalbuminuria: n = 564,257), and AF (n = 1,030,836). The inverse-variance weighted method was used as our main analysis. RESULTS: MR analyses supported a causal effect of CKD (n = 9 SNPs, odds ratio (OR): 1.10, 95% confidence interval (CI): 1.04-1.17, p-value = 1.97 × 10-03), and microalbuminuria (n = 5 SNPs, OR: 1.26, 95% CI: 1.10-1.46, p-value = 1.38 × 10-03) on AF risk. We also observed a causal effect of AF on eGFRcreat (n = 97 SNPs, OR: 1.00, 95% CI: 1.00-1.00, p-value = 6.78 × 10-03), CKD (n = 107 SNPs, OR: 1.06, 95% CI: 1.03-1.09, p-value = 2.97 × 10-04), microalbuminuria (n = 83 SNPs, OR: 1.07, 95% CI: 1.04-1.09, p-value = 2.49 × 10-08), and a suggestive causal effect on eGFRcys (n = 103 SNPs, OR: 0.99, 95% CI: 0.99-1.00, p-value = 4.61 × 10-02). Sensitivity analyses, including weighted median estimator, MR-Egger, the MR pleiotropy residual sum and outlier test, and excluding genetic variants associated with possible confounders and/or horizontal mediators (myocardial infarction/coronary artery disease, heart failure) indicated that these findings were robust. CONCLUSIONS: Our results supported a bidirectional causal association between kidney function and AF. The shared genetic architecture between kidney dysfunction and AF might represent potential important therapeutic targets to prevent both conditions in the general population.

Higher thyrotropin leads to unfavorable lipid profile and somewhat higher cardiovascular disease risk: evidence from multi-cohort Mendelian randomization and metabolomic profiling.

BACKGROUND: Observational studies suggest interconnections between thyroid status, metabolism, and risk of coronary artery disease (CAD), but causality remains to be proven. The present study aimed to investigate the potential causal relationship between thyroid status and cardiovascular disease and to characterize the metabolomic profile associated with thyroid status. METHODS: Multi-cohort two-sample Mendelian randomization (MR) was performed utilizing genome-wide significant variants as instruments for standardized thyrotropin (TSH) and free thyroxine (fT4) within the reference range. Associations between TSH and fT4 and metabolic profile were investigated in a two-stage manner: associations between TSH and fT4 and the full panel of 161 metabolomic markers were first assessed hypothesis-free, then directional consistency was assessed through Mendelian randomization, another metabolic profile platform, and in individuals with biochemically defined thyroid dysfunction. RESULTS: Circulating TSH was associated with 52/161 metabolomic markers, and fT4 levels were associated with 21/161 metabolomic markers among 9432 euthyroid individuals (median age varied from 23.0 to 75.4 years, 54.5% women). Positive associations between circulating TSH levels and concentrations of very low-density lipoprotein subclasses and components, triglycerides, and triglyceride content of lipoproteins were directionally consistent across the multivariable regression, MR, metabolomic platforms, and for individuals with hypo- and hyperthyroidism. Associations with fT4 levels inversely reflected those observed with TSH. Among 91,810 CAD cases and 656,091 controls of European ancestry, per 1-SD increase of genetically determined TSH concentration risk of CAD increased slightly, but not significantly, with an OR of 1.03 (95% CI 0.99-1.07; p value 0.16), whereas higher genetically determined fT4 levels were not associated with CAD risk (OR 1.00 per SD increase of fT4; 95% CI 0.96-1.04; p value 0.59). CONCLUSIONS: Lower thyroid status leads to an unfavorable lipid profile and a somewhat increased cardiovascular disease risk.

Apolipoprotein E genotype, lifestyle and coronary artery disease: Gene-environment interaction analyses in the UK Biobank population.

