Genetic variation in drug transporters in ethnic populations.
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ABSTRACT:
SUBMITTER: Cropp CD
PROVIDER: S-EPMC2976712 | biostudies-literature | 2008 Sep
REPOSITORIES: biostudies-literature
Publications
Genetic variation in drug transporters in ethnic populations.
Cropp C D CD Yee S W SW Giacomini K M KM
Clinical pharmacology and therapeutics 20080604 3
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Project description:Polymorphisms in drug transporters, like the adenosine triposphate-binding cassette (ABC) and solute carrier (SLC) superfamilies, may contribute to the observed diversity in drug response in African patients. This review aims to provide a comprehensive summary and analysis of the frequencies and distributions in African populations of ABC and SLC variants that affect drug pharmacokinetics (PK) and pharmacodynamics (PD). Of polymorphisms evaluated in African populations, SLCO1B1 rs4149056 and SLC22A6 rs1158626 were found at markedly higher frequencies than in non-African populations. SLCO1B1 rs4149056 was associated with reduction in rifampin exposure, which has implications for dosing this important anti-tuberculosis therapy. SLC22A6 rs1158626 was associated with increased affinity for antiretroviral drugs. Genetic diversity in SLC and ABC transporters in African populations has implications for conventional therapies, notably in tuberculosis and HIV. More PK and PD data in African populations are needed to assess potential for a different response to drugs compared with other global populations.
| S-EPMC7485953 | biostudies-literature
Project description:BackgroundAlthough racial and ethnic disparities in health services utilization and outcomes have been extensively studied in several countries, this issue has received little attention in Canada. We therefore analyzed data from the 2001 Canadian Community Health Survey to compare the use of health services by members of visible minority groups and nonmembers (white people) in Canada.MethodsLogistic regression was used to compare physician contacts and hospital admissions during the 12 months before the survey and recent cancer screening tests. Explanatory variables recorded from the survey included visible minority status, sociodemographic factors and health measures.ResultsRespondents included 7057 members of visible minorities and 114,255 white people for analysis. After adjustments for sociodemographic and health characteristics, we found that minority members were more likely than white people to have had contact with a general practitioner (adjusted odds ratio [OR] 1.28, 95% confidence interval [CI] 1.14-1.42), but not specialist physicians (OR 1.01, 95% CI 0.93-1.10). Members of visible minorities were less likely to have been admitted to hospital (OR 0.83, 95% CI 0.70- 0.98), tested for prostate-specific antigen (OR 0.64, 95% CI 0.52-0.79), administered a mammogram (OR 0.68, 95% CI 0.59-0.80) or given a Pap test (OR 0.47, 95% CI 0.39-0.56).InterpretationUse of health services in Canada varies considerably by ethnicity according to type of service. Although there is no evidence that members of visible minorities use general physician and specialist services less often than white people, their utilization of hospital and cancer screening services is significantly less.
| S-EPMC1402387 | biostudies-literature
Project description:Genetic polymorphism in cytochrome P450 (CYP) monooxygenase genes is an important source of interindividual variability of drug response. CYP enzyme activities may change as a result of such polymorphisms which then, may affect drug metabolism. This would result in a change in the severity and frequency of adverse effects in addition to the non-responder phenomenon. CYP2E1, a member of CYP superfamily, affects the metabolism of several clinically important drugs such as halothane, paracetamol, etc. Genetic variation in CYP2E1 is known to cause significant inter-individual differences in drug response and adverse effects. The degree of genetic variation is found to be different in different populations around the world. The frequencies of two important polymorphisms in the CYP2E1*7C, NC_000010.10:g.135340548A>G (rs2070672) and CYP2E1, NC_000010.10:g.135339244G>C (rs3813865), are not known in the Pakistani population. In the present investigation, 636 healthy human volunteers were screened for these two single nucleotide polymorphism. Our results indicate that about 18% (rs2070672) and 28% (rs3813865) of the Pakistani population has a genotype containing at least one low activity allele. A significant interethnic variation in the frequencies of both the polymorphisms was observed. These results suggest that pharmacogenetics screening for low activity genotypes would be a helpful tool for clinicians when they prescribe medications metabolized by CYP2E1, as a significant fraction of the Pakistani population is expected to have a variable response to these drugs.
