Identification of two common variants contributing to serum apolipoprotein B levels in Mexicans

Abstract

Background and purpose: Although the Mexican population has a high predisposition to dyslipidemias and premature coronary artery disease, this population is underinvestigated for the genetic factors conferring the high susceptibility. This study attempted to determine these genetic factors.

Methods and results: First, we investigated apolipoprotein B (apoB) levels in Mexican extended families with familial combined hyperlipidemia using a two-step testing strategy. In the screening step, we screened 5721 single-nucleotide polymorphisms (SNPs) for linkage signals with apoB. In the test step, we analyzed the 130 SNPs residing in regions of suggestive linkage signals for association with apoB. We identified significant associations with two SNPs (ie, rs1424032 [P=6.07x10(-6)] and rs1349411 [P=2.72x10(-4)]) that surpassed the significance level for the number of tests performed in the test step (P<3.84x10(-4)). Second, these SNPs were tested for replication in Mexican hyperlipidemic case-control samples. The same risk alleles as in the families with familial combined hyperlipidemia were significantly associated (P<0.05) with apoB in the case-control samples. The rs1349411 resides near the apoB messenger RNA editing enzyme (APOBEC1) involved in the processing of APOB messenger RNA in the small intestine. The rs1424032 resides in a highly conserved noncoding region predicted to function as a regulatory element.

Conclusions: We identified two novel variants, rs1349411 and rs1424032, for serum apoB levels in Mexicans.

Figure 1. Results of the screening (linkage) and testing (association) steps for apoB in Mexican dyslipidemic families

A. Results of the maximum two-point linkage analysis of dominant and recessive modes of inheritance for apoB status. Markers are ordered according to the chromosome and physical location. B. Multipoint nonparametric (variance-component) maximum lod scores for binary and quantitative apoB ordered according to the chromosome and genetic location (cM). The dashed line in A and B indicates lod score = 2. C. The −log10 of the P-values obtained from the QTDT analyses for quantitative apoB are shown. The dashed line indicates the Bonferroni corrected significance threshold (log₁₀(3.8×10⁻⁴)).

Figure 2. LD structure and cross-species conservation in the region surrounding rs1424032

Cross-species conservation in the 70 kb region surrounding rs1424032 is shown in the top panel with computationally predicted cis-regulatory element indicated by a custom track in UCSC Genome Browser. The conservation Track shows alignments of 28 vertebrate species as described in http://genome.ucsc.edu/. This region is a noncoding conserved region as illustrated by the absence of any known genes, mRNA or spliced expressed sequence tags (ESTs) under the corresponding designated Tracks. In the bottom panel the extent of LD in the 250 kb region surrounding rs1424032 in 50 Mexican-American founders of the HapMap project is shown using r². The red point represents the SNP rs1424032 and the black triangle indicates the 70 kb region of LD.

Figure 3. LD across the APOBEC1 gene (±50 kb) and in the region surrounding (±50 kb) rs1349411

LD calculated in r² using the 50 Mexican-American founders (Left panel) and 60 CEU founders with European ancestry (Right panel) of the HapMap project is shown. The black point represents the region of the SNP rs1349411 and the black rectangle the APOBEC1 gene. A 311kb region between the APOBEC1 gene and rs1349411 region was removed to reduce the LD presentation, as illustrated by the diagonal lines that indicate the physical map positions of the SNPs