Department of Epidemiology, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA.
Carcinogenesis. 2012 Sep;33(9):1699-706. doi: 10.1093/carcin/bgs192. Epub 2012 Jun 4.
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) = 1.08-4.57, P = 0.03], 2.70 (95% CI = 1.33-5.49; P = 0.006) and 4.13 (95% CI = 2.00-8.57; 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.
我们采用两阶段研究设计，在病例对照研究中筛选了位于 73 个凋亡途径基因中的 927 个单核苷酸多态性（SNP），然后在复制人群中快速验证显著 SNP，以鉴定调节肺癌风险的凋亡途径中的序列变异。在由 661 例肺癌病例和 959 例对照组成的发现人群中，有 55 个 SNP 显示出显著相关性。位于三个基因（Bcl-2、CASP9 和 ANKS1B）中的六个 SNP 在包含 1154 例病例和 1373 例对照的复制人群中得到验证。对于五个 SNP（Bcl-2 的 rs1462129 和 rs255102、CASP9 的 rs6685648、ANKS1B 的 rs1549102 和 rs11110099），加性模型是最佳拟合模型，对于一个 SNP（ANKS1B 的 rs10745877），隐性模型是最佳拟合模型。在与未携带不利基因型的个体作为参考组进行联合效应分析时，携带一个、两个和三个或更多不利基因型的个体的比值比（OR）分别为 2.22（95%置信区间 [CI] = 1.08-4.57，P = 0.03）、2.70（95% CI = 1.33-5.49；P = 0.006）和 4.13（95% CI = 2.00-8.57；P = 0.0001）（趋势检验 P 值=6.05E-06）。不利基因型的联合效应也在复制人群中得到验证。鉴定出的 SNP 位于或靠近已知在凋亡调控中发挥重要作用的关键基因，支持我们研究结果的强大生物学相关性。需要进一步的研究来鉴定因果 SNP 并阐明潜在的分子机制。
