Association between SLCO1B1, apolipoprotein E and ABCG2 genes and lipid response to rosuvastatin: a meta-analysis.

Background/Aims:Gout is a common inf lammatory arthritis triggered by the crystallization of uric acid in the joints. Serum uric acid levels are highly heritable, suggesting a strong genetic component. Independent studies to confirm the genetic associations with gout in various ethnic populations are warranted. We investigated the association of polymorphisms in the ABCG2 and SLC2A9 genes with gout in Korean patients and healthy individuals.Methods:We consecutively enrolled 109 patients with gout and 102 healthy controls. The diagnosis of gout was based on the preliminary criteria of the America College of Rheumatology. Genomic DNA was extracted from whole blood samples. We identified single nucleotide polymorphism (SNP) changes in the ABCG2 and SLC2A9 genes using a direct sequencing technique. rs2231142 in ABCG2 and rs6449213 and rs16890979 in SLC2A9 and nearby regions were amplified by polymerase chain reaction.Results:Patients with gout had significantly higher A/A genotype (29.3% vs. 4.9%, respectively) and A allele (52.8% vs. 26.5%, respectively) frequencies of rs2231142 in ABCG2 than did controls (χ2 = 29.42, p < 0.001; odds ratio, 3.32; 95% confidence interval, 2.11 to 5.20). We found novel polymorphisms (c.881A>G and c.1002+78G>A) in the SLC2A9 gene. The univariate logistic regression analysis revealed that the c.881A>G and c.1002+78G>A SNPs were significantly higher in patients than in controls.Conclusions:We demonstrated a significant association between rs2231142 in the ABCG2 gene and gout and identified novel SNPs, c.881A>G and c.1002+78G>A, in the SLC2A9 gene that may be associated with gout in a Korean population.

BACKGROUNDCoronary heart disease (CHD) is a prominent cause of mortality and disability worldwide. Like most complex diseases, the risk of CHD in individuals is regulated by the interaction between genetic factors and lifestyle. APOE and SLCO1B1 genetic polymorphisms and LPA KIV-2 copy number variation may influence the development and progression of CHD. Clarifying gene polymorphisms can guide clinical precision and prevention, thereby improving treatment outcomes.AIMTo investigate the influence of APOE and SLCO1B1 gene polymorphisms, as well as LPA KIV-2 copy number variation on CHD in the Teochew population.METHODSA total of 324 patients with CHD and 143 control participants were involved in this study. Single nucleotide polymorphisms rs429358 and rs7412 in the APOE gene, and rs2306283 and rs4149056 in the SLCO1B1 gene were analyzed via high-resolution melting curve analysis. Additionally, PCR was performed to detect KIV-2 copy number variations. Clinical risk factors and potential effects on CHD patients were subsequently assessed.RESULTSIn the CHD group, the frequencies of APOE allele ε2, ε3, ε4 were 8.02%, 82.97%, and 9.10%, respectively. Compared to the control groups (13.29%, 79.37%, and 7.34%, respectively), the ε2 allele frequency showed a significant difference (8.02% vs 13.29%, P = 0.012). SLCO1B1 allele frequencies in the CHD group were not significantly different from those in the control group (*1a: 26.69% vs 25.52%, *1b: 61.17% vs 65.38%, *5: 0.15% vs 0.35%, *15: 11.83% vs 8.74%). The number of copies of the KIV-2 gene was significantly lower in the CHD group when compared to controls (23.35 ± 8.78 vs 27.21 ± 9.48; P < 0.01). Logistic regression analysis revealed that sex, age, hypertension, diabetes, smoking, the ε2 allele and KIV-2 copy number were factors influencing the presence of CHD.CONCLUSIONIn the Teochew population, the APOE ε2 allele and a higher KIV-2 copy number were associated with a reduced risk of CHD. In contrast, the APOE ε4 allele and SLCO1B1 gene were not associated with CHD.

