title: Mitochondrial DNA content: its genetic heritability and association with renal cell carcinoma.
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).
  
  
  CONCLUSIONS
  mtDNA content appears to have high heritability. Low mtDNA content appears to be associated with increased risk of renal cell carcinoma.
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jinliang
authors.initials: J
authors.lastname: Xing
authors.forename: Meng
authors.initials: M
authors.lastname: Chen
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Wood
authors.forename: Jie
authors.initials: J
authors.lastname: Lin
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Spitz
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Ma
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.forename: Peter G
authors.initials: PG
authors.lastname: Shields
authors.forename: Neal L
authors.initials: NL
authors.lastname: Benowitz
authors.forename: Jian
authors.initials: J
authors.lastname: Gu
authors.forename: Mariza
authors.initials: M
authors.lastname: de Andrade
authors.forename: Gary E
authors.initials: GE
authors.lastname: Swan
authors.forename: Xifeng
authors.initials: X
authors.lastname: Wu
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics*; D016022:Case-Control Studies; D004272:DNA, Mitochondrial / Q000032:analysis* / Q000235:genetics; D019317:Evidence-Based Medicine; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics*; D016015:Logistic Models; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D015999:Multivariate Analysis; D016017:Odds Ratio; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D012307:Risk Factors
chemical_list: D004272:DNA, Mitochondrial; D005819:Genetic Markers