© 2007 The Authors. 702 Journal compilation © 2007 Diabetes UK. Diabetic Medicine, 24, 702–706 DIABETICMedicine DOI: 10.1111/j.1464-5491.2007.02110.x Abstract Aims The glutamate decarboxylase gene (GAD2) encodes GAD65, an enzyme catalysing the production of the γ- aminobutyric acid (GABA) which interacts with neuropeptide Y to stimulate food intake. It has been suggested that in pancreatic islets, GABA serves as a functional regulator of pancreatic hormone release. Conflicting results have been reported concerning the potential impact of GAD2 variation on estimates of energy metabolism. The aim of this study was to elucidate potential associations between the GAD2 -243A→G polymorphism and levels of body mass index (BMI) and estimates of glycaemia. Methods Using high-throughput chip-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, the GAD2 -243A→G (rs2236418) polymorphism was genotyped in a population-based sample (Inter99) of 5857 middle- aged, unrelated Danish White subjects. Results The G-allele was associated with modestly lower BMI (P = 0.01). In a case–control study of obesity, the G-allele frequency in 2582 participants with BMI < 25 kg/m 2 was 19.5% (18.4–20.6) compared with 17.1% (15.5–18.8) in 968 participants having BMI ≥ 30 kg/m 2 (P = 0.03), odds ratio 0.9 (0.7–1.0). Of the 5857 subjects, GG carriers had lower fast- ing plasma glucose levels (mmol/l) [AA (n = 3859) 5.6 ± 0.8; AG (n = 1792) 5.5 ± 0.8; GG (n = 206) 5.5 ± 0.8, P = 0.008] and lower 30-min oral glucose tolerance test (OGTT)-related plasma glucose levels (AA 8.7 ± 1.9; AG 8.6 ± 1.9; GG 8.6 ± 2.0, P = 0.04), adjusted for sex, age and BMI. Analysing subjects who were both normoglycaemic and glucose tolerant (n = 4431) GG carriers still had lower fasting plasma glucose concentrations: AA (n = 2895) 5.3 ± 0.4; AG (n = 1383) 5.3 ± 0.4; GG (n = 153) 5.2 ± 0.4 (P = 9.10 -5 ). Conclusion The present study suggests that the GAD2 -243A→G polymorphism in a population of middle-aged White people associates with a modest reduction in BMI and fasting and OGTT-related plasma glucose levels. Diabet. Med. 24, 702–706 (2007) Keywords association study, body mass index, GAD2, genetics, glucose Abbreviations BMI, body mass index; EMSA, electrophoretic mobility shift assay; GABA, γ-aminobutyric acid; GAD2, glutamate decarboxylase gene; LD, linkage disequilibrium; LOD, logarithm of odds score; NPY, neuropeptide Y; OGTT, oral glucose tolerance test; OR, odds ratio; SNP, single nucleotide polymorphism Correspondence to: Trine Welløv Boesgaard MD, Steno Diabetes Center, Niels Steensens Vej 2, NSH2.14, DK-2820 Gentofte, Copenhagen, Denmark. E-mail: tweb@steno.dk Blackwell Publishing Ltd Oxford, UK DME Diabetic Medicine 0742-3071 Blackwell Publishing, 2007 24 Original Article Original article GAD2variation and energy metabolism T. W. Boesgaard et al. Original Article A -243A→G polymorphism upstream of the gene encoding GAD65 associates with lower levels of body mass index and glycaemia in a population-based sample of 5857 middle-aged White subjects T. W. Boesgaard*, S. I. Castella*, G. Andersen*, A. Albrechtsen*, T. Sparsø*, K. Borch-Johnsen*†‡, T. Jørgensen†, T. Hansen* and O. Pedersen*‡ *Steno Diabetes Center, Copenhagen, †Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup and ‡Faculty of Health Science, University of Aarhus, Aarhus, Denmark Accepted 6 November 2006