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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.

scientific reports

Targeted sequencing of linkage region in Dominican families implicates PRIMA1 and the SPATA7-PTPN21-ZC3H14-EML5-TTC8 locus in carotid-intima media thickness and atherosclerotic events