Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of ...DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.
Higher circulating levels of the branched-chain amino acids (BCAAs; i.e., isoleucine, leucine, and valine) are strongly associated with higher type 2 diabetes risk, but it is not known whether this ...association is causal. We undertook large-scale human genetic analyses to address this question.
Genome-wide studies of BCAA levels in 16,596 individuals revealed five genomic regions associated at genome-wide levels of significance (p < 5 × 10-8). The strongest signal was 21 kb upstream of the PPM1K gene (beta in standard deviations SDs of leucine per allele = 0.08, p = 3.9 × 10-25), encoding an activator of the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) responsible for the rate-limiting step in BCAA catabolism. In another analysis, in up to 47,877 cases of type 2 diabetes and 267,694 controls, a genetically predicted difference of 1 SD in amino acid level was associated with an odds ratio for type 2 diabetes of 1.44 (95% CI 1.26-1.65, p = 9.5 × 10-8) for isoleucine, 1.85 (95% CI 1.41-2.42, p = 7.3 × 10-6) for leucine, and 1.54 (95% CI 1.28-1.84, p = 4.2 × 10-6) for valine. Estimates were highly consistent with those from prospective observational studies of the association between BCAA levels and incident type 2 diabetes in a meta-analysis of 1,992 cases and 4,319 non-cases. Metabolome-wide association analyses of BCAA-raising alleles revealed high specificity to the BCAA pathway and an accumulation of metabolites upstream of branched-chain alpha-ketoacid oxidation, consistent with reduced BCKD activity. Limitations of this study are that, while the association of genetic variants appeared highly specific, the possibility of pleiotropic associations cannot be entirely excluded. Similar to other complex phenotypes, genetic scores used in the study captured a limited proportion of the heritability in BCAA levels. Therefore, it is possible that only some of the mechanisms that increase BCAA levels or affect BCAA metabolism are implicated in type 2 diabetes.
Evidence from this large-scale human genetic and metabolomic study is consistent with a causal role of BCAA metabolism in the aetiology of type 2 diabetes.
Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the ...variation in these measures in populations has become a major goal in the field.
Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels.
This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.
It is unknown whether associations between blood pressure (BP) and stroke vary between Europeans and South Asians, despite higher stroke rates in the latter. We report findings from a UK cohort study ...of 1375 European and 1074 South Asian men, not receiving antihypertensive medication, aged 40 to 69 years at baseline (1988-1991). Assessment included BP, blood tests, anthropometry, and questionnaires. Incident stroke was established at 20 years from death certification, hospital and primary care records, and participant report. South Asians had higher systolic BP, diastolic BP, and mean arterial pressure than Europeans, and similar pulse pressure. Associations between systolic BP or diastolic BP and stroke were stronger in South Asians than Europeans, after adjustment for age, smoking status, waist/hip ratio, total/high-density lipoprotein-cholesterol ratio, diabetes mellitus, fasting glucose, physical activity, and heart rate (systolic BP: Europeans odds ratio, 1.22; 95% confidence interval, 0.98-1.51, South Asians 1.56; 1.24-1.95; ethnic difference P=0.04; diastolic BP: Europeans 0.90; 0.71-1.13, South Asians 1.68; 1.32-2.15; P<0.001). Hemodynamic correlates of stroke risk differed by ethnicity: in combined models, mean arterial pressure but not pulse pressure was detrimentally associated with stroke in South Asians, whereas the converse was true for Europeans. The combination of hyperglycemia and hypertension appeared particularly detrimental for South Asians. There are marked ethnic differences in associations between BP parameters and stroke. Undue focus on systolic BP for risk prediction, and current age and treatment thresholds may be inappropriate for individuals of South Asian ancestry.
3D-speckle tracking echocardiography(3D-STE) allows simultaneous assessment of ejection fraction(EF) and multidirectional strains, but its prognostic utility in the general population is unknown. We ...investigated if 3D-STE strains predicted a composite of major cardiac endpoints(MACE) beyond cardiovascular risk factors(CVDRF), and whether they were superior to 3D-EF. 529 participants in SABRE, a UK-based tri-ethnic general population cohort (69±6y; 76.6% male) with acceptable 3D-STE imaging were studied. Associations between 3D-EF or multidirectional myocardial strains and MACE(coronary heart disease(fatal/non-fatal), heart failure hospitalization, new-onset arrhythmia and cardiovascular mortality) were determined using Cox regression including adjustment for CVDRF and 2D-EF. Whether 3D-EF, global longitudinal strain(3D-GLS) and principle tangential strain(3D-PTS/3D-strain) improved cardiovascular risk stratification over CVDRF was investigated using a likelihood ratio test on a series of nested Cox proportional hazards models and Harrell's C statistics. During follow-up(median, 12y), there were 92 events. 3D-EF, 3D-GLS and 3D-PTS and 3D-RS were associated with MACE in unadjusted and models adjusted for CVDRF but not CVDRF+2D-EF. Compared to 3D-EF, both 3D-GLS and 3D-PTS slightly improved the predictive value over CVDRF for MACE, but the improvement was modest(C statistic increased from 0.698(0.647, 0.749) to 0.715(0.663, 0.766) comparing CVDRF with CVDRF +3D-GLS). 3D-STE-derived LV myocardial strains predicted MACE in a multi-ethnic general population sample of elderly individuals from the UK; however the added prognostic value of 3D-STE myocardial strains was small.
