G2Cdb::Human Disease report

Disease id
D00000153
Name
Obesity
Nervous system disease
no

Genes (3)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00002531 SNAP25
synaptosomal-associated protein, 25kDa
Y (15823421) Polymorphism (P) N
G00002164 IRS1
insulin receptor substrate 1
Y (16030120) Single nucleotide polymorphism (SNP) Y
G00001473 GNAS
GNAS complex locus
Y (15531240) Single nucleotide polymorphism (SNP) N
G00001473 GNAS
GNAS complex locus
Y (15917856) Polymorphism (P) Y

References

  • Association between beta-adrenergic receptor polymorphisms and their G-protein-coupled receptors with body mass index and obesity in women: a report from the NHLBI-sponsored WISE study.

    Terra SG, McGorray SP, Wu R, McNamara DM, Cavallari LH, Walker JR, Wallace MR, Johnson BD, Bairey Merz CN, Sopko G, Pepine CJ and Johnson JA

    Department of Pharmacy Practice, University of Florida College of Pharmacy, Gainesville, FL 32610, USA.

    Objectives: The beta-adrenergic receptor (betaAR) genes are candidate genes for obesity because of their roles in energy homeostasis and promotion of lipolysis in human adipose tissue. Objective is to determine the association between obesity and polymorphisms in genes of the beta(1)AR (ADRB1), beta(2)AR (ADRB2), beta(3)AR (ADRB3), Gs protein alpha (GNAS1), to which all three beta-receptors couple and the G protein beta3 subunit (GNB3), to which beta(3)ARs couple.

    Design: A case-control genetic association study.

    Subjects: A total of 643 black or white women enrolled in Women's Ischemia Syndrome Evaluation (WISE) study.

    Measurements: Genotypes were determined by PCR with single primer extension. Associations between genotype and body mass index (BMI), waist-to-hip ratio (WHR), waist circumference, and obesity were made.

    Results: Polymorphisms in the three betaAR genes, GNAS1, and GNB3 were not associated with BMI, WHR, waist circumference, or obesity. Linear and logistic regression analyses found no contribution of either genotype or haplotype with anthropometric measurements or obesity.

    Conclusions: Our study suggests that among American women with suspected coronary heart disease, polymorphisms in the betaARs and their G-protein-coupled receptors do not contribute to increased BMI, WHR, waist circumference, or obesity. Given that 50% of all women die from coronary heart disease, and a higher percentage have heart disease during their lifetime, our results are likely generalizable to many American women.

    Funded by: NCRR NIH HHS: M01-RR00425; NHLBI NIH HHS: N01-HV68161, N01-HV68162, N01-HV68163, N01-HV68164, R03HL65729, U01-HL64924-01

    International journal of obesity (2005) 2005;29;7;746-54

  • Insulin-like growth factor pathway polymorphisms associated with body size in Hispanic and non-Hispanic white women.

    Sweeney C, Murtaugh MA, Baumgartner KB, Byers T, Giuliano AR, Herrick JS, Wolff R, Caan BJ and Slattery ML

    Health Research Center, Family and Preventive Medicine, University of Utah, Suite A, 375 Chipeta Way, Salt Lake City, UT 84108, USA. carol.sweeney@hrc.utah.edu

    Polymorphisms affecting insulin-like growth factors (IGF), their binding proteins (IGFBP), insulin receptor substrates (IRS), and other IGF regulatory molecules may affect growth, obesity, and obesity-related diseases, including cancer. The objective of this study was to better describe the associations between several IGF pathway variants and body size. Hispanic (n = 462) and non-Hispanic White (n = 1,702) women were recruited as controls in collaborative population-based case-control studies in Arizona, New Mexico, Colorado, Utah, and California. Body size measurements were taken by trained interviewers; genotypes were determined for the IGF1 CA repeat, the IGFBP3 -202 C > A substitution, the IRS1 G972R and IRS2 G1057D substitutions, and the vitamin D receptor (VDR) BsmI and FokI polymorphisms. Two associations were observed that were consistent in both Hispanics and non-Hispanic Whites: IGF1 CA repeat alleles of length other than 19 were associated with higher mean waist-to-hip ratios (WHR), P = 0.01, and women who carried an IGFBP3 A allele, compared with women with the CC genotype, more often reported high birthweight (odds ratio, 1.9; 95% confidence interval, 1.1-3.2). We observed trends for associations between IGFBP3 A allele and taller height, IRS1R allele, and smaller WHR, and VDR FokI ff genotype and larger WHR; each of these trends was present in only one ethnic group, and heterogeneity of effect by ethnicity was detected. These results provide evidence that IGF pathway polymorphisms have functional effects on growth and central obesity and indicate that genotype-phenotype relationships are ethnic specific.

