Characterisation of ethnic differences in DNA methylation between UK-resident South Asians and Europeans.

Ethnic differences in non-communicable disease risk have been described between individuals of South Asian and European ethnicity that are only partially explained by genetics and other known risk factors. DNA methylation is one underexplored mechanism that may explain differences in disease risk. Currently, there is little knowledge of how DNA methylation varies between South Asian and European ethnicities. This study characterised differences in blood DNA methylation between individuals of self-reported European and South Asian ethnicity from two UK-based cohorts: Southall and Brent Revisited and Born in Bradford. DNA methylation differences between ethnicities were widespread throughout the genome (n = 16,433 CpG sites, 3.4% sites tested). Specifically, 76% of associations were attributable to ethnic differences in cell composition with fewer effects attributable to smoking and genetic variation. Ethnicity-associated CpG sites were enriched for EWAS Catalog phenotypes including metabolites. This work highlights the need to consider ethnic diversity in epigenetic research.

Carotid atherosclerosis in people of European, South Asian and African Caribbean ethnicity in the Southall and Brent revisited study (SABRE).

Background: Atherosclerotic cardiovascular disease (ASCVD) risk differs by ethnicity. In comparison with Europeans (EA) South Asian (SA) people in UK experience higher risk of coronary heart disease (CHD) and stroke, while African Caribbean people have a lower risk of CHD but a higher risk of stroke. Aim: To compare carotid atherosclerosis in EA, SA, and AC participants in the Southall and Brent Revisited (SABRE) study and establish if any differences were explained by ASCVD risk factors. Methods: Cardiovascular risk factors were measured, and carotid ultrasound was performed in 985 individuals (438 EA, 325 SA, 228 AC). Carotid artery plaques and intima-media thickness (cIMT) were measured. Associations of carotid atherosclerosis with ethnicity were investigated using generalised linear models (GLMs), with and without adjustment for non-modifiable (age, sex) and modifiable risk factors (education, diabetes, hypertension, total cholesterol, HDL-C, alcohol consumption, current smoking). Results: Prevalence of any plaque was similar in EA and SA, but lower in AC (16, 16, and 6%, respectively; p < 0.001). In those with plaque, total plaque area, numbers of plaques, plaque class, or greyscale median did not differ by ethnicity; adjustment for risk factors had minimal effects. cIMT was higher in AC than the other ethnic groups after adjustment for age and sex, adjustment for risk factors attenuated this difference. Conclusion: Prevalence of carotid artery atherosclerotic plaques varies by ethnicity, independent of risk factors. Lower plaque prevalence in in AC is consistent with their lower risk of CHD but not their higher risk of stroke. Higher cIMT in AC may be explained by risk factors. The similarity of plaque burden in SA and EA despite established differences in ASCVD risk casts some doubt on the utility of carotid ultrasound as a means of assessing risk across these ethnic groups.

Impact of afterload and infiltration on coexisting aortic stenosis and transthyretin amyloidosis.

OBJECTIVE: The coexistence of wild-type transthyretin cardiac amyloidosis (ATTR) is common in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI). However, the impact of ATTR and AS on the resultant AS-ATTR is unclear and poses diagnostic and management challenges. We therefore used a multicohort approach to evaluate myocardial structure, function, stress and damage by assessing age-related, afterload-related and amyloid-related remodelling on the resultant AS-ATTR phenotype. METHODS: We compared four samples (n=583): 359 patients with AS, 107 with ATTR (97% Perugini grade 2), 36 with AS-ATTR (92% Perugini grade 2) and 81 age-matched and ethnicity-matched controls. 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy was used to diagnose amyloidosis (Perugini grade 1 was excluded). The primary end-point was NT-pro Brain Natriuretic Peptide (BNP) and secondary end-points related to myocardial structure, function and damage. RESULTS: Compared with older age controls, the three disease cohorts had greater cardiac remodelling, worse function and elevated NT-proBNP/high-sensitivity Troponin-T (hsTnT). NT-proBNP was higher in AS-ATTR (2844 (1745, 4635) ng/dL) compared with AS (1294 (1077, 1554)ng/dL; p=0.002) and not significantly different to ATTR (3272 (2552, 4197) ng/dL; p=0.63). Diastology, hsTnT and prevalence of carpal tunnel syndrome were statistically similar between AS-ATTR and ATTR and higher than AS. The left ventricular mass indexed in AS-ATTR was lower than ATTR (139 (112, 167) vs 180 (167, 194) g; p=0.013) and non-significantly different to AS (120 (109, 130) g; p=0.179). CONCLUSIONS: The AS-ATTR phenotype likely reflects an early stage of amyloid infiltration, but the combined insult resembles ATTR. Even after treatment of AS, ATTR-specific therapy is therefore likely to be beneficial.