BACKGROUND AND AIMS: The APOE ε4 genotype has a higher risk for developing coronary artery disease (CAD), but there is preliminary evidence that antioxidative lifestyle factors interact with APOE genotype on CAD risk. Here, we assessed the effect modification of physical activity, oily fish and polyunsaturated fatty acid (PUFA) intake with APOE genotype on risk of incident CAD. METHODS: The present study comprised 345,659 white European participants from UK Biobank (mean age: 56.5 years, 45.7% men) without a history of CAD. Information regarding physical activity, oily fish intake and PUFA intake was collected through questionnaires, and information on incident CAD through linkage with hospital admission records. Analyses were performed using Cox proportional hazard models adjusted for age and sex. RESULTS: Higher physical activity level and oily fish intake were both associated with a lower incidence of CAD. However, these associations were similar across the different APOE genotypes (p-values for interaction > 0.05). Most notable, higher PUFA intake was associated with a lower CAD risk in APOE ε4 genotype carriers (hazard ratio: 0.76, 95% confidence interval: 0.63-0.92), and not in APOE ε3/ε3 genotype carriers (0.90; 0.79, 1.02), but without statistical evidence for effect modification (p-valueinteraction = 0.137). CONCLUSIONS: While higher physical activity and high fish and PUFA intake were associated with a lower risk of incident CAD, no evidence for interaction of these lifestyle factors with APOE genotype was observed in UK Biobank participants. Interventions intended to reduce cardiovascular risk might therefore be similarly effective across the APOE genotype carriers.

Genetically Determined Higher TSH Is Associated With a Lower Risk of Diabetes Mellitus in Individuals With Low BMI.

CONTEXT: Thyroid status is hypothesized to be causally related with the risk of diabetes mellitus (DM), but previous results were conflicting possibly because of a complex interaction between thyrotropin (TSH), body mass index (BMI) and DM. OBJECTIVE: This work aims to investigate the causal association between thyroid status with DM and glucose homeostasis and to what extent this association is dependent on BMI. METHODS: A mendelian randomization study was conducted of European-ancestry participants from the UK Biobank population. The present study involved 408 895 individuals (mean age 57.4 years [SD 8.0], 45.9% men), of whom 19 773 had DM. Genetic variants for circulatory TSH, free thyroxine (fT4) concentrations and BMI to calculate weighted genetic risk scores. The main outcome measures included self-reported DM-stratified analyses by BMI. Analyses were repeated for nonfasting glucose and glycated hemoglobin A1c (HbA1c) among individuals without DM. RESULTS: Genetically determined TSH and fT4 levels were not associated with risk of DM in the total UK Biobank population. However, in analyses stratified on genetically determined BMI, genetically determined higher TSH, and not fT4, was associated with a lower risk for DM only in the low BMI group (odds ratio 0.91; 95% CI, 0.85-0.98 in low BMI; P value for interaction = .06). Similar results were observed for glucose and HbA1c among individuals without DM. CONCLUSION: TSH, but not fT4, is a potential causal risk factor for DM in individuals with genetically determined low BMI highlighting potential protective effects of TSH only in low-risk populations.

Investigating the relationships between unfavourable habitual sleep and metabolomic traits: evidence from multi-cohort multivariable regression and Mendelian randomization analyses.

BACKGROUND: Sleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep duration increase coronary artery disease risk. We combined adjusted multivariable regression (AMV) and MR analyses of phenotypes of unfavourable sleep on 113 metabolomic traits to investigate possible biochemical mechanisms linking sleep to cardiovascular disease. METHODS: We used AMV (N = 17,368) combined with two-sample MR (N = 38,618) to examine effects of self-reported insomnia symptoms, total habitual sleep duration, and chronotype on 113 metabolomic traits. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex, and body mass index. For the MR analyses, we used summary results from published European-ancestry genome-wide association studies of self-reported sleep traits and of nuclear magnetic resonance (NMR) serum metabolites. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions. RESULTS: We found consistent evidence from AMV and MR analyses for associations of usual vs. sometimes/rare/never insomnia symptoms with lower citrate (- 0.08 standard deviation (SD)[95% confidence interval (CI) - 0.12, - 0.03] in AMV and - 0.03SD [- 0.07, - 0.003] in MR), higher glycoprotein acetyls (0.08SD [95% CI 0.03, 0.12] in AMV and 0.06SD [0.03, 0.10) in MR]), lower total very large HDL particles (- 0.04SD [- 0.08, 0.00] in AMV and - 0.05SD [- 0.09, - 0.02] in MR), and lower phospholipids in very large HDL particles (- 0.04SD [- 0.08, 0.002] in AMV and - 0.05SD [- 0.08, - 0.02] in MR). Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1 h [0.01, 0.03] in AMV and 0.15SD [0.02, 0.29] in MR) and with isoleucine in MR analyses (0.22SD [0.08, 0.35]). No consistent evidence was observed for effects of chronotype on metabolomic measures. CONCLUSIONS: Whilst our results suggested that unfavourable sleep traits may not cause widespread metabolic disruption, some notable effects were observed. The evidence for possible effects of insomnia symptoms on glycoprotein acetyls and citrate and longer total sleep duration on creatinine and isoleucine might explain some of the effects, found in MR analyses of these sleep traits on coronary heart disease, which warrant further investigation.

