Multilocus Family-Based Association Analysis of Seven Candidate Polymorphisms with Essential Hypertension in an African-Derived Semi-Isolated Brazilian Population

Abstract

Background. It has been widely suggested that analyses considering multilocus effects would be crucial to characterize the relationship between gene variability and essential hypertension (EH). Objective. To test for the presence of multilocus effects between/among seven polymorphisms (six genes) on blood pressure-related traits in African-derived semi-isolated Brazilian populations (quilombos). Methods. Analyses were carried out using a family-based design in a sample of 652 participants (97 families). Seven variants were investigated: ACE (rs1799752), AGT (rs669), ADD2 (rs3755351), NOS3 (rs1799983), GNB3 (rs5441 and rs5443), and GRK4 (rs1801058). Sensitivity analyses were further performed under a case-control design with unrelated participants only. Results. None of the investigated variants were associated individually with both systolic and diastolic BP levels (SBP and DBP, respectively) or EH (as a binary outcome). Multifactor dimensionality reduction-based techniques revealed a marginal association of the combined effect of both GNB3 variants on DBP levels in a family-based design (P = 0.040), whereas a putative NOS3-GRK4 interaction also in relation to DBP levels was observed in the case-control design only (P = 0.004). Conclusion. Our results provide limited support for the hypothesis of multilocus effects between/among the studied variants on blood pressure in quilombos. Further larger studies are needed to validate our findings.

Multivariate meta-analysis of the association of G-protein beta 3 gene (GNB3) haplotypes with cardiovascular phenotypes

“…A total of six studies [23][24][25][26][27][28][29] were found. Of these, one [29] did not met our eligibility criteria (i.e.…”

“…The G-350A promoter variant Four investigations encompassing 7,292 participants (2,738 hypertensives and 4,554 normotensives; 3,550 overweight and 3,742 lean) were available for the association of the G-350A promoter variant with both blood pressure-and adiposity-related phenotypes [23,26,28,30]. All controls groups were in Hardy-Weinberg equilibrium (Supplementary Tables S1-S2).…”

“…Four studies had participants genotyped for both G-350A and C825T variants, enabling haplotypic analyses that encompassed 7,292 participants (2,738 hypertensives and DBP diastolic blood pressure, SBP systolic blood pressure, OR odds ratio, D expected linear increment in the trait per additional copy of the riskallele, s 2 estimated between-study variance, P(Q) P value for the Cochran's Q test 4,554 normotensives; 3,550 overweight and 3,742 lean) [23,26,28,30]. While a distinct pattern of LD among populations of different ancestries is observed, we found evidence for a significant LD and high to moderate D 0 scores between the G-350A variant and the C825T polymorphism (P \ 0.01 for all studies, Supplementary Table S7).…”

“…According to the authors, there was evidence for a complex interaction among GNB3 haplotypes versus obesity versus hypertension. Among the six studies included in the present systematic review, only two [23,28] explicitly investigated and claimed a role for GNB3 haplotypes in cardiovascularrelated phenotypes. For example, Li et al [23] revealed the potential of haplotypic effects when assessing the influence of GNB3 polymorphisms on the risk of hypertension in Chinese.…”

“…For example, Li et al [23] revealed the potential of haplotypic effects when assessing the influence of GNB3 polymorphisms on the risk of hypertension in Chinese. Recently, by using a family-based design and dimensionality reduction techniques, Kimura et al [28] were able to observe that both G-350A and C825T variants might interact to determine DBP levels in an Africanderived Brazilian population. It is important to note that, in all of the three studies mentioned above, significant results were obtained after multiple testing, and were only marginally significant with P values ranging from 0.01 to 0.04.…”