Original Article

Association of the −243A>G, +61450C>A Polymorphisms of the Glutamate Decarboxylase 2 (GAD2) Gene with Obesity and Insulin Level in North Indian Population

Abstract

Background: Obesity associated with type 2 diabetes, and hypertension increased mortality and morbidity. Glutamate decarboxylase 2 (GAD2) gene is associated with obesity and it regulate food intake and insulin level. We investigated the association of GAD-2gene −243A>G (rs2236418) and +61450C>A (rs992990) polymorphisms with obesity and related phenotypes.

Methods: Insulin, glucose and lipid levels were estimated using standard protocols. All subjects were genotyped (PCR-RFLP) method.

Results: The −243A>G polymorphism of the GAD-2 gene was significantly associated with higher risk of obesity (P<0.05).

Conclusion: GAD-2 gene polymorphisms influence obesity and related phenotype in complex manner, probably by regulating the food intake, insulin and body weight.

 

 

Finucane MM, Stevens GA, Cowan MJ, Danaei G, Lin JK, Paciorek CJ, Singh GM, Gutierrez HR, Lu Y, Bahalim AN, Farzadfar F, Riley LM, Ezzati M (2011). Global Burden of Meta¬bolic Risk Factors of Chronic Diseases Collab¬orating Group (Body Mass Index). National, re-gional, and global trends in body-mass index since 1980: systematic analysis of health exam¬ination surveys and epide-miological studies with 960 country-years and 9•1 million partici¬pants. Lancet, 12:557-567.

Flegal K, Kit B, Orpana H, Graubard B (2013). Association of all-cause mortality with over¬weight and obesity using stand-ard body mass index categories: a sys-tematic review and metaanalysis. JAMA, 309:71–82.

Groves CJ, Zeggini E, Walker M, Hitman GA, Levy JC, O'Rahilly S, Hattersley AT, McCarthy MI, Wiltshire S (2006). Significant linkage of BMI to chromosome 10p in the U.K. population and evaluation of GAD2 as a positional candidate. Diabetes, 55:1884-89.

Karlsen AE, Hagopian WA, Grubin CE, Dube S, Disteche CM, Adler DA, Bärmeier H, Mathewes S, Grant FJ, Fos-ter D (1991). Cloning and primary structure of a human islet isoform of glutamic acid decarboxylase from chromosome 10. Proc Natl Acad Sci U S A, 1:8337-41.

Boutin P, Dina C, Vasseur F, Dubois S, Corset L, Séron K, Bekris L, Cabellon J, Neve B, Vasseur-Delannoy V, Chikri M, Charles MA, Clement K, Lernmark A, Froguel P (2003). GAD2 on chromosome 10p12 is a candidate gene for human obesity. PLoS Biol, 1:E68.

Wang C, Mao R, Van de Casteele M, Pipeleers D, Ling Z (2007). Glucagon-like peptide-1 stimulates GABA formation by pancreatic beta-cells at the level of glutamate decarboxylase. Am J Physiol Endocrinol Metab, 292:E1201-6.

Meyre D, Boutin P, Tounian A, Deweirder M, Aout M, Jouret B, Heude B, Weill J, Tauber M, Tounian P, Froguel P (2005). Is glutamate decarboxylase 2 (GAD2) a genetic link between low birth weight and subsequent development of obesity in children? J Clin En¬docrinol Metab, 90:2384-90.

Boesgaard TW, Castella SI, Andersen G, Al-brechtsen A, Sparsø T, Borch-Johnsen K, Jørgensen T, Hansen T, Pedersen O (2007). A -243A-->G polymorphism up-stream of the gene encoding GAD65 as-sociates with lower levels of body mass index and glycaemia in a population-based sample of 5857 middle-aged White subjects. Diabet Med, 24:702-6.

Swarbrick MM, Waldenmaier B, Pennacchio LA, Lind DL, Cavazos MM, Geller F, Merriman R, Ustaszewska A, Malloy M, Scherag A, Hsueh WC, Rief W, Mauvais-Jarvis F, Pullinger CR, Kane JP, Dent R, McPherson R, Kwok PY, Hinney A, Hebebrand J, Vaisse C (2005). Lack of support for the association between GAD2 polymorphisms and severe hu-man obesity. PLoS Biol, 3:e315.

Hunt SC, Xin Y, Wu LL, Hopkins PN, Adams TD (2006). Lack of association of glutamate decarboxylase 2 gene polymorphisms with severe obesity in utah. Obesity, 14:650-55.

