Apolipoprotein E/C1 locus variants modify renal cell carcinoma risk.
Apolipoprotein E/C1 locus variants modify renal cell carcinoma risk.
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DOI：
10.1158/0008-5472.can-09-1734
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发表时间：
2009-10-15
期刊：
影响因子：
11.2
通讯作者：
Rothman N
中科院分区：
文献类型：
--
作者：
Moore LE;Brennan P;Karami S;Menashe I;Berndt SI;Dong LM;Meisner A;Yeager M;Chanock S;Colt J;Schwartz K;Davis F;Zaridze D;Mattveev V;Janout V;Kollarova H;Bencko V;Navratilova M;Szeszenia-Dabrowska N;Mates D;Holcatova I;Boffetta P;Chow WH;Rosenberg PS;Rothman N
脂质过氧化被认为是已知危险因素诱导肾细胞癌（RCC）的统一机制途径。我们假设先天选择的基因在脂质过氧化中的作用会改变癌症的风险。我们在一项大型欧洲病例对照研究中对777例高加索RCC病例和1035例对照进行了38个候选基因的635个单核苷酸多态性（snp）基因分型。在美国的另一项研究中，在718例高加索病例和615例对照中确认了顶级候选snp。在美国研究中复制的三个snp （rs8106822和rs405509）中有两个位于APOE启动子的调控区域内。rs8106822 A b> G变异的比值比（OR）在欧洲研究中为1.22AG和1.41GG (p-trend=0.01)，在美国研究中为1.05AG和1.51GG (p-trend=0.03)，在1485例病例和1639例对照中为1.15AG和1.44GG （p-trend=0.001）。rs405509 G>T变异与欧洲（OR=0.87TG； OR=0.71 tt; p-trend=0.02）、美国（OR=0.68TG； OR=0.71 tt; p-trend=0.02）以及两项研究合并（ORTG=0.79； ORTT= 0.71; p-trend=0.001）的风险相关，G-G单倍型（r2=0.64; p=4.7 × 10-4）也是如此。这种关联在生物学上是合理的，因为SNP rs405509在体外被证明可以改变APOE基因的蛋白质结合和转录活性，并且在LD中具有定义e2， e3， e4等位基因的关键已知变体，这些等位基因可以改变动脉粥样硬化，阿尔茨海默病风险和进展为艾滋病的风险。在两项大型病例对照研究中，我们的研究结果进一步确定了APOE位点上增加RCC易感性的功能区域。
Lipid peroxidation is considered a unifying mechanistic pathway through which known risk factors induce renal cell carcinoma (RCC). We hypothesized that genes selected apriori for their role in lipid peroxidation would modify cancer risk. We genotyped 635 single nucleotide polymorphisms (SNPs) in thirty-eight candidate genes in 777 Caucasian RCC cases and 1035 controls enrolled in a large European case-control study. Top candidate SNPs were confirmed among 718 Caucasian cases and 615 controls in a second study in the United States. Two of the three SNPs (rs8106822 and rs405509) that replicated in the US study were within a regulatory region of the APOE promoter. The odds ratio (OR) for rs8106822 A>G variant was 1.22AG and 1.41GG (p-trend=0.01) in the European study, 1.05AG and 1.51GG (p-trend=0.03) in the US study, and 1.15AG and 1.44GG (p-trend=0.001) among 1485 cases and 1639 controls combined. The rs405509 G>T variant was associated with risk in the European (OR=0.87TG; OR=0.71TT; p-trend=0.02), the US (OR=0.68TG; OR=0.71TT; p-trend=0.02), and both studies combined (ORTG=0.79; ORTT= 0.71; p-trend=0.001), as was the G-G haplotype (r2=0.64; p=4.7 × 10-4). This association is biologically plausible as SNP rs405509 was shown to modify protein binding and transcriptional activity of the APOE gene in vitro and is in LD with key known variants defining the e2, e3, e4 alleles that modify risk of atherosclerosis, Alzheimer's disease risk, and progression to AIDS. In two large case-control studies, our findings further define a functional region of interest at the APOE locus that increases RCC susceptibility.