Genetic variations and frequencies of major haplotypes in SLCO1B1 encoding the transporter OATP1B1 in Japanese subjects: SLCO1B1*17 is more prevalent than *15

A liver-specific transporter organic anion transporting polypeptide 1B1 (OATP1B1, also known as OATP-C) is encoded by SLCO1B1 and mediates uptake of various endogenous and exogenous compounds from blood into hepatocytes. In this study, 15 SLCO1B1 exons (including non-coding exon 1) and their flanking introns were comprehensively screened for genetic variations in 177 Japanese subjects. Sixty-two genetic variations, including 28 novel ones, were found: 7 in the 5'-flanking region, 1 in the 5'-untranslated region (UTR), 13 in the coding exons (9 nonsynonymous and 4 synonymous variations), 5 in the 3'-UTR, and 36 in the introns. Five novel nonsynonymous variations, 311T>A (Met104Lys), 509T>C (Met170Thr), 601A>G (Lys201Glu), 1553C>T (Ser518Leu), and 1738C>T (Arg580Stop), were found as heterozygotes. The allele frequencies were 0.008 for 1738C>T (Arg580Stop) and 0.003 for the four other variations. Arg580Stop having a stop codon at codon 580 results in loss of half of transmembrane domain (TMD) 11, TMD12, and a cytoplasmic tail, which might affect transport activity. In addition, novel variations, IVS12-1G>T at the splice acceptor site and -3A>C in the Kozak motif, were detected at 0.003 and 0.014 frequencies, respectively. Haplotype analysis using -11187G>A, -3A>C, IVS12-1G>T and 9 nonsynonymous variations revealed that the haplotype frequencies for (*)1b, (*)5, (*)15, and (*)17 were 0.469, 0.000 (not detected), 0.037, and 0.133, respectively. These data would provide fundamental and useful information for pharmacogenetic studies on OATP1B1-transported drugs in Japanese.     

Comparison of SLCO1B1 sequence variability among German, Turkish, and African populations

Background OATP1B1 is one of the key hepatocellular uptake transporters providing extraction of diverse compounds, including bile acids, xenobiotics, and a variety of drugs, from portal venous blood into the liver. Polymorphisms of the SLCO1B1 gene have been demonstrated to influence in vitro transport function and the pharmacokinetic profile of compounds. Objective The goal of our study was the comparison of SLCO1B1 gene sequence variability in three ethnic groups as a basis for future genetic association studies. Methods Eighteen exonic SLCO1B1 single nucleotide polymorphisms (SNPs) were genotyped by PCR and RFLP analysis in 300 German, 94 Turkish, and 115 African subjects. Calculation of pairwise linkage disequilibrium and estimation of population haplotype frequencies were carried out, and haplotype block structure was determined. Results Only eight genotyped SNPs (c.388A>G, c.411G>A, c.463C>A, c.521T>C, c.571C>T, c.597C>T, c.1463G>>C, c.1929A>C) were found in at least one of our German, Turkish, or African samples. A total of 12 haplotypes with a frequency ≥1% in at least one of the three populations could be inferred. Between the Caucasian and African samples, significant differences in sequence variability were observed leading to a different haplotype profile in these populations. Conclusion Our results demonstrate a high sequence variability of OATP1B1 within different popuations. In the future, distinct haplotypes should be taken into account when studying the effect of OATP1B1 on drugs in different populations.     

High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C (OATP-C, SLCO1B1)