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Adverse effects of air pollution on cardiovascular mortality are well established.
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There are comparatively fewer studies in the UK compared to North America.
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In two British cohort studies, we ...investigated associations between gases, particulates and cardiovascular mortality.
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Detrimental associations, non-statistically significant, between cardiovascular mortality and particulates were found.
To evaluate QRISK2 and Framingham cardiovascular disease (CVD) risk scores in a tri-ethnic U.K. population.
Cohort study.
West London.
Randomly selected from primary care lists. Follow-up data were ...available for 87% of traced participants, comprising 1866 white Europeans, 1377 South Asians, and 578 African Caribbeans, aged 40-69 years at baseline (1998-1991).
First CVD events: myocardial infarction, coronary revascularisation, angina, transient ischaemic attack or stroke reported by participant, primary care or hospital records or death certificate.
During follow-up, 387 CVD events occurred in men (14%) and 78 in women (8%). Both scores underestimated risk in European and South Asian women (ratio of predicted to observed risk: European women: QRISK2: 0.73, Framingham: 0.73; South Asian women: QRISK2: 0.52, Framingham: 0.43). In African Caribbeans, Framingham over-predicted in men and women and QRISK2 over-predicted in women. Framingham classified 28% of participants as high risk, predicting 54% of all such events. QRISK2 classified 19% as high risk, predicting 42% of all such events. Both scores performed poorly in identifying high risk African Caribbeans; QRISK2 and Framingham identified as high risk only 10% and 24% of those who experienced events.
Neither score performed consistently well in all ethnic groups. Further validation of QRISK2 in other multi-ethnic datasets, and better methods for identifying high risk African Caribbeans and South Asian women, are required.
Early menopause is linked to an increased risk of cardiovascular disease mortality; however, the association between early menopause and incidence and timing of cardiovascular disease is unclear. We ...aimed to assess the associations between age at natural menopause and incidence and timing of cardiovascular disease.
We harmonised and pooled individual-level data from 15 observational studies done across five countries and regions (Australia, Scandinavia, the USA, Japan, and the UK) between 1946 and 2013. Women who had reported their menopause status, age at natural menopause (if postmenopausal), and cardiovascular disease status (including coronary heart disease and stroke) were included. We excluded women who had hysterectomy or oophorectomy and women who did not report their age at menopause. The primary endpoint of this study was the occurrence of first non-fatal cardiovascular disease, defined as a composite outcome of incident coronary heart disease (including heart attack and angina) or stroke (including ischaemic stroke or haemorrhagic stroke). We used Cox proportional hazards models to estimate multivariate hazard ratios (HRs) and 95% CIs for the associations between age at menopause and incident cardiovascular disease event. We also adjusted the model to account for smoking status, menopausal hormone therapy status, body-mass index, and education levels. Age at natural menopause was categorised as premenopausal or perimenopausal, younger than 40 years (premature menopause), 40–44 years (early menopause), 45–49 years (relatively early), 50–51 years (reference category), 52–54 years (relatively late), and 55 years or older (late menopause).
Overall, 301 438 women were included in our analysis. Of these 301 438 women, 12 962 (4·3%) had a first non-fatal cardiovascular disease event after menopause, of whom 9369 (3·1%) had coronary heart disease and 4338 (1·4%) had strokes. Compared with women who had menopause at age 50–51 years, the risk of cardiovascular disease was higher in women who had premature menopause (age <40 years; HR 1·55, 95% CI 1·38–1·73; p<0·0001), early menopause (age 40–44 years; 1·30, 1·22–1·39; p<0·0001), and relatively early menopause (age 45–49 years; 1·12, 1·07–1·18; p<0·0001), with a significantly reduced risk of cardiovascular disease following menopause after age 51 years (p<0·0001 for trend). The associations persisted in never smokers, and were strongest before age 60 years for women with premature menopause (HR 1·88, 1·62–2·20; p<0·0001) and early menopause (1·40, 1·27–1·54; p<0·0001), but were attenuated at age 60–69 years, with no significant association observed at age 70 years and older.