A lack of information regarding whether genetic polymorphisms of SLCO1B1 and ABCG2 affect the pharmacokinetics (PKs)/pharmacodynamics (PDs) of rosuvastatin in elderly subjects prevents optimal individualized pharmacotherapy of rosuvastatin in clinical settings. This study aimed to investigate the effect of age and genetic polymorphisms and possible differences in genetic effects on the PKs/PDs of rosuvastatin between elderly and young subjects. Two separate clinical studies designed as open-label, one-sequence studies with multiple-dose administration for elderly (n = 20) and young (n = 32) subjects were conducted. All subjects received 20 mg of rosuvastatin once daily for 21 days. The exposure to rosuvastatin, characterized by the area under the time curve (AUC), increased by 23% in the elderly subjects compared with that of young subjects, which was not significant. When compared to the subjects with breast cancer resistance protein (BCRP) normal function, the exposure to rosuvastatin increased by 44% in young subjects (p = 0.0021) with BCRP intermediate function (IF) and by 35% and 59% (p > 0.05 for both) in elderly subjects with BCRP IF and low function, respectively. SLCO1B1 521T > C was also partially associated with a higher AUC of rosuvastatin in young subjects and a less pronounced increasing trend in elderly subjects (p > 0.05 for both). The lipid-lowering effect of rosuvastatin was less pronounced in the elderly subjects than in the young subjects, and genetic polymorphisms of neither SLCO1B1 nor ABCG2 significantly affected the PDs of rosuvastatin. The ABCG2 421C > A polymorphism was associated with the PKs of rosuvastatin and was identified as a more important determinant than the SLCO1B1 521T > C polymorphism in both elderly and young subjects.

Background Organic anion-transporting polypeptide 1B1 (OATP1B1) and the ATP-binding cassette subfamily G member 2, ABCG2, are important transporters involved in the transport of endogenous substrates and xenobiotics, including drugs. Genetic polymorphisms of these transporters have effect on transporter activity. There is significant interethnic variability in the frequency of allele variants. Aim To determined allele and genotype frequencies of ABCG2 and SLCO1B1 genes in Croatian populations of European descent. Subjects and methods A total of 905 subjects (482 women) were included. Genotyping for ABCG2 c.421C > A (rs2231142) and for SLCO1B1 c.521T > C (rs4149056), was performed by real-time polymerase chain reaction (PCR) using TaqMan® DME Genotyping Assays. Results For ABCG2 c.421C > A, the frequency of CC, CA and AA genotypes was 81.4%, 17.8% and 0.8% respectively. The frequency of variant ABCG2 421 A allele was 9.7%. For SLCO1B1 c.521T > C, the frequency of TT, TC and CC genotypes was 61.7%, 34.8% and 3.5% respectively. The frequency of variant SLCO1B1 521 C allele was 20.9%. Conclusion The frequency of the ABCG2 and SLCO1B1 allelic variants and genotypes in the Croatian population is in accordance with other European populations. Pharmacogenetic analysis can serve to individualise drug therapy and minimise the risk of developing adverse drug reactions.

The role of drug transporters in pravastatin disposition is underlined by the fact that pravastatin does not undergo significant cytochrome P-450 (CYP)-mediated biotransformation. The organic anion transporting polypeptide 1B1 (OATP1B1), encoded by SLCO1B1, and multidrug resistance-associated protein 2 [MRP2 (ABCC2)], are thought to be the major transporters involved in the pharmacokinetics of pravastatin in humans. Other transporters that may play a role include OATP2B1, organic anion transporter 3 (OAT3), bile salt export pump (BSEP), and the breast cancer resistance protein (BCRP). OATP1B1 and MRP2 mediate the hepatic uptake and biliary excretion of pravastatin, respectively. The SLCO1B1 and ABCC2 polymorphisms probably contribute to the high interindividual variability in pravastatin disposition. Recent small studies have characterized the impact of the SLCO1B1 polymorphism on pravastatin in humans, and especially the c.521T>C single-nucleotide polymorphism (SNP) seems to be an important determinant of pravastatin pharmacokinetics. Pravastatin plasma concentrations may be up to 100% higher in subjects carrying the c.521C variant, as found in the *5, *15, *16, and *17 haplotypes, reflecting diminished OATP1B1-mediated uptake into the major site of pravastatin elimination, the liver. The SLCO1B1 polymorphism seems to have a similar impact on the pharmacokinetics of single- and multiple-dose pravastatin. Overall, 2-5% of individuals in various populations may be expected to show markedly elevated plasma pravastatin concentrations due to the SLCO1B1 polymorphism. Of note, the impact of the SLCO1B1 polymorphism on statins may be dependent on ethnicity. Although individuals with a diminished hepatic uptake of pravastatin might be expected to show reduced cholesterol-lowering efficacy due to lower intracellular pravastatin concentrations, there is preliminary evidence to suggest that the SLCO1B1 polymorphism is not a major determinant of non-response to pravastatin. The possible consequences of drug transporter polymorphisms, especially the SLCO1B1 and ABCC2 polymorphisms, for the lipid-lowering efficacy and tolerability of pravastatin in various ethnic groups warrant further study.