This study aimed to characterize possible relationships between polymorphisms in the drug transporter genes organic anion transporting polypeptide-C (OATP-C, SLCO1B1), OATP-B (SLCO2B1), multidrug resistance-associated protein 2 (MRP2, ABCC2) and multidrug resistance transporter (MDR1, ABCB1) and the pharmacokinetics of pravastatin. We studied 41 healthy Caucasian volunteers who had previously participated in pharmacokinetic studies with pravastatin. Six volunteers had a very high pravastatin AUC value and were defined as outliers according to statistical criteria. The OATP-C gene was sequenced completely in all subjects, and they were also genotyped for selected single nucleotide polymorphisms (SNP) in the OATP-B, MDR1 and MRP2 genes. Of the six outliers, five were heterozygous for the OATP-C 521T>C (Val174Ala) SNP (allele frequency 42%) and three were heterozygous for a new SNP in the promoter region of OATP-C (-11187G>A, allele frequency 25%). Among the remaining 35 subjects, two were homozygous and six were heterozygous carriers of the 521T>C SNP (allele frequency 14%, P = 0.0384 versus outliers) and three were heterozygous carriers of the -11187G>A SNP (allele frequency 4%, P = 0.0380 versus outliers). In subjects with the -11187GA or 521TC genotype, the mean pravastatin AUC0-12 was 98% (P = 0.0061) or 106% (P = 0.0034) higher, respectively, compared to subjects with the reference genotype. These results were substantiated by haplotype analysis. In heterozygous carriers of *15B (containing the 388A>G and 521T>C variants), the mean pravastatin AUC0-12 was 93% (P = 0.024) higher compared to non-carriers and, in heterozygous carriers of *17 (containing the -11187G>A, 388A>G and 521T>C variants), it was 130% (P = 0.0053) higher compared to non-carriers. No significant associations were found between OATP-B, MRP2 or MDR1 polymorphisms and the pharmacokinetics of pravastatin. These results suggest that haplotypes are more informative in predicting the OATP-C phenotype than single SNPs.     

Global analysis of genetic variation in SLCO1B1

INTRODUCTION: Organic anion transporting polypeptide 1B1 (OATP1B1), encoded by the SLCO1B1 gene, mediates the hepatic uptake of endogenous compounds and xenobiotics, including drugs. The aim of this study was to investigate the diversity of the SLCO1B1 gene at the global level. MATERIALS AND METHODS: Distribution of SLCO1B1 alleles was determined in 941 individuals from 52 populations comprising Africa, the Middle East, Asia, Europe, Oceania and the Americas. DNA samples were genotyped at 12 variant sites spanning the entire gene by TaqMan 5 nuclease allelic discrimination assays. RESULTS: The frequency of the low-activity c.521T>C variant varied markedly between populations. The lowest frequencies were observed in Oceania (0.0%; 95% CI: 0.0-6.4%) and sub-Saharan Africa (1.9%; 95% CI: 0.7-4.8%), and the highest frequencies observed in American native populations (24%; 95% CI: 18-32%) and Europe (18%; 95% CI: 14-23%). Moreover, the c.521C allele (r = 0.505, p < 0.001) and the *1B (c.388G-c.521T; r = -0.405, p = 0.006) and *15 (c.388G-c.521C; r = 0.510, p < 0.001) haplotype frequencies correlated significantly with latitude in the northern hemisphere. Overall, SLCO1B1 genetic distances correlated significantly with geographic distances between populations, assuming likely routes of human migration out of Africa via five waypoints (r = 0.235, p = 0.001). SLCO1B1 diversity was generally far greater within than between populations. CONCLUSION: Functionally significant variants of SLCO1B1 are widely distributed and occur at high frequencies around the world. SLCO1B1 diversity is greater within than between populations, and genetic variation in SLCO1B1 is generally similar to that observed for other autosomal markers. However, selective pressure may have acted on SLCO1B1 during human dispersal favoring low-activity variants in the north.     

Single nucleotide polymorphisms of ABCB1 (MDR1) gene and distinct haplotype profile in a West Black African population

Objective The ABCB1 (MDR1) multidrug transporter plays a key role in determining drug bioavailability. Differences in drug response exist among different ethnic groups. However, until now, no haplotype data are available in a Black African population.Methods Exons 2, 7, 10, 11, 12, 14, 17, 21, 26, and the surrounding intronic regions were sequenced using genomic DNA from 111 Beninese subjects to examine 19 intragenic single nucleotide polymorphisms (SNPs). Linkage disequilibrium analysis and haplotypes were generated using the expectation–maximization algorithm.Results We identified 12 SNPs, 3 of which were novel: IVS9-57delA, IVS9-8T>A, 1662G>C (exon 14). The most common SNP was IVS14+38A>G. At the MRD1 locus, 53 haplotypes were inferred from the SNP data sets. The 4 SNPs, IVS6+139C>T, IVS9-44A>G, 1236C>T, and 3435C>T, showed strong linkage disequilibrium with each other, confirming the block concept. Moreover, our findings suggest that ABCB1 exonic SNPs are less frequently observed in our population than in African-Americans.Conclusion Our data are compatible with a close evolutionary relationship in Black Africans from Benin.     

