Lactic acidosis after allogeneic haematopoietic stem cell transplantation potentially related to letermovir.

A 53-year-old woman with a history of acute myeloid leukaemia received a second allogeneic haematopoietic stem cell transplant and was prescribed, among other medications, acyclovir and letermovir (480-mg daily oral dose) for prophylaxis of, respectively, herpes simplex and cytomegalovirus infection. The patient was admitted in the intensive care unit for dyspnoea and oliguria. Laboratory investigations revealed acute kidney injury but also a severe and progressive lactic acidosis. Liver function tests were within normal range. The combination of lactic acidosis, hypoglycaemia and acylcarnitine profile in plasma raised the suspicion of mitochondrial toxicity. Letermovir therapy was interrupted, and determination of plasma letermovir pharmacokinetics revealed a prolonged terminal half-life (38.7 h) that was not significantly influenced by continuous venovenous haemofiltration. Exploration for genetic polymorphisms revealed that the patient was SLCO1B1*5/*15 (c.521T>C homozygous carrier and c.388A>G heterozygous carrier) with a predicted nonfunctional organic anion transporting polypeptide 1B1 protein. The relationship between letermovir accumulation and development of lactic acidosis requires further observations.

ASSOCIATION OF SOLUTE CARRIER ORGANIC ANION TRANSPORTER 1B1 GENE POLYMORPHISM WITH RESPONSE TO ATORVASTATIN AND ASSOCIATED MYOPATHY IN IRAQI DYSLIPIDEMIA PATIENTS.

OBJECTIVE: Aim: The study aims to investigate the effect of solute carriers organic anions transporters 1B1 (SLCO1B1) gene polymorphisms rs4149056, rs2306283, rs55901008, and rs729559745 in a sample of patients with dyslipidemia, and relate it to atorvastatin response and associated myopathy. PATIENTS AND METHODS: Materials and Methods: A cross sectional enrolled 200 patients both males and females of Arabic race, Iraqi nationality aged between 30-65 years. The patients were divided into two groups: Group 1 (Atorvastatin responders and tolerant), Group 2 (Atorvastatin non responder and intolerant). Blood samples collected from the patients for biochemical studies and analyzed statistically by Student T-test and Chi-square, and DNA extracted for polymerase chains reactions (PCR). RESULTS: Results: The results showed insignificant association P≥0.05 between the demographic characteristics of the study population with different genotypes, and significant difference P<0.05 in the biochemical parameters regarding (T-cholesterol, triglycerides, low density lipoproteins, and Creatine kinase-MM) when comparing the two groups. Odds ratio (OR) with confidence intervals CI (95%) used to evaluate the risk association to develop myopathy and poor response to atorvastatin therapy show relevant association for CC and CT genotype of rs4149056, while rs2306283 GG genotype show low association, also rs55901008 show low association for CC genotype, and moderate association for rs72559745 genotypes GG, AG. CONCLUSION: Conclusions: The mutant allele's genotypes of rs4149056, rs55901008, and rs72559745, and the wild allele genotype of rs2306283 show significant association with the development of poor response to atorvastatin and elevated the level of CK-MM plasma concentration.

Effect of Genetic Variation of NAT2 on Isoniazid and SLCO1B1 and CES2 on Rifampin Pharmacokinetics in Ghanaian Children with Tuberculosis.

