The effect of UGT1A and UGT2B polymorphisms on colorectal cancer risk: haplotype associations and gene–environment interactions.
The effect of UGT1A and UGT2B polymorphisms on colorectal cancer risk: haplotype associations and gene–environment interactions.
复制标题
DOI：
10.1002/gcc.22157
复制
发表时间：
2014-06
影响因子：
3.7
通讯作者：
Lazarus, Philip
中科院分区：
文献类型：
--
作者：
Angstadt, Andrea Y.;Hartman, Terryl J.;Lesko, Samuel M.;Muscat, Joshua E.;Zhu, Junjia;Gallagher, Carla J.;Lazarus, Philip
UDP-葡萄糖醛酸转移酶（UGT）在外源性和内源性化合物的II相代谢中起着重要作用。由于结肠直肠癌（CRC）的病因被认为涉及饮食因素的生物转化，UGT多态性可能通过改变暴露水平来影响CRC风险。完成了对1800多名高加索受试者的基因分型，以确定9个UGT 1A和5个UGT 2B基因的遗传变异对CRC风险的作用。进行无条件logistic回归和单体型分析，以确定与CRC风险和潜在基因-环境相互作用的相关性。UGT 1A单倍型分析发现，UGT 1A 10外显子1的T-G单倍型（第2块：rs 17864678，rs 10929251）降低结肠癌风险[近端（OR = 0.28，95% CI=0.11-0.69），远端（OR = 0.32，95%CI =0.12-0.91）]，UGT 1A基因3′端的C-T-G单倍型有共同的外显子（第11区：rs7578153、rs 10203853、rs6728940）男性CRC风险增加（OR = 2.56，95%CI =1.10-5.95）。发现UGT 2B 15中含有功能变体（rs 4148269，K523 T）和内含子SNP（rs6837575）的单倍型影响直肠癌的总体风险（OR = 2.57，95%CI =1.21-5.04）和女性风险（OR = 3.08，95%CI =1.08-8.74）。在UGT 1A共享外显子中，发现高NSAID使用与A-G-T单倍型（第10区：rs6717546、rs 1500482、rs7586006）之间存在相互作用，可降低CRC风险。这表明UGT遗传变异通过解剖学亚位点和性别不同地改变CRC风险，并且UGT 1A共享外显子中的多态性可能对基因表达具有调节作用，这使得NSAID对CRC风险具有保护作用。
UDP-glucuronosyltransferases (UGTs) play an important role in the phase II metabolism of exogenous and endogenous compounds. As colorectal cancer (CRC) etiology is thought to involve the biotransformation of dietary factors, UGT polymorphisms may affect CRC risk by altering levels of exposure. Genotyping of over 1800 Caucasian subjects was completed to identify the role of genetic variation in nine UGT1A and five UGT2B genes on CRC risk. Unconditional logistic regression and haplotype analyses were conducted to identify associations with CRC risk and potential gene-environment interactions. UGT1A haplotype analysis found that the T-G haplotype in UGT1A10 exon 1 (block 2: rs17864678, rs10929251) decreased colon cancer risk [proximal (OR = 0.28, 95% CI=0.11–0.69), distal (OR = 0.32, 95% CI=0.12–0.91)] and that the C-T-G haplotype in the 3′ region flanking the UGT1A shared exons (block 11: rs7578153, rs10203853, rs6728940) increased CRC risk in males (OR = 2.56, 95% CI=1.10–5.95). A haplotype in UGT2B15 containing a functional variant (rs4148269, K523T) and an intronic SNP (rs6837575) was found to affect rectal cancer risk overall (OR = 2.57, 95% CI=1.21–5.04) and in females (OR = 3.08, 95% CI=1.08–8.74). An interaction was found between high NSAID use and the A-G-T haplotype (block 10: rs6717546, rs1500482, rs7586006) in the UGT1A shared exons that decreased CRC risk. This suggests that UGT genetic variation alters CRC risk differently by anatomical sub-site and gender and that polymorphisms in the UGT1A shared exons may have a regulatory effect on gene expression that allows for the protective effect of NSAIDs on CRC risk.
登录
查看更多内容
影响因子：
2.8
作者：
Bellemare, J.;Rouleau, M.;Guillemette, C.
通讯作者：
Guillemette, C.
影响因子：
4.8
作者：
Bellemare, Judith;Rouleau, Melanie;Guillemette, Chantal
通讯作者：
Guillemette, Chantal
影响因子：
6.7
作者：
Duguay, Y;Báár, C;Guillemette, C
通讯作者：
Guillemette, C
影响因子：
3.8
作者：
Gallagher, Carla J.;Muscat, Joshua E.;Lazarus, Philip
通讯作者：
Lazarus, Philip
影响因子：
13.5
作者：
Ehmer, U;Vogel, A;Strassburg, CP
通讯作者：
Strassburg, CP