title: Male-specific association between MT-ND4 11719 A/G polymorphism and ulcerative colitis: a mitochondria-wide genetic association study.
abstract: BACKGROUND
  Ulcerative colitis (UC) is a chronic inflammatory disorder of still unknown pathogenesis. Increasing evidence indicates that alterations in mitochondrial respiration and thus adenosine triphosphate (ATP) production are involved. This may contribute to mucosal energy deficiency and subsequently intestinal barrier malfunction, which is accepted to be a major hallmark of UC. Genetic alterations of the mitochondrial genome are one cause of mitochondrial dysfunction. However, less is known about mitochondrial gene polymorphisms in UC. Therefore, we aimed at identifying genetic associations between mitochondrial polymorphisms and UC.
  
  
  METHODS
  German UC cases (n = 1062) and German healthy controls (n = 3030) were genotyped using the Affymetrix Genome-Wide Human SNP Array 6.0. The primary association analysis was to test for associations between mitochondrial single nucleotide polymorphisms (SNPs) and UC using Fisher's exact test in the total sample and stratified by sex. In addition, we tested for associations between mitochondrial haplogroups and UC and for interactions between the most promising mitochondrial SNPs and nuclear SNPs. An independent set of German subjects with 1625 UC cases and 3575 controls was used for replication.
  
  
  RESULTS
  We identified a genetic association between the MT-ND4 11719 A/G polymorphism and UC in the subgroup of males (rs2853495; odds ratio, 1.40; 95 % confidence interval, 1.13 to 1.73; p = 0.002). This association was replicated in the second independent cohort. In the association analysis based on mitochondrial haplogroups the lowest p values were reached for haplogroups HV and T (p = 0.029 and 0.035). Haplogroup HV is determined by the mitochondrial 11719 A/G polymorphism. Accordingly, this association was only found in the subgroup of males (p = 0.009).
  
  
  CONCLUSIONS
  For the first time, we observed an association between the MT-ND4 11719 A/G polymorphism and UC. The gene MT-ND4 encodes for a subunit of the mitochondrial electron transport chain complex I, which is pivotal for ATP production and might therefore contribute to mucosal energy deficiency. The male-specific association indicates differences between males and females concerning the impact of mitochondrial gene polymorphisms on the development of UC. Further investigations of the functional mechanism underlying this association and the relevance of the gender-specificity are highly warranted.
authors.affiliation: Institute of Medical Biometry and Statistics, University of Lübeck, University Hospital Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23562, Lübeck, Germany.
authors.forename: Theresa
authors.initials: T
authors.lastname: Dankowski
authors.affiliation: Department of Medicine I, University of Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany.|Institute for Systemic Inflammation Research, University of Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Schröder
authors.affiliation: The Lübeck Institute of Experimental Dermatology, University of Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany.|Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Ernst-Heydemann-Straße 8, 18057, Rostock, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Möller
authors.affiliation: Priority Area Asthma & Allergy, Research Center Borstel, Airway Research Center North (ARCN), Members of the German Center for Lung Research (DZL), Parkallee 1-40, 23845, Borstel, Germany.|Xiamen-Borstel Joint Laboratory of Autoimmunity, Medical College of Xiamen University, Xiamen, 361102, China.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Yu
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schittenhelmstraße 12, 24105, Kiel, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Ellinghaus
authors.affiliation: Department of Medicine I, University of Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Bär
authors.affiliation: Department of Medicine I, University of Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Fellermann
authors.affiliation: Department of Medicine I, University of Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Lehnert
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schittenhelmstraße 12, 24105, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schittenhelmstraße 12, 24105, Kiel, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: Department of Medicine I, University of Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Sina
authors.affiliation: The Lübeck Institute of Experimental Dermatology, University of Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany. Saleh.Ibrahim@uksh.de.
authors.forename: Saleh M
authors.initials: SM
authors.lastname: Ibrahim
authors.affiliation: Institute of Medical Biometry and Statistics, University of Lübeck, University Hospital Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23562, Lübeck, Germany. inke.koenig@imbs.uni-luebeck.de.
authors.forename: Inke R
authors.initials: IR
authors.lastname: König
mesh_terms: D016022:Case-Control Studies; D003093:Colitis, Ulcerative / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D060005:Genotyping Techniques; D005858:Germany; D006801:Humans; D007413:Intestinal Mucosa / Q000503:physiopathology; D008297:Male; D008928:Mitochondria / Q000235:genetics* / Q000502:physiology; D009245:NADH Dehydrogenase / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012737:Sex Factors
chemical_list: C098483:NADH dehydrogenase subunit 4; D009245:NADH Dehydrogenase
keywords: ATP; Haplogroup HV; MT-ND4; Male-specific association; Mitochondria-wide association study; Mitochondrial gene polymorphism; Mucosal energy deficiency; Ulcerative colitis; rs2853495