Isoniazid and rifampin are essential components of first-line antituberculosis (anti-TB) therapy. Understanding the relationship between genetic factors and the pharmacokinetics of these drugs could be useful in optimizing treatment outcomes, but this is understudied in children. We investigated the relationship between N-acetyltransferase type 2 (NAT2) genotypes and isoniazid pharmacokinetics, as well as that between the solute carrier organic anion transporter family member 1B1 (encoded by SLCO1B1) and carboxylesterase 2 (CES2) single nucleotide polymorphisms (SNPs) and rifampin pharmacokinetics in Ghanaian children. Blood samples were collected at times 0, 1, 2, 4, and 8 h postdose in children with tuberculosis on standard first-line therapy for at least 4 weeks. Isoniazid and rifampin concentrations were determined by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, and pharmacokinetic parameters were calculated using noncompartmental analysis. Genotyping of NAT2, SLCO1B1, and CES2 SNPs were performed using validated TaqMan genotyping assays. The Kruskal-Wallis test was used to compare pharmacokinetic parameters among the three genotypic groups and was followed by the Wilcoxon rank sum test for pairwise group comparisons. Genotype status inferred by the NAT2 4-SNP and 7-SNP genotyping panels identified children with a slow acetylator phenotype but not the rapid genotype. For rifampin, only the rare SLCO1B1*1b homozygous variant was associated with rifampin pharmacokinetics. Our findings suggest that NAT2 and SCLCO1B1*1b genotyping may have minimal clinical utility in dosing decisions at the population level in Ghanaian children, but it could be useful at the individual level or in populations that have a high frequency of implicated genotypes. Further studies in other populations are warranted.

SLCO1B1 c.521T>C Genotyping in the Austrian Population Using 2 Commercial Real-Time Polymerase Chain Reaction Assays: An Implementation Study.

Statin-induced myopathy is reported to be significantly associated with the SCLO1B1 c.521T>C polymorphism. To date, SLCO1B1 c.521T>C epidemiologic data for the Austrian population is still lacking. Therefore, this study aimed at assessing the genotype and allele frequencies of the SLCO1B1 c.521T>C variant in Austria and evaluating the clinical performance of 2 commercial real-time polymerase chain reaction (PCR) assays. Genomic DNA isolated from 181 healthy individuals was analyzed for the SLCO1B1 c.521T>C polymorphism in a comparative manner using the SLCO1B1 c.521T>C RealFastTM Assay and the BioPro SLCO1B1 Genotyping real-time PCR Kit. A total of 10 (5.5%) and 44 (24.3%) out of 181 individuals were SLCO1B1 c.521T>C C/C-homo- and -C/T-heterozygotes, the genotypes indicative of high and increased risk of statin-induced myopathy, respectively. The SLCO1B1 c.521C allele frequency rate was 17.7%. In conclusion, the genetic predisposition of elevated statin-induced myopathy risk in the Austrian population is frequent. Both real-time PCR assays under investigation here are reliable and robust SLCO1B1 c.521T>C genotyping tools in clinical routine.

Frequencies of single-nucleotide polymorphisms and haplotypes of the SLCO1B1 gene in selected populations of the western balkans.

As a membrane influx transporter, organic anion-transporting polypeptide 1B1 (OATP1B1) regulates the cellular uptake of a number of endogenous compounds and drugs. The aim of this study was to characterize the diversity of the solute carrier organic anion transporter family member 1B1 (SLCO1B1) gene encoding this transporter in two ethnic groups populating the Western Balkans. The distribution of SCLO1B1 alleles was determined at seven variant sites (c.388A>G, c.521T>C, c.571T>C, c.597C>T, c.1086C>T, c.1463G>C and c.*439T>G) in 266 Macedonians and 94 Albanians using the TaqMan allelic discrimination assay. No significant difference in the frequencies of the single nucleotide polymorphisms (SNPs) was observed between these populations. The frequency of the c.521T>C SNP was the lowest (<13.7 and 12.2%, respectively), while the frequencies of all other SNP alleles were above 40.0%. Variant alleles of c.1463G>C and c.1086 C>T SNPs were not identified in either ethnic group. The haplotype analysis revealed 20 and 21 different haplotypes in the Macedonian and Albanian population, respectively. The most common haplotype in both ethnic groups, *1J/*1K/*1L, had a frequency of 39.0% and 26.6%, respectively. In both populations, the variant alleles of the functionally significant c.521T>C and c.388A>G SNPs existed in one major haplotype (*15/*16/*17), with a frequency of 8.6 and 2.4% in the Macedonian and Albanian subjects, respectively. In conclusion, sequence variations of the SLCO1B1 gene in the studied populations occur at high frequencies, which are similar to that of the Caucasian population. Further studies are needed to evaluate the clinical significance of these SNPs and/ or the major SLCO1B1 haplotypes they form for a large number of substrates and for susceptibility to certain diseases.

