title: Mitochondrial polymorphism A10398G and Haplogroup I are associated with Fuchs' endothelial corneal dystrophy.
abstract: OBJECTIVE
  We investigated whether mitochondrial DNA (mtDNA) variants affect the susceptibility of Fuchs endothelial corneal dystrophy (FECD).
  
  
  METHODS
  Ten mtDNA variants defining European haplogroups were genotyped in a discovery dataset consisting of 530 cases and 498 controls of European descent from the Duke FECD cohort. Association tests for mtDNA markers and haplogroups were performed using logistic regression models with adjustment of age and sex. Subset analyses included controlling for additional effects of either the TCF4 SNP rs613872 or cigarette smoking. Our replication dataset was derived from the genome-wide association study (GWAS) of the FECD Genetics Consortium, where genotypes for three of 10 mtDNA markers were available. Replication analyses were performed to compare non-Duke cases to all GWAS controls (GWAS1, N = 3200), and to non-Duke controls (GWAS2, N = 3043).
  
  
  RESULTS
  The variant A10398G was significantly associated with FECD (odds ratio [OR] = 0.72; 95% confidence interval [CI] = [0.53, 0.98]; P = 0.034), and remains significant after adjusting for smoking status (min P = 0.012). This variant was replicated in GWAS1 (P = 0.019) and GWAS2 (P = 0.036). Haplogroup I was significantly associated with FECD (OR = 0.46; 95% CI = [0.22, 0.97]; P = 0.041) and remains significant after adjusting for the effect of smoking (min P = 0.008) or rs613872 (P = 0.034).
  
  
  CONCLUSIONS
  The 10398G allele and Haplogroup I appear to confer significant protective effects for FECD. The effect of A10398G and Haplogroup I to FECD is likely independent of the known TCF4 variant. More data are needed to decipher the interaction between smoking and mtDNA haplogroups.
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina, United States Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, United States.
authors.forename: Yi-Ju
authors.initials: YJ
authors.lastname: Li
authors.affiliation: Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, United States.
authors.forename: Mollie A
authors.initials: MA
authors.lastname: Minear
authors.affiliation: Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, United States.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Qin
authors.affiliation: Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, United States.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Rimmler
authors.affiliation: Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hauser
authors.affiliation: Duke Eye Center, Duke University Medical Center, Durham, North Carolina, United States.
authors.forename: R Rand
authors.initials: RR
authors.lastname: Allingham
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Igo
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Lass
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States.
authors.forename: Sudha K
authors.initials: SK
authors.lastname: Iyengar
authors.affiliation: Duke Eye Center, Duke University Medical Center, Durham, North Carolina, United States Department of Pathology, Duke University Medical Center, Durham, North Carolina, United States.
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Klintworth
authors.affiliation: Duke Eye Center, Duke University Medical Center, Durham, North Carolina, United States Shiley Eye Center, University of California San Diego, La Jolla, California, United States.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Afshari
authors.affiliation: Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, United States.
authors.forename: Simon G
authors.initials: SG
authors.lastname: Gregory
mesh_terms: D000368:Aged; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics*; D042967:Electron Transport Complex I / Q000235:genetics*; D005260:Female; D005642:Fuchs' Endothelial Dystrophy / Q000175:diagnosis / Q000235:genetics*; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D005838:Genotype; D060005:Genotyping Techniques; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012907:Smoking; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics; D044465:White People
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004272:DNA, Mitochondrial; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D042967:Electron Transport Complex I; C114961:MT-ND3 protein, human
keywords: TCF4; genetic association; mitochondrial haplogroup; oxidative stress; smoking