Dataset Information

The frequency of SLCO1B1*5 polymorphism genotypes among Russian and Sakha (Yakutia) patients with hypercholesterolemia.

ABSTRACT: INTRODUCTION:Statins are the most commonly prescribed medicines for treatment of hypercholesterolemia. At the same time, up to 25% of patients cannot tolerate or have to discontinue the statin therapy due to statin-induced myopathy. In a majority of cases, statin-induced myopathy is attributed to SLCO1B1 gene polymorphism. The strongest association between statin-induced myopathy and SLCO1B1 gene polymorphism was described for simvastatin. Our research was focused on the frequency of SLCO1B1*5 genetic variant in the Russian population and in the native population of Sakha (Yakutia). MATERIALS AND METHODS:A total of 1,071 hyperlipidemic Russian and 76 hyperlipidemic Sakha (Yakutian) patients were included in the study. Genotypes of SLCO1B1*5 (c.521T>C, rs4149056) were determined with polymerase chain reaction amplification. The results of our study were compared with data about hyperlipidemic patients in available publications. RESULTS:In the Russian population 665 (62%) patients had TT genotype of SLCO1B1*5, 346 (32%) patients had TC genotype, and in 60 patients (6%) CC variant was found (Hardy-Weinberg's chi-square test was 3.1 P=0.21). In comparison with Brazil, France, the People's Republic of China, Japan, and the native population of Sakha (Yakutia), C-allele, which causes an increased risk of statin-induced myopathy, was found significantly more often in the Russian population. In the native population of Sakha (Yakutia) SLCO1B1 polymorphism was TT - 62 (82%), TC - 11 (14%), CC - 3 (4%) (Hardy-Weinberg's chi-square test was 5.13 P=0.077). In comparison with data from Brazil, France, the People's Republic of China, and Japan, C-allele frequency in the Sakha (Yakutian) population was not significantly different. CONCLUSION:Thus, we have studied the incidence of pathologic SLCO1B1 c.521C-allele in Russian and Sakha hyperlipidemic patients. The presence of SLCO1B1 C-allele in patients with hyperlipidemia forces us to be more careful in hypolipidemic drug prescription, especially statins, according to a higher risk of statin-induced myopathy development. The fact that SLCO1B1 C-allele is rarer among Sakha patients, could be interesting from the point of studying adverse drug effects frequency and statins' effectiveness.

SUBMITTER: Sychev DA

PROVIDER: S-EPMC4889090 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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The frequency of SLCO1B1*5 polymorphism genotypes among Russian and Sakha (Yakutia) patients with hypercholesterolemia.

Sychev Dmitrij Alekseevitch DA Shuev Grigorij Nikolaevich GN Chertovskih Jana Valer'evna JV Maksimova Nadezhda Romanovna NR Grachev Andrej Vladimirovich AV Syrkova Ol'ga Aleksandrovna OA

Pharmacogenomics and personalized medicine 20160525

<h4>Introduction</h4>Statins are the most commonly prescribed medicines for treatment of hypercholesterolemia. At the same time, up to 25% of patients cannot tolerate or have to discontinue the statin therapy due to statin-induced myopathy. In a majority of cases, statin-induced myopathy is attributed to SLCO1B1 gene polymorphism. The strongest association between statin-induced myopathy and SLCO1B1 gene polymorphism was described for simvastatin. Our research was focused on the frequency of SLC ...[more]

