title: Genetic risk factors affecting mitochondrial function are associated with kidney disease in people with Type 1 diabetes.
abstract: OBJECTIVE
  To evaluate the association with diabetic kidney disease of single nucleotide polymorphisms (SNPs) that may contribute to mitochondrial dysfunction.
  
  
  METHODS
  The mitochondrial genome and 1039 nuclear genes that are integral to mitochondrial function were investigated using a case (n = 823 individuals with diabetic kidney disease) vs. control (n = 903 individuals with diabetes and no renal disease) approach. All people included in the analysis were of white European origin and were diagnosed with Type 1 diabetes before the age of 31 years. Replication was conducted in 5093 people with similar phenotypes to those of the discovery collection. Association analyses were performed using the plink genetic analysis toolset, with adjustment for relevant covariates.
  
  
  RESULTS
  A total of 25 SNPs were evaluated in the mitochondrial genome, but none were significantly associated with diabetic kidney disease or end-stage renal disease. A total of 38 SNPs in nuclear genes influencing mitochondrial function were nominally associated with diabetic kidney disease and 16 SNPS were associated with end-stage renal disease, secondary to diabetic kidney disease, with meta-analyses confirming the same direction of effect. Three independent signals (seven SNPs) were common to the replication data for both phenotypes with Type 1 diabetes and persistent proteinuria or end-stage renal disease.
  
  
  CONCLUSIONS
  Our results suggest that SNPs in nuclear genes that influence mitochondrial function are significantly associated with diabetic kidney disease in a white European population.
authors.affiliation: Centre for Public Health, Queen's University of Belfast, Belfast, UK.
authors.forename: E J
authors.initials: EJ
authors.lastname: Swan
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Salem
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Centre, Helsinki, Finland.|Department of Medicine, Division of Nephrology, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: N
authors.initials: N
authors.lastname: Sandholm
authors.affiliation: Nordsjaellands Hospital, Hilleroed, Denmark and Health, Aarhus University, Aarhus, Denmark.|Steno Diabetes Centre, Gentofte, Denmark.
authors.forename: L
authors.initials: L
authors.lastname: Tarnow
authors.affiliation: Steno Diabetes Centre, Gentofte, Denmark.
authors.forename: P
authors.initials: P
authors.lastname: Rossing
authors.affiliation: Steno Diabetes Centre, Gentofte, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Lajer
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Centre, Helsinki, Finland.|Department of Medicine, Division of Nephrology, Helsinki University Central Hospital, Helsinki, Finland.|Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: P H
authors.initials: PH
authors.lastname: Groop
authors.affiliation: Centre for Public Health, Queen's University of Belfast, Belfast, UK.|Regional Nephrology Unit, Belfast City Hospital, Belfast, UK.
authors.forename: A P
authors.initials: AP
authors.lastname: Maxwell
authors.affiliation: Centre for Public Health, Queen's University of Belfast, Belfast, UK.
authors.forename: A J
authors.initials: AJ
authors.lastname: McKnight
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000209:etiology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D054629:Genome, Mitochondrial; D006801:Humans; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D051436:Renal Insufficiency, Chronic / Q000209:etiology / Q000235:genetics
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