Metformin and carotid intima-media thickness in never-smokers with type 1 diabetes: The REMOVAL trial.

AIM: To determine whether metformin's effects on carotid artery intima-media thickness (cIMT) in type 1 diabetes differ according to smoking status. METHODS: Regression model effect estimates for the effect of metformin versus placebo (double-blind) on carotid IMT were calculated as a subgroup analysis of the REMOVAL trial. RESULTS: In 428 randomized participants (227 never-smokers, 201 ever-smokers), averaged mean carotid IMT progression (per year) was reduced by metformin versus placebo in never-smokers (-0.012 mm, 95% CI -0.021 to -0.002; p = .0137) but not in ever-smokers (0.003 mm, 95% CI -0.008 to 0.014; p = .5767); and similarly in non-current smokers (-0.008 mm, 95% CI -0.015 to -0.00001; p = .0497) but not in current smokers (0.013 mm, 95% CI -0.007 to 0.032; p = .1887). Three-way interaction terms (treatment*time*smoking status) were significant for never versus ever smoking (p = .0373, prespecified) and non-current versus current smoking (p = .0496, exploratory). Averaged maximal carotid IMT progression (per year) was reduced by metformin versus placebo in never-smokers (-0.020 mm, 95% CI -0.034 to -0.006; p = .0067) but not in ever-smokers (-0.006 mm, 95% CI -0.020 to 0.008; p = .4067), although this analysis was not supported by a significant three-way interaction term. CONCLUSIONS: This subgroup analysis of the REMOVAL trial provides additional support for a potentially wider role of adjunct metformin therapy in cardiovascular risk management in type 1 diabetes, particularly for individuals who have never smoked cigarettes.

Establishing reference intervals for triglyceride-containing lipoprotein subfraction metabolites measured using nuclear magnetic resonance spectroscopy in a UK population.

BACKGROUND: Nuclear magnetic resonance (NMR) spectroscopy allows triglycerides to be subclassified into 14 different classes based on particle size and lipid content. We recently showed that these subfractions have differential associations with cardiovascular disease events. Here we report the distributions and define reference interval ranges for 14 triglyceride-containing lipoprotein subfraction metabolites. METHODS: Lipoprotein subfractions using the Nightingale NMR platform were measured in 9073 participants from four cohort studies contributing to the UCL-Edinburgh-Bristol consortium. The distribution of each metabolite was assessed, and reference interval ranges were calculated for a disease-free population, by sex and age group (<55, 55-65, >65 years), and in a subgroup population of participants with cardiovascular disease or type 2 diabetes. We also determined the distribution across body mass index and smoking status. RESULTS: The largest reference interval range was observed in the medium very-low density lipoprotein subclass (2.5th 97.5th percentile; 0.08 to 0.68 mmol/L). The reference intervals were comparable among male and female participants, with the exception of triglyceride in high-density lipoprotein. Triglyceride subfraction concentrations in very-low density lipoprotein, intermediate-density lipoprotein, low-density lipoprotein and high-density lipoprotein subclasses increased with increasing age and increasing body mass index. Triglyceride subfraction concentrations were significantly higher in ever smokers compared to never smokers, among those with clinical chemistry measured total triglyceride greater than 1.7 mmol/L, and in those with cardiovascular disease, and type 2 diabetes as compared to disease-free subjects. CONCLUSION: This is the first study to establish reference interval ranges for 14 triglyceride-containing lipoprotein subfractions in samples from the general population measured using the nuclear magnetic resonance platform. The utility of nuclear magnetic resonance lipid measures may lead to greater insights for the role of triglyceride in cardiovascular disease, emphasizing the importance of appropriate reference interval ranges for future clinical decision making.

