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Gene Review

GNB3  -  guanine nucleotide binding protein (G...

Homo sapiens

Synonyms: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3, Transducin beta chain 3
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Disease relevance of GNB3

  • RESULTS: Polymorphisms in the three betaAR genes, GNAS1, and GNB3 were not associated with BMI, WHR, waist circumference, or obesity [1].
  • BACKGROUND & AIMS: In patients with functional dyspepsia, altered alpha-adrenoreceptor function and depression are prevalent, features that are linked to a G-protein beta 3 (GNB3) subunit gene polymorphism (C825T) [2].
  • Common polymorphisms of the GNAS and GNB3 (which encodes Gbeta3) genes have been associated with multigenic disorders (e.g. hypertension and metabolic syndrome) [3].
  • Multiple logistic regression analysis showed that both GNAS1 CC genotype [odds ratio (OR) = 2.79, 95% confidence interval (CI) 1.35-5.79, P = 0.006] and GNB3 C allele (OR = 1.78, 95% CI 1.06-3.00, P = 0.030) were independent risks for orthostatic hypotension [4].
  • Since alterations in left ventricular filling have been identified as an early marker of hypertensive heart disease, the GNB3 C825T polymorphism may influence cardiac adaptation to increased afterload [5].

Psychiatry related information on GNB3


High impact information on GNB3

  • We have detected a novel polymorphism (C825T) in exon 10 of the gene encoding the beta3 subunit of heterotrimeric G proteins (GNB3) [11].
  • The GNB3 825T/T genotype accounted for between 1.6% and 3.3% of the total variation (< or =13% of attributable variation) of the obesity-related traits [12].
  • The potential for a genetic marker of obesity creates opportunities for future studies in the Inuit, not just to confirm the associations, but also to examine prospectively the influence of interventions and possible relationships between GNB3 825T and longer term complications of obesity [12].
  • The GNB3 825T allele encodes a product that has enhanced activation of heterotrimeric G proteins in vitro and could play a role in adipogenesis [12].
  • We estimated the impact of the GNB3 825C>T polymorphism in relatively large-scale association studies of common phenotypes of the metabolic syndrome [13].

Chemical compound and disease context of GNB3


Biological context of GNB3

  • Contrary to the initial analysis, the Glu298Asp variant of the eNOS gene provides no additional information on the genetic basis of alpha(2)-adrenoceptor-induced coronary vasoconstriction, which appears exclusively associated to the 825T allele at GNB3 [16].
  • Haplotype prediction indicated in Germans an almost complete association of GNB3 825T with 1429T, and vice versa [17].
  • Finally, a C1429T polymorphism in the 3' untranslated region of GNB3 was identified that occurred at T allele frequencies of 38%, 17%, and 30% in Africans, Chinese, and Germans, respectively [17].
  • We characterized the entire GNB3 gene, which spans 7.5 kb and is composed of 11 exons and 10 introns [17].
  • The functional activity of the GNB3 promoter was verified with reporter gene assays that also demonstrated its inducibility by phorbol esters [17].

Anatomical context of GNB3


Associations of GNB3 with chemical compounds


Regulatory relationships of GNB3

  • AIMS/HYPOTHESIS: The 825C>T polymorphism in the gene encoding the G protein beta3 subunit (GNB3) causes enhanced G protein activation and increased in vitro cell proliferation [13].
  • Using a classical candidate gene approach, we have described a common C825T polymorphism in the gene GNB3 which encodes the ubiquitously expressed beta3 subunit of heterotrimeric G proteins [26].

Other interactions of GNB3

  • We found that the GNB3 T allele produces a significant risk for AD in individuals homozygous for the ADRB1 C allele, suggesting that the combined effect of both polymorphisms influences AD susceptibility [27].
  • The GNB3 825T allele and the ADD1 460W allele were not significantly associated with prevalence of PAD or incidence of CHD [28].
  • The 825T allele of a polymorphism at GNB3, encoding the G protein beta(3) subunit, is associated with an enhanced coronary blood flow (CBF) reduction in response to alpha(2)-, but not to alpha(1)-adrenoceptor activation [16].
  • Apart from a trend to a reduced frequency of delta32 CCR5 and increased GNB3 825T polymorphism in primary chronic progressive patients, numbers did not reach statistical significance in any group of MS [29].
  • METHODS: In 34 white patients with established mild to moderate essential hypertension (World Health Organization stage I or II, mean age 52 +/- 9 years) genotype analysis of GNB3 C825T polymorphism, insertion/deletion polymorphism of the ACE gene and 1166 A/C polymorphism of the AT1 receptor gene was performed [5].

