UGT1A1*28 genotype and irinotecan-induced neutropenia: dose matters

The Food and Drug Administration and Pfizer changed the package insert for irinotecan to include a patient's UGT1A1*28 genotype as a risk factor for severe neutropenia on the basis of the findings of four pharmacogenetic studies, which found that irinotecan-treated patients who were homozygous for the UGT1A1*28 allele had a greater risk of hematologic toxic effects than patients who had one or two copies of the wild-type allele (UGT1A1*1). Findings of subsequent irinotecan pharmacogenetic studies have been inconsistent. In a meta-analysis, we reviewed data presented in nine studies that included a total of 10 sets of patients (for a total of 821 patients) and assessed the association of irinotecan dose with the risk of irinotecan-related hematologic toxicities (grade III-IV) for patients with a UGT1A1*28/*28 genotype. The risk of toxicity was higher among patients with a UGT1A1*28/*28 genotype than among those with a UGT1A1*1/*1 or UGT1A1*1/*28 genotype at both medium (odds ratio [OR] = 3.22, 95% confidence interval [CI] = 1.52 to 6.81; P = .008) and high (OR = 27.8, 95% CI = 4.0 to 195; P = .005) doses of irinotecan. However, risk was similar at lower doses (OR = 1.80, 95% CI = 0.37 to 8.84; P = .41). Low doses of irinotecan (100-125 mg/m2) are in the commonly used therapeutic range. The risk of experiencing irinotecan-induced hematologic toxicity for patients with a UGT1A1*28/*28 genotype thus appears to be a function of the dose of irinotecan administered.     

The association between TA-repeat polymorphism in the promoter region of UGT1A1 and breast cancer risk: a meta-analysis

Uridine diphospho-glucuronosyltransferase 1A1 (UGT1A1) plays an important role in breast cancer development. To date, many publications have evaluated the correlation between UGT1A1 TA-repeat polymorphism and breast cancer risk. However, the results remain inconclusive. In order to resolve this conflict, a meta-analysis was performed by searching Medline, PubMed, and ISI Web of Knowledge databases. Seven studies including 5,746 cases and 8,365 controls were collected for UGT1A1 TA-repeat polymorphism. The strength of association between UGT1A1 TA-repeat polymorphism and breast cancer risk was assessed by calculating crude ORs with 95% CIs. Overall, no significant associations between UGT1A1 TA-repeat polymorphism and breast cancer susceptibility were found. In the stratified analysis by ethnicity and source of controls, significant associations were only observed for 6/6 versus 7/7 (OR = 0.88; 95% CI: 0.77–0.99; P = 0.425 for heterogeneity) in Caucasians, but no in other genetic models. In conclusion, this meta-analysis suggests that UGT1A1 A(TA)₇TAA allele is a potential risk factor for breast cancer in Caucasians.     

川东北地区人群结直肠癌患者UGT1A1*28基因多态性与伊立替康所致毒副反应的相关性

目的:观察结直肠癌患者UGT1A1*28基因多态性的分布频率,了解UGT1A1*28基因多态性与结直肠癌患者应用伊立替康联合5-氟尿嘧啶化疗毒副反应的相关性。方法:从384例接受伊立替康联合氟尿嘧啶一线化疗的晚期结直肠癌病例中采外周血提取DNA。采用PCR 法扩增目的基因片段,直接测序法分析UGT1A1*28基因多态性。临床观察并评价患者化疗毒副反应分级,统计分析UGT1A1*28基因表型与化疗毒副反应相关性。结果:全部 384例患者 UGT1A1*28基因多态性分布情况:TA6/6野生基因型287例(74.7％),TA6/7杂合基因型73例（19.0％）,TA7/7纯合基因型24例（6.3％）。化疗毒副反应和UGT1A1*28基因多态性进行临床单因素分析显示UGT1A1*28基因纯合型TA7/7、杂合型TA6/7与3-4度白细胞减少、中性粒细胞减少、腹泻、胆红素升高具有明显相关性（P<0.01）,UGT1A1*28基因纯合型TA7/7及杂合型TA6/7患者发生中性粒细胞减少的风险较UGT1A1*28基因野生型TA6/6患者高5.625倍（OR=5.625）。UGT1A1*28基因纯合型TA7/7和UGT1A1*28基因杂合型TA6/7患者发生腹泻的风险较UGT1A1*28基因野生型TA6/6患者高6.778倍（OR=6.778）。结论:UGT1A1*28基因纯合型TA7/7及杂合型TA6/7患者应用伊立替康化疗后发生重度中性粒细胞减少、重度腹泻的风险高于UGT1A1*28基因野生型TA6/6,为临床伊立替康用药选择、剂量调整、毒副反应的提前干预提供理论依据。     

