Therese Tillin

Metabolic syndrome and coronary heart disease in South Asians, African-Caribbeans and white Europeans: a UK population-based cross-sectional study

Aims/hypothesisThe aim of this study was to study differences in the prevalence of the metabolic syndrome and its associations with prevalent CHD according to ethnicity and sex.MethodsWe performed a combined analysis of two population-based cross-sectional studies conducted between 1988 and 1991 that followed identical protocols. Participants (aged 40–69 years) comprised 2,346 Europeans (76% male), 1,711 South Asians (83% male) and 803 African-Caribbeans (57% male) resident in west London. Fasting blood, overnight urine collection, clinical and anthropometric measurements were performed. Clinical history or major ECG changes defined prevalent CHD. The metabolic syndrome was defined according to the criteria recommended by the World Health Organization (WHO) and the National Cholesterol Education Programme (NCEP).ResultsThe prevalence of the metabolic syndrome was highest in South Asians (WHO, men 46%, women 31%; NCEP, men 29%, women 32%) and lowest in European women (WHO, 9%; NCEP, 14%). The prevalence of CHD was 10% in South Asian men, 9% in European men, 5–6% in African-Caribbeans and European women, and 2% in South Asian women. The metabolic syndrome was associated with prevalent CHD in European men [NCEP, odds ratio (OR)=1.6, 95% CI 1.2–2.4; WHO, OR=1.7, 95% CI 1.2–2.5] and South Asian men (NCEP, OR=2.1, 95% CI 1.5–3.1; WHO, OR=1.6, 95% CI 1.1–2.3). Associations with CHD were weaker in African-Caribbeans and were inconsistent among European women.Conclusions/interpretationThe current definitions of the metabolic syndrome give an inconsistent picture of cardiovascular disease risk when applied to different ethnic groups within the UK. Prospective studies are needed to validate workable ethnic-specific definitions.

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.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. # CLINICAL PERSPECTIVE {#article-title-51}

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.

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

BackgroundDNA 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.ResultsIllumina 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.ConclusionsDifferences 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.

Insulin Resistance and Truncal Obesity as Important Determinants of the Greater Incidence of Diabetes in Indian Asians and African Caribbeans Compared With Europeans: The Southall and Brent Revisited (SABRE) cohort

OBJECTIVE To determine the extent of, and reasons for, ethnic differences in type 2 diabetes incidence in the U.K. RESEARCH DESIGN AND METHODS Population-based triethnic cohort. Participants were without diabetes, aged 40–69 at baseline (1989–1991), and followed-up for 20 years. Baseline measurements included fasting and postglucose bloods, anthropometry, and lifestyle questionnaire. Incident diabetes was identified from medical records and participant recall. Ethnic differences in diabetes incidence were examined using competing risks regression. RESULTS Incident diabetes was identified in 196 of 1,354 (14%) Europeans, 282 of 839 (34%) Indian Asians, and 100 of 335 (30%) African Caribbeans. All Indian Asians and African Caribbeans were first-generation migrants. Compared with Europeans, age-adjusted subhazard ratios (SHRs [95% CI]) for men and women, respectively, were 2.88 (95%, 2.36–3.53; P < 0.001) and 1.91 (1.18–3.10; P = 0.008) in Indian Asians, and 2.23 (1.64–3.03; P < 0.001) and 2.51 (1.63–3.87; P < 0.001) in African Caribbeans. Differences in baseline insulin resistance and truncal obesity largely attenuated the ethnic minority excess in women (adjusted SHRs: Indian Asians 0.77 [0.49–1.42]; P = 0.3; African Caribbeans 1.48 [0.89–2.45]; P = 0.13), but not in men (adjusted SHRs: Indian Asians 1.98 [1.52–2.58]; P < 0.001 and African Caribbeans, 2.05 [1.46–2.89; P < 0.001]). CONCLUSIONS Insulin resistance and truncal obesity account for the twofold excess incidence of diabetes in Indian Asian and African Caribbean women, but not men. Explanations for the excess diabetes risk in ethnic minority men remains unclear. Further study requires more precise measures of conventional risk factors and identification of novel risk factors.

Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis

Background 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. Methods and Findings 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. Conclusions 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.

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.

Southall And Brent REvisited: Cohort profile of SABRE, a UK population-based comparison of cardiovascular disease and diabetes in people of European, Indian Asian and African Caribbean origins.

