Evidence that the mitochondrial leucyl tRNA synthetase (LARS2) gene represents a novel type 2 diabetes susceptibility gene
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Evidence that the mitochondrial leucyl tRNA synthetase (LARS2) gene represents a novel type 2 diabetes susceptibility gene. / 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.
In: Diabetes, Vol. 54, No. 6, 2005, p. 1892-5.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Evidence that the mitochondrial leucyl tRNA synthetase (LARS2) gene represents a novel type 2 diabetes susceptibility gene
AU - hart, Leen M
AU - Hansen, Torben
AU - Rietveld, Ingrid
AU - Dekker, Jacqueline M
AU - Nijpels, Giel
AU - Janssen, George M C
AU - Arp, Pascal A
AU - Uitterlinden, André G
AU - Jørgensen, Torben
AU - Borch-Johnsen, Knut
AU - Pols, Huibert A P
AU - Pedersen, Oluf
AU - van Duijn, Cornelia M
AU - Heine, Robert J
AU - Maassen, J Antonie
PY - 2005
Y1 - 2005
N2 - 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.
AB - 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.
KW - Aged
KW - Chromosome Mapping
KW - DNA, Mitochondrial
KW - Diabetes Mellitus, Type 2
KW - Female
KW - Genetic Predisposition to Disease
KW - Humans
KW - Leucine-tRNA Ligase
KW - Male
KW - Middle Aged
KW - Mutation
KW - Polymorphism, Single Nucleotide
M3 - Journal article
C2 - 15919814
VL - 54
SP - 1892
EP - 1895
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 6
ER -
ID: 38456055