Frequencies of single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide 1B1 SLCO1B1 gene in a Finnish population

Objective Organic anion transporting polypeptide 1B1 (OATP1B1) is a drug uptake transporter located at the sinusoidal membrane of hepatocytes. Our aim was to establish high-throughput genotyping assays for the major known single nucleotide polymorphisms (SNP) in the SLCO1B1 gene encoding OATP1B1 and to investigate the frequencies of SNPs and haplotypes of SLCO1B1 in a large Caucasian population.Methods Distribution of SLCO1B1 alleles was determined in 468 healthy Finnish Caucasian subjects at 11 variant sites spanning the entire gene by using allelic discrimination with TaqMan 5′ nuclease assays.Results The allelic frequencies of SLCO1B1 SNPs were 9.7% for g.−11187G>A, 0.4% for g.−11110T>G, 8.0% for g.−10499A>C, 46.2% for c.388A>G, 13.1% for c.411G>A, 13.1% for c.463C>A, 20.2% for c.521T>C, 53.2% for c.571T>C, 46.4% for c.597C>T, 4.0% for c.1929A>C and 48.8% for c.*439T>G. Altogether, 26 haplotypes were statistically inferred. The most common haplotype, with a frequency of 35.6%, contained variant allele C at position c.571, but had the reference nucleotide at all other positions investigated. The functionally significant c.521T>C SNP existed in four major haplotypes, which could be differentiated by the g.−11187G>A, g.−10499A>C and c.388A>G SNPs. The frequencies of these haplotypes were 7.9% for g.−11187G/g.−10499C/c.388G/c.521C (*16), 6.9% for AAGC (*17), 2.7% for GAAC (*5) and 2.4% for GAGC (*15).Conclusion Sequence variations of SLCO1B1 occur at high frequencies in the Caucasian population. Further studies are needed to characterise the effects of SLCO1B1 haplotypes, especially *16, *17, *15 and *5, on drug pharmacokinetics and response, and to determine the frequencies of SLCO1B1 SNPs and haplotypes in different populations.     

Genetic variations and haplotypes of UGT1A4 in a Japanese population

Nineteen genetic variations, including 11 novel ones, were found in exon 1 and its flanking region of the UDP-glucuronosyltransferase (UGT) 1A4 gene from 256 Japanese subjects, consisting of 60 healthy volunteers, 88 cancer patients and 108 arrhythmic patients. These variations include -217T>G and -36G>A in the 5'-flanking region, 30G>A (P10P), 127delA (43fsX22; frame-shift from codon 43 resulting in the termination at the 22nd codon, codon 65), 175delG (59fsX6), 271C>T (R91C), 325A>G (R109G), and 357T>C (N119N) in exon 1, and IVS1+1G>T, IVS1+98A>G and IVS1+101G>T in the following intron. Among them, 127delA and 175delG can confer early termination of translation, resulting in an immature protein that probably lacks enzymatic activity. Variation IVS1+1G>T is located at a splice donor site and thus may lead to aberrant splicing. Since we did not find any significant differences in the frequencies of all the variations among the three subject groups, the data were analyzed as one group. The allele frequencies of the novel variations were 0.006 for IVS1+101G>T, 0.004 for 30G>A (P10P) and 357T>C (N119N), and 0.002 for the 8 other variations. In addition, the two known nonsynonymous single nucleotide polymorphisms (SNPs), 31C>T (R11W) and 142T>G (L48V), were found at 0.012 and 0.129 frequencies, respectively. The SNP 70C>A (P24T), mostly linked with 142T>G (L48V) in German Caucasians, was not detected in this study. Sixteen haplotypes were identified or inferred, and some haplotypes were confirmed by cloning and sequencing. It was shown that most of 142T>G (L48V) was linked with -219C>T, -163G>A, 448T>C (L150L), 804G>A (P268P), and IVS1+43C>T, comprising haplotype *3a; haplotype *4a harbors 31C>T (R11W); 127delA (43fsX22) and 142T>G (L48V) were linked (haplotype *5a); 175delG (59fsX6) was linked with 325A>G (R109G) (*6a haplotype); and -219C>T, -163G>A, 142T>G (L48V), 271C>T (R91C), 448T>C (L150L), 804G>A (P268P), and IVS1+43C>T comprised haplotype *7a. Our results provide fundamental and useful information for genotyping UGT1A4 in the Japanese and probably Asian populations.     

