Genetic Etiology of Isolated Low HDL Syndrome

Abstract

Objective-We have used a multitiered approach to identify genetic and cellular contributors to high-density lipoprotein (HDL) deficiency in 124 human subjects. Methods and Results-We resequenced 4 candidate genes for HDL regulation and identified several functional nonsynonymous mutations including 2 in apolipoprotein A-I (APOA1), 4 in lecithin:cholesterol acyltransferase (LCAT), 1 in phospholipid transfer protein (PLTP), and 7 in the ATP-binding cassette transporter ABCA1, leaving 88% (110/124) of HDL deficient subjects without a genetic diagnosis. Cholesterol efflux assays performed using cholesterol-loaded monocyte-derived macrophages from the 124 low HDL subjects and 48 control subjects revealed that 33% (41/124) of low HDL subjects had low efflux, despite the fact that the majority of these subjects (34/41) were not carriers of dysfunctional ABCA1 alleles. In contrast, only 2% of control subjects presented with low efflux (1/48). In 3 families without ABCA1 mutations, efflux defects were found to cosegregate with low HDL. Conclusions-Efflux defects are frequent in low HDL syndromes, but the majority of HDL deficient subjects with cellular cholesterol efflux defects do not harbor ABCA1 mutations, suggesting that novel pathways contribute to this phenotype.

Genetic causes of high and low serum HDL-cholesterol

“…Nonsynonymous variants were found in 25% of the cases and functional variants in 12% of the cases ( 31 ). Differences in selection criteria and populations may explain the small difference in occurrence of coding variants between the studies.…”

“…FHA is a common fi nding in patients with premature CAD ( 2,30 ). The metabolic etiology in many cases appears to be accelerated catabolism of HDL and its apolipoproteins ( 21 ), and some subjects, but not all, are characterized by small, lipid-poor HDL particles and defective lipid effl ux ( 31 ). FHA was previously considered to be a dominant disorder due to mutations in the ABCA1 gene in some families and of unknown genes in other families ( 32,33 ).…”

“…This may be partially explained by its pattern of expression, suggesting functions in organs such as brain, lung, and the gonads ( 126 ). The gene was screened for sequence variants in low HDL-C population in two independent studies, in 124 individuals with HDL-C levels below the 10 th percentile for age and sex ( 31 ) and in 276 subjects below the ‫ف‬ 20 th percentile for age and sex, as well as in 364 matched controls ( 127 ). Mutations in PLTP were uncommon in these low HDL-C populations.…”

Fibroblast cholesterol efflux to plasma from metabolic syndrome subjects is not defective despite low high-density lipoprotein cholesterol

“…One study in MetS subjects has demonstrated a normal potential of individual skin fibroblasts, a cell system that expresses ABCA1 but hardly any SR-BI (11,12,20,21), to transport cholesterol to purified apo A-I, acting as a cholesterol acceptor (22). On the other hand, cholesterol efflux from monocyte-derived macrophages to apo A-I is defective in a considerable number of subjects with isolated low HDL cholesterol, even in the absence of mutations in ABCA1 (23). Using Fu5AH cells, which express SR-BI but no ABCA1 (11,12), cholesterol efflux to serum or plasma is maintained in hypertriglyceridemic (24) and insulinresistant subjects (25).…”

Beyond the Genetics of HDL: Why Is HDL Cholesterol Inversely Related to Cardiovascular Disease?

“…Also in individuals that were referred to the clinic because of extreme levels of HDL cholesterol, resequencing studies of candidate genes only provided satisfying clues in a minority of the subjects studied (Candini et al 2010;Holleboom et al 2011a, b;Kiss et al 2007). It may be noted, however, that most studies conducted thus far focused only on APOAI, LCAT, and ABCA1 leaving ample room for large-effect variants in other genes.…”