Genomic study in Mexicans identifies a new locus for triglycerides and refines European lipid loci

Abstract

Background: The Mexican population and others with Amerindian heritage exhibit a substantial predisposition to dyslipidemias and coronary heart disease. Yet, these populations remain underinvestigated by genomic studies, and to date, no genome-wide association (GWA) studies have been reported for lipids in these rapidly expanding populations.

Methods and findings: We performed a two-stage GWA study for hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) in Mexicans (n=4361), and identified a novel Mexican-specific genome-wide significant locus for serum triglycerides (TGs) near the Niemann-Pick type C1 protein gene (p=2.43×10(-08)). Furthermore, three European loci for TGs (APOA5, GCKR and LPL), and four loci for HDL-C (ABCA1, CETP, LIPC and LOC55908) reached genome-wide significance in Mexicans. We used cross-ethnic mapping to narrow three European TG GWA loci, APOA5, MLXIPL, and CILP2 that were wide and contained multiple candidate variants in the European scan. At the APOA5 locus, this reduced the most likely susceptibility variants to one, rs964184. Importantly, our functional analysis demonstrated a direct link between rs964184 and postprandial serum apoAV protein levels, supporting rs964184 as the causative variant underlying the European and Mexican GWA signal. Overall, 52 of the 100 reported associations from European lipid GWA meta-analysis generalised to Mexicans. However, in 82 of the 100 European GWA loci, a different variant other than the European lead/best-proxy variant had the strongest regional evidence of association in Mexicans.

Conclusions: This first Mexican GWA study of lipids identified a novel GWA locus for high TG levels; used the interpopulation heterogeneity to significantly restrict three previously known European GWA signals, and surveyed whether the European lipid GWA SNPs extend to the Mexican population.

Figure 1. Manhattan plots of GWA results for hypertriglyceridemia (HTG) and HDL-C levels

The −log10 of the P-values obtained in stage I and in the combined stage I+II samples are shown in open and red solid circles, respectively. Loci surpassing the genome-wide significance threshold (-log₁₀(5×10⁻⁰⁸)=7.3) are designated.

Figure 2. Regional association plots for the novel and APOA5 loci in the Mexican GWA study

Regional plots for both genotyped and imputed (based on the 1000 Genomes Project) SNPs are displayed. The −log10 of the P-values obtained in stage I and in the combined stage I+II samples are shown within circle and diamond shapes, respectively, as a function of genomic distance (NCBI Build 36.1 build hg18) for NPC1 (A), and APOA5 (B) gene region. SNPs are color-coded according to LD with the lead SNP (large red diamond). In B, the arrow indicates the SNP previously suggested as the most plausible functional variant in the APOA5 region. Light blue lines indicate the estimated recombination hot spots in HapMap. The bottom panel shows the genes at each locus as annotated in the UCSC Genome Browser Database. The gray bar indicates associated interval determined as the region spanning SNPs in LD of r² ≥ 0.5 with the lead Mexican SNP. Plots were generated using SNAP.

Figure 3. Cross-ethnic LD comparisons at the shared GWA loci restricted the European GWA signals at APOA5, MLXIPL, and CILP2

The x-axis displays the pair-wise LD in r² with the lead European SNP using the 1000 Genomes CEU data. The y-axis displays pair-wise LD in r² with the lead Mexican SNP (±500 kb) using genotyped and imputed SNPs (based on the 1000 Genomes Project) in 200 Mexican controls. SNPs are color-coded according to the shared LD: the SNPs in high LD (r²≥0.5) with both the lead European and Mexican SNPs in CEU and Mexicans are shown in red; the SNPs in high LD with only the European lead SNPs are shown in green; the SNPs in high LD with only the Mexican lead SNPs are in blue; and the SNPs that are not in high LD with either SNP are shown in gray, respectively. Based on the association and LD data in Mexicans, SNPs color-coded in green are no longer potential functional candidates underlying the GWA signal.

Figure 4. Differential postprandial response of apoAV protein levels between the rs964184 genotype groups

Boxplots show the postprandial response of apoAV calculated as an area under the incremental curve (AUIC) stratified based on the rs964184 genotype groups. The P-value and linear regression line for the additive model has been added to the plot to show the significance and trend of the difference in means.