Abstract 14: Fine Mapping Study Revealed Novel Candidate Genes for Carotid Intima-Media Thickness in Dominicans
Background: Carotid intima-media thickness (CIMT) is a subclinical measure for atherosclerosis, the major underlying cause for stroke and other cardiovascular events. Previously, we have mapped quantitative trait loci (QTLs) for CIMT to chromosomes 7p (MLOD=3.1) and 14q (MLOD=2.3) in 100 extended Dominican Republican (DR) families.
Methods and Results: To identify the genetic variations accounting for CIMT variability at those QTLs, we surveyed the one-LOD-unit-down linkage regions using >2,000 tagging single nucleotide polymorphisms (SNPs). Family-based association tests were performed in the 100 DR families (N=1372) used in the original linkage study, adjusting for significant covariants. Promising SNPs were further examined in the population-based NOMAS subcohort comprised of DR subjects only (N=553). Evidence for association (P<0.001) was found in multiple genes (ANLN, AOAH, FOXN3, CCDC88C, PRiMA1, and an intergenic SNP rs1667498 near FLRT2) with the strongest association at PRiMA1 (P=0.00007, which remained significant after adjusting for multiple testing). The association at these genes, except for PRiMA1, was driven by families with evidence for linkage (53 and 51 families for the 7p and 14q QTL, respectively; P= 0.00004∼0.00092 and 0.13∼0.80 in families with and without evidence for linkage, respectively), suggesting that these genes might collectively account for the QTLs delimited in our family data set. On the other hand, the association at PRiMA1 is significant in both family subsets (P=0.002 and 0.019 in families with and without evidence for linkage, respectively). The association at PRiMA1, but not at other genes, was replicated in the NOMAS DR subcohort (P=0.047), supporting a robust association at PRiMA1.
Conclusions: We identified several candidate genes for CIMT in Dominican Republicans. Some of the genes manifest genetic effects within a specific subset of families and others can be generalized in additional samples. Future studies are needed to further elucidate the contribution of these genes to atherosclerosis.
- © 2012 by American Heart Association, Inc.