Mitochondrial DNA content: Its genetic heritability and association with renal cell carcinoma

Jinliang Xing, Meng Chen, Christopher G. Wood, Jie Lin, Margaret R. Spitz, Jianzhong Ma, Christopher I. Amos, Peter G. Shields, Neal L. Benowitz, Jian Gu, Mariza De Andrade, Gary E. Swan, Xifeng Wu

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Abstract

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). Conclusion: smtDNA content appears to have high heritability. Low mtDNA content appears to be associated with increased risk of renal cell carcinoma.

Original languageEnglish (US)
Pages (from-to)1104-1112
Number of pages9
JournalJournal of the National Cancer Institute
Volume100
Issue number15
DOIs
StatePublished - Aug 1 2008

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Mitochondrial DNA
Renal Cell Carcinoma
Confidence Intervals
Siblings
Lymphocytes
Dizygotic Twins
Twin Studies
Monozygotic Twins
Kidney Neoplasms
Case-Control Studies
Real-Time Polymerase Chain Reaction
Logistic Models
Odds Ratio
Regression Analysis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Mitochondrial DNA content : Its genetic heritability and association with renal cell carcinoma. / 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.

In: Journal of the National Cancer Institute, Vol. 100, No. 15, 01.08.2008, p. 1104-1112.

Research output: Contribution to journalArticle

Xing, J, Chen, M, Wood, CG, Lin, J, Spitz, MR, Ma, J, Amos, CI, Shields, PG, Benowitz, NL, Gu, J, De Andrade, M, Swan, GE & Wu, X 2008, 'Mitochondrial DNA content: Its genetic heritability and association with renal cell carcinoma', Journal of the National Cancer Institute, vol. 100, no. 15, pp. 1104-1112. https://doi.org/10.1093/jnci/djn213
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. / Mitochondrial DNA content : Its genetic heritability and association with renal cell carcinoma. In: Journal of the National Cancer Institute. 2008 ; Vol. 100, No. 15. pp. 1104-1112.
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abstract = "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). Conclusion: smtDNA content appears to have high heritability. Low mtDNA content appears to be associated with increased risk of renal cell carcinoma.",
author = "Jinliang Xing and Meng Chen and Wood, {Christopher G.} and Jie Lin and Spitz, {Margaret R.} and Jianzhong Ma and Amos, {Christopher I.} and Shields, {Peter G.} and Benowitz, {Neal L.} and Jian Gu and {De Andrade}, Mariza and Swan, {Gary E.} and Xifeng Wu",
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AU - Wood, Christopher G.

AU - Lin, Jie

AU - Spitz, Margaret R.

AU - Ma, Jianzhong

AU - Amos, Christopher I.

AU - Shields, Peter G.

AU - Benowitz, Neal L.

AU - Gu, Jian

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N2 - 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). Conclusion: smtDNA content appears to have high heritability. Low mtDNA content appears to be associated with increased risk of renal cell carcinoma.

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