Genetic Determinants of Lipid Traits in Diverse Populations from the Population Architecture using Genomics and Epidemiology (PAGE) Study

Abstract

For the past five years, genome-wide association studies (GWAS) have identified hundreds of common variants associated with human diseases and traits, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. Approximately 95 loci associated with lipid levels have been identified primarily among populations of European ancestry. The Population Architecture using Genomics and Epidemiology (PAGE) study was established in 2008 to characterize GWAS–identified variants in diverse population-based studies. We genotyped 49 GWAS–identified SNPs associated with one or more lipid traits in at least two PAGE studies and across six racial/ethnic groups. We performed a meta-analysis testing for SNP associations with fasting HDL-C, LDL-C, and ln(TG) levels in self-identified European American (∼20,000), African American (∼9,000), American Indian (∼6,000), Mexican American/Hispanic (∼2,500), Japanese/East Asian (∼690), and Pacific Islander/Native Hawaiian (∼175) adults, regardless of lipid-lowering medication use. We replicated 55 of 60 (92%) SNP associations tested in European Americans at p<0.05. Despite sufficient power, we were unable to replicate ABCA1 rs4149268 and rs1883025, CETP rs1864163, and TTC39B rs471364 previously associated with HDL-C and MAFB rs6102059 previously associated with LDL-C. Based on significance (p<0.05) and consistent direction of effect, a majority of replicated genotype-phentoype associations for HDL-C, LDL-C, and ln(TG) in European Americans generalized to African Americans (48%, 61%, and 57%), American Indians (45%, 64%, and 77%), and Mexican Americans/Hispanics (57%, 56%, and 86%). Overall, 16 associations generalized across all three populations. For the associations that did not generalize, differences in effect sizes, allele frequencies, and linkage disequilibrium offer clues to the next generation of association studies for these traits.

Genetic Susceptibility to Lipid Levels and Lipid Change Over Time and Risk of Incident Hyperlipidemia in Chinese Populations

“…Of those, the association of LIPG with HDL-C has been found not to be generalized to diverse populations including African, Indians, Mexican, and Hispanics. 12 We observed that the reported lead SNPs at these 3 loci in Europeans were monomorphic or had low minor allele frequency (<0.1) in the Chinese Han population, whereas these SNPs were polymorphic in European populations (Table V in the Data Supplement). For example, in Europeans, a prominent association was reported for rs6511720, which is not polymorphic in the Chinese, whereas the strongest LDL-C association at LDLR (rs7258950) was detected in the Chinese.…”

“…Some variants may be more common in specific ethnic groups, thereby providing greater statistical power, or the effects of genetic variants on lipid levels may be enlarged in specific ethnic groups. 11,12 Therefore, large-scale studies in Chinese are needed not only to evaluate whether the previous reported loci could be generalized to Chinese population but also to identify new loci or Chinese-specific variants for blood lipids.…”

Leveraging Multi-ethnic Evidence for Risk Assessment of Quantitative Traits in Minority Populations

“…In contrast, for a variety of complex traits studied to date, accumulating evidence suggests considerable numbers of overlap loci between ethnicities. [30][31][32][33] For these traits, a large proportion of SNPs selected based on a large European GWAS are expected to be relevant in non-European populations. Therefore, a set selected based on a large GWAS in a non-matching population is expected to harbor higher fraction of variants for the target population than a set selected on a small dataset in matching population.…”

Epidemiological analysis of dyslipidemia in adults of three ethnicities in Xinjiang, China

“…The prevalence rate of high LDL-C in Han adults (2%) is similar to that of residents in China aged ≥18 years in 2010 (2.1%) but higher than those in Uygur (2.9%) and Kazak adults (2.4%), and increases with increasing age. As part of the Population Architecture using Genomics and Epidemiology (PAGE) Study, Logan et al (Dumitrescu et al, 2011) studied blood lipid genetic factors in different groups on the basis of a genome-wide association study (GWAS); they found that genes decisively influence HDL-C, LDL-C, and TG levels in Europeans, European-Americans, and non-European Americans. In the present study, there were significant differences among the 3 ethnicities with respect to the prevalence rates of the 4 studied blood lipid parameters.…”