    Funded by: NCI NIH HHS: CA048998, CA078552, CA078682, CA078762, CA078802, CA085846, R01 CA078682, R01 CA078682-07

    Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2005;14;7;1802-9

  • The SNAP-25 gene may be associated with clinical response and weight gain in antipsychotic treatment of schizophrenia.

    Müller DJ, Klempan TA, De Luca V, Sicard T, Volavka J, Czobor P, Sheitman BB, Lindenmayer JP, Citrome L, McEvoy JP, Lieberman JA, Honer WG and Kennedy JL

    Neurogenetics Section, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, 250 College Street R30, Toronto, Ont. M5T 1R8, Canada. daniel.mueller@charite.de

    The synaptosomal-associated protein of 25 kDa (SNAP-25) is an essential component of the core complex that mediates presynaptic vesicle trafficking. Thus, SNAP-25 is directly involved in the release of neurotransmitters. Quantitative alterations of SNAP-25 expression have been reported in brain regions and cerebrospinal fluid (CSF) of schizophrenics and in haloperidol treated rats. This observed altered expression may be influenced by genetic variants of SNAP-25. We hypothesized that polymorphisms of the SNAP-25 gene (sites DdeI, MnlI and TaiI in the 3'UTR) are associated with antipsychotic drug response and induced weight gain. A sample of 59 patients with prior suboptimal response to antipsychotic treatment and diagnosed with DSM-IV schizophrenia or schizoaffective disorder was examined. Patients were administered clozapine, haloperidol, olanzapine or risperidone for up to 14 weeks. Clinical response was defined as the difference between the baseline and the endpoint total scores on the Positive and Negative Syndrome Scale (PANSS). Weight was assessed at baseline and at study endpoint. ANOVA revealed that the MnlI and TaiI polymorphisms were associated with response (F[2,53] = 4.57, p = 0.01 and F[2,52] = 3.53, p = 0.03) and with weight gain (F[2,52] = 4.28, p = 0.01 and F[2,51] = 3.38, p = 0.04). When covariates were included, the MnlI polymorphism remained significantly associated with changes of PANSS scores, but not with weight gain. The DdeI polymorphism was not associated with response or weight gain. These findings suggest that SNAP-25 gene variants affect clinical response in patients with prior poor response to antipsychotics. Weight changes do not seem to be associated with polymorphism of the SNAP-25 gene, however, replication in independent samples is warranted.

    Funded by: NIMH NIH HHS: MH MH33127, R10 MH53550

    Neuroscience letters 2005;379;2;81-9

  • G protein polymorphisms do not predict weight loss and improvement of hypertension in severely obese patients.

    Potoczna N, Wertli M, Steffen R, Ricklin T, Lentes KU and Horber FF

    Klinik Hirslanden, Zürich, Switzerland.

    Both the gene encoding the alpha subunit of G stimulatory proteins (GNAS1) and the beta3 subunit gene (GNB3) of G proteins are associated with obesity and/or hypertension. Moreover, the TT/TC825 polymorphism of GNB3 predicts greater weight loss than the CC825 polymorphism in obese patients (mean body mass index, 35 kg/m2) undergoing a structured nonpharmacologic weight loss program. Gastric banding enforces a low-calorie diet by diminishing the need for volitional adherence. It is unknown whether these polymorphisms predict the variable weight loss in patients after bariatric surgery. Three hundred and four severely obese patients (mean +/- SEM age, 42 +/- 1 years; 245 women and 59 men; mean +/- SEM body mass index, 43.9 +/- 0.3 kg/m2) followed prospectively for at least 3 years after surgery were genotyped for the GNB3 C825T, G814A, and GNAS1 T393 polymorphisms. All analyses were performed blinded to the phenotypic characteristics of the study group. Frequencies of polymorphisms were comparable to those previously published. No polymorphism studied predicted 3-year weight loss or was associated with high blood pressure in severely obese patients after gastric banding. Multivariate analysis of potentially confounding factors such as reoperation rate or use of sibutramine or orlistat revealed similar results (P > 0.1). Regardless of the mechanism(s) involved for these discordant findings, GNB3 C825T, G814A, and GNAS1 T393C polymorphisms do not seem to be reliable predictors of long-term weight loss.

    Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract 2004;8;7;862-8; discussion 868

Literature (4)

Pubmed - human_disease

  • Association between beta-adrenergic receptor polymorphisms and their G-protein-coupled receptors with body mass index and obesity in women: a report from the NHLBI-sponsored WISE study.

    Terra SG, McGorray SP, Wu R, McNamara DM, Cavallari LH, Walker JR, Wallace MR, Johnson BD, Bairey Merz CN, Sopko G, Pepine CJ and Johnson JA

    Department of Pharmacy Practice, University of Florida College of Pharmacy, Gainesville, FL 32610, USA.

    Objectives: The beta-adrenergic receptor (betaAR) genes are candidate genes for obesity because of their roles in energy homeostasis and promotion of lipolysis in human adipose tissue. Objective is to determine the association between obesity and polymorphisms in genes of the beta(1)AR (ADRB1), beta(2)AR (ADRB2), beta(3)AR (ADRB3), Gs protein alpha (GNAS1), to which all three beta-receptors couple and the G protein beta3 subunit (GNB3), to which beta(3)ARs couple.

    Design: A case-control genetic association study.

    Subjects: A total of 643 black or white women enrolled in Women's Ischemia Syndrome Evaluation (WISE) study.

    Measurements: Genotypes were determined by PCR with single primer extension. Associations between genotype and body mass index (BMI), waist-to-hip ratio (WHR), waist circumference, and obesity were made.

    Results: Polymorphisms in the three betaAR genes, GNAS1, and GNB3 were not associated with BMI, WHR, waist circumference, or obesity. Linear and logistic regression analyses found no contribution of either genotype or haplotype with anthropometric measurements or obesity.

    Conclusions: Our study suggests that among American women with suspected coronary heart disease, polymorphisms in the betaARs and their G-protein-coupled receptors do not contribute to increased BMI, WHR, waist circumference, or obesity. Given that 50% of all women die from coronary heart disease, and a higher percentage have heart disease during their lifetime, our results are likely generalizable to many American women.

    Funded by: NCRR NIH HHS: M01-RR00425; NHLBI NIH HHS: N01-HV68161, N01-HV68162, N01-HV68163, N01-HV68164, R03HL65729, U01-HL64924-01

    International journal of obesity (2005) 2005;29;7;746-54

  • Insulin-like growth factor pathway polymorphisms associated with body size in Hispanic and non-Hispanic white women.

    Sweeney C, Murtaugh MA, Baumgartner KB, Byers T, Giuliano AR, Herrick JS, Wolff R, Caan BJ and Slattery ML

    Health Research Center, Family and Preventive Medicine, University of Utah, Suite A, 375 Chipeta Way, Salt Lake City, UT 84108, USA. carol.sweeney@hrc.utah.edu

    Polymorphisms affecting insulin-like growth factors (IGF), their binding proteins (IGFBP), insulin receptor substrates (IRS), and other IGF regulatory molecules may affect growth, obesity, and obesity-related diseases, including cancer. The objective of this study was to better describe the associations between several IGF pathway variants and body size. Hispanic (n = 462) and non-Hispanic White (n = 1,702) women were recruited as controls in collaborative population-based case-control studies in Arizona, New Mexico, Colorado, Utah, and California. Body size measurements were taken by trained interviewers; genotypes were determined for the IGF1 CA repeat, the IGFBP3 -202 C > A substitution, the IRS1 G972R and IRS2 G1057D substitutions, and the vitamin D receptor (VDR) BsmI and FokI polymorphisms. Two associations were observed that were consistent in both Hispanics and non-Hispanic Whites: IGF1 CA repeat alleles of length other than 19 were associated with higher mean waist-to-hip ratios (WHR), P = 0.01, and women who carried an IGFBP3 A allele, compared with women with the CC genotype, more often reported high birthweight (odds ratio, 1.9; 95% confidence interval, 1.1-3.2). We observed trends for associations between IGFBP3 A allele and taller height, IRS1R allele, and smaller WHR, and VDR FokI ff genotype and larger WHR; each of these trends was present in only one ethnic group, and heterogeneity of effect by ethnicity was detected. These results provide evidence that IGF pathway polymorphisms have functional effects on growth and central obesity and indicate that genotype-phenotype relationships are ethnic specific.

