Genetic and secondary causes of severe HDL deficiency and cardiovascular disease

Abstract

We assessed secondary and genetic causes of severe HDL deficiency in 258,252 subjects, of whom 370 men (0.33%) and 144 women (0.099%) had HDL cholesterol levels <20 mg/dl. We excluded 206 subjects (40.1%) with significant elevations of triglycerides, C-reactive protein, glycosylated hemoglobin, myeloperoxidase, or liver enzymes and men receiving testosterone. We sequenced 23 lipid-related genes in 201 (65.3%) of 308 eligible subjects. Mutations (23 novel) and selected variants were found at the following gene loci: <i>1</i>) <i>ABCA1</i> (26.9%): 2 homozygotes, 7 compound or double heterozygotes, 30 heterozygotes, and 2 homozygotes and 13 heterozygotes with variants rs9282541/p.R230C or rs111292742/c.-279C>G; <i>2</i>) <i>LCAT</i> (12.4%): 1 homozygote, 3 compound heterozygotes, 13 heterozygotes, and 8 heterozygotes with variant rs4986970/p.S232T; <i>3</i>) <i>APOA1</i> (5.0%): 1 homozygote and 9 heterozygotes; and <i>4</i>) <i>LPL</i> (4.5%): 1 heterozygote and 8 heterozygotes with variant rs268/p.N318S. In addition, 4.5% had other mutations, and 46.8% had no mutations. Atherosclerotic cardiovascular disease (ASCVD) prevalence rates in the <i>ABCA1</i>, <i>LCAT</i>, <i>APOA1</i>, <i>LPL</i>, and mutation-negative groups were 37.0%, 4.0%, 40.0%, 11.1%, and 6.4%, respectively. Severe HDL deficiency is uncommon, with 40.1% having secondary causes and 48.8% of the subjects sequenced having <i>ABCA1</i>, <i>LCAT</i>, <i>APOA1</i>, or <i>LPL</i> mutations or variants, with the highest ASCVD prevalence rates being observed in the <i>ABCA1</i> and <i>APOA1</i> groups.