Genetic Differences between the Determinants of Lipid Profile Phenotypes in African and European Americans: The Jackson Heart Study

Rahul C Deo, David Reich, Arti Tandon, Ermeg Akylbekova, Nick Patterson, Alicja Waliszewska, Sekar Kathiresan, Daniel Sarpong, Herman A Taylor and James G Wilson

PLOS Genetics, 2009, vol. 5, issue 1, 1-11

Abstract: Genome-wide association analysis in populations of European descent has recently found more than a hundred genetic variants affecting risk for common disease. An open question, however, is how relevant the variants discovered in Europeans are to other populations. To address this problem for cardiovascular phenotypes, we studied a cohort of 4,464 African Americans from the Jackson Heart Study (JHS), in whom we genotyped both a panel of 12 recently discovered genetic variants known to predict lipid profile levels in Europeans and a panel of up to 1,447 ancestry informative markers allowing us to determine the African ancestry proportion of each individual at each position in the genome. Focusing on lipid profiles—HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), and triglycerides (TG)—we identified the lipoprotein lipase (LPL) locus as harboring variants that account for interethnic variation in HDL-C and TG. In particular, we identified a novel common variant within LPL that is strongly associated with TG (p = 2.7×10−6) and explains nearly 1% of the variability in this phenotype, the most of any variant in African Americans to date. Strikingly, the extensively studied “gain-of-function” S447X mutation at LPL, which has been hypothesized to be the major determinant of the LPL-TG genetic association and is in trials for human gene therapy, has a significantly diminished strength of biological effect when it is found on a background of African rather than European ancestry. These results suggest that there are other, yet undiscovered variants at the locus that are truly causal (and are in linkage disequilibrium with S447X) or that work synergistically with S447X to modulate TG levels. Finally, we find systematically lower effect sizes for the 12 risk variants discovered in European populations on the African local ancestry background in JHS, highlighting the need for caution in the use of genetic variants for risk assessment across different populations.Author Summary: Single-base changes in DNA can affect biochemical measures, such as blood cholesterol or lipid levels. Such changes or “variants” can be associated with a trait either because they cause the trait or because they are linked to other causal variants. In either case, the associated variant(s) may be useful in predicting the trait. The chromosomes in which DNA is packaged cross over and recombine with each other in each generation, so that in historically separate populations, such as Africans and Europeans, the patterns of genetic linkage between variants differ. In the current study, we analyzed a large group of African Americans, testing genetic variants that had been associated with cholesterol and lipid levels in European-derived populations to assess their predictive value on two different genetic backgrounds within the same cohort. The ability of some variants to predict cholesterol or lipid traits was strongly dependent on genetic background, indicating that they may be tightly linked to other causal variant(s) in European populations and may not, themselves, be directly responsible for trait variability. We conclude that the predictive value of specific variants for risk assessment can differ critically across populations.

Date: 2009
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pgen00:1000342

DOI: 10.1371/journal.pgen.1000342

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