Variation in LPA Is Associated with Lp(a) Levels in Three Populations from the Third National Health and Nutrition Examination Survey

et al. (2011) Variation in LPA Is Associated with Lp(a) Levels in Three Populations from the Third National Health and Nutrition Examination Survey. PLoS ONE 6(1): e16604. doi:10.1371/journal.pone.0016604 Variation in LPA Is Associated with Lp(a) Levels in Three Populations from the Third National Health and Nutrition Examination Survey Logan Dumitrescu 0 Kimberly Glenn 0 Kristin Brown-Gentry 0 Cynthia Shephard 0 Michelle Wong 0 Mark J. Rieder 0 Joshua D. Smith 0 Deborah A. Nickerson 0 Dana C. Crawford 0 Anita Kloss-Brandstaetter, Innsbruck Medical University, Austria 0 1 Center for Human Genetics Research, Vanderbilt University , Nashville , Tennessee, United States of America, 2 Department of Molecular Physiology and Biophysics, Vanderbilt University , Nashville , Tennessee, United States of America, 3 Department of Genome Sciences, University of Washington , Seattle, Washington , United States of America The distribution of lipoprotein(a) [Lp(a)] levels can differ dramatically across diverse racial/ethnic populations. The extent to which genetic variation in LPA can explain these differences is not fully understood. To explore this, 19 LPA tagSNPs were genotyped in 7,159 participants from the Third National Health and Nutrition Examination Survey (NHANES III). NHANES III is a diverse population-based survey with DNA samples linked to hundreds of quantitative traits, including serum Lp(a). Tests of association between LPA variants and transformed Lp(a) levels were performed across the three different NHANES subpopulations (non-Hispanic whites, non-Hispanic blacks, and Mexican Americans). At a significance threshold of p,0.0001, 15 of the 19 SNPs tested were strongly associated with Lp(a) levels in at least one subpopulation, six in at least two subpopulations, and none in all three subpopulations. In non-Hispanic whites, three variants were associated with Lp(a) levels, including previously known rs6919246 (p = 1.18610230). Additionally, 12 and 6 variants had significant associations in non-Hispanic blacks and Mexican Americans, respectively. The additive effects of these associated alleles explained up to 11% of the variance observed for Lp(a) levels in the different racial/ethnic populations. The findings reported here replicate previous candidate gene and genome-wide association studies for Lp(a) levels in European-descent populations and extend these findings to other populations. While we demonstrate that LPA is an important contributor to Lp(a) levels regardless of race/ethnicity, the lack of generalization of associations across all subpopulations suggests that specific LPA variants may be contributing to the observed Lp(a) between-population variance. - Funding: Genotyping services were provided by the Johns Hopkins University under federal contract number (N01-HV-48195) from the National Heart, Lung, and Blood Institute (NHLBI). This work was funded, in part, by NIH grants U01 HL66682 (DAN) and U01 HL66642 (DAN). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: MJR and JDS own stock in Illumina, Inc. To MJR and JDSs knowledge, the remaining authors have no conflicts of interest to disclose. This does not alter the authors adherence to all the PLoS ONE policies on sharing data and materials. Lipoprotein (a) [Lp(a)] levels have long been recognized as an independent risk factor for coronary artery disease (CAD)[13]. However, Lp(a) concentrations and their relationship with cardiovascular disease vary across races/ethnicities. The most notable example of this discrepancy is observed between populations of European- and African-decent. While the mean Lp(a) level is two- to threefold higher in blacks relative to whites[4,5], elevated plasma Lp(a) levels have been reported to be associated with CAD in whites but have not been clearly demonstrated in blacks[610]. The epidemiology of Lp(a) in other US racial/ethnic populations, such as Mexican Americans, is not as well documented and often inconsistent. For example, compared to non-Hispanic whites, studies have shown Mexican Americans to have both higher[11] and lower[12] mean Lp(a) levels. The underlying cause(s) for these between-population differences has not been fully determined; however, there is evidence for the role of multiple, population-specific alleles in LPA[13], the gene that encodes for apolipoprotein(a) [apo(a)], which when bound to apolipoprotein B100 and a low density lipoprotein (LDL)-like particle forms Lp(a). Lp(a) levels not only vary dramatically across populations, they also have a remarkable inter-individual variability that ranges from barely detectable to greater than 250 nmol/l[14]. This interindividual variability has a substantial genetic component. It has been determined that the apolipoprotein(a) gene is the major contributor to Lp(a) levels, accounting for more than 90% of the variance for that trait in European Americans[15]. Two types of genetic variants in LPA have been associated with Lp(a) levels: variations in the number of copies of the kringle IV-2 repeat and single nucleotide polymorphisms (SNPs). It has been estimated that the kringle IV-2 repeat alone explains 6169% of the variability observed in Lp(a) levels in populations of European ancestry[15,16]. In contrast, the kringle repeat appears to explain less of the variability (1944%) in populations of African descent[1719] and Mexican Americans (2248%)[20,21]. While the kringle IV-2 repeat polymorphism accounts for a large percentage of the variability of Lp(a) levels, the remaining variance has yet to be explained. Recent studies have identified common SNPs in LPA as strongly associated with Lp(a) levels, explaining up to 36% of the trait variance in populations of European-descent[2224]. While several studies have indicated certain SNPs are in substantial linkage disequilibrium (LD) with the kringle IV-2 repeat polymorphism[22,23], evidence also exists that some SNPs are in relatively little LD with copy number variation in LPA [25] and may be independent contributors to Lp(a) levels. A recent genomewide association study performed in a Hutterite population with kringle IV-2 repeat polymorphism data identified a SNP associated with Lp(a) levels independent of the kringle repeat, supporting the assumption that some common SNPs in LPA are independent of the kringle repeat polymorphisms (i.e., not in linkage disequilibrium)[24]. To date, relatively few studies have examined associations between LPA common SNPs and Lp(a) levels across multiple, diverse populations and no study has characterized the same panel of LPA common SNPs in populations of European-, African-, and Mexican-descent. To better characterize this genotype-phenotype relationship in more diverse populations, we have genotyped 19 European American and African American LPA tagSNPs in 7,159 participants from the Third National Health and Nutrition Exam (...truncated)