Abstract 3454: Fine Mapping Of A Chromosome 16 Locus Associated With Low High-density Lipoprotein Cholesterol Level (HDL-C) In French Canadian Subjects

Abstract

Low HDL-C is a known independent risk factor for coronary heart disease. Levels of HDL-C are influenced by both genetic and environmental factors. We previously performed a quantitative linkage analysis in two independent studies of the French Canadian founder population: a Quebec-wide study (QUE) consisted of 362 individuals from multigenerational families, and 410 individuals from families of the Saguanay-Lac St-Jean region (SLSJ). The results demonstrated a linkage to the locus 16q23–24 in both studies. This locus has been implicated in previous linkage scans for HDL-C in multiple studies from different populations. All of them resulted in linkage peaks that are less than 12 cM far from our peak, suggesting the existence of one or more genes in this specific locus. We examined the region by SNP fine mapping and used family based association and case-control association analysis. Using families from the QUE study, defining HDL-C <5th percentile (age/gender-matched) as cases, the region was narrowed from 25 cM to 18.1 cM. Affected members from four families share a 2 microsatellite haplotype. SNPs genotyped in this locus allowed us to narrow down the shared haplotype to 4Mb. A case-control association study in the SLSJ study sample (cases <5 percentile HDL-C, controls >40 percentile HDL-C) identified several significant SNPs, one of which was located in the same region as the shared haplotype from the QUE families. Constructing a haplotype of this SNP and a nearby SNP, increased the evidence for association (p =0.016 to 0.0097). The CHST6 gene, located within this region, has been previously identified in macular corneal dystrophy. Because of the presence of occular manifestations with other genes associated with low HDL-C (e.g. LCAT, ApoA1), we sequenced the CHST6 gene and also its homologue CHST5, which is located in the same region. We found three non-synonymous variants in these two genes. One of the variants in the CHST6 gene showed a strong segregation in the four families sharing the microsatellite haplotype. This same variant also demonstrated an odds ratio >2 in the case/control sample, but this was not significant due to the small sample size. Our data present strong evidence for a HDL-C gene on chromosome 16q23–24 that may be related to the CHST6 or CHST5 loci.