This exploratory study aimed to explain the interindividual variabilities of docetaxel pharmacokinetics and pharmacodynamics in Asian nasopharyngeal carcinoma patients (n = 54) through the genotyping of CYP3A4, CYP3A5, ABCB1, ABCC2, ABCG2 and SLCO1B3 genes. Docetaxel was administered over 1 h on days 1, 8, and 15 every 28 days at 30 mg/m(2)/dose. Genomic DNA was isolated from peripheral blood and genotyped for the selected polymorphisms in the candidate genes. Docetaxel pharmacokinetic parameters were estimated by non-compartmental modelling. Patients homozygous for the variant allele (GG) of SLCO1B3 rs11045585 (IVS12-5676A > G) had significantly higher area under the plasma concentration-time curve of docetaxel (P = 0.026) and lower clearance (P = 0.036) compared to patients with AA/AG genotypes. Patients harbouring the heterozygous genotype (GA + GT + TA) for ABCB1 rs2032582 (2677G > T/A) had the highest percentage decrease in nadir haemoglobin from cycle 1 baseline compared to those with GG/TT genotypes (P = 0.006). Similar trend was observed for ABCB1 rs1045642 (3435C > T) with heterozygotes (CT) having the highest percentage decrease in nadir haemoglobin from cycle 1 baseline compared to those with CC/TT genotypes (P = 0.066). This study suggests that the cooperative influence of functional polymorphisms in SLCO1B3 and ABCB1 genes may be responsible for the interindividual variability in docetaxel disposition in Asian nasopharyngeal cancer patients.

We aimed to analyze the correlation between ABCG2 gene polymorphisms of 34 GG/(GA + AA) loci, 421 CC/(AC + AA) loci, and non-small cell lung cancer (NSCLC) therapeutic effects via meta-analysis. With key words, the databases PubMed and EMBASE were searched for clinical studies on ABCG2 polymorphism and NSCLC. RR and 95% CIs were used to compute combined effects, followed by heterogeneity testing. Publication bias was examined using the funnel plot method. Review Manager 5.3 software was used for the meta-analysis. Ten studies were included. No evidence of heterogeneity exists in these studies. The results indicate that two polymorphic loci of ABCG2 gene (34 G>A, and 421 C>A) had no relationship with the curative effect of chemotherapy for NSCLC, except ABCG2 34G>A, which had a significant relationship with the skin toxicity complication. There was no significant relationship between these polymorphisms and complications (skin toxicity, diarrhea, interstitial pneumonia, liver dysfunction, and neutropenia). Begg’s test and Egger’s test indicated that there was no obvious publication bias. The meta-analysis indicated that there was no significant correlation between ABCG2 gene polymorphism and NSCLC outcomes.

