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| Author(s): |
Lilian Kimura
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Instituto de Biociências (IBIOC/SB) |
| Defense date: | 2010-12-09 |
| Examining board members: |
Regina Celia Mingroni Netto;
Pedro Edson Moreira Guimarães;
Diogo Meyer;
Paulo Alberto Otto;
Sidney Emanuel Batista dos Santos
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| Advisor: | Regina Celia Mingroni Netto |
| Abstract | |
Essential hypertension is a worldwide public health problem. Although this pathology has a multi-factorial etiology, the heritability of blood pressure is high, ranging from 25 to 60%. Despite the high prevalence and incidence of essential hypertension among subjects of African ancestry, most genetic association studies has been carried out either in subjects with European descent or in Asian-derived individuals. Thus, the aim of this study was to investigate genetic risk factors putatively associated with essential hypertension in the quilombo populations, which are partially isolated African-derived populations, well characterized in terms of clinical, genealogical and population data, living in the Ribeira River Valley São Paulo, Brazil. A total of 759 adults with clinical and anthropometric data sampled from the 12 populations (Abobral, Galvão, São Pedro, Pedro Cubas, André Lopes, Nhunguara, Sapatu, Pilões, Ivaporunduva, Maria Rosa, Poça and Reginaldo) were studied. Ancestry estimates (based on 48 ancestry informative INDEL markers) suggested that the African, European and Amerindian contributions were 39.7%, 39.0% and 21.3% respectively (N = 307) to the studied sample. These proportions did not differ significantly between hypertensive and normotensive subjects(41.1%, 37.8% , 20.4% and 37.6%, 39.0% e 19.9%, respectively; P = 0.845). Two approaches were employed to investigate potential genetic risk factors for essential hypertension: (i) a cross-sectional study with unrelated individuals (N = 383) and (ii) a family-based association study (N = 759, 79 families). Seven polymorphisms (I/D, Glu298Asp, C825T, G-350A, M235T, A/C, A486V) in six candidate genes with strong functional basis (ACE, NOS3, GNB3, AGT, ADD2 and GRK4) were selected. The cross-sectional study revealed a significant association between the C825T GNB3 polymorphism and essential hypertension (P = 0.036) defined as a SBP > or = 160 mmHg and/or DBP > or = 95 mmHg, or use antihypertensive drugs). Haplotypic analyses of both G-350A and C825T GNB3 variants indicated that each copy of the haplotype C825/G-350 increases in 1.73 the odds of hypertension compared to the reference T825/G-350 haplotype (OR = 1.73, CI 95% = 1.05 - 2.84, P = 0.029). The haplotype C825/G-350 was also associated with augmented levels of both SBP and DBP (expected mean difference, Delta = 6.7, 95% CI: 1.64 10.50, P = 0.007 and Delta = 3.75, CI 95%: 1.16 6.35, P = 0.005, respectively) compared to the reference haplotype. Gene-gene interactions were also investigated by the use of the generalized multifactor dimensionality reduction (GMDR). GMDR prediction models revealed high-order interactions for hypertension between and among the studied variants. The best interaction models were NOS3/GRK4, ACE/GNB3/AGT, and ACE/GNB3/AGT/ADD2/GRK4, with an average testing balanced accuracy of 60% (P = 0.006) 59% (P = 0.019), and 59% (P = 0.025), respectively. The family-based association study showed a significant association of the GNB3 G-350 allele with essential hypertension (P = 0.018) when the diagnosis of essential hypertension was based on the WHO criteria (SBP > or = 140mmHg and / or DBP > or = 90 mmHg, or use of antihypertensive drugs, P = 0.018). Qualitatively analogous results were observed when a more extreme phenotype was considered (i.e. hypertension defined as a SBP > or = 160mmHg and / or DBP > or = 95 mmHg, or use of antihypertensive drugs, P = 0.001) Finally, heritability estimates corroborated the notion that the genetic component of blood pressure is high in these populations. Heritability (adjusted for age, gender and BMI) estimates of 36.1 and 42.9% for SBP and DBP, respectively, were obtained. We presented in this work an extensive and original investigation about the genetic component of essential hypertension in an African-Brazilian population (with peculiar historical, genetical and environmental characteristics). This study strengthens the hypothesis of a polygenic mechanism of regulation of blood pressure in the quilombos from Ribeira River Valley São Paulo. (AU) | |
| FAPESP's process: | 07/53584-9 - Genetic risk factors associated with hypertension in Afro-Brazilian populations |
| Grantee: | Lilian Kimura |
| Support Opportunities: | Scholarships in Brazil - Doctorate (Direct) |