ABCB1(2677T>G)和SLCO1B1(521T>C)基因多态性对阿托伐他汀降脂疗效的影响

目的：探讨新乡地区人群ABCB1（2677T>G）、SLCO1B1（521T>C）基因多态性分布及其与阿托伐他汀降脂疗效的相关性。方法：采用荧光原位杂交方法,检测120例血脂异常患者ABCB1（2677T>G）、SLCO1B1（521T>C）基因型分布;入选患者每晚服用阿托伐他汀20 mg,连续用药4周后,检测用药前后血脂水平,评价降脂疗效。结果：在新乡市中心医院的120例入选患者中,ABCB1（2677T>G）和SLCO1B1（521T>C）基因突变频率分别为70.5%和21.8%,该基因分布符合Hardy-Weinberg平衡。携带ABCB1 2677GG型患者对LDL-C的调节作用显著高于同一位点的其他基因型,而其他血脂指标未见相关性。SLCO1B1（521T>C）各基因型患者间血脂变化差异无统计学意义。结论：携带ABCB1 2677GG基因型的患者接受阿托伐他汀治疗时,降脂疗效较佳。     

Organic anion transporting polypeptide-1B1 haplotypes in Chinese patients

Aim： To detect 388G〉A and 521T〉C variant alleles in the organic anion transporting polypeptide- 1B 1 （OATP 1B 1, encoding gene SLCOIB1） gene. Methods： One hundred and eleven healthy volunteers were screened for OATP1B 1 alleles in our study. PCR-restriction fragment length polymorphism was used to identify the 388G〉A polymorphism and a 1-step tetra-primer method was developed for the determination of 521T〉C mutation. Results： The frequencies of the 388G〉A and 521T〉C variant alleles in the Chinese population were 73.4% and 14.0%, respectively. The frequencies of the SLCO1B1＊ 1b and ＊15 haplotypes were 59.9% and 14.0%, respectively. Condusion： The SLCO1B1＊1b and SLCO1B1＊15 variants are relatively common in the Chinese population. Their frequencies are similar to that in the Japanese, but significantly different from that in Caucasians and blacks.     

Rapid identification of three functionally relevant polymorphisms in the OATP1B1 transporter gene using Pyrosequencing

