Low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and total cholesterol are heritable, modifiable, risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,578 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5×10−8, including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian, and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipids are often associated with cardiovascular and metabolic traits including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio, and body mass index. Our results illustrate the value of genetic data from individuals of diverse ancestries and provide insights into biological mechanisms regulating blood lipids to guide future genetic, biological, and therapeutic research.

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiologic studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P<5×10−8 for each) to examine the role of triglycerides on risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglycerides, and show that the direction and magnitude of both are factors in determining CAD risk. Second, we consider loci with only a strong magnitude of association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol, a polymorphism's strength of effect on triglycerides is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.

OBJECTIVES: This study was undertaken to describe the distribution of blood pressures, hypertension prevalence, and associated risk factors among seven populations of West African origin. METHODS: The rates of hypertension in West Africa (Nigeria and Cameroon), the Caribbean (Jamaica, St. Lucia, Barbados), and the United States (metropolitan Chicago, Illinois) were compared on the basis of a highly standardized collaborative protocol. After researchers were given central training in survey methods, population-based samples of 800 to 2500 adults over the age of 25 were examined in seven sites, yielding a total sample of 10014. RESULTS: A consistent gradient of hypertension prevalence was observed, rising from 16% in West Africa to 26% in the Caribbean and 33% in the United States. Mean blood pressures were similar among persons aged 25 to 34, while the increase in hypertension prevalence with age was twice as steep in the United States as in Africa. Environmental factors, most notably obesity and the intake of sodium and potassium, varied consistently with disease prevalence across regions. CONCLUSION: The findings demonstrate the determining role of social conditions in the evolution of hypertension risk in these populations.

Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant).

Coronary heart disease (CHD) is the leading cause of mortality in African Americans. To identify common genetic polymorphisms associated with CHD and its risk factors (LDL- and HDL-cholesterol (LDL-C and HDL-C), hypertension, smoking, and type-2 diabetes) in individuals of African ancestry, we performed a genome-wide association study (GWAS) in 8,090 African Americans from five population-based cohorts. We replicated 17 loci previously associated with CHD or its risk factors in Caucasians. For five of these regions (CHD: CDKN2A/CDKN2B; HDL-C: FADS1-3, PLTP, LPL, and ABCA1), we could leverage the distinct linkage disequilibrium (LD) patterns in African Americans to identify DNA polymorphisms more strongly associated with the phenotypes than the previously reported index SNPs found in Caucasian populations. We also developed a new approach for association testing in admixed populations that uses allelic and local ancestry variation. Using this method, we discovered several loci that would have been missed using the basic allelic and global ancestry information only. Our conclusions suggest that no major loci uniquely explain the high prevalence of CHD in African Americans. Our project has developed resources and methods that address both admixture- and SNP-association to maximize power for genetic discovery in even larger African-American consortia.

Objective: To describe the influence of maternal weight and weight gain, placental volume and the rate of placental growth in early pregnancy on fetal dimensions measured sonographically. Design: In a prospective study, 712 women were recruited from the antenatal clinic of the University Hospital of the West Indies. Data analysis was confined to 374 women on whom measurements of the placental volume at 14, 17 and 20 weeks gestation were complete. Measurements of maternal anthropometry and fetal size (by ultrasound) were performed. Weight gain in pregnancy between the first antenatal visit (8-10 weeks) and 20 weeks gestation, and the rate of growth of the placenta between 14-17 and 17-20 weeks gestation were calculated. Main outcome measures: Fetal anthropometry (abdominal and head circumferences, femoral length, and biparietal diameter) at 35 weeks gestation. Results: Lower maternal weight at the first antenatal visit was associated with a significantly smaller placental volume at 17 and 20 weeks gestation (Po0.002 and o0.0001 respectively). In all women, maternal weight gain was directly related to fetal anthropometry. Placental volume at 14 weeks gestation and the rate of growth of the placenta between 17 and 20 weeks gestation were significantly related to all four fetal measurements. Conclusion: This study has provided evidence that both placental volume, and the rate of placental growth may influence fetal size. These effects are evident in the first half of pregnancy, and appear to be mediated through maternal weight and weight gain. Sponsorship: This study was supported by a grant from the Wellcome Trust,

Dementia and depression among the elderly living in the Hobart community. PsycholMed 1985;15:771-8. 17 Lindesay J, Briggs C, Murphy E. The Guy's Age Concem survey. Prevalence rates of cognitive impairment, depression and anxiety in an urban elderly community. BrJPsychiatty 1989;153:317-29 Design-Retrospective cohort study. Setting-27 schools closest to University Hospital ofthe West Indies, Kingston, Jamaica.Subjects-2337 children aged 6-16 years who were born at university hospital were recruited, and their birth records were recovered: 1610 had suitable records, 659 had records including birth length, and 610 ofthese were prepubertal.Main outcome measures-Blood pressure, glycated haemoglobin level, serum cholesterol concentration, anthropometry at birth, current anthropometry, and socioeconomic status.Results-Multiple regression analysis showed that children's systolic blood pressure was inversely related to their birth weight (P < 0.0001) and directly related to their current weight. Glycated haemoglobin level was higher in children with thicker triceps skinfolds (P<0.001) and who had been shorter at birth (P=0.003). Serum cholesterol concentration was inversely related to current height (P=0.001) and to length at birth (P=0.09) and was directly related to triceps skinfold thickness and higher socioeconomic status (P < 0.001).Conclusions-Blood pressure in childhood was inversely related to birth weight and directly to current weight. Glycaemic control and serum cholesterol were related to short length at birth, height deficit in childhood, and childhood obesity.

The transition in glucose intolerance from Cameroon to Jamaica and Britain suggests that environment determines diabetes prevalence in these populations of similar genetic origin.