Objective The single nucleotide polymorphisms (SNPs) of APOE and SLCO1B1 were examined to explore their association with the risk and severity of coronary heart disease(CAD). Methods A total of 1 267 cases of consecutive coronary heart disease (CAD)-suspected inpatients visiting department of Cardiology in Peking University Peoples′ Hospital from March 2017 to november were recruited into this case-control study, and then 391 CAD cases and 223 non-CAD controls were enrolled for final analysis after screening by coronary angiography and exclusion criteria. The severity of the CAD cases were evaluated according to Gensini scores. The SNPs of APOE(388T>C, 526C>T) and SLCO1B1(388A>G, 521T>C) were detected using Real-time PCR and further verified using Sanger sequencing. Environmental risk factors were collected, and the correlations between SNPs of APOE and SLCO1B1 and the risk and severity of CAD were performed by SPSS version 16.0. Results The SNPs of all the subjects included in CAD group and non-CAD group were successfully detected, with an accordance of 100% to Sanger sequencing. The distribution of APOE and SLCO1B1 gene were subjected to Hardy-Weinberg. The distributions of APOE gene e3/e3 genotypes and e3 allele were most commonly found in both CAD group and non-CAD group (e3/e3: 70.8%,73.1%;e3: 83.5%,85.2%;respectively). APOE genotypes and alleles were comparable between the CAD cases and non-CAD controls (P>0.05). The frequencies of APOE gene e4+ genotype were more likely to be found in the subgroup of CAD with Gensini score≥72 (P 0.05). Conclusion This study observed no association between SNPs of APOE, SLCO1B1 and the risk of CAD in this population. However, APOE gene e4+ genotype may increase the severity of CAD. Key words: Apolipoproteins E; Solute carrier organic anion transporter family member 1b1; Polymorphism, genetic; Coronary disease; Severity of illness index

To date, the biological significance of breast cancer resistance protein (BCRP) G34A and C421A polymorphisms is largely unknown. Analysis of these two polymorphisms in 156 diffuse large B-cell lymphoma (DLBCL) patients and 376 control subjects revealed an increased risk of DLBCL associated with variant BCRP 421 genotypes (CA and AA), when compared with the wild-type CC genotype [odds ratio = 1.49, 95% confidence interval (CI) 1.02-2.17, P = 0.042]. Moreover, the increased risk was more evident in younger patients (<or=50 years, odds ratio = 2.14, 95% CI 1.25-3.68, P = 0.006). Further evaluation for the association of these polymorphisms with overall survival of DLBCL showed that patients with 34AA alleles displayed worse survival compared with those carrying GG/GA genotypes [hazard ratio (HR) = 3.69, 95% CI 1.56-8.71, P = 0.001]. Significant association between 421CC genotypes and poorer survival of DLBCL was observed in patients younger at diagnosis (<or=50 years, HR = 5.80, 95% CI 1.16-28.90, P = 0.015) or with bulky tumor (HR = 4.36, 95% CI 1.04-18.31, P = 0.027). Furthermore, we found the combined effects of BCRP G34A and C421A on the overall survival. Compared with patients carrying BCRP 34(GG + GA)421(AA + CA) genotype, the individual with 34AA421CC displayed the worst survival (HR = 7.55, 95% CI 2.36-24.17, P = 0.001), while those with 34(GG + GA)421CC and 34AA421(AA + CA) combinations showed the intermediate survival. These results suggest that the BCRP G34A and C421A polymorphisms are associated with the risk and survival of DLBCL. Our finding warrants further investigations on the association of BCRP polymorphisms with susceptibility and clinical outcome of cancer.

Riboflavin (vitamin B2) has been proposed as a biomarker for breast cancer resistance protein (BCRP) activity. In recent studies in mice, cynomolgus monkeys, and humans, BCRP-inhibiting drugs increased the plasma concentration of riboflavin. We showed recently that ticagrelor inhibits BCRP and raises the plasma concentrations of the BCRP substrate rosuvastatin in healthy volunteers. In the same drug-drug interaction study, we now investigated whether ticagrelor affects the plasma concentrations of riboflavin. Intake of 90 mg ticagrelor increased the ratio between the peak plasma riboflavin concentration and the fasting riboflavin concentration before ticagrelor administration by 1.20-fold (90% confidence interval, 1.10-1.32; P = 0.006) compared to placebo. In vitro, riboflavin was transported by BCRP and multidrug-resistance-associated protein 4 (MRP4) but no clear transport was observed by MRP2, MRP3, or the P-glycoprotein. Moreover, ticagrelor inhibited the transport of riboflavin in BCRP- and MRP4-expressing membrane vesicles with unbound 50% inhibitory concentrations of 0.020 and 1.1μM, respectively. Based on vesicle and tissue protein expression data, the small intestinal MRP4-mediated efflux clearance of riboflavin (1.2-1.4 nL/min/mg) was estimated to be similar to that mediated by BCRP (0.23-1.3 nL/min/mg). As MRP4 is expressed in the basolateral membrane of enterocytes, it may facilitate the absorption of riboflavin and impair the utility of riboflavin as a biomarker of intestinal BCRP. To conclude, ticagrelor modestly raises the plasma concentration of riboflavin probably by inhibiting intestinal BCRP. Inhibition of intestinal MRP4 may have reduced the absorption of riboflavin and limited the effect of ticagrelor on riboflavin levels.