INTRODUCTION: Clinical evidence suggests there are three single nucleotide polymorphisms (SNPs) of the solute carrier organic anion transporter family member B1 (SLCO1B1) gene for which in vivo evidence for a functional relevance for organic anion transporter polypeptides subgroup C (OATP1B1, formerly OATP-C) has been provided. These genetic variants have been shown to lead to altered pharmacokinetics of OATP1B1 substrates, mainly pravastatin, but also the irinotecan metabolite SN-38, estrone-3-sulfate, and estradiol-17beta-glucuronide. The authors therefore developed reliable and quick screening assays to identify the SLCO1B1 SNPs -11187G>A, 388A>G and 521T>C, in order to facilitate the judgment of their clinical role and to identify allelic frequencies of SNPs and haplotypes in a Caucasian random sample. METHODS: Three simplex Pyrosequencing assays were developed and the three selected SLCO1B1 SNPs were screened for in 250 DNA samples from healthy young female and male unrelated volunteers of Caucasian ethnicity. SLCO1B1 haplotypes involving DNA positions -11187, 388 and 521 were identified by in silico haplotyping. RESULTS: A clear identification of the three single nucleotide polymorphisms in the 250 DNA samples was possible and was verified by routine implementation of 40 control samples obtained by conventional sequencing. The frequencies of the variant alleles -11187A, 388G and 521C were 0.09, 0.47 and 0.12, respectively. All observed frequencies of heterozygous of homozygous carriers of SLCO1B1 alleles were in agreement with the Hardy-Weinberg equilibrium. SLCO1B1 haplotypes reportedly associated with altered substrate pharmacokinetics, i.e., SLCO1B1*15B (-11187G/388G/521C) and *17 (-11187A/388G/521C), were found at allelic frequencies of 0.09 and 0.02, respectively. CONCLUSION: The presently developed Pyrosequencing assays allowed for quick and reliable identification of those SLCO1B1 SNPs that had been proposed to cause functional alternations in OATP1B1 with shown consequences for the pharmacokinetics of drugs that are OATP1B1 substrates.     

Genetic polymorphisms of SLCO1B1 for drug pharmacokinetics and its clinical implications

Various drug transporters are selectively expressed in single or multiple tissues, such as the intestine, liver and kidney, where these transporters play various roles in drug absorption, distribution and excretion. Genetic polymorphisms in drug transporters as well as drug-metabolizing enzymes are associated with interindividual differences in drug disposition, efficacy and toxicity. Organic anion transporting polypeptide 1B1 (OATP1B1, gene SLCO1B1) is expressed on the basolateral membrane of hepatocytes and can facilitate hepatic uptake of certain clinically relevant drugs such as statins except for fluvastatin, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, antidiabetic drug (repaglinide) and anticancer drugs (SN-38 and methotrexate). Some single nucleotide polymorphisms or haplotypes of the SLCO1B1 gene have been identified and demonstrated to have functional significance for transporter activity. For examples, the SLCO1B1*15 haplotype (or 521T>C genotype) results in decreased uptake activity of SN-38 from systemic circulation, leading to increased plasma concentration of SN-38 and an enhanced risk of neutropenia. This review focuses on the impact of genetic polymorphisms of the SLCO1B1 gene on transport activity, and implications for the clinical efficacy and toxicity of clinically useful drugs.     

SLCO1B1 Polymorphism and Oral Antidiabetic Drugs

Abstract: Organic anion‐transporting polypeptide 1B1 (OATP1B1; gene: SLCO1B1) is an influx transporter expressed on the sinusoidal membrane of human hepatocytes, where it mediates the uptake of its substrates from blood into liver. In vitro, the SLCO1B1 c.521T > C (p.Val174Ala) single‐nucleotide polymorphism (SNP) has been associated with reduced and the c.388A > G (p.Asn130Asp) SNP with both enhanced and reduced transport activity of OATP1B1. In vivo in humans, the c.521C allele (present in SLCO1B1*5 and *15 haplotypes) is associated with decreased hepatic uptake and increased plasma concentrations of several OATP1B1 substrates. The SLCO1B1*1B (c.388G‐c.521T) haplotype is associated with enhanced hepatic uptake and decreased plasma concentrations of some OATP1B1 substrates. The SLCO1B1 c.521CC genotype has been associated with an about 60‐190% increased, and the SLCO1B1*1B/*1B genotype with an about 30% decreased area under the plasma concentration‐time curve of repaglinide. Moreover, SLCO1B1 polymorphism can affect the extent of interaction between OATP1B1 inhibitors and repaglinide. Accordingly, SLCO1B1 genotyping may help in choosing the optimal starting dose of repaglinide. In Chinese individuals, the SLCO1B1 c.521C allele has been associated with increased plasma concentrations of nateglinide, but the association could not be replicated in Caucasians. SLCO1B1 genotype has had no effect on the pharmacokinetics of rosiglitazone, pioglitazone or their metabolites. The hepatic uptake of metformin is mediated by organic cation transporters 1 and 3, and the liver is not important for the elimination or action of the dipeptidylpeptidase 4 inhibitors sitagliptin, vildagliptin and saxagliptin. Therefore, SLCO1B1 polymorphism unlikely affects the response to these antidiabetics. Possible effects of SLCO1B1 polymorphism on sulfonylureas remain to be investigated.     