Associations between UGT1A1*6 or UGT1A1*6/*28 polymorphisms and irinotecan-induced neutropenia in Asian cancer patients

Purpose

Neutropenia is a life-threatening side effect of irinotecan, and uridine diphosphate glucuronosyltransferases (UGTs) gene polymorphisms are considered to be one of the predictive markers of irinotecan-related toxicities. Many studies have demonstrated that patients bearing UGT1A1*28 have a higher risk of severe neutropenia on toxicity of irinotecan. However, UGT1A1 (TA7/TA7) was very rare in Asian populations. Some researches reported that UGT1A1*28 and/or UGT1A1*6 could predict irinotecan-induced toxicities in Asian populations, but controversial conclusions still remained. This study aims to investigate the association between UGT1A1 gene polymorphisms *6, *6/*28 and irinotecan-related neutropenia in Asian cancer patients receiving irinotecan regimen chemotherapy.

Experimental design

Meta-analyses were done to assess the relationship between UGT1A1*6 or UGT1A1*6/*28 and irinotecan-induced neutropenia.

Results

The risk of neutropenia was significantly higher among patients with a UGT1A1*6 genotype than among those carrying the UGT1A1*1 allele(s) [odds ratio (OR) 3.276; 95 % confidence interval (CI) 1.887–5.688; P = 0.000 (*6/*6 vs. *1/*6 or *1/*1)], [OR 1.542; 95 % CI 1.180–2.041; P = 0.001 (*6/*6 or *1/*6 vs. *1/*1)]. Also, the risk was significantly higher among patients with a UGT1A1*6/*28 than among those carrying the UGT1A1*1 allele(s) [OR 3.275; 95 % CI 2.152–4.983; P = 0.000 (*6/*6 or *28/*28 or *6/*28 vs. *1/*6 or *1/*28 or *1/*1)].

Conclusions

In conclusion, the UGT1A1*6 and UGT1A1*6/*28 genotypes were associated with an increased risk of irinotecan-induced neutropenia in Asian cancer patients.     

UGT1A1基因多态性与伊立替康治疗结直肠癌不良反应的关系

背景与目的：尿苷二磷酸葡萄糖醛酸转移酶1A1(uridine diphosphoglucu-ronosyltransferase 1A1,UGTlA1)是伊立替康代谢关键酶,其活性受基因多态性影响显著。本研究探讨结直肠癌患者中,UGT1A1*28和UGT1A1*6基因多态性与伊立替康治疗相关不良反应之间的关系。方法：入组2013年4月—2013年12月于复旦大学附属中山医院肿瘤内科接受治疗的消化道恶性肿瘤患者160例。抽提外周血中基因组DNA,分别采用STR方法和Sanger测序法,检测UGT1A1*28和UGT1A1*6基因型,分析UGT1A1基因多态性分布情况。对其中82例化疗方案中含伊立替康的结直肠癌患者进行随访,记录不良反应发生情况和严重程度,比较不同基因型患者之间的差异。结果：160例消化道肿瘤患者中,UTG1A1*28(启动子TATA盒区域TA重复次数)野生型TA6/6124例(77.5%);杂合子TA6/7 33例(20.5%);纯合子TA7/7 3例(2.0%)。UGT1A1*6位点(211G>A)野生型GG 105例(65.6%),杂合子GA 48例(30.0%);纯合子AA 7例(4.4%)。82例化疗方案中含伊立替康的结直肠癌患者中,*28基因型(TA6/7和TA7/7)显著增加发生3级以上中性粒细胞减少的风险(58.3% vs 0.0%,P<0.001),并增加整体不良反应发生率(76.0% vs 45.6%,P<0.001);*6基因型(GA和AA)、年龄、性别、化疗方案和伊立替康相关不良反应发生无显著相关性。结论：接受伊立替康化疗的结直肠癌患者,UGT1A1*28位点多态性显著增加中性粒细胞减少发生的风险,可预测伊立替康引起的骨髓抑制性不良反应,辅助临床选择合适的化疗方案。     