Anti-Inflammatory Effects of Statins Beyond Cholesterol Lowering

The effects of various polymorphisms in cytochrome P450 (CYP) enzyme and transporter genes on the pharmacokinetics (PK) of simvastatin were evaluated in healthy Korean men. Plasma concentration data for simvastatin and simvastatin acid were pooled from four phase I studies comprising 133 participants. The polymorphisms CYP2D6*4, CYP2D6*5, CYP2D6*14, CYP2D6*41, CYP3A5*3, CYP2C19*2, CYP2C19*3, CYP2A6*7, and CYP2A6*9; SLCO1B1 rs4149056, rs2306283, and rs4149015; ABCB1 rs1128503, rs2032582, and rs1045642; and ABCG2 rs2231142 were evaluated in each participant. Noncompartmental PK results were compared by genotype. CYP2D6*5 and CYP2D6*14 were found to be associated with a higher area under the curve (AUC) for simvastatin, whereas the AUC of simvastatin acid was significantly increased in patients with the SLCO1B1 rs4149056, ABCG2 rs2231142, and CYP2D6*41 allele variants. Patients with the CYP2D6*41 variant showed a higher peak serum concentration (Cmax) of both simvastatin and simvastatin acid. The SLCO1B1 rs4149056 and rs4149015 polymorphisms were associated with an increased AUC ratio (i.e. ratio of simvastatin acid to simvastatin), whereas the SLCO1B1 rs4149056 and CYP2D6*5 variants were related to a higher Cmax ratio. The CYP2D6*5, CYP2D6*14, CYP2D6*41, CYP3A5*3, SLCO1B1 rs4149056 and rs4149015, and ABCG2 rs2231142 genetic polymorphisms are associated with the PK of both simvastatin and simvastatin acid. This could potentially be used as a basis for individualized simvastatin therapy by predicting the clinical outcomes of this treatment.

PurposeDirect oral anticoagulants (DOACs) are widely used for stroke prevention in atrial fibrillation. However, they have a bleeding complication. Breast cancer resistance protein, encoded by ABCG2, is known to be an efflux transporter of apixaban and rivaroxaban among DOACs. This study aimed to investigate the association between gene variants and bleeding complications during treatment with ABCG2 substrates (apixaban and rivaroxaban).Patients and MethodsPatients treated with apixaban and rivaroxaban were enrolled from June 2018 to December 2021. Five single nucleotide polymorphisms (SNPs) of ABCG2 were selected. Previously studied genes (ABCB1, CYP3A4, and CYP3A5) were further analyzed as possible confounders. Finally, a total of 16 SNPs were examined in this case–control study. The outcome was defined as major bleeding and clinically relevant non-major bleeding. Two models were constructed using the multivariable analysis.ResultsAmong 293 patients, 64 were cases. The mean age of the patients was 68.8 years, and males comprised 62.5% of the study population. Model I revealed that a history of bleeding, concurrent use of proton pump inhibitor (PPI), ABCG2 rs3114018, and ABCB1 rs1045642 were significantly associated with bleeding complications; the AORs (95% CI) were 6.209 (2.210–17.442), 2.385 (1.064–5.349), 2.188 (1.156–4.142), and 3.243 (1.371–7.671), respectively. Model II showed that modified HAS-BLED score, concurrent use of PPI, ABCG2 rs3114018, and ABCB1 rs1045642 were significantly associated with bleeding complications.ConclusionThe modified HAS-BLED score, a history of bleeding, concurrent use of PPI, ABCG2 rs3114018, and ABCB1 rs1045642 were significantly associated with the risk of bleeding complications in patients on apixaban and rivaroxaban, after adjusting for other confounders. These findings can be used to develop individualized treatment strategies for patients taking apixaban and rivaroxaban.

