Journal of the National Cancer Institute Advance Access originally published online on July 29, 2008
JNCI Journal of the National Cancer Institute 2008 100(15):1104-1112; doi:10.1093/jnci/djn213
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© The Author 2008. Published by Oxford University Press.
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Mitochondrial DNA Content: Its Genetic Heritability and Association With Renal Cell Carcinoma
Affiliations of authors: Departments of Epidemiology (JX, MC, JL, MRS, JM, CIA, JG, XW) and Urology (CGW), The University of Texas M. D. Anderson Cancer Center, Houston, TX; Cancer Genetics and Epidemiology, Lombardi Comprehensive Cancer Center, Washington, DC (PGS); Department of Biopharmaceutical Sciences, University of California, San Francisco, CA (NLB); Department of Health Sciences Research, Mayo Clinic, Rochester, MN (MdA); Center for Health Sciences, SRI International, Menlo Park, CA (GES)
Correspondence to: Xifeng Wu, MD, PhD, Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX (e-mail: xwu{at}mdanderson.org).
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.
| CONTEXT AND CAVEATS Prior knowledge The extent to which the mitochondrial DNA (mtDNA) content of normal human cells is influenced by genetic factors is yet to be established, and whether inherited variation of mtDNA content in normal cells contributes to cancer susceptibility remains unclear. Study design A classic twin study design was used to estimate the genetic contribution of mtDNA content among individuals. A case–control study with 260 case patients with renal cell carcinoma and 281 control subjects used to examine the association between mtDNA content in peripheral blood lymphocytes and the risk of renal cell carcinoma. Contribution mtDNA content appears to have high heritability (ie, proportion of phenotypic variation in a population that is attributable to genetic variation among individuals). Low mtDNA content appears to be associated with increased risk of renal cell carcinoma. Implications Additional research into the association between mtDNA content and the risk of renal cell carcinoma and other cancers is warranted. Limitations The moderate sample size of the case–control study limits its statistical power. The case–control study was restricted to white individuals, which limits the generalizability of its results. From the Editors
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Manuscript received March 4, 2008; revised May 12, 2008; accepted May 28, 2008.
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J Natl Cancer Inst 2008 100: 1045.
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