SLCO1B1 Variants Research Articles

Genome-wide association of serum bilirubin levels in Korean population

A large-scale, genome-wide association study was performed to identify genetic variations influencing serum bilirubin levels using 8841 Korean individuals. Significant associations were observed at UGT1A1 (rs11891311, P = 4.78 x 10(-148)) and SLCO1B3 (rs2417940, P = 1.03 x 10(-17)), which are two previously identified loci. The two single-nucleotide polymorphisms (SNPs) were replicated (rs11891311, P = 3.18 x 10(-15)) or marginally significant (rs2417940, P = 8.56 x 10(-4)) in an independent cohort of 1096 individuals. In a conditional analysis adjusted for the top UGT1A1 variant (rs11891311), another variant in UGT1A1 (rs4148323, P = 1.22 x 10(-121)) remained significant; this suggests that in UGT1A1 at least two independent genetic variations influence the bilirubin levels in the Korean population. The protein coding variant rs4148323, which is monomorphic in European-derived populations, may be specifically associated with serum bilirubin levels in Asians (P = 2.56 x 10(-70)). The SLCO1B3 variant (rs2417940, P = 1.67 x 10(-18)) remained significant in a conditional analysis for the top UGT1A1 variant. Interestingly, there were significant differences in the associated variations of SLCO1B3 between Koreans and European-derived populations. While the variant rs2417940 at intron 7 of SLCO1B3 was more significantly associated in Koreans, variants rs17680137 (P = 0.584) and rs2117032 (P = 2.76 x 10(-5)), two of the top-ranked SNPs in European-derived populations, did not reach the genome-wide significance level. Also, variants in SLCO1B1 did not reach genome-wide significance in Koreans. Our result supports the idea that there are considerable ethnic differences in genetic association of bilirubin levels between Koreans and European-derived populations.

Hepatic Metabolism and Transporter Gene Variants Enhance Response to Rosuvastatin in Patients With Acute Myocardial Infarction

Background— Pharmacogenetics aims to maximize benefits and minimize risks of drug treatment. Our objectives were to examine the influence of common variants of hepatic metabolism and transporter genes on the lipid-lowering response to statin therapy. Methods and Results— The Genetic Effects On STATins (GEOSTAT-1) Study was a genetic substudy of Secondary Prevention of Acute Coronary Events—Reduction of Cholesterol to Key European Targets (SPACE ROCKET) (a randomized, controlled trial comparing 40 mg of simvastatin and 10 mg of rosuvastatin) that recruited 601 patients after myocardial infarction. We genotyped the following functional single nucleotide polymorphisms in the genes coding for the cytochrome P450 (CYP) metabolic enzymes, CYP2C9*2 (430C>T), CYP2C9*3 (1075A>C), CYP2C19*2 (681G>A), CYP3A5*1 (6986A>G), and hepatic influx and efflux transporters SLCO1B1 (521T>C) and breast cancer resistance protein (BCRP; 421C>A). We assessed 3-month LDL cholesterol levels and the proportion of patients reaching the current LDL cholesterol target of <70 mg/dL (<1.81 mmol/L). An enhanced response to rosuvastatin was seen for patients with variant genotypes of either CYP3A5 ( P =0.006) or BCRP ( P =0.010). Furthermore, multivariate logistic-regression analysis revealed that patients with at least 1 variant CYP3A5 and/or BCRP allele (n=186) were more likely to achieve the LDL cholesterol target (odds ratio: 2.289; 95% CI: 1.157, 4.527; P =0.017; rosuvastatin 54.0% to target vs simvastatin 33.7%). There were no differences for patients with variants of CYP2C9, CYP2C19, or SLCO1B1 in comparison with their respective wild types, nor were differential effects on statin response seen for patients with the most common genotypes for CYP3A5 and BCRP (n=415; odds ratio: 1.207; 95% CI: 0.768, 1.899; P =0.415). Conclusion— The LDL cholesterol target was achieved more frequently for the 1 in 3 patients with CYP3A5 and/or BCRP variant genotypes when prescribed rosuvastatin 10 mg, compared with simvastatin 40 mg. Clinical Trial Registration— URL: http://isrctn.org . Unique identifier: ISRCTN 89508434.

SLCO1B1 variants and the risk of antituberculosis drug-induced hepatotoxicity: a systematic review and meta-analysis.

