GAD2 on chromosome 10p12 is a candidate gene for human obesity.Reportar como inadecuado

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* Corresponding author 1 GMM - Génétique des maladies multifactorielles 2 CHRU Lille - Centre Hospitalier Régional Universitaire Lille 3 Department of Medicine 4 Epidémiologie cardiovasculaire et métabolique 5 Service de nutrition 6 Section of Genomic Medicine

Abstract : The gene GAD2 encoding the glutamic acid decarboxylase enzyme GAD65 is a positional candidate gene for obesity on Chromosome 10p11-12, a susceptibility locus for morbid obesity in four independent ethnic populations. GAD65 catalyzes the formation of gamma-aminobutyric acid GABA, which interacts with neuropeptide Y in the paraventricular nucleus to contribute to stimulate food intake. A case-control study 575 morbidly obese and 646 control subjects analyzing GAD2 variants identified both a protective haplotype, including the most frequent alleles of single nucleotide polymorphisms SNPs +61450 C>A and +83897 T>A OR = 0.81, 95% CI 0.681-0.972, p = 0.0049 and an at-risk SNP -243 A>G for morbid obesity OR = 1.3, 95% CI 1.053-1.585, p = 0.014. Furthermore, familial-based analyses confirmed the association with the obesity of SNP +61450 C>A and +83897 T>A haplotype chi2 = 7.637, p = 0.02. In the murine insulinoma cell line betaTC3, the G at-risk allele of SNP -243 A>G increased six times GAD2 promoter activity p < 0.0001 and induced a 6-fold higher affinity for nuclear extracts. The -243 A>G SNP was associated with higher hunger scores p = 0.007 and disinhibition scores p = 0.028, as assessed by the Stunkard Three-Factor Eating Questionnaire. As GAD2 is highly expressed in pancreatic beta cells, we analyzed GAD65 antibody level as a marker of beta-cell activity and of insulin secretion. In the control group -243 A>G, +61450 C>A, and +83897 T>A SNPs were associated with lower GAD65 autoantibody levels p values of 0.003, 0.047, and 0.006, respectively. SNP +83897 T>A was associated with lower fasting insulin and insulin secretion, as assessed by the HOMA-B% homeostasis model of beta-cell function p = 0.009 and 0.01, respectively. These data support the hypothesis of the orexigenic effect of GABA in humans and of a contribution of genes involved in GABA metabolism in the modulation of food intake and in the development of morbid obesity.

Autor: Philippe Boutin - Christian Dina - Francis Vasseur - Séverine Dubois - Laetitia Corset - Karin Séron - Lynn Bekris - Janice Cab



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