Single-nucleotide polymorphisms in LPA explain most of the ancestry-specific variation in Lp(a) levels in African Americans.

Rahul C Deo,W H Linda Kao,Kim Lawson,Ermeg Akylbekova,Thomas H Mosley,Herman A Taylor,David Reich,Nick Patterson,Eric Boerwinkle,Arti Tandon,James G Wilson,Chao Xing,Jonathan K Pritchard

doi:10.1371/journal.pone.0014581

Abstract

Lipoprotein(a) (Lp(a)) is an important causal cardiovascular risk factor, with serum Lp(a) levels predicting atherosclerotic heart disease and genetic determinants of Lp(a) levels showing association with myocardial infarction. Lp(a) levels vary widely between populations, with African-derived populations having nearly 2-fold higher Lp(a) levels than European Americans. We investigated the genetic basis of this difference in 4464 African Americans from the Jackson Heart Study (JHS) using a panel of up to 1447 ancestry informative markers, allowing us to accurately estimate the African ancestry proportion of each individual at each position in the genome. In an unbiased genome-wide admixture scan for frequency-differentiated genetic determinants of Lp(a) level, we found a convincing peak (LOD = 13.6) at 6q25.3, which spans the LPA locus. Dense fine-mapping of the LPA locus identified a number of strongly associated, common biallelic SNPs, a subset of which can account for up to 7% of the variation in Lp(a) level, as well as >70% of the African-European population differences in Lp(a) level. We replicated the association of the most strongly associated SNP, rs9457951 (p = 6×10−22, 27% change in Lp(a) per allele, ∼5% of Lp(a) variance explained in JHS), in 1,726 African Americans from the Dallas Heart Study and found an even stronger association after adjustment for the kringle(IV) repeat copy number. Despite the strong association with Lp(a) levels, we find no association of any LPA SNP with incident coronary heart disease in 3,225 African Americans from the Atherosclerosis Risk in Communities Study.

Highlights

Lipoprotein(a) (Lp(a)) is a subclass of lipoproteins, consisting of a low-density lipoprotein (LDL)-like particle covalently bound to the LPA gene product
We have extended our earlier work on admixture mapping and genetic association analysis in the Jackson Heart Study (JHS) to the Lp(a) trait and find the amount of African or European ancestry at the LPA locus is strongly associated with Lp(a) level
African Americans in the Atherosclerosis Risk in Communities (ARIC) Study and, we validated the strong association of LPA local ancestry and genotypes at 7 of the 10 SNPs with Lp(a) level, we find no significant association of these variables with incident coronary heart disease (CHD)

Summary

Introduction

Lipoprotein(a) (Lp(a)) is a subclass of lipoproteins, consisting of a low-density lipoprotein (LDL)-like particle covalently bound to the LPA gene product. Serum Lp(a) levels are a risk factor for cardiovascular disease, albeit with more modest effect than LDLcholesterol [1,2,3]. Common variants within the LPA gene have been associated with myocardial infarction, suggesting a causal link between Lp(a) and atherosclerotic heart disease [4,5,6,7]. Lp(a) is highly variable, with over 90% of the variance in Lp(a) levels in European Americans attributable to variation within the LPA gene [4]; the corresponding percentage in African Americans is ,80% [5]. LPA includes a well-characterized 5.6 kilobase-pair copy-number variant (CNV) that encodes a kringle(IV) domain [6,7]. Higher copy numbers for this domain are associated with lower Lp(a) levels [8], presumably due to impaired secretion of the larger protein product [9]. Biallelic SNPs and other CNVs appear to contribute independently to Lp(a) level [10]

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