Dataset Information

Mitochondrial DNA Copy-Number Variation and Pancreatic Cancer Risk in the Prospective EPIC Cohort.

ABSTRACT:

Background

Mitochondrial DNA (mtDNA) copy number in peripheral blood has been found to be associated with risk of developing several cancers. However, data on pancreatic ductal adenocarcinoma (PDAC) are very limited.

Methods

To further our knowledge on this topic, we measured relative mtDNA copy number by a quantitative real-time PCR assay in peripheral leukocyte samples of 476 PDAC cases and 357 controls nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

Results

We observed lower mtDNA copy number with advancing age (P = 6.54 × 10^-5) and with a high body mass index (BMI) level (P = 0.004) and no association with sex, smoking behavior, and alcohol consumption. We found an association between increased mtDNA copy number and decreased risk of developing PDAC with an odds ratios (OR) of 0.35 [95% confidence interval (CI), 0.16-0.79; P = 0.01] when comparing the fifth quintile with the first using an unconditional logistic regression and an OR of 0.19 (95% CI, 0.07-0.52; P = 0.001) with a conditional analysis. Analyses stratified by BMI showed an association between high mtDNA copy number and decreased risk in the stratum of normal weight, consistent with the main analyses.

Conclusions

Our results suggest a protective effect of a higher number of mitochondria, measured in peripheral blood leukocytes, on PDAC risk.

Impact

Our findings highlight the importance of understanding the mitochondrial biology in pancreatic cancer.

SUBMITTER: Gentiluomo M

PROVIDER: S-EPMC7611119 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Mitochondrial DNA copy number (mtDNA CN) has been shown to be highly heritable and associated with traits of interest in humans. However, studies are lacking in the literature for livestock species such as beef cattle. In this study, 2,371 individuals from a crossbred beef population comprising the Germplasm Evaluation program from the U.S. Meat Animal Research Center had samples of blood, leucocyte, or semen collected for low-pass sequencing (LPS) that resulted in both nuclear DNA (nuDNA) and mitochondrial DNA (mtDNA) sequence reads. Mitochondrial DNA CN was estimated based on the ratio of mtDNA to nuDNA coverages. Genetic parameters for mtDNA CN were estimated from an animal model based on a genomic relationship matrix (~87K SNP from the nuDNA). Different models were used to test the effects of tissue, sex, age at sample collection, heterosis, and breed composition. Maternal effects, assessed by fitting a maternal additive component and by fitting eleven SNP on the mtDNA, were also obtained. As previously reported, mtDNA haplotypes were used to classify individuals into Taurine haplogroups (T1, T2, T3/T4, and T5). Estimates of heritability when fitting fixed effects in addition to the intercept were moderate, ranging from 0.11 to 0.31 depending on the model. From a model ignoring contemporary group, semen samples had the lowest mtDNA CN, as expected, followed by blood and leucocyte samples (P ≤ 0.001). The effect of sex and the linear and quadratic effects of age were significant (P ≤ 0.02) depending on the model. When significant, females had greater mtDNA CN than males. The effects of heterosis and maternal heterosis were not significant (P ≥ 0.47). The estimates of maternal and mtDNA heritability were near zero (≤0.03). Most of the samples (98%) were classified as haplogroup T3. Variation was observed in the mtDNA within Taurine haplogroups, which enabled the identification of 24 haplotypes. These results suggest that mtDNA CN is under nuclear genetic control and would respond favorably to selection.