Association between mitochondrial genetic variation and breast cancer risk: The Multiethnic Cohort

• Published in: PloS one Vol. 14; no. 10; p. e0222284
• Main Authors: Li, Yuqing, Giorgi, Elena E, Beckman, Kenneth B, Caberto, Christian, Kazma, Remi, Lum-Jones, Annette, Haiman, Christopher A, Marchand, Loïc Le, Stram, Daniel O, Saxena, Richa, Cheng, Iona
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 02.10.2019; Public Library of Science (PLoS)
• Subjects: Adult; African Americans; Aged; Analysis; Asian Americans; Biology and Life Sciences; Breast cancer; Breast Neoplasms - genetics; Cancer genetics; Cancer research; Carbon dioxide; Care and treatment; Case-Control Studies; Cohort Studies; Cytochrome; Cytochrome c; Cytochrome oxidase; Cytochrome-c oxidase; Cytochromes; Ethnic Groups - genetics; European Continental Ancestry Group - genetics; Female; Future predictions; Genes; Genetic aspects; Genetic diversity; Genetic Predisposition to Disease; Genetic variance; Genetic Variation; Genome, Mitochondrial; Genomes; Genomics; Haplotypes - genetics; Health risk assessment; Health risks; Hormone replacement therapy; Humans; Medical tests; Medicine and Health Sciences; Mexican American literature; Middle Aged; Minority & ethnic groups; Mitochondria; Mitochondria - genetics; Mitochondrial DNA; NADH; NADH dehydrogenase; NADH dehydrogenase (ubiquinone); Nicotinamide adenine dinucleotide; Oxidases; Oxidative phosphorylation; People and places; Phosphorylation; Polymorphism, Single Nucleotide - genetics; Population studies; Preventive medicine; Proteins; Regression analysis; Risk; Risk Factors; RNA; rRNA; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Transfer RNA; tRNA; Ubiquinone; Women's health; Young Adult; United States; Hawaii; Los Angeles California; San Francisco California; California; United States > US; Massachusetts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0222284

The mitochondrial genome encodes for thirty-seven proteins, among them thirteen are essential for the oxidative phosphorylation (OXPHOS) system. Inherited variation in mitochondrial genes may influence cancer development through changes in mitochondrial proteins, altering the OXPHOS process and promoting the production of reactive oxidative species. To investigate the association between mitochondrial genetic variation and breast cancer risk, we tested 314 mitochondrial SNPs (mtSNPs), capturing four complexes of the mitochondrial OXPHOS pathway and mtSNP groupings for rRNA and tRNA, in 2,723 breast cancer cases and 3,260 controls from the Multiethnic Cohort Study. We examined the collective set of 314 mtSNPs as well as subsets of mtSNPs grouped by mitochondrial OXPHOS pathway, complexes, and genes, using the sequence kernel association test and adjusting for age, sex, and principal components of global ancestry. We also tested haplogroup associations using unconditional logistic regression and adjusting for the same covariates. Stratified analyses were conducted by self-reported maternal race/ethnicity. No significant mitochondrial OXPHOS pathway, gene, and haplogroup associations were observed in African Americans, Asian Americans, Latinos, and Native Hawaiians. In European Americans, a global test of all genetic variants of the mitochondrial genome identified an association with breast cancer risk (P = 0.017, q = 0.102). In mtSNP-subset analysis, the gene MT-CO2 (P = 0.001, q = 0.09) in Complex IV (cytochrome c oxidase) and MT-ND2 (P = 0.004, q = 0.19) in Complex I (NADH dehydrogenase (ubiquinone)) were significantly associated with breast cancer risk. In summary, our findings suggest that collective mitochondrial genetic variation and particularly in the MT-CO2 and MT-ND2 may play a role in breast cancer risk among European Americans. Further replication is warranted in larger populations and future studies should evaluate the contribution of mitochondrial proteins encoded by both the nuclear and mitochondrial genomes to breast cancer risk.