Type 2 diabetes does not account for ethnic differences in exercise capacity or skeletal muscle function in older adults.

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 ([Formula: see text]) 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 ([Formula: see text] [ml min-1 kg-1]: ß = -1.2 [95% CI -1.9, -0.4], p = 0.002, and ß -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]: ß = -9 [95% CI -12, -6), p < 0.001, and ß = 6 [95% CI 3, 9], p < 0.001, respectively). South Asians had greater decreases in TSI% and longer τ compared with Europeans (∆TSI% [%]: ß = -0.9 [95% CI -1.7, -0.1), p = 0.024; τ [s]: ß = 11 [95% CI 3, 18], p = 0.006). Ethnic differences in [Formula: see text] and grip strength remained despite adjustment for type 2 diabetes or HbA1c (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 ß-blocker use). The difference in ∆TSI% between Europeans and South Asians was marginally attenuated after adjustment for type 2 diabetes or HbA1c 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.

Age at natural menopause and risk of incident cardiovascular disease: a pooled analysis of individual patient data.

BACKGROUND: 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. METHODS: 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). FINDINGS: 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. INTERPRETATION: 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. FUNDING: Australian National Health and Medical Research Council.

Impact of Kidney Function on Cardiovascular Risk and Mortality: A Comparison of South Asian and European Cohorts.

BACKGROUND: Evidence is limited on ethnic differences in associations between kidney function markers and mortality or cardiovascular disease (CVD). METHODS: Baseline cross-sectional analysis and longitudinal follow-up study of a UK population-based cohort of 1,116 Europeans and 1,104 South Asians of predominantly Indian descent, age 52 ± 7 years at baseline (1988-1991). Kidney function was estimated using Cystatin C and creatinine-based chronic kidney disease (CKD) Epidemiology Collaboration estimated glomerular filtration rate (eGFR) equations, and urinary albumin-creatinine ratio (ACR). Mortality was captured at 27 years, and incident CVD at 22 years, from death certification, medical records and participant report. Longitudinal associations between eGFR/ACR and mortality/incident CVD were examined using Cox models. RESULTS: eGFRcys was lower and ACR higher in South Asians than Europeans. eGFRcys and -eGFRcreat were more strongly associated with outcomes in Europeans than South Asians. Conversely, associations between ACR and outcomes were greater in South Asians than Europeans, for example, for CVD mortality: HRs (95% CI) adjusted for CVD risk factors and ACR/eGFRcys as appropriate, p for ethnicity interaction: eGFRcys: Europeans: 0.76 (0.62-0.92), South Asians: 0.92 (0.78-1.07), p = 0.05, eGFRcreat: Europeans 0.81 (0.67-0.99), South Asians 1.18 (0.97-1.41), p = 0.002, ACR: -Europeans: 1.24 (1.08-1.42), South Asians: 1.39 (1.25-1.57), p= 0.23. Addition of all CKD measures to a standard CVD risk factor model modestly improved prediction capability in -Europeans; in South Asians only ACR contributed to improvement. CONCLUSIONS: Strong associations between ACR and outcomes in South Asians of predominantly Indian origin, and null associations for eGFRcys and eGFRcreat, suggest that ACR may have greater utility in CVD risk prediction in South Asians. Further work is needed to validate these -findings.

