Abstract 15357: Population-based Resequencing of APOA1 in 10,330 Individuals: Spectrum of Genetic Variation, Phenotype, and Comparison with Extreme Phenotype Approach
INTRODUCTION: Rare genetic variants, identified by in-detail resequencing of loci, may contribute to complex traits.
OBJECTIVE: To use population-based resequencing of the apolipoprotein A-I gene (APOA1), a major high-density lipoprotein (HDL) gene, to evaluate the spectrum of genetic variants, the phenotypic characteristics, and how these results compared with results based on the extreme apolipoprotein A-I (apoA-I) phenotype approach.
METHODS: First, we resequenced APOA1 in 10,330 population-based participants in the Copenhagen City Heart Study and determined the spectrum and distribution of genetic variants. Second, the apoA-I and HDL cholesterol phenotype was assessed and validated in the Copenhagen General Population Study (n=45,239). Third, we compared the genetic variants identified and the corresponding observed phenotypes with those predicted using an extreme phenotype approach based on the apoA-I distribution.
RESULTS: First, we identified 40 variants in APOA1 of which only 7 (18%) had minor allele frequencies >1%, and most were exceedingly rare. Second, 0.3% of the population were heterozygous for nonsynonymous variants that associated with substantial reductions in apoA-I (up to 39 mg/dL) and/or HDL cholesterol (up to 0.9 mmol/L), and surprisingly 0.4% were heterozygous for variants previously associated with amyloidosis. Third, using the extreme apoA-I phenotype approach, nonsynonymous variants correctly predicted the apoA-I phenotype observed in the population-based resequencing. However, using the extreme approach, between 79%(screening 0-1st percentile) and 21%(screening 0-20th percentile) of all variants were not identified, among these variants previously associated with amyloidosis.
CONCLUSION: In conclusion, population-based resequencing of APOA1 identified a majority of rare genetic variants which were cumulatively relatively frequent. Approximately 0.3% of the population carried rare variants in APOA1 that associated with substantial reductions in apoA-I and HDL cholesterol, and 0.4% carried variants that previously had been associated with amyloidosis.
- © 2012 by American Heart Association, Inc.