Circulatory MicroRNAs in Plasma and Atrial Fibrillation in the General Population: The Rotterdam Study.

BACKGROUND: MicroRNAs (miRNAs), small non-coding RNAs regulating gene expression, have been shown to play an important role in cardiovascular disease. However, limited population-based data regarding the relationship between circulatory miRNAs in plasma and atrial fibrillation (AF) exist. Moreover, it remains unclear if the relationship differs by sex. We therefore aimed to determine the (sex-specific) association between plasma circulatory miRNAs and AF at the population level. METHODS: Plasma levels of miRNAs were measured using a targeted next-generation sequencing method in 1999 participants from the population-based Rotterdam Study. Logistic regression and Cox proportional hazards models were used to assess the associations of 591 well-expressed miRNAs with the prevalence and incidence of AF. Models were adjusted for cardiovascular risk factors. We further examined the link between predicted target genes of the identified miRNAs. RESULTS: The mean age was 71.7 years (57.1% women), 98 participants (58 men and 40 women) had prevalent AF at baseline. Moreover, 196 participants (96 men and 100 women) developed AF during a median follow-up of 9.0 years. After adjusting for multiple testing, miR-4798-3p was significantly associated with the odds of prevalent AF among men (odds ratio, 95% confidence interval, 0.39, 0.24-0.66, p-value = 0.000248). No miRNAs were significantly associated with incident AF. MiR-4798-3p could potentially regulate the expression of a number of AF-related genes, including genes involved in calcium and potassium handling in myocytes, protection of cells against oxidative stress, and cardiac fibrosis. CONCLUSIONS: Plasma levels of miR-4798-3p were significantly associated with the odds of prevalent AF among men. Several target genes in relation to AF pathophysiology could potentially be regulated by miR-4798-3p that warrant further investigations in future experimental studies.

Metabolomics analyses in non-diabetic middle-aged individuals reveal metabolites impacting early glucose disturbances and insulin sensitivity.

INTRODUCTION: Several plasma metabolites have been associated with insulin resistance and type 2 diabetes mellitus. OBJECTIVES: We aimed to identify plasma metabolites associated with different indices of early disturbances in glucose metabolism and insulin sensitivity. METHODS: This cross-sectional study was conducted in a subsample of the Leiden Longevity Study comprising individuals without a history of diabetes mellitus (n = 233) with a mean age of 63.3 ± 6.7 years of which 48.1% were men. We tested for associations of fasting glucose, fasting insulin, HOMA-IR, Matsuda Index, Insulinogenic Index and glycated hemoglobin with metabolites (Swedish Metabolomics Platform) using linear regression analysis adjusted for age, sex and BMI. Results were validated internally using an independent metabolomics platform (Biocrates platform) and replicated externally in the independent Netherlands Epidemiology of Obesity (NEO) study (Metabolon platform) (n = 545, mean age of 55.8 ± 6.0 years of which 48.6% were men). Moreover, in the NEO study, we replicated our analyses in individuals with diabetes mellitus (cases: n = 36; controls = 561). RESULTS: Out of the 34 metabolites, a total of 12 plasma metabolites were associated with different indices of disturbances in glucose metabolism and insulin sensitivity in individuals without diabetes mellitus. These findings were validated using a different metabolomics platform as well as in an independent cohort of non-diabetics. Moreover, tyrosine, alanine, valine, tryptophan and alpha-ketoglutaric acid levels were higher in individuals with diabetes mellitus. CONCLUSION: We found several plasma metabolites that are associated with early disturbances in glucose metabolism and insulin sensitivity of which five were also higher in individuals with diabetes mellitus.

Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration.

Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.