Severe irinotecan-induced toxicity in a patient with UGT1A1*28 and UGT1A1*6 polymorphisms

Many studies have demonstrated the impact of UGT1A1 on toxicity of irinotecan. In particular, patients bear-ing UGT1A1*28 (TA 7/7) have a higher risk of severe neutropenia and diarrhea. Based on this, prescribers of irinotecan are advised that patients with UGT1A1*28 (TA 7/7) should start with a reduced dose of irinotecan, although a particular dose is not specified. Research in Asian countries has shown a lower incidence of UG-T1A1*28 (TA 7/7), while UGT1A1*6 (A/A) is more often found and is associated with severe irinotecan-related neutropenia. We report here a case of a metastatic colorectal cancer patient who is heterozygous for the UGT1A1*28 polymorphism (TA 6/7) as well as the UG-T1A1*6 polymorphism (G/A). The patient was treated with FOLFIRI for 9 cycles and underwent two irinote-can dose reductions according to pharmacokinetic data regarding exposure to the active metabolite, SN-38. Simultaneous heterozygous UGT1A1*28 and UGT1A1*6 polymorphisms may produce higher exposure to SN-38 and a higher risk of adverse effects related to irinote-can. Additional studies will be necessary to determine the optimal starting dose of irinotecan for patients with both UGT1A1*28 and UGT1A1*6 polymorphisms.     

伊立替康化学治疗的不良反应与UGT1A1＊28基因多态性的关系

目的：研究应用伊立替康化学治疗（化疗）的进展期消化道肿瘤患者不良反应的发生率及严重程度与UGT1A1基因启动子区多态性的关系。方法：选择66例汉族进展期消化道肿瘤患者,使用含伊立替康的方案化疗,观察并记录患者化疗中出现的不良反应、化疗前总胆红素水平和化疗后至Ⅲ度以上严重毒性时间（周）;外周血中抽提基因组DNA,测定UGT1A1基因启动子区TATA盒胸腺嘧啶-腺嘌呤（TA）序列重复次数,统计分析基因型与不良反应的关系,比较不同基因型患者化疗前总胆红素水平和至严重毒性时间的差异。结果：55例患者（83.3%）UGT1A1基因启动子区TA序列6次重复,为纯合野生型（TA）6/（TA）6（UGT1A1＊1/＊1）;11例患者（16.7%）基因型为TA序列6次和7次重复的杂合（TA）6/（TA）7（UGT1A1＊28/＊1）,未发现TA序列7次重复UGT1A1＊28/＊28的纯合突变。以上2组患者发生Ⅲ度以上白细胞或中性粒细胞减少者分别为26例和5例（47.3%比45.5%,P=1.000）,发生Ⅲ度以上腹泻者分别为5例和4例（9.1%比36.4%,P=0.036）。2组治疗前总胆红素水平分别为（15.1±1.1）μmol/L和（20.8±5.1）μmol/L（P=0.09）,至严重毒性时间2组分别为9周和3周（P=0.186）。结论：在应用伊立替康化疗的汉族患者中,UGT1A1启动子区TATA盒基因多态性（TA）6/（TA）7杂合状态可以增加患者发生Ⅲ度以上腹泻的风险,但不会增加患者发生Ⅲ度以上白细胞或中性粒细胞减少的风险。     

Link between colorectal cancer and polymorphisms in the uridine-diphosphoglucuronosyltransferase 1A7 and 1A1 genes