The relationship between sleep quality and all-cause, CVD and cancer mortality: the Southall and Brent REvisited study (SABRE).

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Cortical cerebral blood flow in ageing: effects of haematocrit, sex, ethnicity and diabetes.

OBJECTIVES: Cerebral blood flow (CBF) estimates from arterial spin labelling (ASL) show unexplained variability in older populations. We studied the impact of variation of haematocrit (Hct) on CBF estimates in a tri-ethnic elderly population. MATERIALS AND METHODS: Approval for the study was obtained from the Fulham Research Ethics Committee and participants gave written informed consent. Pseudo-continuous arterial spin labelling was performed on 493 subjects (age 55-90) from a tri-ethnic community-based cohort recruited in London. CBF was estimated using a simplified Buxton equation, with and without correction for Hct measured from blood samples. Differences in perfusion were compared, stratified by sex, ethnicity and diabetes. Results of Student's t tests were reported with effect size. RESULTS: Hct adjustment decreased CBF estimates in all categories except white European men. The decrease for women was 2.7 (3.0, 2.4) mL/100 g/min) (mean (95% confidence interval (CI)), p < 0.001 d = 0.38. The effect size differed by ethnicity with estimated mean perfusion in South Asian and African Caribbean women found to be lower by 3.0 (3.6, 2.5) mL/100 g/min, p < 0.001 d = 0.56 and 3.1 (3.6, 2.5) mL/100 g/min), p < 0.001 d = 0.48, respectively. Estimates of perfusion in subjects with diabetes decreased by 1.8 (2.3, 1.4) mL/100 g/min, p < 0.001 d = 0.23) following Hct correction. Correction for individual Hct altered sample frequency distributions of CBF values, especially in women of non-European ethnicity. CONCLUSION: ASL-derived CBF values in women, non-European ethnicities and individuals with diabetes are overestimated if calculations are not appropriately adjusted for individual Hct. KEY POINTS: • CBF quantification from ASL using a fixed Hct of 43.5%, as recommended in the ISMRM white paper, may lead to erroneous CBF estimations particularly in non-European and female subjects. • Individually measured Hct values improve the accuracy of CBF estimation and, if these are not available, an adjusted value according to gender, ethnicity or diabetes status should be considered. • Hct-corrected ASL could be potentially important for CBF threshold decision making in the fields of neurodegenerative disease and neuro-oncology.

Relationships between intensity, duration, cumulative dose, and timing of smoking with age at menopause: A pooled analysis of individual data from 17 observational studies.