Background This study aimed to investigate the relationships between the expression of apolipoprotein E (APOE) and gene polymorphisms of solute carrier organic anion transporter family member 1B1 (SLCO1B1) with the blood lipid profile and coronary artery disease severity in Han Chinese individuals living in eastern China. Methods This study enrolled 91 patients hospitalized at the Second Affiliated Hospital of Anhui Medical University from June 2024 to December 2024. The serum lipid profiles, including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and lipoprotein(a) [LP(a)], were measured via the Olympus AU5400 system. The genotypes of the APOE and SLCO1B1 genes were determined by Sanger sequencing. The participants were stratified into three groups on the basis of their Gensini scores. Differences in blood lipid levels and APOE/SLCO1B1 genotype distributions among these groups were statistically analyzed. The Gensini score model and myocardial infarction risk model were subsequently constructed via APOE genotyping, LDL-C levels, and other differential biomarkers identified from the analysis. Results Patients with the ApoE ε4 genotype had higher LDL-C and Lp(a) levels and higher Gensini scores (F = 11.591, P &lt; 0.001), indicating more severe coronary artery lesions than the other groups did. Multiple linear regression analysis revealed both LDL-C levels and ApoE genotypes as independent predictors of the severity of coronary artery lesions, whereas SLCO1B1 genotype had a minor effect on lipid levels and coronary artery lesion severity. Notably, this study specifically analyzed the impact of ApoE polymorphisms on the incidence of myocardial infarction and reported a statistically significant difference in the incidence of myocardial infarction among different ApoE genotypes (χ²=6.49, P = 0.039). The prediction model showed excellent predictive performance (area under the curve (AUC): 0.793 in the Gensini score prediction model and AUC: 0.855 in the myocardial infarction prediction model). Conclusion APOE genotype is associated with the concentrations of LDL-C and Lp(a) as well as the severity of coronary artery lesions and the occurrence of myocardial infarction.

IntroductionGenetic polymorphisms of drug transporters influence drug transporter activity and alter pharmacokinetic profiles of the drugs. Organic anion transporting polypeptide 1B1 (OATP1B1) and breast cancer resistance protein (BCRP) are important transporters encoded by solute carrier organic anion transporter family member 1B1 (SLCO1B1) gene and ATP-binding cassette subfamily G member 2 (ABCG2) gene, respectively. Polymorphisms in these genes are associated with increased plasma statins concentrations, statin-induced myopathy and poor response to allopurinol treatment.PurposeWe explored allele and genotype frequencies of SLCO1B1 and ABCG2 genes including their predicted phenotypes in 53 Thai participants. Of these, 17 had chronic kidney disease and were on statins.Materials and MethodsGenotyping analysis for SLCO1B1 c.521T>C (rs4149056), c.388A>G (rs2306283), g.-11187G>A (rs4149015), and ABCG2 c.421C>A (rs2231142) was done by using TaqMan® Real time PCR. All were tested for Hardy–Weinberg Equilibrium.ResultsMost of the participants (80%) had normal function haplotypes SLCO1B1 (*1A and *1B) while decreased (*5, *15, and *17) and unknown (*21) function haplotypes were less observed. Four phenotypes of SLCO1B1 were observed: 69.81% had normal function (*1A/*1A,*1A/*1B, and *1B/*1B), 13.21% had intermediate function (*1A/*17, *1B/*15 and *1B/*17), 9.43% had indeterminate function (*1A/*21 and *1B/*21) and 7.55% had low function (*5/*15, *15/*15, and *15/*17). ABCG2 c.421A allele frequency was 25%. The frequency of ABCG2 c.421CA and AA phenotypes were 37.7% and 5.7%, respectively. The allele and genotype frequencies observed are consistent with reports in Asians. However, there were differences in major allele distributions between Asians and Caucasians for SLCO1B1 c.388A>G; SLCO1B1 c.388G were highly found in Asians, but c.388A were more observed in Caucasians.ConclusionThis study showed that in the Thai population, there were 4 SNPs of SLCO1B1 and ABCG2 genes. This finding may be clinically applied to minimize inter-individual variability of drugs such as statins and allopurinol. Further study with a larger sample size is needed to assess the drug profiles and responses to treatment.