PMID: 27307760

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Project description:BACKGROUND:Sakha--an area connecting South and Northeast Siberia--is significant for understanding the history of peopling of Northeast Eurasia and the Americas. Previous studies have shown a genetic contiguity between Siberia and East Asia and the key role of South Siberia in the colonization of Siberia. RESULTS:We report the results of a high-resolution phylogenetic analysis of 701 mtDNAs and 318 Y chromosomes from five native populations of Sakha (Yakuts, Evenks, Evens, Yukaghirs and Dolgans) and of the analysis of more than 500,000 autosomal SNPs of 758 individuals from 55 populations, including 40 previously unpublished samples from Siberia. Phylogenetically terminal clades of East Asian mtDNA haplogroups C and D and Y-chromosome haplogroups N1c, N1b and C3, constituting the core of the gene pool of the native populations from Sakha, connect Sakha and South Siberia. Analysis of autosomal SNP data confirms the genetic continuity between Sakha and South Siberia. Maternal lineages D5a2a2, C4a1c, C4a2, C5b1b and the Yakut-specific STR sub-clade of Y-chromosome haplogroup N1c can be linked to a migration of Yakut ancestors, while the paternal lineage C3c was most likely carried to Sakha by the expansion of the Tungusic people. MtDNA haplogroups Z1a1b and Z1a3, present in Yukaghirs, Evens and Dolgans, show traces of different and probably more ancient migration(s). Analysis of both haploid loci and autosomal SNP data revealed only minor genetic components shared between Sakha and the extreme Northeast Siberia. Although the major part of West Eurasian maternal and paternal lineages in Sakha could originate from recent admixture with East Europeans, mtDNA haplogroups H8, H20a and HV1a1a, as well as Y-chromosome haplogroup J, more probably reflect an ancient gene flow from West Eurasia through Central Asia and South Siberia. CONCLUSIONS:Our high-resolution phylogenetic dissection of mtDNA and Y-chromosome haplogroups as well as analysis of autosomal SNP data suggests that Sakha was colonized by repeated expansions from South Siberia with minor gene flow from the Lower Amur/Southern Okhotsk region and/or Kamchatka. The minor West Eurasian component in Sakha attests to both recent and ongoing admixture with East Europeans and an ancient gene flow from West Eurasia.

Project description:BackgroundThe efficiency and safety of drug therapy depends on the peculiarities of functioning of the P450 cytochrome group and transporting proteins. There are significant differences for single-nucleotide polymorphism (SNP) frequency.Materials and methodsWe studied the peculiarities of P450 cytochrome polymorphisms, SLCO1B1 transporting protein, and P-glycoprotein carriage in healthy volunteers in the Nanai ethnic group living in Russia, and compared them to the carriage of SNPs in the Russian population according to literature data.ResultsAfter performing the real-time polymerase chain reactions on the samples from 70 healthy volunteers from the Nanai group, for the CYP2C9*2C430T polymorphism we determined 70 CC-genotype carriers. As for the CYP2C9*3A1075C polymorphism, we found 62 AA-genotype carriers and eight AC-genotype carriers. For the CYP2C19*2G681A polymorphism, we determined 39 GG-genotype carriers and 28 GA-genotype carriers, for the CYP2C19*3G636A polymorphism 58 GG-genotype carriers and 12 GA-genotype carriers, and for the CYP2C19*17C806T polymorphism 67 CC-genotype carriers and three CT-genotype carriers. For the CYP2D6*4G1846A polymorphism, the GG genotype had 68 carriers, and the GA genotype two carriers. For the ABCB1*6C3435T polymorphism, there were 19 CC-genotype carriers and 39 CT-genotype carriers. For the SLCO1B1*5T521C polymorphism, the TT genotype had 41 carriers and the CT genotype 25 carriers. The distribution of genotypes fitted the Hardy-Weinberg equilibrium for all the polymorphisms, except those of CYP2C9*2. There were also significant differences in allele frequencies for some polymorphisms between the Nanais and the Russians.ConclusionIn the Nanai population, there are polymorphisms connected with the decrease in safety and efficiency of drug therapy. Studying the ethnic differences might influence the determination of priority in the introduction of pharmacogenetic tests in clinical practice in different regions of Russia.