AIM: To investigate the relationship between single nucleotide polymorphisms in the uridine-diphosphoglucurono-syltransferase (UGT) UGT1A7 and UGT1A1 genes and patients suffering from colorectal cancer (CRC). METHODS: A case-control study was designed in order to investigate the genotypes of the UGT1A7 and UGT1A1 genes, which were identified by the polymerase chain reaction-restriction fragment length polymorphism (RFLP) method, for 268 CRC patients and 441 healthy controls. RESULTS: The results of simple logistical regressions revealed odds ratios (ORs) of 1.97 (P<0.001),1.91 (P<0.001),and 2.03 (P<0.001) for patients who carried the UGT1A7*1/*3 genotype,UGT1A7*3 allele,and variant-211 UGT1A1 allele.The interaction of UGT1A7*3 allele and variant-211 UGT1A1 allele produced an additive effect on the risk for the development of CRC [observed OR (2.34) greater than expected OR (1.59)]. For the 268 patients, the results of simple logistical regressions indicated that the OR of developing metastases was 4.90 (P<0.001) and 4.89 (P<0.001) for the individuals possessing UGT1A7*3 allele and variant-211 UGT1A1 allele, respectively. The results of multivariate logistical regressions confirmed these findings (OR = 2.51, P= 0.01; and OR=2.71,P=0.01,respectively).The interaction of these two variants resulted in an additive effect on the risk for metastases amongst patients [observed OR (6.83) greater than expected OR (4.56)]. CONCLUSION: In conclusion, carriage of the UGT1A7*3 allele, as well as variant-211 UGT1A1 allele represents a risk factor for the development of, and a determinant for, metastases associated with CRC patients.     

UGT1A1*28基因多态性与小细胞肺癌

尿苷二磷酸葡糖醛酸转移酶1A1 (uridine diphosphate glucuronosyl transferase 1A1,UGT1A1)是伊立替康(Irinotecan,CPT-11)活性产物的主要代谢酶,其活性与CPT-11的疗效和不良反应均密切相关,而UGT1A1* 28基因多态性可显著降低UGT1A1酶的表达与活性.IP(伊立替康+顺铂)方案是广泛期小细胞肺癌的一线化疗方案,UGT1A1* 28基因多态性可影响IP方案的疗效及不良反应,检测UGT1A1* 28基因多态性对于指导小细胞肺癌患者的个体化治疗具有一定的临床意义.     

UGT1A1 gene polymorphism： Impact on toxicity and efficacy of irinotecan-based regimens in metastatic colorectal cancer

AIM: To investigate the correlation between uridine diphosphate glucuronosyl transferase 1A1 ( UGT1A1) gene polymorphisms and irinotecan-associated side effects and parameters of drug efficacy in patients with metastatic colorectal cancer (mCRC) receiving a lowdose weekly irinotecan chemotherapeutic regimen.METHODS: Genotypes were retrospectively evaluated by gene scan analysis on the ABI 310 sequencer of the TATAA box in the promoter region of the UGT1A1 gene in blood samples from 105 patients who had received 1st line irinotecan-based chemotherapy for mCRC.RESULTS: The distribution of the genotypes was as follows: wild type genotype (WT) ( 6/6) 39.0%,heterozygous genotype ( 6/7) 49.5%, and homozygous genotype ( 7/7) 9.5%. The overall response rate (OR) was similar between patients carrying the ( 6/7, 7/7) or the WT genotype ( 6/6) (44.3% vs 43.2%, P = 0.75).Neither time to progression [(TTP) 8.1 vs 8.2 mo, P = 0.97] nor overall survival [(OS) 21.2 vs 18.9 mo, P = 0.73] differed significantly in patients who carried the ( 6/6) when compared to the ( 6/7, 7/7) genotype. No significant differences in toxicity were observed: Grade 3 and 4 delayed diarrhoea [( 6/7, 7/7) vs ( 6/6); 13.0% vs 6.2%, P =0.08], treatment delays [( 6/7, 7/7) vs ( 6/6); 25.1% vs 19.3%, P = 0.24] or dose reductions [( 6/7, 7/7) vs ( 6/6); 21.5% vs 27.2%, P = 0.07].CONCLUSION: This analysis demonstrates the nonsignificant influence of the UGT1A1 gene polymorphism on efficacy and rate of irinotecan-associated toxicity in mCRC patients receiving low-dose irinotecan based chemotherapy.     