UGT1A1基因多态性与伊立替康临床用药安全性及疗效的关系

目的：研究 UGT1A1基因多态性与伊立替康治疗结直肠癌患者的不良反应及疗效之间的关系。方法：自外周血中抽提基因组 DNA,进行 PCR 扩增,应用直接测序法分析2012年3月至2013年3月,于我院行基因检测的65例结直肠癌患者 UGT1A1*28和 UGT1A1*6基因多态性的分布情况。并对这65例应用含伊立替康方案化疗的患者出现的不良反应及化疗疗效,进行观察记录,比较不同基因型间的差异。结果：65例患者中,UGT1A1*28野生型 TA6／6有49例（75．4％）,杂合突变型 TA6／7有14例（21．5％）,纯合突变型TA7／7有2例（3．1％）。UGT1A1*6野生型 G／G 有47例（72．3％）,杂合突变型 G／A 有15例（23．1％）,纯合突变型 A ／A 有3例（4．6％）。在以上65例结直肠癌患者中,UGT1A1基因启动子区28位点,TA6／6、TA6／7和TA7／7型,发生3级以上腹泻者分别为8．2％、37．5％;发生3级以上中性粒细胞减少者分别为28．6％、62．5％。UGT1A1基因启动子区6位点,G／G、G／A 和 A ／A 型,发生3级以上腹泻者分别为12．8％、44．4％;发生3级以上中性粒细胞减少者分别为14．9％、22．2％。各组之间疗效无统计学差异。结论：患者 UGT1A1*28和UGT1A1*6多态性分布基本一致,UGT1A1*28突变型可以使应用含伊立替康化疗患者发生3级以上腹泻和中性粒细胞减少的风险增加。UGT1A1*6突变型可增加3级以上腹泻的发生风险。因此,UGT1A1基因型的检测对伊立替康相关的不良反应有一定的预测作用,可提高用药安全性,在临床用药中起到了指导作用。     

UGT1A1基因不同表型与FOLFIRI方案治疗晚期结直肠癌疗效及毒副反应的相关性

目的:回顾性分析UGT1A1基因不同表型与FOLFIRI方案治疗晚期结直肠癌疗效及毒副反应的相关性。方法:收集贵州医科大学附属肿瘤医院腹部肿瘤科2014年1月至2018年12月收治的临床分期为Ⅳ期结直肠癌或根治性手术后复发转移的晚期结直肠癌患者240例的临床病理资料,所有患者初次行FOLFIRI方案化疗前抽血,提取全血中的DNA,采用PCR技术行UGT1A1基因型检测;接受FOLFIRI化疗方案治疗直至疾病进展或者发生不可耐受的毒性反应。分别采用Binary Logistic Regression模型分析UGT1A1基因不同表型与FOLFIRI化疗疗效的相关性,分解模型及广义估计方程多应变量回归分析UGT1A1基因不同表型与FOLFIRI化疗毒副反应的相关性。结果:本组患者共发现3种UGT1A1基因表型,分别为UGT1A1*1/*1(纯合野生型TA6/6型 188/240 78.3%)、UGT1A1*28/*1(杂合突变型TA6/7型 47/240 19.6%)和UGT1A1*28/*28(纯合突变型TA7/7型 5/240 2.1%)。UGT1A1基因型中TA6/7型TA6/6型相比,FOLFIRI化疗无应答风险增加16%,但无统计学差异;本组转移器官＞2个的患者中TA6/7型和TA6/6型相比,血液学及非血液学毒副反应发生的风险均增加了9.377 3倍（P=0.007 9）,其中消化道毒副反应发生风险增加了42.806 6倍（P=0.025 9）;本组行FOLFIRI化疗≥4周期的患者中,TA6/7型比TA6/6型的患者发生血液学毒性的风险增加了22.324 6倍（P=0.003 5）。结论:TA6/6型为我省结直肠癌患者最为常见的UGT1A1基因表型,而TA7/7型罕见;晚期结直肠癌转移器官数超过2个行FOLFIRI化疗的患者中UGT1A1基因TA6/7型较TA6/6型患者血液学及非血液学毒副反应发生的风险均明显增加,其中消化道毒副反应发生的风险更胜。     

UGT1A1 polymorphism can predict hematologic toxicity in patients treated with irinotecan.

