Molecular Genetic Study of Finns With Hypoalphalipoproteinemia and Hyperalphalipoproteinemia

Abstract

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 <0.2 mmol/L and subsequently screened two large cohorts of smoking men, one with very low (0.2 to 0.7 mmol/L, n=156) and the other with elevated (1.9 to 3.6 mmol/L, n=160) HDL-C levels, for the newly detected mutations as well as some other mutations proposed to affect HDL-C levels. One of the probands had corneal opacities, microalbuminuria, hypertriglyceridemia, and reduced LDL apoprotein B concentration; the other had anemia and presented with stomatocytosis in his peripheral blood. The first proband was found to be homozygous for a novel LCAT Gly 230 Arg (LCAT Fin ) mutation, and the second was homozygous for an Arg 399 Cys 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 Arg 399 Cys were identified. In addition, the frequency of the lipoprotein lipase (LPL) Asn 291 Ser 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 Gly 230 Arg mutation (LCAT Fin ), which, together with the LPL Asn 291 Ser 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.