Current place of high-dose irinotecan chemotherapy in patients with metastatic colorectal cancer

Introduction  Irinotecan has an important place in the treatment of metastatic colorectal cancer. It was initially administered as monotherapy, but is now generally used in combination with 5-fluorouracil or targeted therapies (cetuximab or bevacizumab), with various doses. Methods  We here review the main studies assessing irinotecan doses escalation, and discuss the potent advantages of this escalation. Results  Several studies have demonstrated a dose–intensity relationship for irinotecan, and high doses (up to 600 mg/m² as monotherapy, 260 mg/m² in combination therapy) have been used with satisfactory safety and higher objective response rates. It is possible that, in practice, some patients receive insufficient doses of irinotecan. Dose escalation could be considered in carefully selected patients: young patients with a good performance status and normal liver function. This approach could be useful in patients with liver metastases, which may become resectable in the case of a major tumour response. It is wise to perform UGT1A1 genotyping prior to dose escalation to detect patients at high risk of toxicity (genotype 7/7). The role of another laboratory parameter, which needs to be evaluated is the KRAS status of the tumour. A KRAS mutation confers resistance to cetuximab, which reduces treatment options, especially in first-line. However, in the CRYSTAL trial comparing FOLFIRI to FOLFIRI-cetuximab as first-line therapy, the presence of a KRAS mutation did not appear to influence the efficacy of FOLFIRI. The value of irinotecan dose escalation needs to be determined in this setting. Conclusion  Irinotecan dose escalation is potentially of interest in highly selected patients, but this concept is only based on phase I or II trials and must be validated by a randomized trial. Its value regarding other regimens such as FOLFIRINOX or combinations with targeted therapies also needs to be determined.     

Predictive effects of bilirubin on response of colorectal cancer to irinotecan-based chemotherapy

AIM: To examine the predictive effects of baseline serum bilirubin levels and UDP-glucuronosyltransferase(UGT) 1A1*28 polymorphism on response of colorectal cancer to irinotecan-based chemotherapy.METHODS: The present study was based on a prospective multicenter longitudinal trial of Chinese metastatic colorectal cancer(m CRC) patients treated with irinotecan-based chemotherapy(NCT01282658). Baseline serum bilirubin levels, including total bilirubin(TBil) and unconjugated bilirubin(UBil), were measured,and genotyping of UGT1A1*28 polymorphism was performed. Receiver operating characteristic curve(ROC) analysis was used to determine cutoff values of TBil and UBil. The TBil values were categorized into 13.0 or ≤ 13.0 groups; the UBil values were categorized into 4.1 or ≤ 4.1 groups. Combining the cutoff values of TBil and UBil, which was recorded as Co Bil, patients were classified into three groups. The classifier's performance of UGT1A1*28 and Co Bil for predicting treatment response was evaluated by ROC analysis. Associations between response and Co Bil or UGT1A1*28 polymorphism were estimated using simple and multiple logistic regression models. RESULTS: Among the 120 m CRC patients, the serum bilirubin level was significantly different between the UGT1A1*28 wild-type and mutant genotypes. Patients with the mutant genotype had an increased likelihood of a higher TBil(P = 0.018) and a higher UBil(P = 0.014) level compared with the wild-type genotype. Patients were stratified into three groups based on Co Bil. Group 1 was patients with TBil 13.0 and UBil 4.1; Group 2 was patients with TBil ≤ 13.0 and UBil 4.1; and Group 3 was patients with TBil ≤ 13.0 and UBil ≤ 4.1. Patients in Group 3 had more than a 10-fold higher likelihood of having a response in the simple(OR = 11.250; 95%CI: 2.286-55.367; P = 0.003) and multiple(OR = 16.001; 95%CI: 2.802-91.371; P = 0.002) analyses compared with the Group 1 individuals. Patients carrying the UGT1A1*28(TA)7 allele were 4-fold less likely to present with a response compared with the individuals harboring a homozygous(TA)6 genotype in the simple(OR = 0.267; 95%CI: 0.100-0.709; P = 0.008) and multiple(OR = 0.244; 95%CI: 0.088-0.678; P = 0.007) analyses. Classifier's performance of Co Bil and UGT1A1*28 were comparable.CONCLUSION: Co Bil and UGT1A1*28 are both independent biomarkers for predicting the treatment response of m CRC patients to irinotecan-based chemotherapy. After validation, Co Bil, an easily determinable index in the clinic, might be helpful in facilitating stratification of m CRC patients for individualized treatment options.     

