Multivariate meta-analysis of the association of G-protein beta 3 gene (GNB3) haplotypes with cardiovascular phenotypes
- 289 Downloads
The objective of the present study was to review previous investigations on the association of haplotypes in the G-protein β3 subunit (GNB3) gene with representative cardiovascular risk factors/phenotypes: hypertension, overweight, and variation in the systolic and diastolic blood pressures (SBP and DBP, respectively) and as well as body mass index (BMI). A comprehensive literature search was undertaken in Pubmed, Web of Science, EMBASE, Biological Abstracts, LILACS and Google Scholar to identify potentially relevant articles published up to April 2011. Six genetic association studies encompassing 16,068 participants were identified. Individual participant data were obtained for all studies. The three most investigated GNB3 polymorphisms (G-350A, C825T and C1429T) were considered. Expectation–maximization and generalized linear models were employed to estimate haplotypic effects from data with uncertain phase while adjusting for covariates. Study-specific results were combined through a random-effects multivariate meta-analysis. After carefully adjustments for relevant confounding factors, our analysis failed to support a role for GNB3 haplotypes in any of the investigated phenotypes. Sensitivity analyses excluding studies violating Hardy–Weinberg expectations, considering gender-specific effects or more extreme phenotypes (e.g. obesity only) as well as a fixed-effects “pooled” analysis also did not disclose a significant influence of GNB3 haplotypes on cardiovascular phenotypes. We conclude that the previous cumulative evidence does not support the proposal that haplotypes formed by common GNB3 polymorphisms might contribute either to the development of hypertension and obesity, or to the variation in the SBP, DBP and BMI.
KeywordsMeta-analysis Haplotypes GNB3 Polymorphism Hypertension
This work was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, Brazil, to T.V.P.). This work was also supported in part by the Global Center of Excellence Program (No. F03, to M.D.) founded by the Japan Society for the Promotion of Science, Japan (to Y.S.) and Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Numbers 18209023, 18018021, and 19659149 to Y.Y.).
Conflict of interest
- 4.Angeli CB, Kimura L, Auricchio MT, Vicente JP, Mattevi VS, Zembrzuski VM, Hutz MH, Pereira AC, Pereira TV, Mingroni-Netto RC (2011) Multilocus analyses of seven candidate genes suggest interacting pathways for obesity-related traits in Brazilian populations. Obesity 19(6):1244–1251CrossRefPubMedGoogle Scholar
- 11.Pereira TV, Rudnicki M, Cheung BM, Baum L, Yamada Y, Oliveira PS, Pereira AC, Krieger JE (2007) Three endothelial nitric oxide (NOS3) gene polymorphisms in hypertensive and normotensive individuals: meta-analysis of 53 studies reveals evidence of publication bias. J Hypertens 25(9):1763–1774CrossRefPubMedGoogle Scholar
- 17.Burkett K, Graham J, McNeney B (2006) hapassoc: software for likelihood inference of trait associations with SNP haplotypes and other attributes. J Stat Softw 16:1–19Google Scholar
- 19.White IR (2009) Multivariate random-effects meta-analysis. Stata J 9(1):40–56Google Scholar
- 24.Suwazono Y, Kobayashi E, Uetani M, Miura K, Morikawa Y, Ishizaki M, Kido T, Nakagawa H, Nogawa K (2006) G-protein beta 3 subunit polymorphism C1429T and low-density lipoprotein receptor-related protein 5 polymorphism A1330V are risk factors for hypercholesterolemia in Japanese males—a prospective study over 5 years. Metabolism 55(6):751–757CrossRefPubMedGoogle Scholar
- 27.Daimon M, Sato H, Sasaki S, Toriyama S, Emi M, Muramatsu M, Hunt SC, Hopkins PN, Karasawa S, Wada K, Jimbu Y, Kameda W, Susa S, Oizumi T, Fukao A, Kubota I, Kawata S, Kato T (2008) Salt consumption-dependent association of the GNB3 gene polymorphism with type 2 DM. Biochem Biophys Res Commun 374(3):576–580CrossRefPubMedGoogle Scholar
- 28.Kimura L, Angeli CB, Auricchio MT, Fernandes GR, Pereira AC, Vicente JP, Pereira TV, Mingroni-Netto RC (2012) Multilocus family-based association analysis of seven candidate polymorphisms with essential hypertension in an african-derived semi-isolated Brazilian population. Int J Hypertens 2012:859219PubMedCentralCrossRefPubMedGoogle Scholar
- 34.Takeuchi F, Yamamoto K, Katsuya T, Sugiyama T, Nabika T, Ohnaka K, Yamaguchi S, Takayanagi R, Ogihara T, Kato N (2012) Reevaluation of the association of seven candidate genes with blood pressure and hypertension: a replication study and meta-analysis with a larger sample size. Hypertens Res 35(8):825–831CrossRefPubMedGoogle Scholar