    Funded by: NCI NIH HHS: CA048998, CA078552, CA078682, CA078762, CA078802, CA085846, R01 CA078682, R01 CA078682-07

    Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2005;14;7;1802-9

  • The SNAP-25 gene may be associated with clinical response and weight gain in antipsychotic treatment of schizophrenia.

    Müller DJ, Klempan TA, De Luca V, Sicard T, Volavka J, Czobor P, Sheitman BB, Lindenmayer JP, Citrome L, McEvoy JP, Lieberman JA, Honer WG and Kennedy JL

    Neurogenetics Section, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, 250 College Street R30, Toronto, Ont. M5T 1R8, Canada. daniel.mueller@charite.de

    The synaptosomal-associated protein of 25 kDa (SNAP-25) is an essential component of the core complex that mediates presynaptic vesicle trafficking. Thus, SNAP-25 is directly involved in the release of neurotransmitters. Quantitative alterations of SNAP-25 expression have been reported in brain regions and cerebrospinal fluid (CSF) of schizophrenics and in haloperidol treated rats. This observed altered expression may be influenced by genetic variants of SNAP-25. We hypothesized that polymorphisms of the SNAP-25 gene (sites DdeI, MnlI and TaiI in the 3'UTR) are associated with antipsychotic drug response and induced weight gain. A sample of 59 patients with prior suboptimal response to antipsychotic treatment and diagnosed with DSM-IV schizophrenia or schizoaffective disorder was examined. Patients were administered clozapine, haloperidol, olanzapine or risperidone for up to 14 weeks. Clinical response was defined as the difference between the baseline and the endpoint total scores on the Positive and Negative Syndrome Scale (PANSS). Weight was assessed at baseline and at study endpoint. ANOVA revealed that the MnlI and TaiI polymorphisms were associated with response (F[2,53] = 4.57, p = 0.01 and F[2,52] = 3.53, p = 0.03) and with weight gain (F[2,52] = 4.28, p = 0.01 and F[2,51] = 3.38, p = 0.04). When covariates were included, the MnlI polymorphism remained significantly associated with changes of PANSS scores, but not with weight gain. The DdeI polymorphism was not associated with response or weight gain. These findings suggest that SNAP-25 gene variants affect clinical response in patients with prior poor response to antipsychotics. Weight changes do not seem to be associated with polymorphism of the SNAP-25 gene, however, replication in independent samples is warranted.

    Funded by: NIMH NIH HHS: MH MH33127, R10 MH53550

    Neuroscience letters 2005;379;2;81-9

  • G protein polymorphisms do not predict weight loss and improvement of hypertension in severely obese patients.

    Potoczna N, Wertli M, Steffen R, Ricklin T, Lentes KU and Horber FF

    Klinik Hirslanden, Zürich, Switzerland.

    Both the gene encoding the alpha subunit of G stimulatory proteins (GNAS1) and the beta3 subunit gene (GNB3) of G proteins are associated with obesity and/or hypertension. Moreover, the TT/TC825 polymorphism of GNB3 predicts greater weight loss than the CC825 polymorphism in obese patients (mean body mass index, 35 kg/m2) undergoing a structured nonpharmacologic weight loss program. Gastric banding enforces a low-calorie diet by diminishing the need for volitional adherence. It is unknown whether these polymorphisms predict the variable weight loss in patients after bariatric surgery. Three hundred and four severely obese patients (mean +/- SEM age, 42 +/- 1 years; 245 women and 59 men; mean +/- SEM body mass index, 43.9 +/- 0.3 kg/m2) followed prospectively for at least 3 years after surgery were genotyped for the GNB3 C825T, G814A, and GNAS1 T393 polymorphisms. All analyses were performed blinded to the phenotypic characteristics of the study group. Frequencies of polymorphisms were comparable to those previously published. No polymorphism studied predicted 3-year weight loss or was associated with high blood pressure in severely obese patients after gastric banding. Multivariate analysis of potentially confounding factors such as reoperation rate or use of sibutramine or orlistat revealed similar results (P > 0.1). Regardless of the mechanism(s) involved for these discordant findings, GNB3 C825T, G814A, and GNAS1 T393C polymorphisms do not seem to be reliable predictors of long-term weight loss.

    Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract 2004;8;7;862-8; discussion 868

© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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