Determination of probability distribution of diplotype configuration (<i>diplotype distribution</i>) for each subject from genotypic data using the EM algorithm

Kitamura, Yutaka; Moriguchi, Masato; Kaneko, Hirotaka; Morisaki, Hiroko; Morisaki, Takayuki; Toyama, Keiko; Kamatani, Naoyuki

doi:10.1046/j.1469-1809.2002.00112.x

Cited by 75 publications

(60 citation statements)

References 12 publications

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“…(29) In the present study, homozygosity for the reference allele at the CBR1c.627C>T and +967G>A loci was observed to be associated with increased clearance and reduced exposure levels of doxorubicin in Asian breast cancer patients. The reasons for the lack of influence of the homozygous variant alleles at the CBR1 c.627C>T and +967G>A loci on doxorubicin pharmacokinetic parameters are unknown and could possibly be due to a smaller cohort of breast cancer patients studied.…”

Section: Discussionmentioning

confidence: 85%

CBR1 and CBR3 pharmacogenetics and their influence on doxorubicin disposition in Asian breast cancer patients

et al. 2008

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The present study aimed to identify polymorphic genes encoding carbonyl reductases (CBR1, CBR3) and investigate their influence on doxorubicin disposition in Asian breast cancer patients (n = 62). Doxorubicin (60 mg/m 2 ) was administered every 3 weeks for four to six cycles and the pharmacokinetic parameters were estimated using non-compartmental analysis (WinNonlin). The Mann-Whitney U-test was used to assess genotypic-phenotypic correlations. (1) The phase I and II enzymes are expressed abundantly in hepatic tissues and display large interindividual variations in their metabolic capacities toward a wide array of therapeutic agents.The CBR are ubiquitously expressed monomeric NADPHdependent cytosolic enzymes that catalyze the reduction of chemically diverse substrates such as aldehydes, ketones, quinones, and other xenobiotics.(2,3) Apart from the metabolism of endogenous compounds and drug detoxification, CBR are also assumed to participate in cellular processes such as signal transduction, (4) apoptosis,mutagenesis,carcinogenesis,and drug resistance.(8) Four CBR isoforms (CBR1, CBR2, CBR3, and CBR4) that were initially assigned to the aldo-keto reductase (AKR) family are now classified under the family of short-chain dehydrogenases and represent one of the largest protein families identified to date.(9) CBR1 is the major carbonyl reductase and is expressed widely in different tissues. The CBR1 gene is mapped to chromosome 21q22.12, has three exons spanning 3.3 kb, and encodes a 30-kDa monomeric protein comprising 277 amino acids. The CBR1 gene lacks a CAAT and TATA box and contains a GC-rich island extending into the first exon, a structure characteristic of genes having a housekeeping function.(4) The identified substrates of human CBR1 include endogenous compounds (prostaglandins and steroids) and drugs such as loxoprofen, (4) metyrapone, (10) haloperidol, (11) bromoperidol,timirepone, (13) and doxorubicin. (14) CBR2 has low sequence identity with CBR1 and has not been identified in human tissues. The CBR3 gene contains three exons spanning a region of 11.2 kb and has a 72% sequence similarity with CBR1. It is located 62 kb telomeric to the CBR1 gene. Although widely expressed, the relative expression of CBR3 is much lower than CBR1 in most of the tissues analyzed.(15) The CBR4 gene is located on human chromosome 4 (4q32.3) and encodes a protein composed of 237 amino acids, but its enzymatic properties and tissue distribution remain unknown. (15) To date, there are limited studies investigating the influence of genetic polymorphisms in the CBR genes on the pharmacokinetics and pharmacodynamics of drugs. Avramopoulos et al. identified the CBR1 3′-untranslated region (UTR) G>A transition for the linkage mapping of the CBR gene on chromosome 21. (16) However, the effect of the polymorphism on enzyme activity and tissue expression is not known. Gonzalez-Covarrubias et al. reported the V88I (262G>A, rs1143663), L73L (312G>C, rs25678), A209A (720C>T, rs20572), and V231V (786G>A, rs2230192) polymorphisms by scree...