Aims: To evaluate the association between SLCO1B1 gene polymorphisms and susceptibility of antituberculosis drug-induced hepatotoxicity (ATDH). Methods: We searched the PubMed, Cochrane Library, Embase, Web of Science, Wan Fang and China National Knowledge Infrastructure database from inception to 2022. Results: Nine case-control studies with 1129 cases and 2203 controls were included. Among four SNPs reported in two or more studies, the final results indicated that SNP rs4149014 was significantly associated with decreased ATDH risk (dominant model, odds ratio:0.73; 95% CI: 0.55-0.97; p=0.03; allele model,odds ratio:0.69;95% CI: 0.55-0.86;p=0.001), and the trial sequential analysis also confirmed this significant association. Conclusion: SLCO1B1 gene SNP rs4149014 was significantly associated with lower risk of ATDH susceptibility.

Genome-wide association meta-analysis for total serum bilirubin levels

Variation in serum bilirubin is associated with altered cardiovascular disease risk and drug metabolism. We aimed to identify genetic contributors to variability in serum bilirubin levels by combining results from three genome-wide association studies (Framingham heart study, n = 3424; Rotterdam study, n = 3847; Age, Gene, Environment and Susceptibility-Reykjavik, n = 2193). Meta-analysis showed strong replication for a genetic influence on serum bilirubin levels of the UGT1A1 locus (P < 5 x 10(-324)) and a 12p12.2 locus. The peak signal in the 12p12.2 region was a non-synonymous SNP in SLCO1B1 (rs4149056, P = 6.7 x 10(-13)), which gives rise to a valine to alanine amino acid change leading to reduced activity for a hepatic transporter with known affinity for bilirubin. There were also suggestive associations with several other loci. The top variants in UGT1A1 and SLCO1B1 explain approximately 18.0 and approximately 1.0% of the variation in total serum bilirubin levels, respectively. In a conditional analysis adjusted for individual genotypes for the top UGT1A1 variant, the top SLCO1B1 variant remained highly significant (P = 7.3 x 10(-13)), but no other variants achieved genome-wide significance. In one of the largest genetic studies of bilirubin to date (n = 9464), we confirm the substantial genetic influence of UGT1A1 variants, consistent with past linkage and association studies, and additionally provide strong evidence of a role for allelic variation in SLCO1B1. Given the involvement of bilirubin in a number of physiological and disease processes, and the roles for UGT1A1 and SLCO1B1 in drug metabolism, these genetic findings have potential clinical importance. In analyses for association with gallbladder disease or gallstones, top bilirubin SNPs in UGT1A1 and SLCO1B1 were not associated.

Impact of pharmacogenetics on therapeutic drug monitoring

Pharmacogenetics and its application to TDM is an emerging field. Valid pharmacogenomic biomarkers listed by the FDA include the drug metabolising enzymes CYP2C9 + , CYP2C19, CYP2D6, DPD, NAT, TPMT + , UGT1A1 + as well as HLA-B * 5701 + and VKORC1 + . Genomic biomarkers for which testing is recommended are marked (+). There is a lack of evidence supporting a clear association between ABCB1 (MDR1) genotype and clinical drug response or toxicity. The CYP2D6 polymorphism plays an important role for the metabolism of antipsychotic as well as antidepressant drugs and tamoxifen. Thiopurine-S-methyltransferase (TPMT) deficiency causes thiopurine intolerance accompanied with severe myelosuppression. Testing for TPMT phenotype/genotype is now a useful practice. An inosine triphosphatase mutation ( ITPA 94C>A) appears to be a further promising marker for thiopurine interolerance. A significant difference in dose-adjusted tacrolimus blood levels has been demonstrated between CYP3A5 expressors compared to non-expressors. HLA-B*5701 genotyping is useful to identify patients at greatest risk for a hypersensitivity reaction to abacavir. Genome-wide association studies are increasingly being used and, e.g., have identified SLCO1B1 variants that are strongly associated with statin-induced myopathy. Expression profiling has the potential to identify gene-expression patterns related to drug response. Both approaches may be complementary and take into account that response to most drugs is influenced by multiple genes. In addition to TDM, drug disposition marker genotyping is a promising tool for individualisation of drug dosing.

