Common Variants ofHMGCR, CETP, APOAI, ABCB1, CYP3A4, andCYP7A1Genes as Predictors of Lipid-Lowering Response to Atorvastatin Therapy

Abstract

There is interindividual variation in lipid-lowering response to statins. The objective of this study was to investigate whether common variation in genes involved in lipid and statin metabolism modify the effect of statins on serum total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), and high-density lipoprotein-cholesterol concentration in coronary artery disease (CAD) patients. We studied the association between 18 single-nucleotide polymorphisms (SNPs) in six genes (HMGCR, CETP, APOAI, ABCB1, CYP3A4, CYP7A1) in response to atorvastatin therapy (20 mg/day) in 265 newly diagnosed CAD patients using multivariable adjusted general linear regression. Variant alleles of ABCB1 (-41A/G), HMGCR SNP29 G/T, rs5908A/G, rs12916C/T, and CYP7A1-204A/C polymorphisms were significantly associated with attenuated LDL-C reduction and variant alleles of CETP TaqI, -629C/A, and APOAI PstI polymorphisms were associated with higher increase in high-density lipoprotein-cholesterol. A three-loci interaction model consisting of CYP7A1rs892871AA/APOAIPstIP1P1/HMGCR rs12916CT was a better predictor for LDL-C lowering, when compared with single polymorphisms analysis on statin response. Variant genotypes of APOAI -2500C/T, CETP 405I/V, and ABCB1 3435C/T showed higher risk of myocardial infarction events (p < 0.05) in a 1-year follow-up of CAD patients. These results suggest that SNPs in lipid and statin pathway genes are associated with reduced LDL-C lowering by statins and identify individuals who may be resistant to maximal LDL-C lowering by statins.

Frequencies of Genetic Polymorphisms of the Cholesterol and Statin Metabolic Pathway Genes among Healthy South Indian Tamil Population

“…24 In a study by Poduri et al, in North Indian population, the variant genotypes of HMGCR rs17238540 was associated with significantly higher LDL-C levels after atorvastatin therapy compared to wild type. 25 However, in a study by Thompson et al, this SNP was not associated with response to atorvastatin. 21 In few studies, HMGCR rs17238540 was not associated with baseline lipid values.…”

“…18,23,24 In the multi-ethnic study of atherosclerosis the HMGCR haplotypes, 26 and these genotypes among North Indians were associated with baseline lipid levels respectively. 25 It was also observed that the HMGCR rs17238540 might negate some of the observed pleiotropic effects of statins, such as improved endothelial function, decreased platelet aggregability and reduced vascular inflammation and was also found to be associated with stroke risk in the EPICNorfolk study. 27 The HMGCR rs12916 locus has been associated with total cholesterol and LDL-C levels among Europeans as well as East Asians and South Asians in a genome wide study.…”

“…28 In candidate gene studies the mean percentage reduction in LDL-C with HMGCR rs12916 polymorphisms among Chinese were found to be highest for homozygous variant, least for wild genotype and intermediate for heterozygous individuals after treatment with statins 29 while, studies among North Indians revealed that variant genotypes of this polymorphisms were responsible for poor response to atorvastatin in terms of LDL-C lowering. 25 Given the high prevalence of this genetic polymorphism among Tamilians, it would be of interest to determine the effect of this polymorphism on the lipid levels in our population. LDL receptor gene (LDLR) is a commonly studied genetic locus for dyslipidemias.…”

A novel CYP7A1 polymorphism is associated with the low-density lipoprotein cholesterol response to atorvastatin

“…Previous pharmacogenetics studies aiming at evaluating the potential contribution of CYP7A1 polymorphisms to the observed variability in response to atorvastatin therapy have accumulated evidence of a causal relationship between them. In Caucasians, SNP rs3808607 (A-240C) has been reported to be associated with plasma LDL cholesterol level [16] and LDL cholesterol lowering reduction in response to atorvastatin [12,13]. Besides, three-loci interaction comprising of CYP7A1(rs8192871AA)/APOAI(PstP1P1)/HMGCR (rs12916CT) was found to be associated with a maximum decrease in LDL cholesterol levels.…”

“…Therefore, the gene CYP7A1 was chosen as a major candidate gene to investigate the individual sensitivity response to atorvastatin. At present, several studies have reported that CYP7A1 polymorphisms influence the LDL cholesterol-lowering response to atorvastatin [12][13][14][15], such as the CYP7A1 A-204C*A in Caucasians and rs8192870*T in Chineses have a greater reduction in LDL cholesterol level response to atorvastatin as compared with variant allele-carrying genotype. Above information have urged us to research optimal atorvastatin treatment options, which aims at maximizing reduction of LDL cholesterol at the risk of minimal adverse effects.…”