| S-EPMC7443092 | biostudies-literature
Project description:BackgroundThe lung cancer risk of smokers varies by race/ethnicity even after adjustment for smoking. Evaluating the role of genetics in nicotine metabolism is likely important in understanding these differences, as disparities in risk may be related to differences in nicotine dose and metabolism.MethodsWe conducted a genome-wide association study in search of common genetic variants that predict nicotine and cotinine glucuronidation in a sample of 2,239 smokers (437 European Americans, 364 African Americans, 453 Latinos, 674 Japanese Americans, and 311 Native Hawaiians) in the Multiethnic Cohort Study. Urinary concentration of nicotine and its metabolites were determined.ResultsAmong 11,892,802 variants analyzed, 1,241 were strongly associated with cotinine glucuronidation, 490 of which were also associated with nicotine glucuronidation (P < 5×10(-8)). The vast majority were within chromosomal region 4q13, near UGT2B10. Fifteen independent and globally significant SNPs explained 33.2% of the variation in cotinine glucuronidation, ranging from 55% for African Americans to 19% for Japanese Americans. The strongest single SNP association was for rs115765562 (P = 1.60 × 10(-155)). This SNP is highly correlated with a UGT2B10 splice site variant, rs116294140, which together with rs6175900 (Asp67Tyr) explains 24.3% of the variation. The top SNP for nicotine glucuronidation (rs116224959, P = 2.56 × 10(-43)) was in high LD (r(2) = 0.99) with rs115765562.ConclusionsGenetic variation in UGT2B10 contributes significantly to nicotine and cotinine glucuronidation but not to nicotine dose.ImpactThe contribution of genetic variation to nicotine and cotinine glucuronidation varies significantly by racial/ethnic group, but is unlikely to contribute directly to lung cancer risk.
| S-EPMC4294952 | biostudies-literature
Project description:Patient and providers' fear of fetal exposure to medications may lead to discontinuation of treatment, disease relapse, and maternal morbidity. Placental drug transporters play a critical role in fetal exposure through active transport but the majority of data are limited to the 3rd trimester, when the majority of organogenesis has already occurred. Our objective was to define gestational age (GA) dependent changes in protein activity, expression and modifications of five major placental drug transporters: SERT, P-gp, NET, BCRP and MRP3. Apical brush border membrane fractions were prepared from fresh 1st, 2nd and 3rd trimester human placentas collected following elective pregnancy termination or planned cesarean delivery. A structured maternal questionnaire was used to identify maternal drug use and exclude exposed subjects. Changes in placental transporter activity and expression relative to housekeeping proteins were quantified. There was evidence for strong developmental regulation of SERT, NET, P-gp, BCRP and MRP3. P-gp and BCRP decreased with gestation (r = -0.72, p < 0.001 and r = -0.77, p < 0.001, respectively). Total SERT increased with gestation but this increase was due to a decrease in SERT cleavage products across trimesters. Uncleaved SERT increased with GA (r = 0.89, p < 0.001) while cleaved SERT decreased with GA (r = -0.94, p < 0.001). Apical membrane NET overall did not appear to be developmentally regulated (r = -0.08, p = 0.53). Two forms of MRP3 were identified; the 50 kD form did not change across GA; the 160 kD form was steady in the 1st and 2nd trimester and increased in the 3rd trimester (r = 0.24, p = 0.02). The 50 kD form was expressed at higher levels. The observed patterns of SERT, NET P-gp, BCRP and MRP3 expression and activity may be associated with transporter activity or decreased placental permeability in the 1st trimester to transporter specific substrates including commonly used psychoactive medications such as anti-depressants, anti-psychotics, and amphetamines, while transport of nutrients and serotonin is important in the 1st trimester. Overall these observations are consistent with a strong protective effect during organogenesis. 3rd trimester estimates of fetal exposure obtained from cord blood likely significantly overestimate early fetal exposure to these medications at any fixed maternal dose.
