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- Title
Evidence that the mitochondrial leucyl tRNA synthetase (LARS2) gene represents a novel type 2 diabetes susceptibility gene.
- Authors
't Hart, Leen M.; Hansen, Torben; Rietveld, Ingrid; Dekker, Jacqueline M.; Nijpels, Giel; Janssen, George M. C.; Arp, Pascal A.; Uitterlinden, André G.; Jørgensen, Torben; Borch-Johnsen, Knut; Pols, Huibert A. P.; Pedersen, Oluf; van Duijn, Cornelia M.; Heine, Robert J.; Maassen, J. Antonie; Uitterlinden, André G; Jørgensen, Torben
- Abstract
Previously, we have shown that a mutation in the mitochondrial DNA-encoded tRNALeu(UUR) gene is associated with type 2 diabetes. One of the consequences of this mutation is a reduced aminoacylation of tRNALeu(UUR). In this study, we have examined whether variants in the leucyl tRNA synthetase gene (LARS2), involved in aminoacylation of tRNALeu(UUR), associate with type 2 diabetes. Direct sequencing of LARS2 cDNA from 25 type 2 diabetic subjects revealed eight single nucleotide polymorphisms. Two of the variants were examined in 7,836 subjects from four independent populations in the Netherlands and Denmark. A -109 g/a variant was not associated with type 2 diabetes. Allele frequencies for the other variant, H324Q, were 3.5% in type 2 diabetic and 2.7% in control subjects, respectively. The common odds ratio across all four studies was 1.40 (95% CI 1.12-1.76), P = 0.004. There were no significant differences in clinical variables between carriers and noncarriers. In this study, we provide evidence that the LARS2 gene may represent a novel type 2 diabetes susceptibility gene. The mechanism by which the H324Q variant enhances type 2 diabetes risk needs to be further established. This is the first report of association between an aminoacyl tRNA synthetase gene and disease. Our results further highlight the important role of mitochondria in glucose homeostasis. Diabetes 54:1892-1895, 2005 previously, we have shown that an A3243G mutation in the mitochondrial DNA-encoded tRNA[sup Leu(UUR)] gene is associated with maternally inherited diabetes and deafness(1,2). Carriers of the 3243 mutation have a reduced glucose-stimulated insulin secretion. Biochemical studies indicate that mutant mitochondrial TRNA[sup Leucine] is less efficiently aminoacylated in comparison with the wild-type tRNA(2). Furthermore, it has been shown that there is an altered balance between mitochondrial and nuclear-encoded proteins in mutant mitochondria, resulting in mitochondrial dysfunction(2).
- Subjects
TRANSFER RNA; GENES; TYPE 2 diabetes; MITOCHONDRIA; PEOPLE with diabetes
- Publication
Diabetes, 2005, Vol 54, Issue 6, p1892
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/diabetes.54.6.1892