Veterans Health Administration: Implementation of pharmacogenomic clinical decision support with statin medications and the SLCO1B1 gene as an exemplar.

PURPOSE: To describe the implementation of clinical decision support tools for alerting prescribers of actionable drug-gene interactions in the Veterans Health Administration (VHA). SUMMARY: Drug-gene interactions have been the focus of clinicians for years. Interactions between SCLO1B1 genotype and statin medications are of particular interest as these can inform risk for statin-associated muscle symptoms (SAMS). VHA identified approximately 500,000 new users of statin medications prescribed in VHA in fiscal year 2021, some of whom could benefit from pharmacogenomic testing for the SCLO1B1 gene. In 2019, VHA implemented the Pharmacogenomic Testing for Veterans (PHASER) program to offer panel-based, preemptive pharmacogenomic testing and interpretation. The PHASER panel includes SLCO1B1, and VHA utilized Clinical Pharmacogenomics Implementation Consortium statin guidelines to build its clinical decision support tools. The program's overarching goal is to reduce the risk of adverse drug reactions such as SAMS and improve medication efficacy by alerting practitioners of actionable drug-gene interactions. We describe the development and implementation of decision support for the SLCO1B1 gene as an example of the approach being used for the nearly 40 drug-gene interactions screened for by the panel. CONCLUSION: The VHA PHASER program identifies and addresses drug-gene interactions as an application of precision medicine to reduce veterans' risks for adverse events. The PHASER program's implementation of statin pharmacogenomics utilizes a patient's SCLO1B1 phenotype to alert providers of the risk for SAMS with the statin being prescribed and how to lower that risk through a lower dose or alternative statin selection. The PHASER program may help reduce the number of veterans who experience SAMS and may improve their adherence to statin medications.

Association between single nucleotide polymorphism SLCO1B1 gene and simvastatin pleiotropic effects measured through flow-mediated dilation endothelial function parameters.

BACKGROUND: Atherosclerosis is a condition in which the medium to large arteries become inflamed over time. The cornerstone to the atherosclerosis process is endothelial dysfunction. Simvastatin is a cholesterol-lowering drug known for its endothelial cell pleiotropic properties. The role of genetic polymorphisms in simvastatin-resistance difficulties has recently piqued people's interest. This problem is thought to be linked to the pleiotropic action of simvastatin, particularly in terms of restoring endothelial function. The goal of this study is to see if there is a link between the single nucleotide polymorphism (SNP) c.521T>C and the pleiotropic effect of simvastatin as determined by the endothelial function parameter, flow-mediated dilation (FMD). METHODS: This research was a multicentre cross-sectional study including 71 hypercholesterolemia patients who have been on simvastatin for at least 3 months. The real-time polymerase chain reaction identified SNP c.521T>C. The right brachial artery ultrasonography was used to measure FMD. RESULTS: In 71 hypercholesterolemia patients, the SNP c.521T>C was found in 9.9% of them. On χ2 analysis, there was no significant association between SNP c.521T>C (TC genotype) and FMD (p = 0.973). On logistic regression analysis, the duration of simvastatin medication was linked with an increased incidence (Adj. OR (adjusted odds ratio) = 2.424; confidence interval (CI) = 1.117-5.260, p = 0.025) and a reduction in systolic blood pressure (Adj. OR = 0.92; CI = 0.025-0.333, p = 0.001). CONCLUSION: There was no association between FMD and the SNP c.521T>C (TC genotype). The duration of simvastatin medication and systolic blood pressure were both associated to FMD.

Effect of SLCO1B1 gene polymorphisms and vitamin D on statin-induced myopathy.

