High baseline serum total and LDL cholesterol levels are associated with MDR1 haplotypes in Brazilian hypercholesterolemic individuals of European descent

Abstract

The MDR1 gene encodes the P-glycoprotein, an efflux transporter with broad substrate specificity. P-glycoprotein has raised great interest in pharmacogenetics because it transports a variety of structurally divergent drugs, including lipid-lowering drugs. The synonymous single-nucleotide polymorphism C3435T and the nonsynonymous single-nucleotide polymorphism G2677T/A in MDR1 have been indicated as potential determinants of variability in drug disposition and efficacy. In order to evaluate the effect of G2677T/A and C3435T MDR1 polymorphisms on serum levels of lipids before and after atorvastatin administration, 69 unrelated hypercholesterolemic individuals from São Paulo city, Brazil, were selected and treated with 10 mg atorvastatin orally once daily for four weeks. MDR1 polymorphisms were analyzed by PCR-RFLP. C3435T and G2677T polymorphisms were found to be linked. The allelic frequencies for C3435T polymorphism were 0.536 and 0.464 for the 3435C and 3435T alleles, respectively, while for G2677T/A polymorphism allele frequencies were 0.580 for the 2677G allele, 0.384 for the 2677T allele and 0.036 for the 2677A allele. There was no significant relation between atorvastatin response and MDR1 polymorphisms (repeated measures ANOVA; P > 0.05). However, haplotype analysis revealed an association between T/T carriers and higher basal serum total (TC) and LDL cholesterol levels (TC: 303 ± 56, LDL-C: 216 ± 57 mg/dl, respectively) compared with non-T/T carriers (TC: 278 ± 28, LDL-C: 189 ± 24 mg/dl; repeated measures ANOVA/Tukey test; P < 0.05). These data indicate that MDR1 polymorphism may have an important contribution to the control of basal serum cholesterol levels in Brazilian hypercholesterolemic individuals of European descent.

Frequency of Common Variants in Genes Involved in Lipid-Lowering Response to Statins in Chilean Subjects with Hypercholesterolemia

“…The results are similar to the frequencies observed by Wielandt et al (2004) in Mapuche and Mestizo ethnicities of our country, having allelic frequencies of 0.35 and 0.33, respectively. Similarly, in Brazilian hypercholesterolemic subjects, the frequency was 0.47 for T allele (Rodrigues et al, 2005). In addition, the frequency found in our study, for the T allele of the variant 3435C> T is similar to that observed in Asian population such as Koreans (0.37) (Yi et al, 2004), higher in Rapanui populations (0.75) (Wielandt et al), and differs significantly from that observed in Afro-Americans (0.21) (Kajinami et al, 2004b), Africans (0.17), European Caucasian (0.52) (Ameyaw et al, 2001) and Oceania population (0.53) (Roberts et al, 2002).…”

“…This includes genes relevant to metabolizing enzymes such a CYP3A4 and CYP3A5 gene (Lee et al, 2002), transport protein MDR1 (ABCB1) gene (Ayrton & Morgan, 2001), cholesterol biosynthesis (HMGCR). In these studies, different common variants were identified -260A>G (CYP3A4) (Kajinami et al, 2004a), 6986A>G (CYP3A5) (Kim et al, 2007) and 3435C>T (ABCB1 or MDR1) (Rodrigues et al, 2005) which were associated to a possible response variation and with efficacy of lipid-lowering therapy. CYP3A5*3 allele, was found to cause alternative splicing and protein truncation, resulting in the absence of functional CYP3A5 from liver tissue (Kuehl et al, 2001).…”

“…The integrity of the genomic DNA was evaluated by electrophoresis in a 1.5% agarose gel. The 3535C>T (ABCB1), -290A>G (CYP3A4) and 6986A>G (CYP3A5) gene polymorphisms were detected using polymerase chain reaction followed by restriction fragment length polymorphism (PCR-RFLP) in according to conditions previously described (Cavalli et al, 2001;Rodrigues et al, 2005;Kim et al). As positive control a homozygous sample for each variant was included.…”

The role of Multidrug Resistance-1 (MDR1) variants in response to atorvastatin among Jordanians

“…For example, in a study from USA, common variants of MDR1 gene such as the C3435T, were associated with a smaller reduction in LDL and with a larger increase in HDL levels, relative to variant allele carriers (Kajinami et al 2004). However, other studies among Brazilian of European descents and USA populations, found no significant relation between atorvastatin response and MDR1 C3435T polymorphism (Mega et al 2009;Rodrigues et al 2005). In the current study, we examined the influence of three common MDR1 gene variants on lipid response to atorvastatin treatment among Jordanians.…”

Effect of Genes Slco1b1 and Mdr1 Polymorphism on Atorvastatin Pharmacokinetics and Pharmacodynamics in Patients With Primary Hypercholesterolemia: Results of Pilot Pharmacogenetics Study

“…У носителей этого аллельного варианта (как гетерозигот, так и гомозигот) наблюдается сниже-ние экспрессии гена MDR1, что может приводить к сни-жению количества гликопротеина-Р в печени, кишеч-нике, почках и т.д. Данные некоторых исследований по-зволяют предположить, что полиморфизм гена MDR1 существенно не влияет на эффективность аторвастатина [9,10], хотя этот вопрос остается открытым.…”