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

  1. Leen M. ‘t Hart1,
  2. Torben Hansen2,
  3. Ingrid Rietveld3,
  4. Jacqueline M. Dekker4,
  5. Giel Nijpels4,
  6. George M.C. Janssen1,
  7. Pascal A. Arp5,
  8. André G. Uitterlinden5,
  9. Torben Jørgensen6,
  10. Knut Borch-Johnsen27,
  11. Huibert A.P. Pols5,
  12. Oluf Pedersen27,
  13. Cornelia M. van Duijn3,
  14. Robert J. Heine4 and
  15. J. Antonie Maassen14
  1. 1Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands
  2. 2Steno Diabetes Center and Hagedorn Research Institute, Gentofte, Denmark
  3. 3Department of Genetic Epidemiology and Biostatistics, Erasmus University Medical Center, Rotterdam, the Netherlands
  4. 4Institute for Research in Extramural Medicine, Free University Medical Center, Amsterdam, the Netherlands
  5. 5Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
  6. 6Research Center for Prevention and Health, Copenhagen County, Glostrup University Hospital, Glostrup, Denmark
  7. 7Faculty of Health Science, Aarhus University, Aarhus, Denmark
  1. 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 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.

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.
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