| S-EPMC9019509 | biostudies-literature
Project description:Genetic polymorphism of drug metabolizing enzymes and transporters may influence drug response. The frequency varies substantially between ethnicities thus having implications on appropriate selection and dosage of various drugs in different populations. The distribution of genetic polymorphisms in healthy Pakistanis has so far not been described. In this study, 155 healthy adults (98 females) were included from all districts of Karachi. DNA was extracted from saliva and genotyped for relevant SNVs in CYP1A1, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A5 as well as ALDH3A1, GSTA1, ABCB1 and ABCC2. About 64% of the participants were born to parents who were unrelated to each other. There was generally a higher prevalence (p < 0.05) of variant alleles of CYP450 1A2, 2B6, 2C19, 3A5, ALDH3A1, GSTM1 as well as ABCB1 and ABCC2 in this study cohort than in other ethnicities reported in the HapMap database. In contrast, the prevalence of variant alleles was lower in GSTA1. Therefore, in the Pakistani population sample from Karachi a significantly different prevalence of variant drug metabolizing enzymes and ABC transporters was observed as compared to other ethnicities, which could have putative clinical consequences on drug efficacy and safety.
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Project description:AimIn this study, we used a series of diallelic genetic marker insertion/deletion polymorphism (indel) to investigate three populations of Yao, Kelao, and Zhuang groups in the Guangxi region of China and to evaluate their efficiency in forensic application.ResultNo deviations for all 30 loci were observed from the Hardy-Weinberg equilibrium after Bonferroni correction (p > 0.05/30 = 0.0017). The allele frequencies of the short allele (DIP-) for the above three populations were in the range of 0.0520-0.9480, 0.0950-0.8780, and 0.0850-0.915, respectively. The observed heterozygosity of the 30 loci for the three populations was in the ranges 0.0802-0.5802, 0.1908-0.6053, and 0.1400-0.5600, respectively. The cumulative power of exclusion and combined discrimination power for Yao, Kelao, and Zhuang groups were (0.9843 and 0.9999999999433), (0.9972 and 0.9999999999184), and (0.9845 and 0.9999999999608), respectively. The DA distance, principal component analysis, and cluster analysis indicated a clear regional distribution. In addition, Zhuang groups had close genetic relationships with the Yao and Kelao populations in the Guangxi region.ConclusionThis study indicated that the 30 loci were qualified for personal identification; moreover, they could be used as complementary genetic markers for paternity testing in forensic cases for the studied populations.
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Project description:Although sequencing a single human genome was a monumental effort a decade ago, more than 1000 genomes have now been sequenced. The task ahead lies in transforming this information into personalized treatment strategies that are tailored to the unique genetics of each individual. One important aspect of personalized medicine is patient-to-patient variation in drug response. Pharmacogenomics addresses this issue by seeking to identify genetic contributors to human variation in drug efficacy and toxicity. Here, we present a summary of the current status of this field, which has evolved from studies of single candidate genes to comprehensive genome-wide analyses. Additionally, we discuss the major challenges in translating this knowledge into a systems-level understanding of drug physiology, with the ultimate goal of developing more effective personalized clinical treatment strategies.
| S-EPMC3448823 | biostudies-other
Project description:We investigated levels of nucleotide polymorphism within and among populations of the highly self-fertilizing Brassicaceous species, Arabidopsis thaliana. Four-cutter RFLP data were collected at one mitochondrial and three nuclear loci from 115 isolines representing 11 worldwide population collections, as well as from seven commonly used ecotypes. The collections include multiple populations from North America and Eurasia, as well as two pairs of collections from locally proximate sites, and thus allow a hierarchical geographic analysis of polymorphism. We found no variation at the mitochondrial locus Nad5 and very low levels of intrapopulation nucleotide diversity at Adh, Dhs1, and Gpa1. Interpopulation nucleotide diversity was also consistently low among the loci, averaging 0.0014. gst, a measure of population differentiation, was estimated to be 0.643. Interestingly, we found no association between geographical distance between populations and genetic distance. Most haplotypes have a worldwide distribution, suggesting a recent expansion of the species or long-distance gene flow. The low level of polymorphism found in this study is consistent with theoretical models of neutral mutations and background selection in highly self-fertilizing species.
| S-EPMC1460032 | biostudies-other
Project description:Genome wide DNA methylation profiling of smokers and non-smokers in PBMC samples. The Illumina Infinium 450k Human DNA methylation Beadchip v1.1 was used to obtain DNA methylation profiles across 485,577 CpGs in PBMC samples. Samples included 24 smokers and 28 non-smokers.
2017-02-13 | GSE59550 | GEO