ATP binding cassette transporter G5 and G8 genotypes and plasma lipoprotein levels before and after treatment with atorvastatin

Abstract

The mechanisms responsible for interindividual variation in response to statin therapy remain uncertain. It has been shown that hepatic cholesterol synthesis is associated with ATP binding cassette transporter G5 and G8 (ABCG5/8) activities. To test the hypothesis that genetic variation in ABCG5/8 might influence the plasma lipid response to statin therapy, we examined five nonsynonymous polymorphisms at the ABCG5/8 loci (Q604E, D19H, Y54C, T400K, and A632V) in 338 hypercholesterolemic patients treated with 10 mg atorvastatin. In carriers of the D19H variant, means of posttreatment values and adjusted percent reductions in LDL cholesterol (LDLC) were significantly lower ( P ϭ 0.028) and greater ( P ϭ 0.036) (112 mg/ dl, 39.7%) than those of noncarriers (119 mg/dl, 36.2%), respectively, while no significant difference was observed in percent reductions in total cholesterol. Stepwise multiple regression analysis revealed significant and independent associations with absolute or percent reduction between D19H genotype and posttreatment LDL cholesterol levels. The other polymorphisms were not significantly associated with treatment effects. These results suggest that, in patients with hypercholesterolemia, the ABCG8 D19H variant is associated with greater LDLC-lowering response to atorvastatin therapy. -Kajinami, K., M. E. Brousseau, C. Nartsupha, J. M. Ordovas, and E. J. Schaefer. ATP binding cassette transporter G5 and G8 genotypes and plasma lipoprotein levels before and after treatment with atorvastatin. In hepatocytes, the reduction in cholesterol content, in turn, causes a decrease in the secretion of apolipoprotein B (apoB)-containing lipoproteins and an upregulation of LDL receptor activity, both of which contribute to the reduction in plasma LDL cholesterol (LDLC) levels observed with statin therapy. ATP binding cassette transporters G5 and G8 (ABCG5/8) are unique proteins located in the plasma membrane, as well as in the intracellular membranes of enterocytes and hepatocytes. Mutations in the genes encoding for ABCG5/8 have been identified as the cause of sitosterolemia (9-11), a rare inborn error of metabolism characterized by elevated plasma levels of plant sterols due to hyperabsorption and decreased biliary sterol secretion. Impairment of these pathways results in a decrease of cholesterol biosynthesis in hepatocytes (12, 13), raising the possibility that interindividual variation in plasma cholesterol concentrations (14,15), and possibly the response to statin treatment, is, in part, due to variation in the ABCG5/8 genes.We, and others, have previously shown that apoE genotype is associated with the plasma lipid response to statin therapy (16,17). The present study was undertaken to test the hypothesis that polymorphisms at the ABCG5/8 gene loci are associated with plasma lipid response to statin treatment. SUBJECTS AND METHODSStudy subjects were the same patient group, in which we found the gender-specific effects of apoE genotype on plasma

Significant association of ABCG8:D19H gene polymorphism with hypercholesterolemia and insulin resistance

“…These results clearly demonstrated that the D19H polymorphism, even though it was rare, significantly contributed to an independent genetic risk of developing high total cholesterol and LDL-C levels. As reports have shown previously, this points to the fact that subjects with D19H/19H (GC or CC) variants are disposed to having a lower cholesterol absorption efficiency Hubáček et al 2004;Kajinami et al 2004aKajinami et al , 2004b. However, the cholesterol absorption efficiency of the intestine is inversely proportional to the rate of hepatic cholesterol biosynthesis.…”

“…However, subjects with D19H/19H variants were noted to exhibit greater reductions in LDL-C levels with statin treatment under the NCEP step 1 diet throughout the study. The greater response of LDL-C to statin treatment could be explained by a compensatory increase in endogenous cholesterol synthesis in subjects with D19H/19H variants compared to the D19 variant (Kajinami et al 2004a(Kajinami et al , 2004b. The discordance between our results for the serum total cholesterol and LDL-C levels in our subjects with D19H and previous results may be attributed to the following reasons: (1) the populations studied had different recruitment criteria for serum lipid levels; (2) dietary habits of different races; (3) different dietary interventions within the study period.…”

“…At the physiological level, the serum cholesterol level is maintained mainly by de novo synthesis in the liver and partially by the absorption efficiency of the intestine (Wang 2007;Davis et al 2004;Temel et al 2007). Based on the findings of Gylling et al (2004) and Kajinami et al (2004a), subjects with D19H/19H have a lower cholesterol absorption efficiency but respond more to statin treatment than D19 subjects. Upon comparing our results with those in previous reports, we rationally assumed that consuming a higher ratio of plant sterols to cholesterol in the diet may influence the relative absorption efficiency of cholesterol in subjects with D19H variants, causing a much lower cholesterol absorption and therefore increasing hepatic cholesterol biosynthesis, thus resulting in higher serum total cholesterol and LDL-C levels than those of D19 variants.…”

“…However, D19H of the ABCG8 gene, which has a frequency of less than 5%, was also chosen because of its strong correlation to cholesterol homeostasis as reported in the literature Hubáček et al 2004;Kajinami et al 2004aKajinami et al , 2004b. Five nonsynonymous polymorphisms, including Q604E (rs6720173) of the ABCG5 gene and D19H (rs11887534), C54Y (rs4148211), T400K (rs4148217) and A632V (rs6544718) of the ABCG8 gene, were chosen for genotyping (http://www.ncbi.nlm.nih.gov/).…”

Genetic Regulation of Serum Phytosterol Levels and Risk of Coronary Artery Disease

“…25 Indeed, there are published data about an association between the D19H variant and serum cholesterol levels. 26,27 Moreover, recent genome-wide studies identified an association of LDL cholesterol with proxies to D19H and the other ABCG8 variant rs4245791. 22,23 This effect could be confirmed in the present study (online-only Data Supplement Figure VI), albeit the association of D19H (and the other variants we identified) with serum cholesterol levels was only weak, and effects on phytosterols remained highly significant after normalization to cholesterol (Table) or adjustment to LDL cholesterol (online-only Data Supplement Table XVII).…”