Compared with women who had menopause at age 50–51 years, women with premature and early menopause had a substantially increased risk of a non-fatal cardiovascular disease event before the age of 60 years, but not after age 70 years. Women with earlier menopause need close monitoring in clinical practice, and age at menopause might also be considered as an important factor in risk stratification of cardiovascular disease for women.
Australian National Health and Medical Research Council.
Both long and short sleep duration increase risk of mortality. Most previous studies have been performed in Europeans and have focused on sleep duration. Thus, we aimed to investigate the association ...between sleep quality and mortality across three different ethnic groups.
We used data from the Southall and Brent REvisited Study (SABRE) cohort, which comprises first generation migrant South Asian and African Caribbean men and women, aged 40–69 years, recruited between 1988 and 1991. In sum, 4399 participants provided complete data at baseline and follow-up. Of those, 1656 died by December 2017. Our exposures (eg, difficulty falling asleep, early morning waking and waking up tired in the morning) were self-reported and our primary outcome was mortality. We used Cox proportional hazards models to analyse our data, adjusting for baseline-measured confounders.
None of the sleep measures were strongly associated with all-cause mortality in Europeans or African Caribbeans, whilst in South Asians difficulty falling asleep was related to an increased risk of all-cause mortality (HR = 1.28, 95%CI = 1.01; 1.61). In Europeans, early morning waking was associated with a moderately increased risk of cardiovascular death (HR = 1.31, 95%CI = 1.05; 1.63); alternately, this association was not as strong in the other groups.
Our findings suggest that the relationship between sleep quality and mortality may differ by ethnic group, but formal heterogeneity tests indicated that the strongest difference in HRs was observed for early morning waking and cardiovascular disease (CVD) mortality across the three groups (Cochran's Q test p = 0.036). As such, these results are novel and provide support for ethnic differences in sleep quality and mortality, and may have implications for precision medicine.
•We explored the association between sleep quality and cancer, CVD and all-cause mortality.•We used data from a white Europeans, African Caribbeans and South Asians.•Early morning waking was associated with greater CVD mortality risk in Europeans.•Findings suggest ethnic differences in these effects, warranting further investigation.
Aims/hypothesis
The aim of this study was to compare exercise capacity, strength and skeletal muscle perfusion during exercise, and oxidative capacity between South Asians, African Caribbeans and ...Europeans, and determine what effect ethnic differences in the prevalence of type 2 diabetes has on these functional outcomes.
Methods
In total, 708 participants (aged mean±SD 73 ± 7 years, 56% male) were recruited from the Southall and Brent Revisited (SABRE) study, a UK population-based cohort comprised of Europeans (
n
= 311) and South Asian (
n
= 232) and African Caribbean (
n
= 165) migrants. Measurements of exercise capacity using a 6 min stepper test (6MST), including measurement of oxygen consumption (
V
̇
O
2
) and grip strength, were performed. Skeletal muscle was assessed using near infrared spectroscopy (NIRS); measures included changes in tissue saturation index (∆TSI%) with exercise and oxidative capacity (muscle oxygen consumption recovery, represented by a time constant τ). Analysis was by multiple linear regression.
Results
When adjusted for age and sex, in South Asians and African Caribbeans, exercise capacity was reduced compared with Europeans (
V
̇
O
2
ml min
−1
kg
−1
: β = −1.2 95% CI –1.9, −0.4,
p
= 0.002, and β −1.7 95% CI –2.5, −0.8,
p
< 0.001, respectively). South Asians had lower and African Caribbeans had higher strength compared with Europeans (strength kPa: β = −9 95% CI –12, −6),
p
< 0.001, and β = 6 95% CI 3, 9,
p
< 0.001, respectively). South Asians had greater decreases in TSI% and longer τ compared with Europeans (∆TSI% %: β = −0.9 95% CI –1.7, −0.1),
p
= 0.024; τ s: β = 11 95% CI 3, 18,
p
= 0.006). Ethnic differences in
V
̇
O
2
and grip strength remained despite adjustment for type 2 diabetes or HbA
1c
(and fat-free mass for grip strength). However, the differences between Europeans and South Asians were no longer statistically significant after adjustment for other possible mediators or confounders (including physical activity, waist-to-hip ratio, cardiovascular disease or hypertension, smoking, haemoglobin levels or β-blocker use). The difference in ∆TSI% between Europeans and South Asians was marginally attenuated after adjustment for type 2 diabetes or HbA
1c
and was also no longer statistically significant after adjusting for other confounders; however, τ remained significantly longer in South Asians vs Europeans despite adjustment for all confounders.
Conclusions/interpretation
Reduced exercise capacity in South Asians and African Caribbeans is unexplained by higher rates of type 2 diabetes. Poorer exercise tolerance in these populations, and impaired muscle function and perfusion in South Asians, may contribute to the higher morbidity burden of UK ethnic minority groups in older age.
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