Background Statin therapy used to lower cholesterol levels results in a substantial reduction in cardiovascular complications. Previous observations in different ethnic populations showed that rs2306283A>G, p.Asn130Asp and rs4149056T>C, p.Val174Ala in solute carrier organic anion transporter 1B1 (SLCO1B1) gene encoding the organic transporter protein may be responsible for statin uptake, thus explaining the majority of statin-associated symptoms. In addition to the genetic component, vitamin D (vit D) deficiency is common in Saudi Arabia and worldwide and may cause muscle dysfunction and ache. The aim of the present study was first to reveal an effect of vit D, rs2306283A>G, and rs4149056T>C and related haplotypes on statin-associated myopathy (SAM) and then to investigate a possible interaction between low vit D levels and the above-mentioned variants. Methods The genomic DNA obtained from 50 individuals diagnosed with hypercholesterolemia was genotyped using light SNiP hybridization probes. Results Low vit D levels were associated with SAM (OR=3.6, p=0.03); however, CK levels, rs2306283A>G, and rs4149056T>C did not show any association. Interestingly, rs4149056T>C was interacting with vit D to influence SAM (p=0.02). Haplotype analysis showed that SLCO1B1 *1B and *15 were more prevalent in individuals with SAM (p=0.05). When stratified according to vit D levels, rs2306283A allele showed an increase in individuals having SAM along with low vit D (p=0.03). Conclusions Although preliminary, our results show an involvement of vit D and rs4149056T>C of SLCO1B1 in SAM.

Meta-Analysis of the SLCO1B1 c.521T>C Variant Reveals Slight Influence on the Lipid-Lowering Efficacy of Statins.

BACKGROUND: Several studies have focused on the association between the lipid-lowering efficacy of statins and the SLCO1B1 c.521T>C polymorphism; however, the results are conflicting. The effects of statins show significant variability between individuals. This meta-analysis aimed to investigate the effects of the SLCO1B1 c.521T>C polymorphism on the lipid-lowering effects of statins. METHODS: We systematically searched PubMed and Web of Science to screen relevant studies. Meta-analysis was performed to identify the association between SLCO1B1 c.521 polymorphisms and the lipid-lowering effects of statins on the basis of the standard mean difference (SMD) and 95% confidence intervals (CIs). Additionally, we checked for heterogeneity (I(2)) among studies and evidence of publication bias. We obtained eight studies including 2,012 wild genotype (T/T) and 526 variant genotype (T/C and C/C) cases. RESULTS: No significant difference was observed in the lipid-lowering efficacy of statins between the wild and variant genotypes of SLCO1B1, with a pooled SMD of 0.03 (95% CI: -0.07-0.13). Furthermore, there was no significant effect in the meta-analyses of the variant heterozygote, homozygote, and Chinese populations. Subgroup meta-analysis indicated that the time required for the statin to take effect did not significantly affect the association between lipid-lowering efficacy of statins and SLCO1B1 c.521T>C polymorphism. However, the wild genotype improved the lipid-lowering efficacy of simvastatin with a pooled SMD of -0.26 (95% CI: -0.47- -0.05). CONCLUSIONS: No significant association was detected between the lipid-lowering efficacy of statins and the SLCO1B1 c.521T>C polymorphism, with the exception of simvastatin.

Study on Relationships of Gene Polymorphism of MTRR and SLCO1B1 with Blood Concentration of MTX and HD-MTX- induced ADR in ALL Children / 中国药房

