In a multiethnic sample representative of the U.S. population, we tested DNA sequence variants at 19 loci that had been discovered in individuals of European descent. We addressed the hypothesis that these same variants would relate to blood lipid traits in other ethnic groups. At five loci (CELSR2/PSRC1/SORT1, HMGCR, CETP, LPL, and APOA5), we found that the same variant identified in whites was nominally associated in both non-Hispanic blacks and Mexican Americans. At other loci, there was mixed evidence for SNPs by ethnic group.
For SNPs at five loci discovered in whites, the same polymorphism was confirmed across all three NHANES III ethnic groups. This suggests that these loci impact blood lipid traits across multiple ethnic groups. These results set the stage for fine-mapping and resequencing of these gene regions in all three ethnic groups.
For the remaining loci, variable replication among ethnicities likely occurred for one or more of the following reasons. First, individual genetic variants contributing to complex traits have very modest effect sizes. Therefore, each individual ethnic group may have been underpowered to detect an association. This problem could be addressed by genotyping the polymorphisms in additional individuals of African-American or Hispanic ancestry. Second, the locus discovered in whites may be relevant in other ethnicities but the specific polymorphisms associated with lipids may differ across ethnicities. Older populations such as those of African descent have a more complex linkage disequilibrium (LD) structure.19
Therefore, if the causal variant in African Americans is poorly correlated with the index SNP discovered from whites, no association will be detected. In this case, testing a comprehensive set of variants that tag the entire locus (i.e. fine-mapping the region in other ethnicities) would be required to detect the relevant polymorphism(s). Finally, genetic variants in different ethnicities may lie in regions of the genome distinct from those observed in whites. New variant discovery through additional GWA studies or resequencing efforts in other ethnicities would be necessary to locate these variants. Such efforts are currently underway.
In prior literature, several of the loci have been studied in African-Americans and/or Hispanic-Americans including LDLR
, and APOA5
. Our study supports and builds upon these prior reports. While other variants have been reported in multi-ethnic groups20
, we are the first to describe associations of the LDLR
intronic SNPs rs6511720 and rs1529729 with LDL cholesterol in a sample including African-Americans and Mexican-Americans. We confirm that rs11591147 (R46L) in the PCSK9
gene is common and decreases LDL cholesterol in whites (minor allele frequency of 3%) but is rare in African-Americans (minor allele frequency of 0.4%).9, 21
As in our study, associations between polymorphisms in the CETP
genes and HDL cholesterol have been consistently reported in cohorts including African American and/or Hispanic subjects.22–24
Finally, we confirm the robust association between APOA5
and triglycerides in all three ethnic groups.25, 26
By reproducing previously reported findings, we demonstrate that our patient sample is representative and that our methods are valid.
Our study has several strengths and limitations. To our knowledge, this is the first study to assess loci recently discovered through GWA studies in a multiethnic cohort. Next, compared to prior studies assessing few variants in multiethnic cohorts, our study queried a larger set of lipid loci. Finally, because the NHANES III cohort over-sampled minority groups in the U.S. population, our sample includes a large number of African-Americans and Mexican Americans. That being said, due to the modest contribution of each polymorphism to trait variation, low statistical power is a key limitation. Lipids in NHANES III were measured in both fasting and non-fasting samples and our use of both may have further reduced statistical power, particularly for lipid variables sensitive to fasting status such as triglycerides. In addition, in NHANES III, ethnic groups are designated by self-reported ethnicity and this assessment is not always accurate. For a more precise assessment of ethnicity using genetic data, ancestry-informative markers are necessary. Lastly, we did not evaluate a comprehensive set of 'tag' SNPs across each of the 19 loci. Such an effort would be required to definitively study each locus in African-Americans and Mexican-Americans.
In conclusion, we evaluated 21 SNPs in 19 loci from recent GWA studies for blood lipids in a U.S. population-based multi-ethnic sample. We found that at five loci, the exact same SNP identified in whites was also associated with lipids in both African-Americans and Mexican-Americans. At 1p13 near CELSR2/PSRC1/SORT1, the strongest new locus identified in GWA studies of LDL cholesterol, the same index SNP was associated with LDL cholesterol in all three ethnic groups, suggesting that this locus is of broad relevance. Our findings set the stage for comprehensive fine-mapping and sequencing efforts across these loci in multiple ethnic groups.