Abstract
Polymorphisms in the mitochondrial genome are hypothesized to be associated with risk of various diseases, including cancer. However, there has been conflicting evidence for associations between a common polymorphism in the mitochondrial genome (A10398G, G10398A in some prior reports) and breast cancer risk. Reactive oxygen species, a by-product of mitochondrial energy production, can lead to oxidative stress and DNA damage in both the mitochondria and their cells. Alcohol consumption, which may also lead to oxidative stress, is associated with breast cancer risk. Therefore, we hypothesized that polymorphisms in the mitochondrial genome interact with alcohol consumption to alter breast cancer risk. We genotyped the A10398G polymorphism in a case-control study nested within the Nurses' Health Study (NHS, 1,561 cases, 2,209 controls). We observed an interaction between alcohol consumption (yes/no) and A10398G on breast cancer risk (p-int = 0.03). The risk associated with alcohol consumption was limited to carriers of the 10398G allele (Odds Ratio 1.52, 95% Confidence Interval 1.10–2.08 comparing drinkers to non-drinkers). However, we were unable to replicate these findings in the Women's Health Study (WHS, 678 cases, 669 controls), although the power to detect this interaction in the WHS was low (power = 0.57). Further examination of this interaction, such as sufficiently powered epidemiological studies of cancer risk or associations with biomarkers of oxidative stress, may provide further evidence for GxE interactions between the A10398G mitochondrial polymorphism and alcohol consumption on breast cancer risk.
Highlights
Mitochondria are very important cellular organelles, playing active roles in various functions, such as energy balance and cell cycle control
It is hypothesized that polymorphisms in the mitochondria that cause the mitochondria to be less efficient in energy exchange, creating more heat and reactive oxygen species, allowed early humans an adaptive advantage when migrating to cooler climates, such as from Africa to Europe [1], and advances in genotyping and sequencing technology have led to greater understanding and fine-scale resolution of human migrations based on mitochondrial genetics [2]
We did not observe any association between the A10398G polymorphism in the mitochondrial NADH dehydrogenase subunit 3 (ND3) gene and breast cancer risk in either the Nurses’ Health Study (NHS) (Odds Ratio (OR) 1.01, 95% Confidence Interval (CI) 0.85–1.19) or Women’s Health Study (WHS) (Table 1.)
Summary
Mitochondria are very important cellular organelles, playing active roles in various functions, such as energy balance and cell cycle control. By transforming energy into a form that the cell can use, mitochondria produce reactive oxygen species (ROS) that can lead to damage of key components of the cell, proteins and DNA. All of these facets of mitochondrial biology make them of interest with respect to cancer biology. It is hypothesized that polymorphisms in the mitochondria that cause the mitochondria to be less efficient in energy exchange, creating more heat and reactive oxygen species, allowed early humans an adaptive advantage when migrating to cooler climates, such as from Africa to Europe [1], and advances in genotyping and sequencing technology have led to greater understanding and fine-scale resolution of human migrations based on mitochondrial genetics [2]. Other polymorphisms have more recently been investigated for association with various diseases, including diabetes [1,3,4,5,6], Parkinson’s disease [7,8,9], Alzheimer’s disease [8,10,11,12], and breast cancer [13,14,15,16]
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