BACKGROUND: Cigarette smoking is associated with earlier menopause, but the impact of being a former smoker and any dose-response relationships on the degree of smoking and age at menopause have been less clear. If the toxic impact of cigarette smoking on ovarian function is irreversible, we hypothesized that even former smokers might experience earlier menopause, and variations in intensity, duration, cumulative dose, and age at start/quit of smoking might have varying impacts on the risk of experiencing earlier menopause. METHODS AND FINDINGS: A total of 207,231 and 27,580 postmenopausal women were included in the cross-sectional and prospective analyses, respectively. They were from 17 studies in 7 countries (Australia, Denmark, France, Japan, Sweden, United Kingdom, United States) that contributed data to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE). Information on smoking status, cigarettes smoked per day (intensity), smoking duration, pack-years (cumulative dose), age started, and years since quitting smoking was collected at baseline. We used multinomial logistic regression models to estimate multivariable relative risk ratios (RRRs) and 95% confidence intervals (CIs) for the associations between each smoking measure and categorised age at menopause (<40 (premature), 40-44 (early), 45-49, 50-51 (reference), and ≥52 years). The association with current and former smokers was analysed separately. Sensitivity analyses and two-step meta-analyses were also conducted to test the results. The Bayesian information criterion (BIC) was used to compare the fit of the models of smoking measures. Overall, 1.9% and 7.3% of women experienced premature and early menopause, respectively. Compared with never smokers, current smokers had around twice the risk of experiencing premature (RRR 2.05; 95% CI 1.73-2.44) (p < 0.001) and early menopause (1.80; 1.66-1.95) (p < 0.001). The corresponding RRRs in former smokers were attenuated to 1.13 (1.04-1.23; p = 0.006) and 1.15 (1.05-1.27; p = 0.005). In both current and former smokers, dose-response relationships were observed, i.e., higher intensity, longer duration, higher cumulative dose, earlier age at start smoking, and shorter time since quitting smoking were significantly associated with higher risk of premature and early menopause, as well as earlier menopause at 45-49 years. Duration of smoking was a strong predictor of age at natural menopause. Among current smokers with duration of 15-20 years, the risk was markedly higher for premature (15.58; 11.29-19.86; p < 0.001) and early (6.55; 5.04-8.52; p < 0.001) menopause. Also, current smokers with 11-15 pack-years had over 4-fold (4.35; 2.78-5.92; p < 0.001) and 3-fold (3.01; 2.15-4.21; p < 0.001) risk of premature and early menopause, respectively. Smokers who had quit smoking for more than 10 years had similar risk as never smokers (1.04; 0.98-1.10; p = 0.176). A limitation of the study is the measurement errors that may have arisen due to recall bias. CONCLUSIONS: The probability of earlier menopause is positively associated with intensity, duration, cumulative dose, and earlier initiation of smoking. Smoking duration is a much stronger predictor of premature and early menopause than others. Our findings highlight the clear benefits for women of early smoking cessation to lower their excess risk of earlier menopause.

Associations Between Prediabetes, by Three Different Diagnostic Criteria, and Incident CVD Differ in South Asians and Europeans.

OBJECTIVE: We examined longitudinal associations between prediabetes and cardiovascular disease (CVD) (coronary heart disease [CHD] and stroke) in Europeans and South Asians. RESEARCH DESIGN AND METHODS: This was a U.K. cohort study of 1,336 Europeans and 1,139 South Asians, aged 40-69 years at baseline (1988-1991). Assessment included blood pressure, blood tests, anthropometry, and questionnaires. Prediabetes was determined by OGTT or HbA1c, using either International Expert Committee (IEC) (HbA1c 6.0-6.5% [42-48 mmol/mol]) or American Diabetes Association (ADA) (HbA1c 5.7-6.5% [39-48 mmol/mol]) cut points. Incident CHD and stroke were established at 20 years from death certification, hospital admission, primary care record review, and participant report. RESULTS: Compared with normoglycemic individuals, IEC-defined prediabetes was related to both CHD and CVD risk in Europeans but not South Asians (subhazard ratio for CHD 1.68 [95% CI 1.19, 2.38] vs. 1.00 [0.75, 1.33], ethnicity interaction P = 0.008, and for CVD 1.49 [1.08, 2.07] vs. 1.03 [0.78, 1.36], ethnicity interaction P = 0.04). Conversely, IEC-defined prediabetes was associated with stroke risk in South Asians but not Europeans (1.73 [1.03, 2.90] vs. 0.85 [0.44, 1.64], ethnicity interaction P = 0.11). Risks were adjusted for age, sex, smoking, total-to-HDL cholesterol ratio, waist-to-hip ratio, systolic blood pressure, and antihypertensive use. Associations were weaker for OGTT or ADA-defined prediabetes. Conversion from prediabetes to diabetes was greater in South Asians, but accounting for time to conversion did not account for these ethnic differences. CONCLUSIONS: Associations between prediabetes and CVD differed by prediabetes diagnostic criterion, type of CVD, and ethnicity, with associations being present for overall CVD in Europeans but not South Asians. Substantiation of these findings and investigation of potential explanations are required.

Ethnic Differences in Associations Between Blood Pressure and Stroke in South Asian and European Men.

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.

The impact of health behaviours on incident cardiovascular disease in Europeans and South Asians--a prospective analysis in the UK SABRE study.

