Molecular Genetic Study of Finns With Hypoalphalipoproteinemia and Hyperalphalipoproteinemia

Abstract

—In an attempt to identify genetic factors underlying extreme alterations of serum HDL cholesterol (HDL-C) concentrations, we examined two probands with HDL-C levels 230Arg (LCAT_Fin ) mutation, and the second was homozygous for an Arg³⁹⁹Cys mutation we described previously. Transient expression of the mutant LCAT_Fin cDNA in COS cells disclosed markedly diminished LCAT enzyme activity. In the low–HDL-C group of men (n=156), 8 carriers of LCAT_Fin and 1 carrier of the LCAT Arg³⁹⁹Cys were identified. In addition, the frequency of the lipoprotein lipase (LPL) Asn²⁹¹Ser mutation was significantly (P<.05) higher in the low–HDL-C group (4.8%) than in the high–HDL-C group (1.6%). In addition, we identified 1 carrier of the intron 14G→A mutation of cholesterol ester transfer protein (CETP) in the high–HDL-C group and subsequently demonstrated cosegregation of the mutant allele with elevated HDL-C levels in the proband’s family. In conclusion, we have identified a novel LCAT gene Gly²³⁰Arg mutation (LCAT_Fin), which, together with the LPL Asn²⁹¹Ser mutation, represents a relatively common genetic cause of diminishing HDL-C levels, at least among Finns. This article also reports occurrence of a CETP mutation in subjects having non-Japanese roots.