Association of Genes, Pathways, and Haplogroups of the Mitochondrial Genome with the Risk of Colorectal Cancer: The Multiethnic Cohort.
The mitochondrial genome encodes for the synthesis of 13 proteins that 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 role of the OXPHOS pathway and mitochondrial genes in colorectal cancer (CRC) risk, we tested 185 mitochondrial SNPs (mtSNPs), located in 13 genes that comprise four complexes of the OXPHOS pathway and mtSNP groupings for rRNA and tRNA, in 2,453 colorectal cancer cases and 11,930 controls from the Multiethnic Cohort Study. Using the sequence kernel association test, we examined the collective set of 185 mtSNPs, as well as subsets of mtSNPs grouped by mitochondrial pathways, complexes, and genes, adjusting for age, sex, principal components of global ancestry, and self-reported maternal race/ethnicity. We also tested for haplogroup associations using unconditional logistic regression, adjusting for the same covariates. Stratified analyses were conducted by self-reported maternal race/ethnicity. In European Americans, a global test of all genetic variants of the mitochondrial genome identified an association with CRC risk (P = 0.04). In mtSNP-subset analysis, the NADH dehydrogenase 2 (MT-ND2) gene in Complex I was associated with CRC risk at a P-value of 0.001 (q = 0.015). In addition, haplogroup T was associated with CRC risk (OR = 1.66, 95% CI: 1.19-2.33, P = 0.003). No significant mitochondrial pathway and gene associations were observed in the remaining four racial/ethnic groups--African Americans, Asian Americans, Latinos, and Native Hawaiians. In summary, our findings suggest that variations in the mitochondrial genome and particularly in the MT-ND2 gene may play a role in CRC risk among European Americans, but not in other maternal racial/ethnic groups. Further replication is warranted and future studies should evaluate the contribution of mitochondrial proteins encoded by both the nuclear and mitochondrial genomes to CRC risk.
Cancer Prevention Institute of California, Fremont, California, United States of America; Stanford Cancer Institute, Palo Alto, California, United States of America.
Yuqing
Y
Li
University of Minnesota Genomics Center, Minneapolis, Minnesota, United States of America.
Kenneth B
KB
Beckman
Epidemiology Program, University of Hawaii Cancer Center, University of Hawaii, Honolulu, Hawaii, United States of America.
Christian
C
Caberto
Centre National de Génotypage, CEA, Evry, France; Biomarker Development, Novartis Institutes for BioMedical Research, Basel, Switzerland.
Remi
R
Kazma
Epidemiology Program, University of Hawaii Cancer Center, University of Hawaii, Honolulu, Hawaii, United States of America.
Annette
A
Lum-Jones
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
Christopher A
CA
Haiman
Epidemiology Program, University of Hawaii Cancer Center, University of Hawaii, Honolulu, Hawaii, United States of America.
Loïc
L
Le Marchand
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
Daniel O
DO
Stram
Center for Human Genetic Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Program of Medical and Population Genetics, The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
Richa
R
Saxena
Cancer Prevention Institute of California, Fremont, California, United States of America; Stanford Cancer Institute, Palo Alto, California, United States of America.
Iona
I
Cheng
D000368:Aged; D044466:Asian People; D044383:Black People; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000208:ethnology* / Q000235:genetics* / Q000473:pathology; D005260:Female; D054629:Genome, Mitochondrial; D006239:Haplotypes; D006630:Hispanic or Latino; D006801:Humans; D040582:Inheritance Patterns; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics*; D009245:NADH Dehydrogenase / Q000235:genetics*; D044468:Native Hawaiian or Pacific Islander; D010085:Oxidative Phosphorylation; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D044465:White People; D001741:Black or African American
D024101:Mitochondrial Proteins; D009245:NADH Dehydrogenase; C521326:NADH dehydrogenase subunit 2, human