OBJECTIVE： To study the relationships of polymorphism of MTRR gene rs1801394 locus and SLCO1B1 gene rs11045879 locus with drug concentration of methotrexate （MTX） and high-dose MTX （HD-MTX）-induced ADR in acute lymphoblastic leukemia （ALL） children. METHODS： From Oct. 2015 to Sept. 2018， 70 ALL hospitalized children of Han nationality in Sichuan area who received HD-MTX treatment and were in consolidation chemotherapy were selected retrospectively from Sichuan People’s Hospital. The blood concentration of MTX at 48 and 72 hours after administration was measured by EMIT. The genetic typing of MTRR gene rs1801394 locus and SLCO1B1 gene rs11045879 locus were detected with real-time PCR. The relationships of the polymorphism of MTRR gene and SLCO1B1 gene with MTX blood concentration [dose-corrected concentration （c48 h/D，48 h）， the proportion of children with different concentration of MTX （≤0.1， ＞0.1 μmol/L）] and ADR （such as myelosuppression， liver function damage， gastrointestinal response， mucosal damage， rash， etc.） were analyzed. Binary Logistic regression analysis for the correlation of ADR with different influencing factors （gene polymor- phism， blood concentration of MTX， immunophenotyping， body mass index， etc.） was carried out by Wald method. RESULTS： Totally 31， 32， 7 children with MTRR gene AA， AG and GG genotype， while 23， 37， 10 children with SLCO1B1 gene TT， TC and CC genotype were detected. The distribution of each genotype in 70 children conformed to Hardy-Weinberg equilibrium （P＞0.05）. There was no significant difference in c48 h/D（48 h） of children and the proportion of children with different concentration of MTX （72 h） among difterent genotypes of MTRR and SLCO1B1 gene （P＞0.05）. There was statistical significance in the incidence of liver function injury in children with different genotypes of MTRR gene （P＜0.05）， and the AA genotype was significantly higher than the AG+GG genotype （P＜0.05）. There was no correlation of MTRR gene polymorphism with the incidence of other ADR， neither SLCO1B1 gene polymorphism with the incidence of ADR （P＞0.05）. The results of Binary Logistic regression analysis showed that liver function damage in ALL children was related to the gene polymorphism of MTRR； gastrointestinal reaction was related to whether the plasma concentration was more than 0.1 μmol/L at 72 h； mucosal damage was related to the immune type and BMI of children； the occurrence of skin allergy was correlated with body weight of children（P＜0.05）. CONCLUSIONS： Gene polymorphism of MTRR rs1801394 locus may associated with the occurrence of HD-HTX-induced liver function injury in ALL children， but its polymorphism and gene polymorphism of SLCO1B1 rs11045879 locus are not related to MTX blood concentration in ALL children.

Analysis of Dyslipidemia Correlation and Polymorphisms of ApoE and SLCO1B1 Gene in Dyslipidemia People / 现代检验医学杂志

Objective To investigate the frequency distribution of ApoE and SLCO1B1 genotypes in abnormal blood lipid lev-els in Xiangya Hospital,explore the correlation of ApoE and SLCO1B1 genotypes with various indicators of dyslipidemia,and provide evidence for prevention and treatment of atherosclerotic diseases.Methods Blood lipid data including TG,TC,LDL-C and HDL-C in 87 cases of dyslipidemia people in Xiangya Hospital from June in 2016 to April in 2017 were collected.The ApoE and SLCO1B1 genotypes were detected by PCR fluoroscopy in 87 cases of dyslipidemia.The distribution of gene fre-quency was analyzed and the differences of blood lipid indexes among the genotypes were compared.Results The frequen-cies of each ApoE genotype in 87 cases of dyslipidemia were E2/E2 1.15%,E2/E3 13.79%,E2/E4 1.15%,E3/E3 56.32%,E3/E4 26.44% and E4/E4 1.15%,respectively.The highest proportion of allele frequency was E3 with the per-cent of 76.44%,E2 and E4 occupied 8.62% and 14.94%,respectively.The concentration of LDL-C in E4 phenotype group was higher than that in E2 group and E3 group,and there was no significant difference in the levels of TG,TC,LDL-C and HDL-C.The frequencies of each SLCO1B1 genotype were *1a/*1a 6.90%,*1a/*1b 36.70%,*1a/*15 13.79%,*1b/*1b 26.44% and *1b/*15 16.09%.The highest frequency of each haplotype was *1b with the percent of 52.87%,*1a and *15 occupied 32.18% and 14.94%,respectively,and no * 5 type was detected.There were no significant differ-ences in TG,TC,LDL-C and HDL-C concentrations between SLCO1B1 groups.Conclusion ApoE gene frequency distribu-tion was uneven.Its polymorphism be related with the lipid levels.The frequency distribution of SLCO1B1 gene had racial differences,and its polymorphism was not related with lipid level.According to the the genotypes of ApoE and SLCO1B1, clinician can choose the right dose of drug to prevent coronary atherosclerotic disease.