Analytical, diagnostic and therapeutic context of GNB3


  1. 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, S.G., McGorray, S.P., Wu, R., McNamara, D.M., Cavallari, L.H., Walker, J.R., Wallace, M.R., Johnson, B.D., Bairey Merz, C.N., Sopko, G., Pepine, C.J., Johnson, J.A. International journal of obesity (2005) (2005) [Pubmed]
  2. G-protein beta 3 subunit 825 CC genotype is associated with unexplained (functional) dyspepsia. Holtmann, G., Siffert, W., Haag, S., Mueller, N., Langkafel, M., Senf, W., Zotz, R., Talley, N.J. Gastroenterology (2004) [Pubmed]
  3. Genetic diseases associated with heterotrimeric G proteins. Weinstein, L.S., Chen, M., Xie, T., Liu, J. Trends Pharmacol. Sci. (2006) [Pubmed]
  4. Polymorphisms of genes encoding components of the sympathetic nervous system but not the renin-angiotensin system as risk factors for orthostatic hypotension. Tabara, Y., Kohara, K., Miki, T. J. Hypertens. (2002) [Pubmed]
  5. 825T allele of the G-protein beta3 subunit gene (GNB3) is associated with impaired left ventricular diastolic filling in essential hypertension. Jacobi, J., Hilgers, K.F., Schlaich, M.P., Siffert, W., Schmieder, R.E. J. Hypertens. (1999) [Pubmed]
  6. Sildenafil response is influenced by the G protein beta 3 subunit GNB3 C825T polymorphism: a pilot study. Sperling, H., Eisenhardt, A., Virchow, S., Hauck, E., Lenk, S., Porst, H., Stief, C., Wetterauer, U., Rubben, H., Muller, N., Siffert, W. J. Urol. (2003) [Pubmed]
  7. Association between a G-protein beta 3 subunit gene polymorphism and the symptomatology and treatment responses of major depressive disorders. Lee, H.J., Cha, J.H., Ham, B.J., Han, C.S., Kim, Y.K., Lee, S.H., Ryu, S.H., Kang, R.H., Choi, M.J., Lee, M.S. Pharmacogenomics J. (2004) [Pubmed]
  8. Association analysis of a functional G protein beta3 subunit gene polymorphism (C825T) in mood disorders. Lin, C.N., Tsai, S.J., Hong, C.J. Neuropsychobiology (2001) [Pubmed]
  9. Interaction between TPH1 and GNB3 genotypes and electroconvulsive therapy in major depression. Anttila, S., Huuhka, K., Huuhka, M., Rontu, R., Mattila, K.M., Leinonen, E., Lehtimäki, T. Journal of neural transmission (Vienna, Austria : 1996) (2007) [Pubmed]
  10. Association study of C825T polymorphism of the G-protein b3 subunit gene with schizophrenia and mood disorders. Kunugi, H., Kato, T., Fukuda, R., Tatsumi, M., Sakai, T., Nanko, S. Journal of neural transmission (Vienna, Austria : 1996) (2002) [Pubmed]
  11. Association of a human G-protein beta3 subunit variant with hypertension. Siffert, W., Rosskopf, D., Siffert, G., Busch, S., Moritz, A., Erbel, R., Sharma, A.M., Ritz, E., Wichmann, H.E., Jakobs, K.H., Horsthemke, B. Nat. Genet. (1998) [Pubmed]
  12. G-protein beta3 subunit gene splice variant and body fat distribution in Nunavut Inuit. Hegele, R.A., Anderson, C., Young, T.K., Connelly, P.W. Genome Res. (1999) [Pubmed]
  13. Studies of the association of the GNB3 825C>T polymorphism with components of the metabolic syndrome in white Danes. Andersen, G., Overgaard, J., Albrechtsen, A., Glümer, C., Borch-Johnsen, K., Jørgensen, T., Hansen, T., Pedersen, O. Diabetologia (2006) [Pubmed]
  14. GNB3 C825T polymorphism and response to interferon-alfa/ribavirin treatment in patients with hepatitis C virus genotype 1 (HCV-1) infection. Sarrazin, C., Berg, T., Weich, V., Mueller, T., Frey, U.H., Zeuzem, S., Gerken, G., Roggendorf, M., Siffert, W. J. Hepatol. (2005) [Pubmed]
  15. Prediction of successful weight reduction under sibutramine therapy through genotyping of the G-protein beta3 subunit gene (GNB3) C825T polymorphism. Hauner, H., Meier, M., Jöckel, K.H., Frey, U.H., Siffert, W. Pharmacogenetics (2003) [Pubmed]
  16. Role of the eNOS Glu298Asp variant on the GNB3825T allele dependent determination of alpha-adrenergic coronary constriction. Naber, C.K., Baumgart, D., Heusch, G., Siffert, W., Oldenburg, O., Huesing, J., Erbel, R. Pharmacogenetics (2003) [Pubmed]
