Abstract 599: Elucidating the Genetic Determinants of Extreme High-density Lipoprotein Phenotypes Using Next-generation Sequencing

Abstract

HDL cholesterol (HDL-C) levels strongly associate with cardiovascular disease risk, and as a complex trait, are influenced by genetic and environmental factors. Extreme HDL-C concentrations are largely genetically determined; monogenic disorders of HDL-C have been well-characterized, including the primary candidate genes driving each extreme phenotype, which typically show autosomal recessive or co-dominant inheritance. Within genes causing syndromes of both HDL-C extremes, numerous disease-causing variants have been identified and functionally validated. In a unique cohort of patients with extreme HDL-C profiles ( N =255), we applied our targeted next-generation sequencing panel LipidSeq TM , which is designed for clinical re-sequencing of genes associated with dyslipidemia and other metabolic disorders. We found that 20.6% and 11.8% of low ( N =136) and high ( N =119) HDL-C patients, respectively, carry heterozygous, large-effect mutations in pertinent genes explaining their phenotypes. To further characterize the genetic variation contributing to HDL-C levels, we next investigated the integrated polygenic contribution from multiple small-effect genetic variants using a polygenic trait score (PTS). We developed two scores to assess an individual’s burden of small-effect variants: one each for lowering and raising HDL-C levels. As a whole, low HDL-C patients had a significantly greater mean PTS for low HDL-C than normolipidemic controls ( P <0.001); furthermore, there was no difference in PTS among carriers and non-carriers of large-effect variants. In contrast, high HDL-C patients’ mean PTS for high HDL-C in carriers of large-effect variants was not different from non-carrier or controls, while PTS in non-carriers was significantly greater than controls (both P <0.001). The findings confirm the complexity of extreme HDL-C levels and the differences in contributions of rare large-effect and common small-effect variants to these extremes.