Systematic evaluation of apoptotic pathway gene polymorphisms and lung cancer risk
Systematic evaluation of apoptotic pathway gene polymorphisms and lung cancer risk
复制标题
DOI：
10.1093/carcin/bgs192
复制
发表时间：
2012-09-01
期刊：
影响因子：
4.7
通讯作者：
Wu, Xifeng
中科院分区：
文献类型：
--
作者：
Lin, Jie;Lu, Charles;Wu, Xifeng
我们采用两阶段研究设计，在病例对照研究中筛选了73个凋亡途径基因中的927个单核苷酸多态(SNPs)，然后对复制人群中显著的SNPs进行快速验证，以确定调控肺癌风险的凋亡途径中的序列变异。55个SNP在发现人群中显示出显著的相关性，其中包括661例肺癌病例和959名对照。其中6个SNP位于3个基因(Bcl2、CASP9和ANKS1B)中，在1154例患者和第1373名对照的复制人群中得到验证。加性模型对5个SNP(Bcl2的rs1462129和rs255102，CASP9的rs6685648和ANKS1B的rs1549102，rs11110099)最适合，隐性模型最适合一个SNP(ANKS1B的rs10745877)。在以无不良基因携带者为参照组的联合效应分析中，携带1个、2个和3个以上不良基因携带者的OR值分别为2.22[95%可信区间=1.084.57，P=0.03]、2.70(95%CI=1.335.49；P=0.006)和4.13(95%CI=2.008.57；P=0.0001)。在复制群体中也证实了不利基因类型的联合作用。已确定的SNP位于已知在细胞凋亡调控中发挥重要作用的关键基因或其附近，支持我们的发现具有很强的生物学相关性。需要进一步的研究来确定致病的SNPs，并阐明其潜在的分子机制。
We adopted a two-stage study design to screen 927 single nucleotide polymorphisms (SNPs) located in 73 apoptotic-pathway genes in a case-control study and then performed a fast-track validation of the significant SNPs in a replication population to identify sequence variations in the apoptotic pathway modulating lung cancer risk. Fifty-five SNPs showed significant associations in the discovery population comprised of 661 lung cancer cases and 959 controls. Six of these SNPs located in three genes (Bcl-2, CASP9 and ANKS1B) were validated in a replication population with 1154 cases and 1373 controls. Additive model was the best-fitting model for five SNPs (rs1462129 and rs255102 of Bcl-2, rs6685648 of CASP9 and rs1549102, rs11110099 of ANKS1B) and recessive model was the best fit for one SNP (rs10745877 of ANKS1B). In the analysis of joint effects with subjects carrying no unfavorable genotypes as the reference group, those carrying one, two, and three or more unfavorable genotypes had an odds ratio (OR) of 2.22 [95% confidence interval (CI) = 1.084.57, P = 0.03], 2.70 (95% CI = 1.335.49; P = 0.006) and 4.13 (95% CI = 2.008.57; P = 0.0001), respectively (P for trend = 6.05E-06). The joint effect of unfavorable genotypes was also validated in the replication population. The SNPs identified are located in or near key genes known to play important roles in apoptosis regulation, supporting the strong biological relevance of our findings. Future studies are needed to identify the causal SNPs and elucidate the underlying molecular mechanisms.