Association between dietary heterocyclic amine levels,genetic polymorphisms of NAT2, CYP1A1, and CYP1A2 and risk of colorectal cancer: A hospital-based case-control study in Japan

Objective. Although associations between dietary HCA intake and colorectal cancer risk have been investigated, results have been suggestive but inconsistent. The aim of this hospital-based case-control study was to examine the impact of heterocyclic amine (HCA) intake on colorectal cancer risk. A further objective was to investigate the possible effect of genetic polymorphisms of NAT2, CYP1A1, and CYP1A2 on colorectal cancer. Material and methods. HCA exposure data were assessed using a self-administered food frequency questionnaire, and estimated HCA intake was verified by measuring the PhIP value in human hair. A total of 117 cases and 238 controls were included in these analyses. Odds ratios (ORs) were calculated using conditional logistic regression analysis to compare intake levels between the first and third tertiles. Results. No statistically significant increase in the risk of colorectal cancer with respect to total HCA intake was shown by analysis (OR = 0.99, 95% CI = 0.21–4.81). Furthermore, no association with risk was seen for individual HCAs, including PhIP, MeIQ, and MeIQx. Although variant alleles of CYP1A2 were associated with colorectal cancer (OR = 0.27; 95% CI = 0.07–0.99), genetic polymorphisms of NAT2, CYP1A1, and CYP1A2 did not influence the association of HCA intake with colorectal cancer. Conclusions. In the present study in subjects with low HCA exposure and with a limited sample size, no association was found between HCA intake and colorectal cancer, or any evidence of influence by genetic polymorphisms of NAT2, CYP1A1, and CYP1A2.     

No association between the Arg201Gly polymorphism of the DCC gene and colorectal cancer.

BACKGROUND AND AIMS: In one small study, the DCC Arg201Gly polymorphism has been observed more frequently in colorectal cancer cases compared with controls. We wondered whether these results could be replicated in a much larger study. METHODOLOGY: The DCC Arg201 Gly polymorphism was genotyped in 625 unselected Caucasian colorectal cancer patients and 220 controls. Association analysis was used to search for a difference between patients and controls. Subgroup analyses were performed for site of tumour, gender, age at diagnosis, family history of colorectal cancer and modified Dukes classification. RESULTS: The association analyses revealed no difference in Arg201Gly genotype frequency between patients and controls, neither overall nor for different subgroups according to site of tumour, gender, age at diagnosis, family history of colorectal cancer and modified Dukes classification. CONCLUSION: No association was observed between the Arg201Gly polymorphism of DCC and colorectal cancer risk.     

UGT1A1 gene polymorphism as a potential factor inducing iron overload in the pathogenesis of type 1 hereditary hemochromatosis

Aim  Hereditary hemochromatosis is a common genetic disorder characterized by iron overload and subsequent organ damage. It is caused in most cases by HFE gene mutations which penetrance can be affected by many factors. The aim of this study was to establish the role of UGT1A1 gene polymorphism and serum bilirubin concentration in the pathogenesis of hereditary hemochromatosis.
Methods  Biochemical, histopathological and genetic data indicating iron excess and serum total bilirubin concentration were determined in 32 patients with the type 1 hereditary hemochromatosis. Fluorescent molecular probes assays were used for genotyping of UGT1A1*28 and UGT1A1*60 mutations in these individuals.
Results  High incidence and a significant correlation of UGT1A1 gene mutations with increased serum bilirubin level and lower grades of liver tissue inflammatory activity were observed in study participants. UGT1A1*28 and UGT1A1*60 mutations were strongly linked together. Two of the subjects presented very rare genotypes of UGT1A1 gene: (TA)_5/7 and c.-64G>C heterozygotes.
Conclusions  UGT1A1 gene polymorphism and as its consequence of high serum bilirubin level may promote iron accumulation in hemochromatosis patients by reducing the activity of inflammation. We proposed a possible mechanism of this interaction.     