Prakash J, Srivastava N, Awasthi S, Agarwal C, Natu S, Rajpal N, Mittal B (2012). As-sociation of PPAR-γ gene polymor-phisms with obesity and obesity-associated phenotypes in North Indian population. Am J Hum Biol, 24:454-59.

Prakash J, Mittal B, Awasthi S, Agarwal CG, Srivastava N (2013). K121Q ENPP1/PC-1 gene polymorphism is associated with insulin resistance in a North Indian population. J Genet, 92:571-76.

Yoo J, Seo B, Kim Y (2005). SNP Analyzer: a web-based integrated workbench for single-nucleotide polymorphism analysis. Nucleic Acids Res, 33:W483-88.

Ovesjo ML, Gamstedt M, Collin M, Meister B (2001). GABAergic nature of hypothalamic leptin target neurones in the ventromedial arcuate nucleus. J Neuroendocrinol, 13:505-16.

Cowley MA, Smart JL, Rubinstein M, Cerdán MG, Diano S, Horvath TL, Cone RD, Low MJ (2001). Leptin activates ano-rexigenic POMC neurons through a neu-ral network in the arcuate nucleus. Nature, 24:480-84.

Bannai M, Ichikawa M, Nishihara M, Takahashi M (1998). Effect of injection of antisense oligodeoxynucleotides of GAD isozymes into rat ventromedial hypothalamus on food intake and locomotor activity. Brain Res, 784:305-15.

Denbow DM (1991). Induction of food intake by a GABAergic mechanism in the turkey. Physiol Behav, 49:485-88.

Niswender KD, Morrison CD, Clegg DJ, Olson R, Baskin DG, Myers MG Jr, See-ley RJ, Schwartz MW (2003). Insulin acti-vation of phosphatidylinositol 3-kinase in the hypotha¬lamic arcuate nucleus: a key mediator of insu¬lin-induced anorexia. Di-abetes, 52:227-31.

Ma YH, Hu JH, Zhou XG, Zeng RW, Mei ZT, Fei J, Guo LH (2000). Transgenic mice over¬expressing gamma-aminobutyric acid trans¬porter subtype I develop obesity. Cell Res, 10:303-310.

Gu XH, Kurose T, Kato S, Masuda K, Tsu-da K, Ishida H, Seino Y. (1993). Suppres-sive effect of GABA on insulin secretion from the pan¬creatic beta-cells in the rat. Life Sci, 52:687-94.

Rorsman P, Berggren PO, Bokvist K, Eric-son H, Möhler H, Ostenson CG, Smith PA (1989). Glucose-inhibition of gluca-gon secretion in¬volves activation of GABAA-receptor chlo¬ride channels. Na-ture, 21:233-36.

Shi Y, Kanaani J, Menard-Rose V, Ma YH, Chang PY, Hanahan D, Tobin A, Grod-sky G, Baekkeskov S (2000). Increased expression of GAD65 and GABA in pancreatic beta-cells impairs first-phase insulin secretion. Am J Phys¬iol Endocrinol Metab, 279:E684-94.

Goossens GH, Petersen L, Blaak EE, Hul G, Arner P, Astrup A, Froguel P, Patel K, Pedersen O, Polak J, Oppert JM, Martinez JA, Sørensen TI, Saris WH (2009). Several obesity- and nutrient-related gene pol-ymorphisms but not FTO and UCP variants modulate postabsorptive resting energy expenditure and fat-induced thermogenesis in obese individuals: the NUGENOB study. Int J Obes (Lond), 33:669-79.

Chen KC, Lin YC, Chao WC, Chung HK, Chi SS, Liu WS, Wu WT (2012). Association of genetic polymorphisms of glutamate decarboxylase 2 and the dopamine D2 receptor with obesityin Taiwanese subjects. Ann Saudi Med, 32:121-26.

Choquette AC, Lemieux S, Tremblay A, Drapeau V, Bouchard C, Vohl MC, Pérusse L (2009). GAD2 gene sequence variations are associated with eating behaviors and weight gain in women from the Quebec family study. Physiol Behav,19:505-10.

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IssueVol 45 No 4 (2016) QRcode
SectionOriginal Article(s)
Keywords
Obesity Insulin GAD-2 Food intake Polymorphism

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How to Cite
1.
PRAKASH J, MITTAL B, AWASTHI S, SRIVASTAVA N. Association of the −243A>G, +61450C&gt;A Polymorphisms of the Glutamate Decarboxylase 2 (GAD2) Gene with Obesity and Insulin Level in North Indian Population. Iran J Public Health. 2016;45(4):460-468.