Abstract
Carotid intima-media thickness (cIMT) is a subclinical marker for atherosclerosis. Previously, we reported a quantitative trait locus (QTL) for total cIMT on chromosome 14q and identified PRiMA1, FOXN3 and CCDC88C as candidate genes using a common variants (CVs)-based approach. Herein, we further evaluated the genetic contribution of the QTL to cIMT by resequencing. We sequenced all exons within the QTL and genomic regions of PRiMA1, FOXN3 and CCDC88C in Dominican families with evidence for linkage to the QTL. Unrelated Dominicans from the Northern Manhattan Study (NOMAS) were used for validation. Single-variant-based and gene-based analyses were performed for CVs and rare variants (RVs). The strongest evidence for association with CVs was found in PRiMA1 (p = 8.2 × 10(-5) in families, p = 0.01 in NOMAS at rs12587586), and in the five-gene cluster SPATA7-PTPN21-ZC3H14-EML5-TTC8 locus (p = 1.3 × 10(-4) in families, p = 0.01 in NOMAS at rs2274736). No evidence for association with RVs was found in PRiMA1. The top marker from previous study in PRiMA1 (rs7152362) was associated with fewer atherosclerotic events (OR = 0.67; p = 0.02 in NOMAS) and smaller cIMT (β = -0.58, p = 2.8 × 10(-4) in Family). Within the five-gene cluster, evidence for association was found for exonic RVs (p = 0.02 in families, p = 0.28 in NOMAS), which was enriched among RVs with higher functional potentials (p = 0.05 in NOMAS for RVs in the top functional tertile). In summary, targeted resequencing provided validation and novel insights into the genetic architecture of cIMT, suggesting stronger effects for RVs with higher functional potentials. Furthermore, our data support the clinical relevance of CVs associated with subclinical atherosclerosis.