TIMP-3和RASSF1A在大肠癌中的表达及临床意义

目的:探讨TIMP-3和RASSF1A在大肠癌发生发展中的作用及与临床病理特征之间的关系,并且研究TIMP-3和RASSF1A之间的相关性.方法:应用免疫组织化学法检测大肠癌组织,大肠癌旁组织及正常大肠黏膜组织中TIMP-3和RASSF1A蛋白的表达量并结合患者的年龄、性别、分化程度、淋巴结转移等临床病理因素进行综合分析.采用Spearman等级相关分析TIMP-3和RASSF1A之间的相关性.结果:在正常大肠黏膜、癌旁和腺癌中TIMP-3的阳性率分别为90.0%、70.0%和16.7%,RASSF1A阳性率分别为83.3%、63.3%和23.3%.大肠癌中TIMP-3和RASSF1A的表达量与淋巴结转移(P<0.05;P<0.01)、浸润深度(P<0.05;P<0.01)及分化程度(P<0.05;P<0.05)有关.运用Spearman等级相关分析,TIMP-3和RASSF1A的表达呈正相关(r=0.256,P<0.05).结论:在大肠癌中TIMP-3和RASSF1A具有明显相关性,TIMP-3和RASSF1A的表达下调可能与大肠癌的发生有关,可以作为鉴别大肠良恶性肿瘤的指标.     

UGT1A1 predicts outcome in colorectal cancer treated with irinotecan and fluorouracil

AIM: To evaluate effects of UDP-glucuronosyltransferase1A1 (UGT1A1) and thymidylate synthetase (TS) gene polymorphisms on irinotecan in metastatic colorectal cancer (mCRC).METHODS: Two irinotecan- and fluorouracil-based regimens, FOLFIRI and IFL, were selected as second-line therapy for 138 Chinese mCRC patients. Genomic DNA was extracted from peripheral blood samples before treatment. UGT1A1 and TS gene polymorphisms were determined by direct sequencing and restriction fragment length polymorphism, respectively. Gene polymorphisms of UGT1A1*28, UGT1A1*6 and promoter enhancer region of TS were analyzed. The relationship between genetic polymorphisms and clinical outcome, that is, response, toxicity and survival were assessed. Pharmacokinetic analyses were performed in a subgroup patients based on different UGT1A1 genotypes. Plasma concentration of irinotecan and its active metabolite SN-38 and inactive metabolite SN-38G were determined by high performance liquid chromatography. Differences in irinotecan and its metabolites between UGT1A1 gene variants were compared.RESULTS: One hundred and eight patients received the FOLFIRI regimen, 29 the IFL regimen, and one irinotecan monotherapy. One hundred and thirty patients were eligible for toxicity and 111 for efficacy evaluation. One hundred and thirty-six patients were tested for UGT1A1*28 and *6 genotypes and 125 for promoter enhancer region of TS. Patients showed a higher frequency of wild-type UGT1A1*28 (TA6/6) compared with a Caucasian population (69.9% vs 45.2%). No significant difference was found between response rates and UGT1A1 genotype, although wild-type showed lower response rates compared with other variants (17.9% vs 24.2% for UGT1A1*28, 15.7% vs 26.8% for UGT1A1*6). When TS was considered, the subgroup with homozygous UGT1A1*28 (TA7/7) and non-3RG genotypes showed the highest response rate (33.3%), while wild-type UGT1A1*28 (TA6/6) with non-3RG only had a 13.6% response rate, but no significant difference was found. Logistic regression showed treatment duration was closely linked to clinical response. In toxicity comparison, UGT1A1*28 TA6/6 was associated with lower incidence of grade 2-4 diarrhea (27.8% vs 100%), and significantly reduced the risk of grade 4 neutropenia compared with TA7/7 (7.8% vs 37.5%). Wild-type UGT1A1*6 (G/G) tended to have a lower incidence of grade 3/4 diarrhea vs homozygous mutant (A/A) genotype (13.0% vs 40.0%). Taking UGT1A1 and TS genotypes together, lower incidence of grade 2-4 diarrhea was found in patients with non-3RG TS genotypes, when TA6/6 was compared with TA7/7 (35.3% vs 100.0%). No significant association with time to progression (TTP) and overall survival (OS) was observed with either UGT1A1 or TS gene polymorphisms, although slightly longer TTP and OS were found with UGT1A1*28 (TA6/6). Irinotecan PK was investigated in 34 patients, which showed high area under concentration curve (AUC) of irinotecan and SN-38, but low AUC ratio (SN-38G / SN-38) in those patients with UGT1A1*28 TA7/7.CONCLUSION: A distinct distribution pattern of UGT1A1 genotypes in Chinese patients might contribute to relatively low toxicity associated with irinotecan and 5-fluorouracil in mCRC patients.     

