Ser_447stopMutation in Lipoprotein Lipase Is Associated With Elevated HDL Cholesterol Levels in Normolipidemic Males

Abstract

This report describes the association between a frequent mutation in the lipoprotein lipase (LPL) gene and HDL cholesterol levels. It concerns a previously described defect that predicts a premature truncation of the LPL protein (447stop). We determined the frequency of this mutation in three groups of healthy men with low-, middle-, and upper-decile HDL cholesterol. The number of carriers of the 447stop allele was significantly greater in the high HDL group than in either the groups with normal HDL (P = .017) or low HDL (P < .0001). Additional functional assessment of this mutation did not reveal distinct differences between wild-type LPL and the LPL447stop protein. In conclusion, we have shown that the 447stop mutation is associated with increased HDL cholesterol in healthy Dutch males, although the underlying mechanism remains to be elucidated. Because HDL cholesterol is strongly inversely related with CAD, this genotype might be of potential benefit to its carriers.

Effects of hepatic lipase gene promoter nucleotide variations on serum HDL cholesterol concentration in the general Japanese population

“…The LPL S447X polymorphism has been associated with higher LPL activity, lower TG, and higher HDL-C levels in several studies (Wittrup et al 1999;Kuivenhoven 1997), which is compatible with the higher LPL activity of S447X in a transfection study (Kozaki et al 1993;Zhang et al 1996). However, that association was not found in this study, probably because of the relatively small sample size.…”

“…D442G and IVS14 ϩ 1G Ͼ A of the CETP gene were determined as described elsewhere (Inazu et al 1994). The S447X polymorphism of the LPL gene was determined using MnlI (Daiichi Chemicals) digestion, as described by Kuivenhoven et al (1997). The HL promoter Ϫ250G/A polymorphism was determined using DraI (Toyobo, Tokyo, Japan) digestion, as described by Zambon et al (1998).…”

Functional significance of lipoprotein lipase HindIII polymorphism associated with the risk of coronary artery disease

“…Compared to the wild type, the LPL activity associated with the X447 mutation was higher in one, lower in another, but comparable in three studies [reviewed in 22]. In association studies, although the X447 allele has been reported to be associated with a favorable lipid profile in some studies [7][8]22] the results have not been confirmed in other studies [15]. Similarly, the association of the S447X polymorphism with CAD is inconsistent [10][11][12][13][14][15][16][17][18].…”

“…Several common LPL genetic variants have been widely studied, and among them HindIII in intron 8 (T→G at position 481), and S447X in exon 9 are of particular interest because of their common occurrence (25% and 9% of the less common alleles, respectively in most populations) and their associations with plasma lipid profile [6][7][8][9][10][11] and susceptibility to CAD [10][11][12][13][14][15] in several studies, although some inconsistent results have also been reported [16][17][18]. Since the HindIII polymorphism is located in the middle of intron 8, it is not considered to be functional but rather in linkage disequilibrium with a putative functional variant.…”

Study of Common Genetic Variant S447X in Lipoprotein Lipase and Its Association with Lipids and Lipoproteins in Type 2 Diabetic Patients

“…Kuivenhoven et al [32] found significantly greater number of carriers of the S447X in the high HDL-C group than in either the groups with normal or low HDL-C.…”