SLCO1B1 variants associated with statin-induced myopathy

SLCO1B1 variants associated with statin-induced myopathy

SLCO1B1 variants and increased risk of statin-induced myopathy

SLCO1B1 variants and increased risk of statin-induced myopathy

SLCO1B1 variants and increased risk of statin-induced myopathy

SLCO1B1 variants and increased risk of statin-induced myopathy

SLCO1B1Variants and Statin-Induced Myopathy — A Genomewide Study

Lowering low-density lipoprotein cholesterol with statin therapy results in substantial reductions in cardiovascular events, and larger reductions in cholesterol may produce larger benefits. In rare cases, myopathy occurs in association with statin therapy, especially when the statins are administered at higher doses and with certain other medications. We carried out a genomewide association study using approximately 300,000 markers (and additional fine-mapping) in 85 subjects with definite or incipient myopathy and 90 controls, all of whom were taking 80 mg of simvastatin daily as part of a trial involving 12,000 participants. Replication was tested in a trial of 40 mg of simvastatin daily involving 20,000 participants. The genomewide scan yielded a single strong association of myopathy with the rs4363657 single-nucleotide polymorphism (SNP) located within SLCO1B1 on chromosome 12 (P=4x10(-9)). SLCO1B1 encodes the organic anion-transporting polypeptide OATP1B1, which has been shown to regulate the hepatic uptake of statins. The noncoding rs4363657 SNP was in nearly complete linkage disequilibrium with the nonsynonymous rs4149056 SNP (r(2)=0.97), which has been linked to statin metabolism. The prevalence of the rs4149056 C allele in the population was 15%. The odds ratio for myopathy was 4.5 (95% confidence interval [CI], 2.6 to 7.7) per copy of the C allele, and 16.9 (95% CI, 4.7 to 61.1) in CC as compared with TT homozygotes. More than 60% of these myopathy cases could be attributed to the C variant. The association of rs4149056 with myopathy was replicated in the trial of 40 mg of simvastatin daily, which also showed an association between rs4149056 and the cholesterol-lowering effects of simvastatin. No SNPs in any other region were clearly associated with myopathy. We have identified common variants in SLCO1B1 that are strongly associated with an increased risk of statin-induced myopathy. Genotyping these variants may help to achieve the benefits of statin therapy more safely and effectively. (Current Controlled Trials number, ISRCTN74348595.)

Global Analysis of Genetic Variation in SLCO1B1

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. 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. 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. 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.

Duplex pyrosequencing assay of the 388A > G and 521T > C SLCO1B1 polymorphisms in three Asian populations

Background We developed a method for detecting important SLCO1B1 polymorphisms and compared the haplotype frequencies in 3 Asian populations. Methods We designed a duplex pyrosequencing assay to detect simultaneously the 388A > G and 521T > C variants of SLCO1B1; this method can identify SLCO1B1⁎1b, SLCO1B1⁎5, and SLCO1B1⁎15. The method was validated by direct sequencing of 96 Korean subjects. In addition, duplex genotyping and the monoplex method were compared and validated with 469 Korean subjects. To characterize the haplotype frequencies based on the 2 polymorphisms, we genotyped 106 Chinese and 104 Vietnamese subjects, as well as Korean subjects, using the new method. Results The results showed 100% concordance among the monoplex and duplex pyrosequencing assays and direct sequencing method. The allele frequencies were similar in the 3 Asian populations: the most common allele was SLCO1B1⁎1b, while SLCO1B1⁎5 was rare or absent. The frequencies of functional SLCO1B1⁎15 alleles differed statistically between Chinese (8.2%) and Korean (14.0%) and Vietnamese (16.3%) ( p < 0.05, χ 2-test). Conclusions The duplex pyrosequencing assay appears to be an accurate, rapid, and cost-effective genotyping method to detect major SLCO1B1 important alleles in Asian populations.

SLCO1B1 (OATP1B1, an Uptake Transporter) and ABCG2 (BCRP, an Efflux Transporter) Variant Alleles and Pharmacokinetics of Pitavastatin in Healthy Volunteers

To investigate the contribution of genetic polymorphisms of SLCO1B1 and ABCG2 to the pharmacokinetics of a dual substrate, pitavastatin, 2 mg of pitavastatin was administered to 38 healthy volunteers and pharmacokinetic parameters were compared among the following groups: 421C/C(*)1b/(*)1b (group 1), 421C/C(*)1b/(*)15 (group 2), 421C/C(*)15/(*)15 and 421C/A(*)15/(*)15 (group 3), 421C/A(*)1b/(*)1b (group 4), 421A/A(*)1b/(*)1b (group 5), and 421C/A(*)1b/(*)15 (group 6). In SLCO1B1, pitavastatin area under plasma concentration-time curve from 0 to 24 h (AUC(0-24)) for groups 1, 2, and 3 was 81.1+/-18.1, 144+/-32, and 250+/-57 ng h/ml, respectively, with significant differences among all three groups. In contrast to SLCO1B1, AUC(0-24) in groups 1, 4, and 5 was 81.1+/-18.1, 96.7+/-35.4, and 78.2+/-8.2 ng h/ml, respectively. Although the SLCO1B1 polymorphism was found to have a significant effect on the pharmacokinetics of pitavastatin, a nonsynonymous ABCG2 variant, 421C>A, did not appear to be associated with the altered pharmacokinetics of pitavastatin.

