Details

Autor(en) / Beteiligte

• '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

Titel

Evidence that the Mitochondrial Leucyl tRNA Synthetase (LARS2) Gene Represents a Novel Type 2 Diabetes Susceptibility Gene

Ist Teil von

• Diabetes (New York, N.Y.), 2005-06, Vol.54 (6), p.1892-1895

Ort / Verlag

Alexandria, VA: American Diabetes Association

Erscheinungsjahr

2005

Quelle

MEDLINE

Beschreibungen/Notizen

• Evidence that the Mitochondrial Leucyl tRNA Synthetase ( LARS2 ) Gene Represents a Novel Type 2 Diabetes Susceptibility Gene Leen M. ‘t Hart 1 , Torben Hansen 2 , Ingrid Rietveld 3 , Jacqueline M. Dekker 4 , Giel Nijpels 4 , George M.C. Janssen 1 , Pascal A. Arp 5 , André G. Uitterlinden 5 , Torben Jørgensen 6 , Knut Borch-Johnsen 2 7 , Huibert A.P. Pols 5 , Oluf Pedersen 2 7 , Cornelia M. van Duijn 3 , Robert J. Heine 4 and J. Antonie Maassen 1 4 1 Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands 2 Steno Diabetes Center and Hagedorn Research Institute, Gentofte, Denmark 3 Department of Genetic Epidemiology and Biostatistics, Erasmus University Medical Center, Rotterdam, the Netherlands 4 Institute for Research in Extramural Medicine, Free University Medical Center, Amsterdam, the Netherlands 5 Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands 6 Research Center for Prevention and Health, Copenhagen County, Glostrup University Hospital, Glostrup, Denmark 7 Faculty of Health Science, Aarhus University, Aarhus, Denmark Address correspondence and reprint requests to L.M. ‘t Hart, PhD, Leiden University Medical Center, Department of Molecular Cell Biology, Wassenaarseweg 72, 2333 AL Leiden, Netherlands. E-mail: l.m.t_hart{at}lumc.nl Abstract Previously, we have shown that a mutation in the mitochondrial DNA–encoded tRNA Leu(UUR) gene is associated with type 2 diabetes. One of the consequences of this mutation is a reduced aminoacylation of tRNA Leu(UUR) . In this study, we have examined whether variants in the leucyl tRNA synthetase gene ( LARS2 ), involved in aminoacylation of tRNA Leu(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. NGT, normal glucose tolerant OGTT, oral glucose tolerance test SNP, single nucleotide polymorphism Footnotes Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted March 21, 2005. Received November 25, 2004. DIABETES