: imported for journal id 300 on Dec 03, 2001, no letter sent Sent to referee - Referee Sent: 03-May-00 Expected: 03-Jun-00 Arrived: 24-May-00 MsID: IJE/2000/000175 - Major Revision - Last reminder: Sent to Editor - Editor Sent: 27-Oct-00 Expected: 27-Nov-00 Arrived: 06-Nov-00 MsID: IJE/2000/000321 - Reject - Last reminder: Sent to Editor - Editor Sent: 07-Feb-01 Expected: 07-Mar-01 Arrived: 12-Mar-01 MsID: IJE/2000/000381 - Major Revision - Last reminder: Sent to Editor - Editor Sent: 16-Mar-01 Expected: 16-Apr-01 Arrived: 03-Apr-01 MsID: IJE/2000/000462 - Major Revision - Last reminder: Sent to Editor - Editor Sent: 15-Dec-00 Expected: 15-Jan-01 Arrived: 15-Jan-01 MsID: IJE/2000/000486 - Major Revision - Last reminder: Sent to Editor - Editor Sent: 22-Mar-01 Expected: 22-Apr-01 Arrived: 03-May-01 MsID: IJE/2000/000486 - - Last reminder: Sent to Editor - Editor Sent: 07-Mar-01 Expected: 07-Apr-01 Arrived: 20-Mar-01 MsID: IJE/2000/000509 - - Last reminder: Sent to Editor - Editor Sent: 01-Jun-01 Expected: 10-Jun-01 Arrived: 15-Jun-01 MsID: IJE/2001/000115 - Revise Paper - Last reminder: Sent to Editor - Editor Sent: 05-Mar-01 Expected: 20-Mar-01 Arrived: 20-Mar-01 MsID: IJE/2001/000120 - Reject - Last reminder: Sent to Editor - Editor Sent: 14-Jun-01 Expected: 14-Jul-01 Arrived: 03-Jul-01 MsID: IJE/2001/000327 - Reject - Last reminder: Sent to Editor - Editor Sent: 31-Aug-01 Expected: 30-Sep-01 Arrived: 17-Sep-01 MsID: IJE/2001/000348 - Revise Paper - Last reminder: Sent to Editor - Editor Sent: 11-Jul-01 Expected: 11-Sep-01 Arrived: 23-Jul-01 MsID: IJE/2001/000382 - Reject - Last reminder: Sent to Editor - Editor Sent: 05-Oct-01 Expected: 05-Oct-01 Arrived: 15-Oct-01 MsID: IJE/2001/000531 - - Last reminder: Sent to Editor - Editor Sent: 05-Nov-01 Expected: 05-Nov-01 Arrived: MsID: IJE/2001/000541 - - Last reminder: Sent to Editor - Editor Sent: 14-Nov-01 Expected: 21-Nov-01 Arrived: MsID: IJE/2001/000584 - - Last reminder: (Chaturvedi, Nish)

Ethnicity and prediction of cardiovascular disease: performance of QRISK2 and Framingham scores in a UK tri-ethnic prospective cohort study (SABRE—Southall And Brent REvisited)

Objective To evaluate QRISK2 and Framingham cardiovascular disease (CVD) risk scores in a tri-ethnic UK population. Design Cohort study. Setting West London. Participants 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). Main outcome measures First CVD events: myocardial infarction, coronary revascularisation, angina, transient ischaemic attack or stroke reported by participant, primary care or hospital records or death certificate. Results 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. Conclusions 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.

Excess Pressure Integral Predicts Cardiovascular Events Independent of Other Risk Factors in the Conduit Artery Functional Evaluation Substudy of Anglo-Scandinavian Cardiac Outcomes Trial

Excess pressure integral (XSPI), a new index of surplus work performed by the left ventricle, can be calculated from blood pressure waveforms and may indicate circulatory dysfunction. We investigated whether XSPI predicted future cardiovascular events and target organ damage in treated hypertensive individuals. Radial blood pressure waveforms were acquired by tonometry in 2069 individuals (aged, 63±8 years) in the Conduit Artery Functional Evaluation (CAFE) substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). Measurements of left ventricular mass index (n=862) and common carotid artery intima media thickness (n=923) were also performed. XSPI and the integral of reservoir pressure were lower in people treated with amlodipine±perindopril than in those treated with atenolol±bendroflumethiazide, although brachial systolic blood pressure was similar. A total of 134 cardiovascular events accrued during a median 3.4 years of follow-up; XSPI was a significant predictor of cardiovascular events after adjustment for age and sex, and this relationship was unaffected by adjustment for conventional cardiovascular risk factors or Framingham risk score. XSPI, central systolic blood pressure, central augmentation pressure, central pulse pressure, and integral of reservoir pressure were correlated with left ventricular mass index, but only XSPI, augmentation pressure, and central pulse pressure were associated positively with carotid artery intima media thickness. Associations between left ventricular mass index, XSPI, and integral of reservoir pressure and carotid artery intima media thickness and XSPI were unaffected by multivariable adjustment for other covariates. XSPI is a novel indicator of cardiovascular dysfunction and independently predicts cardiovascular events and targets organ damage in a prospective clinical trial.