title: Mitochondrial DNA sequence variation and risk of pancreatic cancer.
abstract: Although the mitochondrial genome exhibits high mutation rates, common mitochondrial DNA (mtDNA) variation has not been consistently associated with pancreatic cancer. Here, we comprehensively examined mitochondrial genomic variation by sequencing the mtDNA of participants (cases = 286, controls = 283) in a San Francisco Bay Area pancreatic cancer case-control study. Five common variants were associated with pancreatic cancer at nominal statistical significance (P < 0.05) with the strongest finding for mt5460g in the ND2 gene [OR = 3.9; 95% confidence interval (CI), 1.5-10; P = 0.004] which encodes an A331T substitution. Haplogroup K was nominally associated with reduced pancreatic cancer risk (OR = 0.32; 95% CI, 0.13-0.76; P = 0.01) when compared with the most common haplogroup, H. A total of 19 haplogroup-specific rare variants yielded nominal statistically significant associations (P < 0.05) with pancreatic cancer risk, with the majority observed in genes involved in oxidative phosphorylation. Weighted-sum statistics were used to identify an aggregate effect of variants in the 22 mitochondrial tRNAs on pancreatic cancer risk (P = 0.02). While the burden of singleton variants in the HV2 and 12S RNA regions was three times higher among European haplogroup N cases than controls, the prevalence of singleton variants in ND4 and ND5 was two to three times higher among African haplogroup L cases than in controls. Together, the results of this study provide evidence that aggregated common and rare variants and the accumulation of singleton variants are important contributors to pancreatic cancer risk.
authors.affiliation: Institute for Human Genetics, University of California, San Francisco, California, USA.
authors.forename: Ernest T
authors.initials: ET
authors.lastname: Lam
authors.forename: Paige M
authors.initials: PM
authors.lastname: Bracci
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Holly
authors.forename: Catherine
authors.initials: C
authors.lastname: Chu
authors.forename: Annie
authors.initials: A
authors.lastname: Poon
authors.forename: Eunice
authors.initials: E
authors.lastname: Wan
authors.forename: Krystal
authors.initials: K
authors.lastname: White
authors.forename: Pui-Yan
authors.initials: PY
authors.lastname: Kwok
authors.forename: Ludmila
authors.initials: L
authors.lastname: Pawlikowska
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Tranah
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D004272:DNA, Mitochondrial / Q000737:chemistry / Q000235:genetics*; D005260:Female; D050259:Genes, Mitochondrial / Q000235:genetics; D014644:Genetic Variation; D054629:Genome, Mitochondrial / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics; D059645:Mutation Rate; D010190:Pancreatic Neoplasms / Q000453:epidemiology / Q000235:genetics*; D012335:RNA, Ribosomal / Q000235:genetics; D012343:RNA, Transfer / Q000235:genetics; D018570:Risk Assessment; D012307:Risk Factors; D012495:San Francisco / Q000453:epidemiology; D017422:Sequence Analysis, DNA / Q000379:methods
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D012335:RNA, Ribosomal; D012343:RNA, Transfer