BACKGROUND: There is consistent evidence on the impact of health behaviours on risk of cardiovascular disease (CVD) in European populations. As South Asians in the UK have an excess risk of CVD and coronary heart disease (CHD) compared to Europeans, we investigated whether a similar association between combined health behaviours and risk of CVD and CHD among this high-risk group exists, and estimated the population impact. METHODS AND FINDINGS: In a prospective cohort of 1090 Europeans and 1006 South Asians (40-69 y) without prevalent CVD at baseline (1988-1990), followed up for 21 years to 2011, there were 601 incident CVD events [Europeans n = 255; South Asians n = 346] of which 520 were CHD events [n = 207 and 313 respectively]. Participants scored between 0 to 4 points for a composite score including four baseline healthy behaviours (non-smoker, moderate alcohol intake, physically active, frequent fruit/vegetable intake). Adjusted hazard ratios (95% confidence intervals) for incident CHD in Europeans who had three, two, one, and zero compared to four health behaviours were 1.33 (0.78-2.29), 1.96 (1.15-3.33), 1.36 (0.74-2.48) and 2.45 (1.18-5.10), respectively, p-trend = 0.025. In South Asians, corresponding HRs were 2.88 (1.33-6.24), 2.28 (1.06-4.91), 3.36 (1.53-7.39) and 3.48 (1.38-8.81), p-trend = 0.022. The results were similar for incident CVD; Europeans HR 2.12 (1.14-3.94), p-trend = 0.014; South Asians HR 2.73 (1.20-6.21), p-trend = 0.018. The population attributable fraction in Europeans was 43% for CHD and 28% for CVD. In South Asians it was 63% and 51% respectively. CONCLUSIONS: Lack of adherence to four combined health behaviours was associated with 2 to 3-fold increased risk of incident CVD in Europeans and South Asians. A substantial population impact in the South Asian group indicates important potential for disease prevention in this high-risk group by adherence to healthy behaviours.

Ethnic differences in associations between fat deposition and incident diabetes and underlying mechanisms: the SABRE study.

OBJECTIVE: To examine ethnic differences in ectopic fat and associations with incident diabetes. METHODS: In a UK cohort study, 1338 Europeans, 838 South Asians, and 330 African Caribbeans living in London were aged 40-69 years at baseline. Baseline assessment included blood tests, anthropometry, and questionnaires. Anthropometry-based prediction equations estimated baseline visceral adipose tissue (VAT). Incident diabetes was ascertained from record review, self-report, or oral glucose tolerance testing. RESULTS: South Asians had more and African Caribbeans less estimated VAT than Europeans. Both ethnic minorities had larger truncal skinfolds than Europeans. In men, adjustment for risk factors (BMI, smoking, systolic blood pressure, and HDL-cholesterol) markedly attenuated the association between estimated VAT and diabetes in Europeans (standardized subhazard ratios [95% CI]: from 1.74 [1.49, 2.03] to 1.16 [0.77, 1.76]) and African Caribbeans (1.72 [1.26, 2.35] to 1.44 [0.69, 3.02]) but not South Asians (1.60 [1.38, 1.86] to 1.90 [1.37, 2.64]). In women, attenuation was observed only for South Asians (1.80 [1.01, 3.23] to 1.07 [0.49, 2.31]). Associations between truncal skinfolds and diabetes appeared less affected by multivariable adjustment in South Asians and African Caribbeans than Europeans (1.24 [0.97, 1.57] and 1.28 [0.89, 1.82] versus 1.02 [0.77, 1.36] in men; 1.91 [1.03, 3.56] and 1.42 [0.86, 2.34] versus 1.23 [0.74, 2.05] in women). CONCLUSIONS: Differences in overall truncal fat, as well as VAT, may contribute to the excess of diabetes in South Asian and African Caribbean groups, particularly for women.

Metabolite profiling and cardiovascular event risk: a prospective study of 3 population-based cohorts.

