Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
PLoS One. 2012;7(2):e30665. doi: 10.1371/journal.pone.0030665. Epub 2012 Feb 17.
Telomeres are critical in maintaining genomic stability. Genetic variants in telomere pathway genes may affect telomere and telomerase function, and subsequently cancer risk. We evaluated 126 SNPs from 10 genes related to telomere regulation in relation to bladder cancer risk. Five SNPs, 4 from TEP1 gene and 1 from PINX1 gene, were found to be highly significant (P<0.01). Out of these, the most significant association was found in rs2228041 of TEP1 (OR 1.66, 95% CI 1.19-2.31) while rs1469557 of PINX1 had a protective effect (OR 0.75, 95% CI 0.61-0.93). Haplotype analysis showed that a TEP1 haplotype consisting of the variant alleles of 7 SNPs exhibited a 2.28 fold increased risk (95% CI 1.13-4.60). We then performed cumulative analysis of multiple risk variants, as well as Classification and Regression Tree (CART) to look for gene-gene interactions. In cumulative effect analysis, the group with 4-5 risk variants had an OR of 2.57 (95% CI = 1.62-4.09) versus the reference group with 0 risk variants. The CART analysis categorized individuals into five subgroups with different bladder cancer risk profiles based on their distinct genotype background. To our knowledge, this is one of the largest, most comprehensive studies on bladder cancer risk concerning telomere-regulating pathway gene SNPs and our results support that genetic variations of telomere maintenance modulate bladder cancer risk individually and jointly.
端粒在维持基因组稳定性方面至关重要。端粒通路基因中的遗传变异可能会影响端粒和端粒酶的功能，进而影响癌症风险。我们评估了与端粒调控相关的 10 个基因中的 126 个 SNP 与膀胱癌风险的关系。发现 5 个 SNP（TEP1 基因中的 4 个和 PINX1 基因中的 1 个）具有高度显著性（P<0.01）。在这些 SNP 中，TEP1 基因的 rs2228041 关联最为显著（OR 1.66，95%CI 1.19-2.31），而 PINX1 基因的 rs1469557 则具有保护作用（OR 0.75，95%CI 0.61-0.93）。单体型分析表明，由 7 个变异等位基因组成的 TEP1 单体型表现出 2.28 倍的风险增加（95%CI 1.13-4.60）。然后，我们对多个风险变异进行了累积分析，以及分类和回归树（CART）分析，以寻找基因-基因相互作用。在累积效应分析中，与参考组（0 个风险变异）相比，具有 4-5 个风险变异的组的 OR 为 2.57（95%CI=1.62-4.09）。CART 分析根据不同的基因型背景将个体分为五个具有不同膀胱癌风险特征的亚组。据我们所知，这是关于端粒调节途径基因 SNP 与膀胱癌风险的最大、最全面的研究之一，我们的结果支持遗传变异可以单独和共同调节端粒维持的膀胱癌风险。