CYP1A1 Ile462Val polymorphism contributes to colorectal cancer risk: a meta-analysis

AIM:To study the relation between CYP1A1 Ile462Val polymorphism and colorectal cancer risk by meta-analysis. METHODS:A meta-analysis was performed to investigate the relation between CYP1A1 Ile462Val polymorphism and colorectal cancer risk by reviewing the related studies until September 2010.Data were extracted and analyzed.Crude odds ratio(OR) with 95% confidence interval(CI) was used to assess the strength of relation between CYP1A1 Ile462Val polymorphism and colorectal cancer risk. RESULTS:Thirteen publ...     

二磷酸尿苷葡萄糖苷转移酶1A7基因多态性与国人结直肠癌的相关性研究

目的探讨二磷酸尿苷葡萄糖苷转移酶(UGT)1A7基因第1外显子3处单核苷酸多态性与国人结直肠癌(CRC)的相关性,及其在我国自然人群中的分布频率。方法采用人群为基础的成组匹配病例对照研究,以半巢式聚合酶链反应(PCR)、等位基因特异PCR和PCR-限制性内切酶片段长度多态性(RFLP)联用分析技术对140例CRC患者和280例正常对照者的UGT1A7基因型进行检测分析。结果CRC患者携带变异等位基因(~*2,~*3,~*4)频率明显高于对照组(50．0%比38．6%,P＜0．01)。CRC患者携带变异纯合基因型频率(28．6%)明显高于对照组(14．3%),差异有统计学意义(P＜0．01)。与野生型相比,变异杂合型及纯合型OR比值增高趋势有统计学意义(X~2=12．15,P＜0．01)。红烧熏炸食品摄入与CRC发病有关,与低摄人量组(≤5．40 kg/年)相比,中(≤14．35kg/年)、高(＞14．35kg/年)摄入量组风险明显增高,在中摄入量组风险增高差异有统计学意义(P＜0．05,OR=1．84,95% CI∶1．09～3．11)。以红烧熏炸、腌制食品摄人以及吸烟、饮酒状况为分层因素,分析UGT1A7基因多态性与CRC发病的相关性,仅在吸烟个体观察到有相关效应,差异有统计学意义(P＜0．05,OR=3．13,95%CI∶1．03～9．52),在饮酒个体观察到的相关效应临界于显著性水平(P=0．05,OR=2．89,95%CI∶0．99～8．46)。结论UGT1A7基因多态性与CRC的发病呈正相关关系,同时与吸烟、饮酒等环境危险因素可能存在一定的协同作用。     

