Abstract 16138: Identification of Rare Variants for Low Levels of Serum High-Density Lipoprotein Cholesterol
Low level of serum high density lipoprotein cholesterol (HDL-C) is a well-established risk factor for coronary artery disease (CAD). CAD is the major cause of mortality world-wide. We used exome sequencing to search for rare variants for low HDL-C. We conducted exome sequencing in a multigenerational French Canadian family with low HDL-C and high triglycerides. We captured and sequenced ∼50 Mb of transcribed sequences of closely related, affected family members with HDL-C<5th age-sex percentiles. We detected ∼80,000 variants in each affected individual. In the subsequent analysis, we focused on variants shared by the affected family members. We also filtered the variants based on their type, frequency, gene expression, and functional predictions. Filtering for missense variants that were novel or exhibited a minor allele frequency <5% and that were shared by all affected individuals resulted in 83 nonsynonymous variants of which 54 were both expressed in a relevant tissue and predicted to be functional using PolyPhen and SIFT. These variants were further genotyped in the entire extended French Canadian low HDL-C family with 35 family members with DNA available for study. We also had previous genome-wide linkage data available for this extended family to guide the follow-up analysis. Fifteen chromosomal regions provided a two-point lod score >1.0 in the family using a dominant or recessive mode of inheritance and the Mendel program. The highest lod score (1.9) was observed on chromosome 6. Among the 54 identified variants, six variants in the ATG7, WRNIP1, NOL8, OBP2A, PIH1D2, and FDXACB1 genes resided in the regions with a lod score>1.0. These six nonsynonymous variants are further investigated for variance explained and gene-gene interactions in the extended family as well as for prevalence in French Canadian cases and controls to identify the underlying rare susceptibility variants for familial low HDL-C.
- © 2012 by American Heart Association, Inc.