Male-specific association between MT-ND4 11719 A/G polymorphism and ulcerative colitis: a mitochondria-wide genetic association study View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2016-12

AUTHORS

Theresa Dankowski, Torsten Schröder, Steffen Möller, Xinhua Yu, David Ellinghaus, Florian Bär, Klaus Fellermann, Hendrik Lehnert, Stefan Schreiber, Andre Franke, Christian Sina, Saleh M. Ibrahim, Inke R. König

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. More... »

PAGES

118

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/s12876-016-0509-1

DOI

http://dx.doi.org/10.1186/s12876-016-0509-1

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1039929808

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/27716073


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