BACKGROUND: High-throughput profiling of circulating metabolites may improve cardiovascular risk prediction over established risk factors. METHODS AND RESULTS: We applied quantitative nuclear magnetic resonance metabolomics to identify the biomarkers for incident cardiovascular disease during long-term follow-up. Biomarker discovery was conducted in the National Finnish FINRISK study (n=7256; 800 events). Replication and incremental risk prediction was assessed in the Southall and Brent Revisited (SABRE) study (n=2622; 573 events) and British Women's Health and Heart Study (n=3563; 368 events). In targeted analyses of 68 lipids and metabolites, 33 measures were associated with incident cardiovascular events at P<0.0007 after adjusting for age, sex, blood pressure, smoking, diabetes mellitus, and medication. When further adjusting for routine lipids, 4 metabolites were associated with future cardiovascular events in meta-analyses: higher serum phenylalanine (hazard ratio per standard deviation, 1.18; 95% confidence interval, 1.12-1.24; P=4×10(-10)) and monounsaturated fatty acid levels (1.17; 1.11-1.24; P=1×10(-8)) were associated with increased cardiovascular risk, while higher omega-6 fatty acids (0.89; 0.84-0.94; P=6×10(-5)) and docosahexaenoic acid levels (0.90; 0.86-0.95; P=5×10(-5)) were associated with lower risk. A risk score incorporating these 4 biomarkers was derived in FINRISK. Risk prediction estimates were more accurate in the 2 validation cohorts (relative integrated discrimination improvement, 8.8% and 4.3%), albeit discrimination was not enhanced. Risk classification was particularly improved for persons in the 5% to 10% risk range (net reclassification, 27.1% and 15.5%). Biomarker associations were further corroborated with mass spectrometry in FINRISK (n=671) and the Framingham Offspring Study (n=2289). CONCLUSIONS: Metabolite profiling in large prospective cohorts identified phenylalanine, monounsaturated fatty acids, and polyunsaturated fatty acids as biomarkers for cardiovascular risk. This study substantiates the value of high-throughput metabolomics for biomarker discovery and improved risk assessment.

Differences in smoking associated DNA methylation patterns in South Asians and Europeans.

BACKGROUND: DNA methylation is strongly associated with smoking status at multiple sites across the genome. Studies have largely been restricted to European origin individuals yet the greatest increase in smoking is occurring in low income countries, such as the Indian subcontinent. We determined whether there are differences between South Asians and Europeans in smoking related loci, and if a smoking score, combining all smoking related DNA methylation scores, could differentiate smokers from non-smokers. RESULTS: Illumina HM450k BeadChip arrays were performed on 192 samples from the Southall And Brent REvisited (SABRE) cohort. Differential methylation in smokers was identified in 29 individual CpG sites at 18 unique loci. Interaction between smoking status and ethnic group was identified at the AHRR locus. Ethnic differences in DNA methylation were identified in non-smokers at two further loci, 6p21.33 and GNG12. With the exception of GFI1 and MYO1G these differences were largely unaffected by adjustment for cell composition. A smoking score based on methylation profile was constructed. Current smokers were identified with 100% sensitivity and 97% specificity in Europeans and with 80% sensitivity and 95% specificity in South Asians. CONCLUSIONS: Differences in ethnic groups were identified in both single CpG sites and combined smoking score. The smoking score is a valuable tool for identification of true current smoking behaviour. Explanations for ethnic differences in DNA methylation in association with smoking may provide valuable clues to disease pathways.

The relationship between metabolic risk factors and incident cardiovascular disease in Europeans, South Asians, and African Caribbeans: SABRE (Southall and Brent Revisited) -- a prospective population-based study.

