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Diabetes 54:1892-1895, 2005
© 2005 by the American Diabetes Association, Inc.

Brief Genetics Reports

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

Leen M. ‘t Hart1, Torben Hansen2, Ingrid Rietveld3, Jacqueline M. Dekker4, Giel Nijpels4, George M.C. Janssen1, Pascal A. Arp5, André G. Uitterlinden5, Torben Jørgensen6, Knut Borch-Johnsen2,7, Huibert A.P. Pols5, Oluf Pedersen2,7, Cornelia M. van Duijn3, Robert J. Heine4, and J. Antonie Maassen1,4

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

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.

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

Abbreviations: NGT, normal glucose tolerant; OGTT, oral glucose tolerance test; SNP, single nucleotide polymorphism


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Copyright © 2005 by the American Diabetes Association.