PURPOSE: Irinotecan (CPT-11) is approved in metastatic colorectal cancer treatment and can cause severe toxicity. The main purpose of our study was to assess the role of different polymorphisms on the occurrence of hematologic toxicities and disease-free survival in high-risk stage III colon cancer patients receiving 5-fluorouracil (5FU) and CPT-11 adjuvant chemotherapy regimen in a prospective randomized trial. EXPERIMENTAL DESIGN: Four hundred patients were randomized in a phase III trial comparing LV5FU2 to LV5FU2 + CPT-11. DNA from 184 patients was extracted and genotyped to detect nucleotide polymorphism: 3435C>T for ABCB1, 6986A>G for CYP3A5, UGT1A1*28 and -3156G>A for UGT1A1. RESULTS: Genotype frequencies were similar in both treatment arms. In the test arm, no significant difference was observed in toxicity or disease-free survival for ABCB1 and CYP3A5 polymorphisms. UGT1A1*28 homozygous patients showed more frequent severe hematologic toxicity (50%) than UGT1A1*1 homozygous patients (16.2%), P = 0.06. Moreover, patients homozygous for the mutant allele of -3156G>A UGT1A1 polymorphism showed more frequent severe hematologic toxicity (50%) than patients homozygous for wild-type allele (12.5%), P = 0.01. This toxicity occurred significantly earlier in homozygous mutant than wild-type homozygous patients (P = 0.043). In a Cox model, the hazard ratio for severe hematologic toxicity is significantly higher for patients with the A/A compared with the G/G genotype [hazard ratio, 8.4; 95% confidence interval, 1.9-37.2; P = 0.005]. CONCLUSIONS: This study supports the clinical utility of identification of UGT1A1 promoter polymorphisms before LV5FU2 + CPT-11 treatment to predict early hematologic toxicity. The -3156G>A polymorphism seems to be a better predictor than the UGT1A1 (TA)(6)TAA>(TA)(7)TAA polymorphism.     

Genetic polymorphisms in uridine diphospho-glucuronosyltransferase 1A1 and breast cancer risk in Africans

The UDP-glucuronosylatransferase 1A1 (UGT1A1) gene is involved in the metabolism of estrogen and detoxification of potential carcinogens. The number of TA repeats in the promoter region of UGT1A1 has been linked to breast cancer risk, but results varied by race. We performed a comprehensive assessment of genetic polymorphisms in the UGT1A1 gene, and examined these polymorphisms and TA repeats in relation to breast cancer risk in a case-control study in Nigeria. 512 breast cancer cases and 226 community controls were genotyped for UGT1A1. Compared with high-activity TA repeat genotypes, the odds ratios (OR) for low-activity and moderate-activity genotypes were 0.47 (95% confidence interval CI, 0.26-0.83) and 0.64 (95% CI, 0.39-1.06), respectively, in premenopausal women (P = 0.009 for trend), but no association was observed in postmenopausal women (P = 0.24). The effect of TA repeats was also differentiated by age: the OR was 0.39 (95% CI 0.21-0.71) for low-activity genotypes and 0.58 (95% CI 0.33-1.00) for moderate-activity genotypes in women <45 years old (P = 0.002 for trend), but no association was observed in women >/=45 years old (P = 0.15). Haplotype analysis showed that UGT1A1 haplotypes were highly diverse with blocked structures. We found a specific haplotype in block 2 that was significantly associated with a 2.1-fold elevated risk (95% CI 1.05-4.39; P = 0.04). In contrast with previous studies, we found low-activity TA repeat alleles were protective against breast cancer among premenopausal indigenous Africans, suggesting that the role of UGT1A1 in breast cancer development may vary by population, presumably due to different environmental and genetic modifier effects.     

UGT1A1*28 polymorphism in ovarian cancer patients

(Uridino-diphosphate)glucuronosyl-transferase enzyme 1A1 isoform (UGT1A1) is involved in glucuronidation of antineoplastic drugs such as SN38, the active metabolite of irinotecan, as well as estrogens and their metabolites. UGT1A1*28 polymorphism decreases UGT1A1 expression and could alter estrogens disposition influencing tumour growth in hormone sensitive tissues. The UGT1A1*28 distribution among an ovarian cancer patient (OCP) population of 217 mono-institutional individuals was investigated to clarify its possible involvement in the pathogenesis and chemotherapy of ovarian cancer. Data were compared with those of 205 female healthy blood donors. In 160 patients also the tumour tissue was genotyped to describe the occurrence of loss of heterozygosity (LOH). A PCR based assay followed by automated fragment analysis was used. Odds ratios (OR), and 95% confidence intervals (95% CI), were computed by a multiple logistic regression model using as dependent variable in a case-control or in a case-case approach the histological classification. No significant prevalence of the polymorphism was observed in the cases versus controls. In a case-case approach, a higher frequency of the polymorphism was observed in patients with mucinous tumours (6/11, 54.6%) compared to non-mucinous (30/206, 14.6%) (p=0.009, OR=7.20; 95% CI 2.06-25.19). LOH was observed in 12 cases out of 160 (7.5%) and was associated with non-mucinous tumours, 10 (83.3%) cases determined a retention of the wild-type allele. In conclusion, the prevalence of UGT1A1*28 found in mucinous OCP could suggest a role in the development of specific histologic sub-groups and could become a marker to be considered when planning ovarian cancer chemotherapy.     

