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


Autoři: Yuqing Li aff001;  Elena E. Giorgi aff002;  Kenneth B. Beckman aff003;  Christian Caberto aff004;  Remi Kazma aff005;  Annette Lum-Jones aff004;  Christopher A. Haiman aff006;  Loïc Le Marchand aff004;  Daniel O. Stram aff006;  Richa Saxena aff007;  Iona Cheng aff001
Působiště autorů: Department of Epidemiology and Biostatistics, School of Medicine, University of California, San Francisco, California, United States of America aff001;  Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico aff002;  University of Minnesota Genomics Center, Minneapolis, Minnesota, United States of America aff003;  Epidemiology Program, University of Hawaii Cancer Center, University of Hawaii, Honolulu, Hawaii, United States of America aff004;  Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Switzerland aff005;  Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America aff006;  Center for Human Genetic Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America aff007;  Program of Medical and Population Genetics, The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America aff008
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0222284

Souhrn

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Klíčová slova:

Breast cancer – Europe – Haplogroups – Mitochondria – Mitochondrial DNA – Transfer RNA – African American people – Mitochondrial genetics


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