Haplotypes in the lipoprotein lipase gene influence high-density lipoprotein cholesterol response to statin therapy and progression of atherosclerosis in coronary artery bypass grafts

Abstract

Lipoprotein lipase (LPL) hydrolyzes circulating triglycerides (TGs). We previously showed that 3 0 -end haplotypes in the LPL gene influence atherosclerosis and insulin resistance. This study asked whether these LPL haplotypes influence response to lipid-lowering therapy among 829 subjects from the Post-Coronary Artery Bypass Graft trial. Lipid profiles were obtained at baseline and 4-5 years after treatment with lovastatin. Haplotypes were based on 12 SNPs. The fourth most frequent haplotype, 12-4, was associated with a decreased increment in high-density lipoprotein-cholesterol (HDL-C) following treatment. Haplotypes 12-6, 12-7 and 12-8 were each associated with increased HDL-C response to therapy, and haplotype 12-2 with decreased TG response. The most common haplotype, 12-1, was protective against graft worsening or occlusion. Haplotype 12-4 reduced HDL-C response to lovastatin, possibly consistent with our prior observations of this haplotype as predisposing to coronary artery disease. LPL may influence atherosclerosis risk through pleiotropic effects on each aspect of the metabolic syndrome.

Lipoprotein lipase HindIII polymorphism influences HDL-cholesterol levels in statin-treated patients with coronary artery disease

“…On the other hand, the absence of association between the LPL HindIII genotype and lipids in patients without statin treatment in our study may be related to the effect of environmental factors leading to decreased LPL activity, as observed in patients with coronary artery disease [26], and thus masking the small beneficial effect of the LPL HindIII polymorphism. Indeed, existence of an interaction between the LPL genotype and statin treatment with respect to HDL-cholesterol levels was examined in three pharmacogenetic studies, with two of the studies yielding positive findings [25,27,28]. However, in contrast to our results (i.e.…”

“…Importantly, both lovastatin and fluvastatin have failed to significantly increase LPL activity [24,29,30]. Thus, the observed lipid changes in the studies involving lovastatin and fluvastatin may be attributable to mechanisms of statin action other than interaction with LPL [25]. On the other hand, for simvastatin, which was used by 74% of the statin-treated patients in our study, there are several lines of evidence showing its positive effect on LPL activity [19,21,22,24].…”

“…However, in contrast to our results (i.e. the highest HDL-cholesterol was in the H-H-genotype), those two pharmacogenetic studies showed a smaller increase of HDL-cholesterol levels in the carriers of the related LPL 447Ter allele during fluvastatin treatment (3% vs. 11%, P = 0.06, LCAS Study) [27] or during treatment with lovastatin in patients carrying the haplotype containing the LPL H-allele and compared with the alternative genotypes or haplotypes (Post-CABG-Trial) [25].…”

“…Although the precise mechanisms remain to be explained, several studies provide evidence for transcriptional up-regulation of the LPL gene by some statins [19,20,23]. Based on this evidence, true biological interaction between the pharmacological effect of statin and the LPL genotype with respect to HDL-cholesterol levels cannot be excluded [9,19,25]. In the present study population, a relatively small genetic effect of LPL HindIII polymorphism on plasma HDL-cholesterol level could have been more pronounced in patients on statin treatment, since it is possible that statins act synergistically with the LPL HindIII genotype to further enhance LPL activity.…”

Erratum: Statin-induced expression change of INSIG1 in lymphoblastoid cell lines correlates with plasma triglyceride statin response in a sex-specific manner

“…A number of pharmacogenetic studies have sought to identify singlenucleotide polymorphisms (SNPs) that influence LDL-C statin response using candidate-gene and genome-wide association approaches, but the findings to date account for less than 10% of the variation in statin-induced LDL-C lowering variability, [12][13][14][15][16][17][18][19][20] with variants near the apolipoprotein E (APOE) and lipoprotein, Lp(a) (LPA) genes showing some of the strongest and most replicated signals. 17,18,20 Genetic association studies of TG statin response have been even less fruitful, with two published genome-wide association studies revealing no genome-wide significant hits 15,16 and only a modest number of significant associations reported with genetic variation in candidate genes, such as lipoprotein lipase (LPL), 21 cholesteryl ester transfer protein, plasma (CETP), ATP-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1) 22 and APOE. Interestingly, the APOE locus was only associated with TG statin response in men, 23 indicating that there may be sex-specific differences in the genetic basis of TG statin response.…”