Frequencies of Single‐Nucleotide Polymorphisms of SLCO1A2, SLCO1B3 and SLCO2B1 Genes in a Finnish Population

Abstract: Organic anion transporting polypeptides 1A2, 1B3 and 2B1 (OATP1A2, OATP1B3 and OATP2B1) are expressed in tissues important for pharmacokinetics, and mediate the cellular influx of various endogenous and exogenous compounds, including drugs. The aim of the study was to investigate the frequencies of single‐nucleotide polymorphisms (SNP) of SLCO1A2, SLCO1B3 and SLCO2B1 in a Finnish population. The distribution of nine non‐synonymous SLCO1A2, SLCO1B3 and SLCO2B1 SNPs was determined in 552 healthy Finnish Caucasian participants by using allelic discrimination with TaqMan 5′nuclease assays. The SLCO1A2 c.38T>C (p.Ile13Thr) and c.516C>T (p.Glu172Asp) SNPs were found with variant allele frequencies of 12.9% (95% confidence interval: 11.0–15.0) and 7.2% (5.8–8.8). The variant allele frequencies of SLCO1B3 c.334T>G (p.Ser112Ala), c.699G>A (p.Met233Ile) and c.767G>C (p.Gly256Ala) were 77.0% (74.4–79.4), 76.9% (74.3–79.3) and 12.8% (10.9–14.9), respectively. None of the participants carried the SLCO1B3 c.1309G>A (p.Gly437Ser) SNP. The SLCO2B1 c.601G>A (p.Val201Met), c.935G>A (p.Arg312Gln) and c.1457C>T (p.Ser486Phe) variant allele frequencies were 2.1% (1.4–3.1), 13.6% (11.7–15.7) and 2.8% (2.0–4.0), respectively. The SLCO1B3 c.334T>G and c.699G>A SNPs were in a nearly complete linkage disequilibrium (r² = 0.99, D′ = 1.00), all other SNP pairs showed only a weak correlation. In conclusion, non‐synonymous sequence variations of SLCO1A2, SLCO1B3 and SLCO2B1 occur at high frequencies in the Finnish population.     

Extreme differences in SLCO1B3 functional polymorphisms in Roma and Hungarian populations

Variants in SLCO1B3 transporter are linked to disposition and uptake of drugs and show high degree of heterogeneity between populations. A total of 467 Roma and 448 Hungarian subjects were genotyped for SLCO1B3 c.334T>G and c.1683-5676A>G variant alleles by PCR-RFLP assay and direct sequencing. We found significant differences in the frequencies of homozygous variant genotypes of SLCO1B3 334GG (41.54% vs. 8.04%, p < 0.001) and 1683-5676GG (0.43% vs. 2.01%, p = 0.028) between Romas and Hungarians. A significantly increased prevalence was found in SLCO1B3 1683-5676G allele frequency in Hungarians compared to the Roma population (15.07% vs. 3.43%, p ≤ 0.001). The frequency of SLCO1B3 334G allele was significantly increased in Roma population compared to Hungarians (70.56% vs. 52.23%, p = 0.001). The LD values between the examined SNPs were 80 and 90 in Roma and in Hungarian samples, respectively. Our results highlight notable pharmacogenetic differences between Roma and Hungarian populations, which may have therapeutic implications.     