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Section: Discussionmentioning

confidence: 85%

CBR1 and CBR3 pharmacogenetics and their influence on doxorubicin disposition in Asian breast cancer patients

et al. 2008

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“…We applied the genotypic data to the LDSUPPORT program 25 to estimate the haplotype frequencies in the population and to calculate the posterior probability of diplotype distribution for each subject. This program was designed for typing of haplotype using a maximum likelihood estimation method which is based on the expectation maximization (EM) algorithm assuming Hardy-Weinberg's equilibrium for the population.…”

Section: Typing Of Haplotype and Diplotype Configurationsmentioning

confidence: 99%

Association between adult-onset Still's disease and interleukin-18 gene polymorphisms

et al. 2002

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Recently, we reported that serum concentration of IL-18 is strikingly high in patients with adult-onset Still's disease (AOSD). The aim of the present study was to screen for genetic polymorphisms in the human IL-18 (hIL-18) gene and to determine the association of polymorphisms with susceptibility to AOSD. We investigated the 6.7 kb region upstream of exon 2 of hIL-18 gene, in which a promoter activity had been reported. Sixteen AOSD patients, 144 rheumatoid arthritis (RA) patients and 92 healthy control individuals were studied. We found seven single nucleotide polymorphisms and a single 9 bp insertion which were frequently present in the AOSD patients. Three haplotypes including a unique combination of these polymorphisms were also determined. Of them, haplotype S01 contained all eight of these polymorphisms. The frequency of individuals carrying a diplotype configuration, ie a combination of two haplotypes, of S01/S01 was significantly higher in the AOSD patients than in the healthy controls (P ¼ 0.00059, Fischer's exact probability test, odds ratio [OR] ¼ 7.81, 95% confidence interval [95% CI] ¼ 2. 48-24.65) and the RA patients (P ¼ 0.015, Fischer's exact probability test, OR ¼ 4.0, 95% CI ¼ 1.39-11.54). We therefore conclude that possession of the diplotype configuration of S01/S01 is a major genetic risk factor for susceptibility to AOSD.

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“…Some haplotypes were unambiguously identified from subjects with homozygous variations at all sites or a heterozygous variation at only one site. Diplotype configurations were inferred by LDSUPPORT software, which determines the posterior probability distribution of the diplotype for each subject based on the estimated haplotype frequencies (Kitamura et al 2002). Although the nomenclature for nonsynonymous DPYD alleles (DPYD*1 to DPYD*13) have been already publicized CollieDuguid et al 2000;Johnson et al 2002), several reported alleles remain unassigned.…”

Section: Pcr Conditions For Dna Sequencingmentioning

confidence: 99%

Genetic variations and haplotype structures of the DPYD gene encoding dihydropyrimidine dehydrogenase in Japanese and their ethnic differences

et al. 2007

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Dihydropyrimidine dehydrogenase (DPD) is an inactivating and rate-limiting enzyme for 5-fluorouracil (5-FU), and its deficiency is associated with a risk for developing a severe or fatal toxicity to 5-FU. In this study, to search for genetic variations of DPYD encoding DPD in Japanese, the putative promoter region, all exons, and flanking introns of DPYD were sequenced from 341 subjects including cancer patients treated with 5-FU. Fifty-five genetic variations, including 38 novel ones, were found and consisted of 4 in the 5 0 -flanking region, 21 (5 synonymous and 16 nonsynonymous) in the coding exons, and 30 in the introns.

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Determination of probability distribution of diplotype configuration (diplotype distribution) for each subject from genotypic data using the EM algorithm

Cited by 75 publications

References 12 publications

CBR1 and CBR3 pharmacogenetics and their influence on doxorubicin disposition in Asian breast cancer patients

CBR1 and CBR3 pharmacogenetics and their influence on doxorubicin disposition in Asian breast cancer patients

Association between adult-onset Still's disease and interleukin-18 gene polymorphisms

Genetic variations and haplotype structures of the DPYD gene encoding dihydropyrimidine dehydrogenase in Japanese and their ethnic differences

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