Functional characterization of SLCO1B1 (OATP-C) variants, SLCO1B1*5, SLCO1B1*15 and SLCO1B1*15+C1007G, by using transient expression systems of HeLa and HEK293 cells

SLCO1B1*5 and SLCO1B1*15 have been reported to reduce the clearance of pravastatin in healthy volunteers. However, there remains controversy in the effects of SLCO1B1*5 on the activity of OATP1B1 in vitro. In addition, the effect of SLCO1B1*15 on the function of OATP1B1 has not been studied using cDNA-expression systems. Object of the present study was to study the influence of SLCO1B1*5, *15 and *15+C1007G, a novel haplotype found in a patient with pravastatin-induced myopathy, on the functional properties of OATP1B1 by transient expression systems of HEK293 and HeLa cells using endogenous conjugates and statins as substrates. Transporting assays for endogenous substrates were performed using tritium labeled estradiol-17beta-D-glucuronide and estrone-3-sulfate. Quantitation of pravastatin, atorvastatin, cerivastatin and simvastatin were carried out using HPLC tandem mass spectrometry. The transporting activities of cells expressing SLCO1B1*5, *15 and *15+C1007G decreased significantly but those of SLCO1B1*1b, *1a+C1007G and *1b+C1007G were not altered for all of the substrates tested except for simvastatin. Kinetic analysis of pravastatin and atorvastatin showed that Km values were not altered but Vmax values decreased significantly in cells expressing SLCO1B1*5, *15 and *15+C1007G. Immunocytochemical study showed that SLCO1B1*5, *15 and *15+C1007G proteins are localized not only at the plasma membrane but also in the intracellular space. These findings suggest that 521T>C, existing commonly in SLCO1B1*5, *15 and *15+C1007G, is the key single nucleotide polymorphism (SNP) that determines the functional properties of SLCO1B1*5, *15 and *15+C1007G allelic proteins and that decreased activities of these variant proteins are mainly caused by a sorting error produced by this SNP.

Irinotecan (CPT-11) pharmacokinetics (PK) and neutropenia: interaction among UGT1A1 and transporter genes

2006 Background: We have previously shown that UGT1A1 and ABCC2 gene polymorphisms are likely to play an important role in CPT-11 PK variability. Among several variants tested, -3156G>A in UGT1A1 and 3972C>T in ABCC2 showed the strongest phenotypic effect. However, several other ABCC2 variants have been shown to affect ABCC2 expression in vitro. The organic anion transporter polypeptide-1B1 (OATP-1B1, SLCO1B1) is involved in the liver uptake of several compounds. This study aims to evaluate the effects of ABCC2 haplotypes and SLCO1B1 genotypes on CPT-11 PK and neutropenia. Methods: We studied 65 pts previously assessed for PK and toxicity (JCO, 2004). Six SNPs in ABCC2 were genotyped [-1549G>A, -1019A>G, -24C>T, 1249G>A, intron 27 -34C>T, 3972C>T] and haplotypes were estimated. Two SNPs in SLCO1B1 [*1b (388A>G) and *5 (521T>C)] were also genotyped. Results: Twelve ABCC2 haplotypes were identified, with haplotypes 2, 3, 4, 7, and 6 having a frequency of 0.33, 0.22, 0.14, 0.12, and 0.05, respectively. Haplotype 4 was correlated with SN-38G/SN-38 AUC ratios (p<0.0001). SLCO1B1*5 genotype was correlated with SN-38G AUC (p=0.001) and CPT-11 AUC (p<0.0001). Pts with SLCO1B1*5 CT+CC genotype had a higher CPT-11 AUC compared to TT genotype (29.5±8.8 vs. 22.3±5.1 μg*h/ml, p=0.0001). SLCO1B1*1b was associated with an increased ln(ANC nadir), although with borderline significance (p=0.07). The best multivariate model for ln(ANC nadir) included UGT1A1 -3156G>A (p=0.03), SLCO1B1*1b (p=0.03), ABCC2 haplotype 4 (p=0.02), total bilirubin (p<0.0001), and gender (p=0.04) (r2=0.49, p<0.0001). Conclusions: SLCO1B1*5 appears to affect CPT-11 clearance. SLCO1B1, ABCC2 and UGT1A1 gene variants may have additive effects on neutropenia. Additional studies of the relationship of common ABCC2 and SLCO1B1 variants to CPT-11 PK and toxicity are warranted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration FDA