GAD2 on chromosome 10p12 is a candidate gene for human obesity.
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 (chi(2) = 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.
Boutin
Philippe
P
Institute of Biology-Centre National de la Recherche Scientifique, Pasteur Institute, Lille, France.
Dina
Christian
C
Vasseur
Francis
F
Dubois
Séverine
S
Corset
Laetitia
L
Séron
Karin
K
Bekris
Lynn
L
Cabellon
Janice
J
Neve
Bernadette
B
Vasseur-Delannoy
Valérie
V
Chikri
Mohamed
M
Charles
M Aline
MA
Clement
Karine
K
Lernmark
Ake
A
Froguel
Philippe
P
D000328:Adult; D000368:Aged; D000483:Alleles; D001323:Autoantibodies / Q000737:chemistry; D016022:Case-Control Studies; D002384:Catalysis; D002460:Cell Line; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics* / Q000648:ultrastructure*; D004435:Eating; D005192:Family Health; D005247:Feeding Behavior; D005260:Female; D008040:Genetic Linkage; D005838:Genotype; D005968:Glutamate Decarboxylase / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D006239:Haplotypes; D006801:Humans; D006815:Hunger; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D008126:Lod Score; D008156:Luciferases / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009478:Neuropeptide Y / Q000378:metabolism; D009765:Obesity / Q000235:genetics*; D009767:Obesity, Morbid / Q000235:genetics*; D016017:Odds Ratio; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012306:Risk; D011795:Surveys and Questionnaires; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D001323:Autoantibodies; D007328:Insulin; D007527:Isoenzymes; D009478:Neuropeptide Y; D005680:gamma-Aminobutyric Acid; D008156:Luciferases; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2