Polymorphisms in the RAC1 gene are associated with hypertension risk factors in a Chilean pediatric population.
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 (χ(2) = 15.2, 2 df; P = 0.0005) and allelic (X(2)=5.5, 1 df; 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: χ(2)=0.2, 1 df; 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.
Department of Endocrinology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
Alejandra
A
Tapia-Castillo
Cristian A
CA
Carvajal
Carmen
C
Campino
Andrea
A
Vecchiola
Fidel
F
Allende
Sandra
S
Solari
Lorena
L
García
Sergio
S
Lavanderos
Carolina
C
Valdivia
Cristobal
C
Fuentes
Carlos F
CF
Lagos
Alejandro
A
Martínez-Aguayo
Rene
R
Baudrand
Marlene
M
Aglony
Hernán
H
García
Carlos E
CE
Fardella
D000293:Adolescent; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure / Q000235:genetics*; D016009:Chi-Square Distribution; D002648:Child; D002675:Child, Preschool; D002677:Chile / Q000453:epidemiology; D003430:Cross-Sectional Studies; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D018836:Inflammation Mediators / Q000097:blood; D007438:Introns; D008297:Male; D016017:Odds Ratio; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D012307:Risk Factors; D020830:rac1 GTP-Binding Protein / Q000235:genetics*
D015415:Biomarkers; D018836:Inflammation Mediators; C107953:RAC1 protein, human; D020830:rac1 GTP-Binding Protein
PCR-HRM; RAC1 gene.; blood pressure; hypertension; normotensive; polymorphisms