Haplotype analysis of ABCB1/MDR1 blocks in a Japanese population reveals genotype-dependent renal clearance of irinotecan

We performed comprehensive haplotyping of ABCB1/MDR1 gene blocks using 49 genetic polymorphisms, including seven novel ones, obtained from 145 Japanese subjects. The ABCB1/MDR1 gene was divided into four blocks (Blocks -1, 1, 2, and 3) based on linkage disequilibrium analysis of polymorphisms. Using an expectation-maximization based program, 1, 2, 8, and 3 haplotype groups (3, 12, 32, and 18 haplotypes) were identified in Blocks -1, 1, 2, and 3, respectively. Within Block 2, haplotype groups *1, *2, *4, *6, and *8 reported by Kim and colleagues (Clin Pharmacol Ther 2001; 70:189-199) were found, and additional three groups (*9 to *11) were newly defined. We analyzed the association of haplotypes with the renal clearance of irinotecan and its metabolites in 49 Japanese cancer patients given irinotecan intravenously. There was a significant association of the *2 haplotype in Block 2, which includes 1236C>T, 2677G>T and 3435C>T, with a reduced renal clearance of those compounds. Moreover, tendencies of reduced and increased renal clearance were also observed with *1f in Block 2 and *1b in Block 3, respectively. These findings suggest that the P-glycoprotein encoded by ABCB1/MDR1 in the proximal tubules plays a substantial role in renal exclusion of drugs and, moreover, that block-haplotyping is valuable for pharmacogenetic studies.     

Association between genetic polymorphisms of SLCO1B1 and susceptibility to methimazole‐induced liver injury

Methimazole (MMI) has been used in the therapy of Grave's disease (GD) since 1954, and drug‐induced liver injury (DILI) is one of the most deleterious side effects. Genetic polymorphisms of drug‐metabolizing enzymes and drug transporters have been associated with drug‐induced hepatotoxicity in many cases. The aim of this study was to investigate genetic susceptibility of the drug‐metabolizing enzymes and drug transporters to the MMI‐DILI. A total of 44 GD patients with MMI‐DILI and 118 GD patients without MMI‐DILI development were included in the study. Thirty‐three single nucleotide polymorphisms (SNPs) in twenty candidate genes were genotyped. We found that rs12422149 of SLCO2B1, rs2032582_AT of ABCB1, rs2306283 of SLCO1B1 and rs4148323 of UGT1A1 exhibited a significant association with MMI‐DILI; however, no significant difference existed after Bonferroni correction. Haplotype analysis showed that the frequency of SLCO1B1*1a (388A521T) was significantly higher in MMI‐DILI cases than that in the control group (OR = 2.21, 95% CI = 1.11‐4.39, P = 0.023), while the frequency of SLCO1B1*1b (388G521T) was significantly higher in the control group (OR = 0.52, 95% CI = 0.29‐0.93, P = 0.028). These results suggested that genetic polymorphisms of SLCO1B1 were associated with susceptibility to MMI‐DILI. The genetic polymorphism of SLCO1B1 may be important predisposing factors for MMI‐induced hepatotoxicity.     

Thirty novel genetic variations in the SLC29A1 gene encoding human equilibrative nucleoside transporter 1 (hENT1)

Thirty-nine genetic variations, including thirty novel ones, were found in the human SLC29A1 gene, which encodes equilibrative nucleoside transporter 1, from 256 Japanese cancer patients administered gemcitabine. The found novel variations included -8,166G>A, -81,10A>G, -7,947G>A, -7,789T>C, -5,595G>A, -3,803_-3,783delTCGGGGAGGTGGCAGTGGGCG, -3,548G>C, -3,414G>A, -1355T>C, -34C>G, IVS1+141G>A, IVS1+260C>T, IVS1-82C>T, 177C>G, IVS3-6C>T, 564C>T, IVS8+44T>C, IVS8+90T>C, IVS8+97T>C, IVS8+131C>T, IVS8+169G>A, 933T>C, 954C>T, IVS11-52G>C, IVS11-46G>A, 1,288G>A, 1,641C>G, 1,703_1,704delGT, 1812C>T, and 1861C>T. The frequencies were 0.051 for IVS8+169G>A, 0.012 for -7,947G>A, 0.006 for IVS1+141G>A and 1,703_1,704delGT, 0.004 for -8,166G>A, -8,110A>G, -3,548G>C, -1,355T>C, -34C>G, IVS8+44T>C, and 1,812C>T, and 0.002 for the other 19 variations. Among them, 177C>G and 1,288G>A resulted in amino acid substitutions Asp59Glu and Ala430Thr, respectively. Using the detected polymorphisms, linkage disequilibrium analysis was performed, and 28 haplotypes were identified or inferred. Our findings would provide fundamental and useful information for genotyping SLC29A1 in the Japanese and probably other Asian populations.     