OBJECTIVES: This study sought to determine whether ethnic differences in diabetes, dyslipidemia, and ectopic fat deposition account for ethnic differences in incident cardiovascular disease. BACKGROUND: Coronary heart disease risks are elevated in South Asians and are lower in African Caribbeans compared with Europeans. These ethnic differences map to lipid patterns and ectopic fat deposition. METHODS: Cardiovascular risk factors were assessed in 2,049 Europeans, 1,517 South Asians, and 630 African Caribbeans from 1988 through 1991 (mean age: 52.4 ± 6.9 years). Fatal and nonfatal events were captured over a median 20.5-year follow-up. Subhazard ratios (SHR) were calculated using competing risks regression. RESULTS: Baseline diabetes prevalence was more than 3 times greater in South Asians and African Caribbeans than in Europeans. South Asians were more and African Caribbeans were less centrally obese and dyslipidemic than Europeans. Compared with Europeans, coronary heart disease incidence was greater in South Asians and less in African Caribbeans. The age- and sex-adjusted South Asian versus European SHR was 1.70 (95% confidence interval [CI]: 1.52 to 1.91, p < 0.001) and remained significant (1.45, 95% CI: 1.28 to 1.64, p < 0.001) when adjusted for waist-to-hip ratio. The African Caribbean versus European age- and sex-adjusted SHR of 0.64 (95% CI: 0.52 to 0.79, p < 0.001) remained significant when adjusted for high-density lipoprotein and low-density lipoprotein cholesterol (0.74, 95% CI: 0.60 to 0.92, p = 0.008). Compared with Europeans, South Asians and African Caribbeans experienced more strokes (age- and sex-adjusted SHR: 1.45 [95% CI: 1.17 to 1.80, p = 0.001] and 1.50 [95% CI: 1.13 to 2.00, p = 0.005], respectively), and this differential was more marked in those with diabetes (age-adjusted SHR: 1.97 [95% CI: 1.16 to 3.35, p = 0.038 for interaction] and 2.21 [95% CI: 1.14 to 4.30, p = 0.019 for interaction]). CONCLUSIONS: Ethnic differences in measured metabolic risk factors did not explain differences in coronary heart disease incidence. The apparently greater association between diabetes and stroke risk in South Asians and African Caribbeans compared with Europeans merits further study.

Measurement of pulse wave velocity: site matters.

BACKGROUND: Aortic pulse wave velocity (PWV) predicts mortality from cardiovascular disease, ischaemic heart disease and stroke. However, a comparison of associations between PWV measured at different sites and atherosclerosis in coronary, carotid and femoral arteries has not been made. METHODS: In 159 men (ages 45-82 years) with and without known coronary artery disease, PWV measurements were made between carotid-femoral, carotid-radial and femoral-posterior tibial sites, using an ultrasound technique. Coronary artery calcification (CAC) scores were measured by multislice computed tomography. Carotid and femoral intima-media thickness (IMT) and presence of plaque were determined by ultrasound. Known coronary artery disease was confirmed by angiography. Participants were grouped into four categories of CAC score: 0-10, 11-100, 101-400, > 400 Hounsfield Units (HU). Measurements of blood pressure, heart rate and fasting bloods were made in all individuals. RESULTS: Carotid-femoral PWV correlated positively with CAC score and increased with incremental coronary calcification category (median carotid-femoral PWV 16.8 m/s in those with CAC score > 400 HU and 13.8 m/s in those with CAC score < 10 HU; P = 0.003). Carotid-femoral PWV also correlated with carotid and femoral IMT (P < 0.001, P = 0.004, respectively) and with carotid and femoral plaque (P = 0.001, P = 0.038, respectively). Increased carotid-femoral PWV also correlated with increasing age (P < 0.001), systolic blood pressure (P < 0.001), mean arterial pressure and pulse pressure (P < 0.001). Carotid-radial and femoral-posterior tibial PWV were not significantly associated with CAC score, carotid or femoral IMT or carotid plaque. CONCLUSIONS: Carotid-femoral PWV is a better indicator of atherosclerosis than either carotid-radial or femoral-posterior tibial PWV, and should be used preferentially in studies of atherosclerosis and in stratifying risk in clinical settings.