Project description:UnlabelledPatients with familial hypercholesterolemia (FH) may be at increased risk for statin-associated muscle symptoms because they require long-term treatment with high-intensity statin therapy. We sought to determine (1) whether other predisposing factors, including the well-known genetic variant associated with statin-associated muscle symptoms-solute carrier organic anion transporter family, member 1B1 (SLCO1B1) rs4149056-also increase the risk of statin-associated muscle symptoms in FH patients, and (2) the natural history and management for FH patients with statin-associated muscle symptoms.MethodsWe queried electronic records (2004-2014) of 278 genetically screened FH patients (113 men, 165 women; mean [SD] pretreatment low-density lipoprotein cholesterol [LDL-C] 259 [72] mg/dL) recruited from lipid clinics in the Dallas, TX, area from 2004 to 2014. Statin-associated muscle symptoms were defined as muscle symptoms arising while taking a statin and interrupting therapy.ResultsThe risk of muscle symptoms was associated with age (odds ratio 1.6 [95% CI 1.2-2.2]), body mass index in non-African Americans (0.90 [0.83-0.97]), and hypertension (0.4 [0.2-0.9]). Simvastatin was the most commonly used statin, and it was the statin most associated with muscle symptoms. Among FH patients with muscle symptoms, 41% (n = 40) reestablished statin therapy ("eventually tolerant") and 29% (n = 28) never reestablished statin therapy ("never tolerant"). Rosuvastatin (43%) and pravastatin (30%) were the most common eventually tolerated statins, and eventually tolerant patients achieved lower treated LDL-C levels (eventually tolerant 127 vs never tolerant 192 mg/dL, P < .001). Never tolerant patients also developed muscle symptoms on nonstatins (16% vs 50%, P = .003). SLCO1B1 rs4149056 genotyping revealed 224 wild-type patients (TT) and 49 heterozygotes (TC). SLCO1B1 genotype was not associated with the risk of statin-associated muscle symptoms (odds ratio 1.40 [95% CI 0.74-2.64]).ConclusionAge, not SLCO1B1 rs4149056 genotype, was the strongest risk factor for statin-associated muscle symptoms in FH patients. After developing muscle symptoms, many patients reestablished statin therapy and achieved significant LDL-C reductions. Overall, 10% of all FH patients had statin-associated muscle symptoms and never reestablished statin therapy. Such patients developed muscle symptoms even on nonstatin lipid-lowering drugs and continued to have elevations in LDL-C. Further insight is needed into the relationship between FH and statin-associated muscle symptoms so all FH patients can be adequately treated.

Project description:Sakha – an area connecting South and Northeast Siberia – is significant for understanding the history of peopling of Northeast Eurasia and the Americas. Previous studies have shown a genetic contiguity between Siberia and East Asia and the key role of South Siberia in the colonization of Siberia. We report the results of a high-resolution phylogenetic analysis of 701 mtDNAs and 318 Y chromosomes from five native populations of Sakha (Yakuts, Evenks, Evens, Yukaghirs and Dolgans) and of the analysis of more than 500,000 autosomal SNPs of 758 individuals from 55 populations, including 40 previously unpublished samples from Siberia. Phylogenetically terminal clades of East Asian mtDNA haplogroups C and D and Y-chromosome haplogroups N1c, N1b and C3, constituting the core of the gene pool of the native populations from Sakha, connect Sakha and South Siberia. Analysis of autosomal SNP data confirms the genetic continuity between Sakha and South Siberia. Maternal lineages D5a2a2, C4a1c, C4a2, C5b1b and the Yakut-specific STR sub-clade of Y-chromosome haplogroup N1c can be linked to a migration of Yakut ancestors, while the paternal lineage C3c was most likely carried to Sakha by the expansion of the Tungusic people. MtDNA haplogroups Z1a1b and Z1a3, present in Yukaghirs, Evens and Dolgans, show traces of different and probably more ancient migration(s). Analysis of both haploid loci and autosomal SNP data revealed only minor genetic components shared between Sakha and the extreme Northeast Siberia. Although the major part of West Eurasian maternal and paternal lineages in Sakha could originate from recent admixture with East Europeans, mtDNA haplogroups H8, H20a and HV1a1a, as well as Y-chromosome haplogroup J, more probably reflect an ancient gene flow from West Eurasia through Central Asia and South Siberia. Our high-resolution phylogenetic dissection of mtDNA and Y-chromosome haplogroups as well as analysis of autosomal SNP data suggests that Sakha was colonized by repeated expansions from South Siberia with minor gene flow from the Lower Amur/Southern Okhotsk region and/or Kamchatka. The minor West Eurasian component in Sakha attests to both recent and ongoing admixture with East Europeans and an ancient gene flow from West Eurasia.

Dataset Information

The frequency of SLCO1B1*5 polymorphism genotypes among Russian and Sakha (Yakutia) patients with hypercholesterolemia.

Publications

The frequency of SLCO1B1*5 polymorphism genotypes among Russian and Sakha (Yakutia) patients with hypercholesterolemia.

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