title: Genetic association analysis of 13 nuclear-encoded mitochondrial candidate genes with type II diabetes mellitus: the DAMAGE study.
abstract: Mitochondria play an important role in many processes, like glucose metabolism, fatty acid oxidation and ATP synthesis. In this study, we aimed to identify association of common polymorphisms in nuclear-encoded genes involved in mitochondrial protein synthesis and biogenesis with type II diabetes mellitus (T2DM) using a two-stage design. In the first stage, we analyzed 62 tagging single nucleotide polymorphisms (SNPs) in the Hoorn study (n=999 participants) covering all common variation in 13 biological candidate genes. These 13 candidate genes were selected from four clusters regarded essential for correct mitochondrial protein synthesis and biogenesis: aminoacyl tRNA synthetases, translation initiation factors, tRNA modifying enzymes and mitochondrial DNA transcription and replication. SNPs showing evidence for association with T2DM were measured in second stage genotyping (n=10164 participants). After a meta-analysis, only one SNP in SIRT4 (rs2522138) remained significant (P=0.01). Extending the second stage with samples from the Danish Steno Study (n=1220 participants) resulted in a common odds ratio (OR) of 0.92 (0.85-1.00), P=0.06. Moreover, in a large meta-analysis of three genome-wide association studies, this SNP was also not associated with T2DM (P=0.72). In conclusion, we did not find evidence for association of common variants in 13 nuclear-encoded mitochondrial proteins with T2DM.
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, The Netherlands.
authors.forename: Erwin
authors.initials: E
authors.lastname: Reiling
authors.forename: Jana V
authors.initials: JV
authors.lastname: van Vliet-Ostaptchouk
authors.forename: Esther
authors.initials: E
authors.lastname: van 't Riet
authors.forename: Timon W
authors.initials: TW
authors.lastname: van Haeften
authors.forename: Pascal A
authors.initials: PA
authors.lastname: Arp
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.forename: Dennis
authors.initials: D
authors.lastname: Kremer
authors.forename: Marlous J
authors.initials: MJ
authors.lastname: Groenewoud
authors.forename: Els C
authors.initials: EC
authors.lastname: van Hove
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Romijn
authors.forename: Jan W A
authors.initials: JW
authors.lastname: Smit
authors.forename: Giel
authors.initials: G
authors.lastname: Nijpels
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Heine
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Maassen
authors.forename: Marten H
authors.initials: MH
authors.lastname: Hofker
authors.forename: Leen M
authors.initials: LM
authors.lastname: 't Hart
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Dekker
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002467:Cell Nucleus / Q000235:genetics*; D015331:Cohort Studies; D003718:Denmark; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D014176:Protein Biosynthesis / Q000235:genetics*