  17. G protein beta 3 gene: structure, promoter, and additional polymorphisms. Rosskopf, D., Busch, S., Manthey, I., Siffert, W. Hypertension (2000) [Pubmed]
  18. Identification and characterization of G beta 3s2, a novel splice variant of the G-protein beta 3 subunit. Rosskopf, D., Manthey, I., Habich, C., Kielbik, M., Eisenhardt, A., Nikula, C., Urban, M., Kohnen, S., Graf, E., Ravens, U., Siffert, W. Biochem. J. (2003) [Pubmed]
  19. Enhanced vasoconstriction to endothelin-1, angiotensin II and noradrenaline in carriers of the GNB3 825T allele in the skin microcirculation. Wenzel, R.R., Siffert, W., Bruck, H., Philipp, T., Schäfers, R.F. Pharmacogenetics (2002) [Pubmed]
  20. G protein beta 3 subunit 825T allele carriage and risk of coronary artery disease. von Beckerath, N., Schusterschitz, Y., Koch, W., Griesser, K., Mehilli, J., Gorchakova, O., Schömig, A., Kastrati, A. Atherosclerosis (2003) [Pubmed]
  21. Association of C825T polymorphism of G protein beta3 subunit with the autonomic nervous system in young healthy Japanese individuals. Matsunaga, T., Nagasumi, K., Yamamura, T., Gu, N., Nishikino, M., Ueda, Y., Moritani, T., Aoki, N., Tsuda, K., Yasuda, K. Am. J. Hypertens. (2005) [Pubmed]
  22. C825T polymorphism in the human G protein beta 3 subunit gene and preeclampsia; a case control study. Jansen, M.W., Bertina, R.M., Vos, H.L., Bloemenkamp, K.W., Helmerhorst, F.M., Wladimiroff, J.W., de Groot, C.J. Hypertension in pregnancy : official journal of the International Society for the Study of Hypertension in Pregnancy. (2004) [Pubmed]
  23. Heterogeneity in hand veins responses to acetylcholine is not associated with polymorphisms in the G-protein beta3-subunit (C825T) and endothelial nitric oxide synthase (G894T) genes but with serum low density lipoprotein cholesterol. Grossmann, M., Dobrev, D., Siffert, W., Kirch, W. Pharmacogenetics (2001) [Pubmed]
  24. Cooperative effect of GNB3 825C>T and GPIIIa PI(A) polymorphisms in enhanced platelet aggregation. Frey, U.H., Aral, N., Müller, N., Siffert, W. Thromb. Res. (2003) [Pubmed]
  25. Hydrochlorothiazide efficacy and polymorphisms in ACE, ADD1 and GNB3 in healthy, male volunteers. Vormfelde, S.V., Sehrt, D., Bolte, D., Pahl, S., Tzvetkov, M., Brockmöller, J. Eur. J. Clin. Pharmacol. (2006) [Pubmed]
  26. Molecular genetics of G proteins and atherosclerosis risk. Siffert, W. Basic Res. Cardiol. (2001) [Pubmed]
  27. Polymorphism in genes involved in adrenergic signaling associated with Alzheimer's. Bullido, M.J., Ramos, M.C., Ruiz-Gómez, A., Tutor, A.S., Sastre, I., Frank, A., Coria, F., Gil, P., Mayor, F., Valdivieso, F. Neurobiol. Aging (2004) [Pubmed]
  28. ADD1 460W allele associated with cardiovascular disease in hypertensive individuals. Morrison, A.C., Bray, M.S., Folsom, A.R., Boerwinkle, E. Hypertension (2002) [Pubmed]
  29. Frequencies of the G-protein beta3 subunit C825T polymorphism and the delta 32 mutation of the chemokine receptor-5 in patients with multiple sclerosis. Haase, C.G., Schmidt, S., Faustmann, P.M. Neurosci. Lett. (2002) [Pubmed]
  30. Insulin-mediated venodilation is impaired in young, healthy carriers of the 825T allele of the G-protein beta3 subunit gene (GNB3). Mitchell, A., Pace, M., Nürnberger, J., Wenzel, R.R., Siffert, W., Philipp, T., Schäfers, R.F. Clin. Pharmacol. Ther. (2005) [Pubmed]
  31. 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, K.U., Horber, F.F. J. Gastrointest. Surg. (2004) [Pubmed]
  32. G-protein beta-3 subunit gene 825C>T dimorphism is associated with left ventricular hypertrophy but not essential hypertension. Mahmood, M.S., Mian, Z.S., Afzal, A., Frossard, P.M. Med. Sci. Monit. (2005) [Pubmed]
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