Clinical Observations on Associations Between the UGT1A1 Genotype and Severe Toxicity of Irinotecan

Background: Severe toxicity is commonly observed in cancer patients receiving irinotecan (CPT-11)UDPglucuronosyltransferase1A1 (UGT1A1) catalyzes the glucuronidation of the active metabolite SN-38 but therelationship between UGT1A1 and severe toxicity remains unclear. Our study aimed to assess this point to guideclinical use of CPT-11. Materials and Methods: 89 cancer patients with advanced disease received CPT-11-basedchemotherapy for at least two cycles. Toxicity, including GI and hematologic toxicity was recorded in detail andUGT1A1 variants were genotyped. Regression analysis was used to analyse relationships between these variablesand tumor response. Results: The prevalence of grade III-IV diarrhea was 10.1%, this being more common inpatients with the TA 6/7 genotype (5 of 22 patients, 22.7%) (p<0.05). The prevalence of grade III-IV neutropeniawas 13.4%and also highest in patients with the TA 6/7 genotype (4 of 22 patients; 18.2%) but without significance(p>0.05). The retreatment total bilirubin levels were significantly higher in TA6/7 patients (mean, 12.75μmol/L)with compared to TA6/6 (mean, 9.92 μmol/L) with p<0.05. Conclusions: Our study support the conclusion thatpatients with a UGT1A1*28 allele (s) will suffer an increased risk of severe irinotecan-induced diarrhea, whetherwith mid-or low-dosage. However, the UGT1A1*28 allele (s) did not increase severe neutropenia. Higher serumtotal bilirubin is an indication that patients UGT1A1 genotype is not wild-type, with significance for clinic usageof CPT-11.     

SULT1A1 genotype and susceptibility to colorectal cancer

Several procarcinogens that are present in cooked red meat and tobacco smoke are substrates for sulfotransferase 1A1 (SULT1A1). The association between environmental exposures and colorectal cancer risk may be modified by individual differences in the metabolism. Thus, we investigated the effect of a common polymorphism in the SULT1A1 gene associated with decreased enzyme activity on the susceptibility to colorectal cancer in a population-based case-control study. Patients (505) and 604 age- and sex-matched controls provided detailed risk factor information and were genotyped for SULT1A1 G638A using a fluorescence-based melting curve analysis method. Multivariate logistic regression analysis was used to estimate colorectal cancer risk associated with environmental exposures by SULT1A1 genotype. SULT1A1 genotype was not an independent risk factor for colorectal cancer. Risk of colorectal cancer associated with frequent consumption of red meat was significantly elevated among carriers of the SULT1A1*2 allele but not increased among subjects with the SULT1A1*1/*1 genotype (odds ratio (OR) 2.1, 95% confidence interval (CI) 1.1-4.1 and OR 1.0, 95% CI 0.5-2.1, respectively). Colorectal cancer risk associated with 30+ pack-years of active smoking was higher among carriers of the SULT1A1*2 allele (OR 1.7, 95% CI 1.0-3.2) than among individuals with the SULT1A1*1/*1 genotype (OR 1.1, 95% CI 0.6-2.1). Our results do not support a main effect of SULT1A1 genotype with regard to colorectal cancer but suggest that individuals with the low activity SULT1A1*2 allele may be at higher risk following carcinogen exposure than those with the SULT1A1*1/*1 genotype.     

中国人尿苷二磷酸葡糖苷酸转移酶1A基因多态性与伊立替康毒性的相关性

目的评价伊立替康(CVT-11)联合5-氟尿嘧啶(5-Fu)和亚叶酸钙(LV)治疗晚期大肠癌的毒性与尿苷二磷酸葡糖苷酸转移酶1A(UGT1A)基因多态性的相关性。方法收集70例晚期大肠癌患者及健康志愿者的外周血,提取基因组DNA,PCR法扩增目的基因片段,直接测序法分析UGT1A基因多态性,并与毒性进行相关性分析。结果70例晚期大肠癌患者的3～4度中性粒细胞减少发生率为20.O%(14/70);2～4度迟发性腹泻发生率为22.9%(16/70),其中3-4度迟发性腹泻率仅为5.7%(4/70)。UGT1A1*28的野生基因型TA6/6患者的2-4度迟发性腹泻发生率为15.7%,低于TA6/7和TA7/7基因型的患者(P=0.027)。健康人群和大肠癌患者UGT1A基因家族中各个基因多态性的分布无差别。结论UGT1A1*28的野生基因型TA6/6在中国人中分布频率较高,这也是CPT-11为主方案治疗晚期大肠癌发生严重迟发性腹泻较少的原因。     