Establishment of allele-specific real-time polymerase chain reaction for detecting neonatal hyperbilirubinemia related gene SLCO1B1 A388G polymorphism / 中华实用儿科临床杂志

Objective To establish the allele-specific real-time polymerase chain reaction (ASPCR) for detection of neonatal hyperbilirubinemia related gene SLCO1B1 A388G polymorphism and apply this assay to identify the clinical samples.Methods According to SLCO1B1 A388G polymorphism loci,specific primers were designed and the assay was established.Wide type plasmid and mutant plasmid were constructed.Fifty clinical samples were selected,including 30 samples of neonatal hyperbilirubinemia that had been diagnosed with SLCO1B1 A388G mutant and 20 samples of healthy newborns without SLCO1B1 A388G mutant were selected as the controls.Wide type plasmid,mutant plasmid and clinical samples were tested by specific and non-specific primers.A388G polymorphism was determined by difference in Ct (cycle threshold) between specific and non-specific primers.Then,the accuracy,sensitivity and specificity of assay were evaluated.Results The difference in Ct (cycle threshold) between specific and non-specific primers that amplified equivalent wide type template was 13.97 ±0.75.The assay could correctly distinguish the wide type and mutant plasmid.Probit regression analysis showed the sensitivity of the assay could reach to 5.28 copies/μL.For clinical samples,the Ct values of the samples with A388G mutation was less than 37.75 and showed positive results,while the samples without A388G mutation did not show any amplification nor Ct values were larger than 37.75,which showed negative results.Conclusions ASPCR is a fast,simple and effective method for SLCO1B1 A388G polymorphism detection of the clinical simples.It can be used for large sample screening for neonatal hyperbilirubinemia gene loci.

Meta-Analysis of the SLCO1B1 c.521T>C Variant Reveals Slight Influence on the Lipid-Lowering Efficacy of Statins

BACKGROUND: Several studies have focused on the association between the lipid-lowering efficacy of statins and the SLCO1B1 c.521T>C polymorphism; however, the results are conflicting. The effects of statins show significant variability between individuals. This meta-analysis aimed to investigate the effects of the SLCO1B1 c.521T>C polymorphism on the lipid-lowering effects of statins. METHODS: We systematically searched PubMed and Web of Science to screen relevant studies. Meta-analysis was performed to identify the association between SLCO1B1 c.521 polymorphisms and the lipid-lowering effects of statinson the basis of the standard mean difference (SMD) and 95% confidence intervals (CIs). Additionally, we checked for heterogeneity (I 2) among studies and evidence of publication bias. We obtained eight studies including 2,012 wild genotype (T/T) and 526 variant genotype (T/C and C/C) cases. RESULTS: No significant difference was observed in the lipid-lowering efficacy of statins between the wildand variant genotypes of SLCO1B1, with a pooled SMD of 0.03 (95% CI: -0.07-0.13). Furthermore, there was no significant effect in the meta-analyses of the variant heterozygote, homozygote, and Chinese populations. Subgroup meta-analysis indicated that the timerequired for the statin to take effectdid notsignificantly affect the association between lipid-lowering efficacy of statins and SLCO1B1 c.521T>C polymorphism. However, thewild genotype improved the lipid-lowering efficacy of simvastatin with a pooled SMD of -0.26 (95% CI: -0.47- -0.05). CONCLUSIONS: No significant association was detected between the lipid-lowering efficacy of statins and the SLCO1B1 c.521T>C polymorphism, with the exception of simvastatin.