Genetic polymorphisms of UGT1A6 in a Japanese population

Thirteen single nucleotide polymorphisms (SNPs), including 6 novel ones, were found in exon 1 and its flanking region of UDP-glucuronosyltransferase (UGT) 1A6 from 195 Japanese subjects. Several novel SNPs were identified, including 269G>A (R90H), 279A>G (S93S), and 308C>A (S103X) in exon 1, and IVS1+109C>T, IVS1+120A>G, and IVS1+142C>T in the intron downstream of exon 1. Among these SNPs, 308C>A confers termination of translation at codon 103, resulting in the production of an immature protein that probably lacks enzymatic activity. The allele frequencies were 0.003 for all the 6 SNPs. In addition, the 3 known nonsynonymous SNPs were detected: 19T>G (S7A), 541A>G (T181A), and 552A>C (R184S) with frequencies of 0.226, 0.218, and 0.226, respectively. High linkage disequilibrium was observed among 19T>G (S7A), 315A>G (L105L), 541A>G (T181A), 552A>C (R184S), and IVS1+130G>T, as reported in Caucasian and African-American populations. Then, 11 haplotypes in UGT1A6 were estimated. The novel nonsynonymous variant, 269A or 308A, was shown to be located on the same DNA strand together with 19G, 315G, 541G, 552C, and IVS1+130T. Our results provide fundamental and useful information for genotyping UGT1A6 in the Japanese, and probably Asian populations.     

<Emphasis Type="Italic">SLCO1B1</Emphasis> haplotypes are not associated with atorvastatin-induced myalgia in Brazilian patients with familial hypercholesterolemia

Purpose  

Recent studies reported the association of SLCO1B1 haplotypes with the development of musculoskeletal side effects during simvastatin use. The aim was to evaluate the pharmacogenetic association of SLCO1B1 haplotypes with atorvastatin-induced myalgia in a sample of individuals on high-dose atorvastatin regimens.     

Single nucleotide polymorphisms and haplotype frequencies of UGT2B4 and UGT2B7 in a Japanese population.

Both UDP-glucuronosyltransferase 2B4 (UGT2B4) and UGT2B7 are expressed mainly in the human liver and have several overlapping substrates; e.g., catechol estrogens, bile acids, codeine, and carvedilol. To identify novel single nucleotide polymorphisms (SNPs) and haplotypes in a Japanese population, the enhancer/promoter regions, all the exons, and the surrounding intronic regions of UGT2B4 and UGT2B7 were sequenced from 136 Japanese individuals. We found 16 and 21 polymorphisms, including 10 and 4 novel ones in UGT2B4 and UGT2B7, respectively. The novel nonsynonymous SNPs were 1364A>G (K455R) and 1531T>C (C511R) in UGT2B4 and 1192G> A (D398N) in UGT2B7. From linkage disequilibrium analysis, several SNPs in UGT2B7 were found to be highly linked with each other. No close linkage between the SNPs in UGT2B4 and UGT2B7 was observed, indicating that each gene is located within an independent haplotype block. Thus, haplotype analysis was separately performed for the two genes. In UGT2B4, we unambiguously determined 8 haplotypes and inferred an additional 12 haplotypes using an expectation-maximization-based program. In UGT2B7, five haplotypes were unambiguously assigned and an additional eight haplotypes were inferred. The haplotype structure of UGT2B7 was more diverse than that of UGT2B4 in terms of the number of frequent SNPs. In addition, ethnic differences in the UGT2B4(*)2 and UGT2B7(*)2 haplotypes between the Japanese and the Caucasian and/or African populations were found. Our findings provide fundamental and useful information for genotyping UGT2B4 and UGT2B7 in the Japanese, and probably other populations.