Association of serum bilirubin and promoter variations in HMOX1 and UGT1A1 genes with sporadic colorectal cancer

Heme oxygenase-1 (HMOX1) and bilirubin UDP-glucuronosyltransferase (UGT1A1) enzymes, both involved in bilirubin homeostasis, play an important role in the oxidative stress defense. The objective of our study was to assess the effect of promoter variations of HMOX1 and UGT1A1 genes and of serum bilirubin on the risk of sporadic colorectal cancer (CRC). This exploratory case-control study was based on 777 CRC patients and 986 controls from the Czech Republic. The (GT)(n) and (TA)(n) dinucleotide variations in HMOX1 and UGT1A1 gene promoters, respectively, were determined by fragment analysis. In addition, the A(-413)T variant in HMOX1 promoter was also analyzed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Serum bilirubin levels were compared in a subset of 174 cases and 247 controls, for whom biochemical data were available. After adjustment for age, a significant association between CRC risk and UGT1A1*28 allele carrier status was detected [odds ratio (95% confidence intervals) = 0.80 (0.60-0.97), p = 0.022]. No association between CRC risk and individual HMOX1 gene variants was observed, although a diplotype analysis revealed an increased risk for a specific HMOX1 genotype combination. These effects were more pronounced in males. Substantially lower serum bilirubin levels were detected in CRC patients compared to the controls (p < 0.001); each 1 μmol/L decrease in serum bilirubin was associated with a 7% increase of CRC risk (p < 0.001). In conclusion, UGT1A1*28 allele carrier status might be a protective factor against the development of CRC in the male population, whereas low serum bilirubin levels are associated with an increased risk of CRC in both genders.     

Linkage disequilibrium of UGT1A1 *6 and UGT1A1 *28 in relation to UGT1A6 and UGT1A7 polymorphisms

UDP-glucuronosyltransferase (UGT) enzymes are responsible for the glucuronidation and detoxification of many endogenous or exogenous xenobiotics. Gilbert's syndrome (GS) and Crigler Najjar syndrome type 2 (CNS-II) are characterized by unconjugated hyperbilirubinemia due to reduced enzymatic activity of UGT1A1. Recent studies have demonstrated the frequent co-existence of UGT1A1 *28 (-53 [TA]6>7) with other polymorphisms of UGT1A6 and UGT1A7. This finding suggests the occurrence of linkage disequilibrium (LD) among UGT1A1, UGT1A6 and UGT1A7 polymorphisms. UGT1A1 *6 (211G>A, G71R) and UGT1A1 *28 are common in Asian populations. In the present study, we investigated the LD of UGT1A1 *6 and UGT1A1 *28 in relation to UGT1A6 and UGT1A7 polymorphisms. Exon 1 of UGT1A1, UGT1A6 and UGT1A7 was sequenced using genomic DNA isolated from peripheral leukocytes of 390 Japanese subjects. LD and haplotypes were analyzed using SNPAlyze ver. 5.0 software. UGT1A1 *6 had a strong LD in relation to UGT1A6 variants including 541A>G and 552A>C (D'=0.846-0.848, r(2)=0.413-0.438) and UGT1A7 variants including 387T>G, 391C>A, 392G>A and 622T>C (D'=0.667-0.858, r(2)=0.207-0.413). UGT1A1 *28 had a lower degree of LD than UGT1A1 *6 in relation to these variants (D'=0.245-0.401, r(2)=0.025-0.063). All the haplotypes with G71R lacked -53[TA]6>7. The present study showed for the first time that the LD of UGT1A1 *6 in relation to UGT1A6 and 1A7 polymorphisms is far stronger than UGT1A1 *28. The UGT1A1 *6 allele appears to be independent of the UGT1A1 *28 allele. Although patients with GS and CNS-II are believed to have good prognosis, a subgroup of GS or CNS-II patients with the UGT1A1 *6 polymorphism might be at risk of abnormal drug metabolism and of developing malignant disease.