Influence of microsomal triglyceride transfer protein promoter polymorphism −493 GT on fasting plasma triglyceride values and interaction with treatment response to atorvastatin in subjects with heterozygous familial hypercholesterolaemia

Abstract

Familial hypercholesterolaemia (FH) is an autosomal dominant disease characterized by elevated levels of low-density lipoprotein-cholesterol (LDL-C). Phenotypic expression is highly variable, being influenced by diet, age, gender, body mass index, apolipoprotein E genotype and type of LDL-receptor gene mutation. Microsomal triglyceride (TG) transfer protein (MTP) is a protein involved in lipid metabolism. Polymorphism MTP -493 GT has been shown to modulate lipid levels in several populations. To analyse the effect of this polymorphism in the lipid phenotype expression of FH and treatment response, we studied a sample of 222 Spanish FH patients, of whom 147 were studied before and after treatment with 20 mg of atorvastatin daily during 6 weeks. The variant was analysed by polymerase chain reaction amplification and single-strand confirmation polymorphism. Treatment reduced LDL-C, total cholesterol and TGs. Baseline fasting TGs and very-low-density lipoprotein cholesterol levels were lower in female T allele carriers (TG: 111+/-51 mg/dl GG, 89+/-35 mg/dl GT, 83+/-26 mg/dl TT, P=0.022; very-low-density lipoprotein cholesterol: 24+/-13 mg/dl GG, 16+/-5 mg/dl GT, 17+/-5 mg/dl TT, P=0.018). Triglyceride response to atorvastatin was modulated by this polymorphism in men (P=0.009), but not in women, although differences between genotypes were maintained after treatment. In conclusion, the MTP -493 GT polymorphism modulates pre- and post-treatment plasma TG values of FH in Spanish subjects in a gender-specific way. Other environmental and genetic factors likely also modulate this response.

Functional analysis of promoter variants in the microsomal triglyceride transfer protein (MTTP) gene

“…Since oleate [Qiu et al, 2005] as well as polyunsaturated fatty acids [Sekiya et al, 2003] reduce SREBP-1 activity, the resulting abrogate suppression of MTTP could be more effective in À164T than in À164C carriers. This possible diet-gene interaction may explain conflicting results of association studies [Bernard et al, 2000;Berthier et al, 2004;Bjorn et al, 2000;Chen et al, 2003;Couture et al, 2000;Garcia-Garcia et al, 2005;Herrmann et al, 1998;Juo et al, 2000;Karpe et al, 1998;Ledmyr et al, 2002Ledmyr et al, , 2004Lundahl et al, 2002Lundahl et al, , 2006Phillips et al, 2004;Rubin et al, 2006;St-Pierre et al, 2002;Stan et al, 2005;Yamada et al, 2006] and should be tested in intervention studies or case-control cohorts. Notably, polymorphic sites in the SREBP1 locus are associated with type 2 diabetes and obesity [Eberle et al, 2004;Laudes et al, 2004].…”

“…In humans, loss-of-function mutations of MTTP resulted in hypo-and abetaliproteinemia associated with hypocholesterolemia, mild fat malabsorption, and hepatic steatosis [Linton et al, 1993;Scanu et al, 1974]. The physiological importance of MTTP was also emphasized by association studies, which provide evidence that a haplotype, defined by the minor alleles of polymorphisms Ile128Thr, À164T4C, and À493G4T, is associated with a slight decrease in LDL cholesterol and other traits of the metabolic syndrome [Bernard et al, 2000;Bjorn et al, 2000;Garcia-Garcia et al, 2005;Karpe et al, 1998;Ledmyr et al, 2002Ledmyr et al, , 2004Lundahl et al, 2006;Phillips et al, 2004;Rubin et al, 2006;St-Pierre et al, 2002;Yamada et al, 2006]. Here we provided functional investigations of MTTP promoter haplotypes composed of polymorphisms À164T4C, À400A4T, and À493G4T in human hepatic and intestinal cells.…”

“…Since MTTP is a key protein in lipid metabolism, associations between MTTP variants and lipid parameters or related phenotypes have been investigated. There is evidence from several studies that the minor alleles of linked [Ledmyr et al, 2002] promoter rs1800591:G4T/rs1800804:T4C (À493G4T/ À164T4C; numbering relative to transcriptional start site) and rs3816873:T4C (Ile128Thr) polymorphisms correspond to lower LDL levels and protect against other traits of the metabolic syndrome [Bernard et al, 2000;Bjorn et al, 2000;Garcia-Garcia et al, 2005;Karpe et al, 1998;Ledmyr et al, 2002Ledmyr et al, , 2004Lundahl et al, 2006;Phillips et al, 2004;Rubin et al, 2006;St-Pierre et al, 2002;Yamada et al, 2006]. No associations or opposite associations were found in other studies [Berthier et al, 2004;Chen et al, 2003;Couture et al, 2000;Herrmann et al, 1998;Juo et al, 2000;Lundahl et al, 2002;Stan et al, 2005].…”

Sex-specific association of fatty acid binding protein 2 and microsomal triacylglycerol transfer protein variants with response to dietary lipid changes in the 3-mo Medi-RIVAGE primary intervention study

“…The TT subjects, as a whole, showed a significantly higher response in reducing fasting cholesterol, apo B-48, TRL phospholipids, 16:0, and 18:1 and in increasing 18:2 values, but only TT men showed a major improvement of the Framingham score. This sex-related sensitivity to diet can be linked to the recent finding that, in men with familial hypercholesterolemia but not in women, this polymorphism modulated after-treatment plasma triacylglycerol values (32).…”

Clinical implications of pharmacogenomics of statin treatment

“…Single studies have reported that a promoter variant in MTP is associated with triglyceride response and recurring risk of coronary events, an LPL variant may alter TC or HDLC response, and an LIPC variant may alter HDLC response. [79][80][81][82][83][84][85] Removal of cholesterol from peripheral cells requires active transport and is mediated by ABCA1. Preliminary pharmacogenetic analysis suggests that an ABCA1 haplotype may attenuate ApoAI response to statin treatment.…”