Inherited variants in mitochondrial biogenesis genes may influence epithelial ovarian cancer risk.
Inherited variants in mitochondrial biogenesis genes may influence epithelial ovarian cancer risk.
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DOI：
10.1158/1055-9965.epi-10-1224
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发表时间：
2011-06
期刊：
影响因子：
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通讯作者：
Sellers TA
中科院分区：
文献类型：
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作者：
Permuth-Wey J;Chen YA;Tsai YY;Chen Z;Qu X;Lancaster JM;Stockwell H;Dagne G;Iversen E;Risch H;Barnholtz-Sloan J;Cunningham JM;Vierkant RA;Fridley BL;Sutphen R;McLaughlin J;Narod SA;Goode EL;Schildkraut JM;Fenstermacher D;Phelan CM;Sellers TA
线粒体有助于氧化应激，这是一种与卵巢癌发生有关的现象。我们假设卵巢相关基因的遗传变异影响上皮性卵巢癌（EOC）的易感性。通过对1，815例白人EOC病例和1，900例对照的多中心研究，我们调查了EOC风险与线粒体基因组（mtDNA）内22个基因/区域的128个单核苷酸多态性（SNP）和位于线粒体生物发生相关的138个基因的2，839个核编码SNP之间的关系。（BIO，n=35）、类固醇激素代谢（HOR，n=13）和氧化磷酸化（OXP，n=90）途径。采用非条件Logistic回归估计基因型与病例状态之间的比值比（OR）和95%置信区间（CI）。使用Fisher方法结合联合收割机SNP水平证据评估每个基因和通路的总体显著性。在SNP水平上，我们研究了终生排卵、激素替代治疗（HRT）和吸烟是否是相关性的混杂因素或修饰因素。涉及BIO的个体间变异与EOC风险最强相关（经验P=0.050），尤其是NRF 1、MTERF、PPARGC 1A、ESRRA和CAMK 2D。一些SNP水平的协会加强后，调整非遗传因素，特别是MTERF。分别用MTERF和CAMK 2D SNP观察了吸烟和HRT使用的统计学相互作用。mtDNA、HOR和OXP的总体变异无统计学意义（经验P >0.10）。我们提供了新的证据表明，线粒体生物发生基因的变异可能会影响EOC的易感性。深入了解线粒体生物发生和氧化应激的复杂机制可能有助于制定降低EOC发病率和死亡率的策略。
Mitochondria contribute to oxidative stress, a phenomenon implicated in ovarian carcinogenesis. We hypothesized that inherited variants in mitochondrial-related genes influence epithelial ovarian cancer (EOC) susceptibility. Through a multi-center study of 1,815 Caucasian EOC cases and 1,900 controls, we investigated associations between EOC risk and 128 single nucleotide polymorphisms (SNPs) from 22 genes/regions within the mitochondrial genome (mtDNA) and 2,839 nuclear-encoded SNPs localized to 138 genes involved in mitochondrial biogenesis (BIO, n=35), steroid hormone metabolism (HOR, n=13), and oxidative phosphorylation (OXP, n=90) pathways. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) between genotype and case status. Overall significance of each gene and pathway was evaluated using Fisher’s method to combine SNP-level evidence. At the SNP-level, we investigated whether lifetime ovulation, hormone replacement therapy (HRT), and cigarette smoking were confounders or modifiers of associations. Inter-individual variation involving BIO was most strongly associated with EOC risk (empirical P=0.050), especially for NRF1, MTERF, PPARGC1A, ESRRA, and CAMK2D. Several SNP-level associations strengthened after adjustment for non-genetic factors, particularly for MTERF. Statistical interactions with cigarette smoking and HRT use were observed with MTERF and CAMK2D SNPs, respectively. Overall variation within mtDNA, HOR, and OXP was not statistically significant (empirical P >0.10). We provide novel evidence to suggest that variants in mitochondrial biogenesis genes may influence EOC susceptibility. A deeper understanding of the complex mechanisms implicated in mitochondrial biogenesis and oxidative stress may aid in developing strategies to reduce morbidity and mortality from EOC.