Polymorphisms in sulfotransferase 1A1 and glutathione S-transferase P1 genes in relation to colorectal cancer risk and patients＇ survival

AIM: To examine whether polymorphisms in SULT1A1 and GSTP1 genes contribute to colorectal cancer development and whether they are associated with clinicopathological variables are not well identified.METHODS: We examined the genotypes of 125 colorectal cancer patients and 666 healthy controls in a Swedish population by using PCR-restriction fragment length polymorphism (RFLP).RESULTS: SULT1A1 *2/*2 genotype (OR=2.49, 95%CI=1.48-4.19, P=0.0002) and *2 allele (OR=1.56, 95%CI=1.16-2.10, P=0.002) had an effect on colorectal cancer susceptibility, while GSTP1 genotype was without effect. However, GSTP1 G-type predicted a worse prognosis in the patients independently of gender, age, Dukes' stage, growth pattern, and differentiation (P=0.03). CONCLUSION:Polymorphism in SULT1A1 may predispose to colorectal cancer and GSTP1 may be a biological indicator of prognosis in the patients.     

hOGG1基因多态与结直肠癌和肝细胞癌遗传易感性

目的探讨hOGG1基因第326密码子多态（Ser326Cys）与中国人群结直肠癌（CRC）和肝细胞癌（HCC）遗传易感性的关系。方法采用TaqMan方法检测345例CRC与670例对照以及175例HCC与119例对照的hOGG1Ser326Cys基因型分布及差异。结果总体上，hOGG1 Ser326Cys基因型分布在HCC-对照、CRC-对照以及不吸烟的CRC-对照人群间均无显著性差异（P〉O．05）。但在吸烟人群中，326Cys是CRC发生的危险因素（OR=1．58，95％CI=1．14～2．19，P=0．006）；与Ser／Ser基因型及Ser等位基因携带者（Ser／Ser、Ser／Cys基因型）相比，Cys／Cys基因型的CRC风险显著增加至2．40倍（95％CI=1．20～4．78，P=0．013）及2．02倍（95％CI=1．21-3．37，P=0．008）。结论hOGG1Ser326Cys多态可能与HCC发病风险无关，但Cys／Cys基因型增加中国吸烟人群的CRC发病风险。     

Effects of variant UDP-glucuronosyltransferase 1A1 gene, glucose-6-phosphate dehydrogenase deficiency and thalassemia on cholelithiasis

AIM: To test the hypothesis that the variant UDPglucuronosyltransferase 1A1 (UGT1A1) gene, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and thalassemia influence bilirubin metabolism and play a role in the development of cholelithiasis. METHODS: A total of 372 Taiwan Chinese with cholelithiasis who had undergone cholecystectomy and 293 healthy individuals were divided into case and control groups, respectively. PCR and restriction fragment length polymorphism were used to analyze the promoter area and nucleotides 211, 686, 1 091, and 1 456 of the UGT1A1 gene for all subjects and the gene variants for thalassemia and G6PD deficiency. RESULTS: Variation frequencies for the cholelithiasis patients were 16.1%, 25.8%, 5.4%, and 4.3% for A(TA)_6 TAA/A(TA)_7 TAA (6/7), heterozygosity within the coding region, compound heterozygosity, and homozygosity of the UGT1A1 gene, respectively. Comparing the case and control groups, a statistically significant difference in frequency was demonstrated for the homozygous variation of the UGT1A1 gene (P=0.012, x~2 test), but not for the other variations. Further, no difference was demonstrated in a between-group comparison of the incidence of G6PD deficiency and thalassemia (2.7% vs 2.4% and 5.1% vs 5.1%, respectively). The bilirubin levels for the cholelithiasis patients with the homozygous variant-UGT1A1 gene were significantly different from the control analog (18.0±6.5 and 12.7±2.9μmol/L, respectively; P<0.001, Student's ttest). CONCLUSION: Our results show that the homozygous variation in the UGT1A1 gene is a risk factor for the development of cholelithiasis in Taiwan Chinese.