Abstract 116: A Targeted Sequencing Approach in Subjects with Extremely High HDL-C Identifies individuals with Potentially Causal Mutations in Both Alleles of 53 Genes
Introduction The molecular etiology of extremely elevated HDL-C is poorly understood. Genome-wide association studies (GWAS) have identified many genetic loci associated with HDL-C, but very few of these harbor genes in which rare mutations are known to cause extremely elevated HDL-C levels. We performed targeted sequencing of exons in genes at GWAS lipid loci on subjects with extremely high HDL-C compared with those with low HDL-C in order to identify individuals with nonsynonymous mutations that could be causal for the extreme high HDL-C phenotype.
Methods 389 cases with HDL-C >95th percentile (102±19 mg/dL), and 387 controls with HDL-C <25th percentile (32±5 mg/dL) underwent targeted sequencing of exons in genes ±300 kb around each of 95 recently identified GWAS loci associated with lipid parameters. Candidate variants were identified by the following criteria: (1) missense, nonsense, and frameshift variants; (2) predicted to be deleterious by at least 1 of 3 in silico prediction methods; (3) a ratio of high HDL-C heterozygotes to low HDL-C heterozygotes >1.5:1; (4) absence of any low HDL-C homozygotes; (5) MAF <0.01. Individuals with a potentially causal low-frequency variant in both alleles of a specific gene were identified for further phenotypic characterization.
Results 46 individuals with extremely high HDL-C were identified to have potentially causal low-frequency variants in both alleles of the same gene. These individuals were homozygous or compound heterozygous for mutations in 53 distinct genes. Most of these genes were not known to play defined roles in HDL metabolism, and include ARHGAP1, BTN2A2, CAMK2B, LILRA3, and OSCAR. These individuals are currently being called back for detailed phenotyping.
Conclusions A targeted sequencing approach focused on genes at GWAS HDL-C loci in subjects with extremely high HDL-C identified 46 individuals with potentially causal low-frequency variants in both alleles of the same gene, including genes not known to play a role in HDL metabolism. More detailed phenotyping and family studies are underway, and are likely to provide new information regarding the phenotypic consequences of loss-of-function mutations in both alleles of several genes that influence HDL metabolism.
- © 2013 by American Heart Association, Inc.