Polymorphisms in the RAC1 Gene Are Associated With Hypertension Risk Factors in a Chilean Pediatric Population

• Published in: American journal of hypertension 2014-03, Vol.27 (3), p.299-307
• Main Authors: Tapia-Castillo, Alejandra, Carvajal, Cristian A., Campino, Carmen, Vecchiola, Andrea, Allende, Fidel, Solari, Sandra, García, Lorena, Lavanderos, Sergio, Valdivia, Carolina, Fuentes, Cristobal, Lagos, Carlos F., Martínez-Aguayo, Alejandro, Baudrand, Rene, Aglony, Marlene, García, Hernán, Fardella, Carlos E.
• Format: Article
• Language: English
• Subjects: Adolescent; Biomarkers - blood; Blood Pressure - genetics; Chi-Square Distribution; Child; Child, Preschool; Chile - epidemiology; Cross-Sectional Studies; Cytokines; Disease Progression; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype & phenotype; Humans; Hypertension; Hypertension - blood; Hypertension - enzymology; Hypertension - epidemiology; Hypertension - genetics; Hypertension - physiopathology; Inflammation Mediators - blood; Introns; Male; Medical research; Odds Ratio; Pedigree; Phenotype; Polymorphism, Single Nucleotide; rac1 GTP-Binding Protein - genetics; Risk Assessment; Risk Factors; Rodents
• ISSN: 0895-7061; 1941-7225
• DOI: 10.1093/ajh/hpt277

BACKGROUND The GTPase Rac1 has been implicated in hypertension as a modulator of mineralocorticoid receptor activity. Our aim is to investigate the frequency of polymorphisms rs10951982 (intron 1, G>A) and rs836478 (intron 3, T>C) in the RAC1 gene and perform association studies with clinical and biochemical parameters in a Chilean pediatric cohort. METHODS Two hundred two normotensive (NT) subjects (aged 4-16 years) were divided into 2 groups: NT subjects with hypertensive parents (NH; n = 103) and NT subjects with NT parents (NN; n = 99). We measured markers of inflammation (high-sensitivity C-reactive protein, interleukin 6 (IL-6), interleukin 8, and tumor necrosis factor α), endothelial damage (Plasminogen activator inhibitor-1 metalloproteinase-9, and metalloproteinase-2), and oxidative stress (malondialdehyde). Data were expressed as median and interquartile range (IQR). RESULTS We found differences in polymorphism rs836478 (intron 3, C>T) in both genotypic (χ2 = 15.2, 2df; P = 0.0005) and allelic (X2=5.5, 1df; P = 0.01) frequencies in NH vs. NN subjects. NH subjects with a TT genotype showed increase MMP9 expression (median = 2.3, IQR - 1.6-3.2; vs. median = 1.6, IQR = 1.6-2.3 AU; P = 0.01) and lower IL-6 expression (median = 8.8, IQR = 7.0-11.8; vs. median = 12.1, IQR = 8.2-14.7 pg/ml; P = 0.02) compared with subjects with TC/CC genotype. No difference in the allelic frequency distribution was seen in the polymorphism rs10951982 (NH vs. NN: χ2=0.2, 1df; P = 0.6). For this SNP, NN subjects with GA/AA genotype showed decreased diastolic BP indexes compared with subjects with native GG genotype (median = 1.08, IQR = 1.0-1.2; vs. median = 0.99, IQR = 0.94-1.1; P = 0.02). CONCLUSIONS We report the frequency of polymorphisms rs836478 and rs10951982 of the RAC1 gene in a Spanish-Amerindian cohort. The polymorphism rs836478 was associated with an increased expression in markers of inflammation and endothelial damage (MMP9 and IL-6) in pediatric subjects with a hypertensive genetic background.