Pooling-Based Genome-Wide Association Study Implicates Gamma-Glutamyltransferase 1 (GGT1) Gene in Pancreatic Carcinogenesis
Pooling-Based Genome-Wide Association Study Implicates Gamma-Glutamyltransferase 1 (GGT1) Gene in Pancreatic Carcinogenesis
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DOI：
10.1159/000236023
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发表时间：
2010-01-01
期刊：
影响因子：
3.6
通讯作者：
Whitcomb, David C.
中科院分区：
文献类型：
--
作者：
Diergaarde, Brenda;Brand, Randall;Whitcomb, David C.
背景/目的：关于影响胰腺癌风险的遗传因素的知识目前有限。为了确定新的胰腺癌易感基因座，我们进行了两阶段全基因组关联研究。方法：在筛选阶段使用Affyellow（R）全基因组人类SNP阵列6.0和DNA池。26个单核苷酸多态性（SNPs）被选为后续行动。通过合并群体和独立验证群体的个体基因分型来评估这26个前导SNP和针对前导SNP周围区域的额外选择的tagSNP。结果：在前导SNP中，发现与γ-谷氨酰转移酶1（GGT 1）基因中的rs 4820599相关性最强。在验证人群和组合数据集中，该SNP与胰腺癌风险显著相关（分别为p（基于等位基因）= 0.019和p（基于等位基因）= 0.003）。还观察到与两个GGT 1 tagSNP：rs 2017869和rs 8135987的统计学显著关联。前导SNP rs 4820599处于高度连锁不平衡（LD;成对r（2）：0.69），并且tagSNP rs 2017869与SNP rs 5751901处于强LD（成对r（2）：0.96），已报道其与增加的GGT 1血清水平相关。GGT在胰腺中表达，在谷胱甘肽代谢中起关键作用。结论：我们的研究结果表明，GGT 1基因的常见变异可能会影响胰腺癌的风险。版权所有（C）2010 S. Karger AG、巴塞尔和IAP
Background/Aims: Knowledge regarding genetic factors that influence pancreatic cancer risk is currently limited. To identify novel pancreatic cancer susceptibility loci, we conducted a two-stage genome-wide association study. Methods: The Affymetrix(R) Genome-Wide Human SNP Array 6.0 and DNA pooling were used in the screening stage. Twenty-six single-nucleotide polymorphisms (SNPs) were selected for follow-up. These 26 lead SNPs and additionally selected tagSNPs for the regions around the lead SNPs were evaluated by individual genotyping of the pooling population and an independent validation population. Results: Of the lead SNPs, the strongest association was found with rs4820599 located in the gamma-glutamyltransferase 1 (GGT1) gene. This SNP was significantly associated with pancreatic cancer risk in the validation population and the combined dataset (p(allele-based) = 0.019 and p(allele-based) = 0.003, respectively). Statistically significant associations were also observed with two GGT1 tagSNPs: rs2017869 and rs8135987. Lead SNP rs4820599 is in high linkage disequilibrium (LD; pairwise r(2):0.69) and tagSNP rs2017869 is in strong LD (pairwise r(2):0.96) with SNP rs5751901, which has been reported to be associated with increased GGT1 serum levels. GGT is expressed in the pancreas and plays a key role in glutathione metabolism. Conclusion: Our results suggest that common variation in the GGT1 gene may affect the risk of pancreatic cancer. Copyright (C) 2010 S. Karger AG, Basel and IAP