线粒体DNA含量：其遗传遗传性及与肾细胞癌的关联。
Mitochondrial DNA content: its genetic heritability and association with renal cell carcinoma.
作者信息
Xing Jinliang, Chen Meng, Wood Christopher G, Lin Jie, Spitz Margaret R, Ma Jianzhong, Amos Christopher I, Shields Peter G, Benowitz Neal L, Gu Jian, de Andrade Mariza, Swan Gary E, Wu Xifeng
机构信息
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
出版信息
J Natl Cancer Inst. 2008 Aug 6;100(15):1104-12. doi: 10.1093/jnci/djn213. Epub 2008 Jul 29.
BACKGROUND
The extent to which mitochondrial DNA (mtDNA) content (also termed mtDNA copy number) in normal human cells is influenced by genetic factors has yet to be established. In addition, whether inherited variation of mtDNA content in normal cells contributes to cancer susceptibility remains unclear. Renal cell carcinoma accounts for 85% of all renal cancers. No studies have investigated the association between mtDNA content and the risk of renal cell carcinoma.
METHODS
We first used a classic twin study design to estimate the genetic contribution to the determination of mtDNA content. mtDNA content was measured by quantitative real-time polymerase chain reaction in peripheral blood lymphocytes from 250 monozygotic twins, 92 dizygotic twins, and 33 siblings (ie, individual siblings of a pair of twins). We used biometric genetic modeling to estimate heritability of mtDNA content. We then used a case-control study with 260 case patients with renal cell carcinoma and 281 matched control subjects and multivariable logistic regression analysis to examine the association between mtDNA content in peripheral blood lymphocytes and the risk of renal cell carcinoma. All statistical tests were two-sided.
RESULTS
The heritability (ie, proportion of phenotypic variation in a population that is attributable to genetic variation among individuals) of mtDNA content was 65% (95% confidence interval [CI] = 50% to 72%; P < .001). Case patients with renal cell carcinoma had a statistically significantly lower mtDNA content (1.18 copies) than control subjects (1.29 copies) (difference = 0.11, 95% CI = 0.03 to 0.17; P = .006). Low mtDNA content (ie, less than the median in control subjects) was associated with a statistically significantly increased risk of renal cell carcinoma, compared with high content (odds ratio = 1.53, 95% CI = 1.07 to 2.19). In a trend analysis, a statistically significant dose-response relationship was detected between lower mtDNA content and increasing risk of renal cell carcinoma (P for trend <.001).
CONCLUSIONS
mtDNA content appears to have high heritability. Low mtDNA content appears to be associated with increased risk of renal cell carcinoma.
背景
正常人类细胞中线粒体DNA（mtDNA）含量（也称为mtDNA拷贝数）受遗传因素影响的程度尚未确定。此外，正常细胞中mtDNA含量的遗传变异是否会导致癌症易感性仍不清楚。肾细胞癌占所有肾癌的85%。尚无研究调查mtDNA含量与肾细胞癌风险之间的关联。
方法
我们首先采用经典的双生子研究设计来估计遗传因素对mtDNA含量测定的贡献。通过定量实时聚合酶链反应测量了250对同卵双胞胎、92对异卵双胞胎和33名同胞（即一对双胞胎中的单个同胞）外周血淋巴细胞中的mtDNA含量。我们使用生物统计学遗传模型来估计mtDNA含量的遗传力。然后，我们采用一项病例对照研究，纳入260例肾细胞癌病例患者和281名匹配的对照受试者，并进行多变量逻辑回归分析，以研究外周血淋巴细胞中mtDNA含量与肾细胞癌风险之间的关联。所有统计检验均为双侧检验。
结果
mtDNA含量的遗传力（即人群中表型变异归因于个体间遗传变异的比例）为65%（95%置信区间[CI]=50%至72%；P<.001）。肾细胞癌病例患者的mtDNA含量（1.18拷贝）在统计学上显著低于对照受试者（1.29拷贝）（差异=0.11，95%CI=0.03至0.17；P=.006）。与高含量相比，低mtDNA含量（即低于对照受试者的中位数）与肾细胞癌风险在统计学上显著增加相关（比值比=1.53，95%CI=1.07至2.19）。在趋势分析中，检测到较低的mtDNA含量与肾细胞癌风险增加之间存在统计学上显著的剂量反应关系（趋势P<.001）。
结论
mtDNA含量似乎具有较高的遗传力。低mtDNA含量似乎与肾细胞癌风险增加有关。
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