A novel polymorphism in RAC1 gene is associated with hypertension risk factor in Chilean pediatric population

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 723-757-Renin-Angiotensin-Aldosterone System/Endocrine Hypertension
Bench to Bedside
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-742
Alejandra Tapia-Castillo*1, Cristian A Carvajal1, Andrea Vecchiola1, Carmen Campino1, Carolina Valdivia1, Fidel Allende1, Sandra Solari1, Lorena García2, Sergio Lavanderos2, Cristobal A Fuentes1, Carlos F Lagos1, Alejandro Martínez-Aguayo1, Rene Baudrand1, Marlene Aglony1, Hernan García1 and Carlos E Fardella1
1Pontificia Universidad Catolica de Chile, Santiago, Chile, 2Universidad de Chile, Santiago, Chile

The GTPase Rac1 has been implicated in hypertension (HTA) as modulator of mineralocorticoid receptor (MR) activity and inductor of superoxide generation. Polymorphisms (SNP) located in RAC1 gene may lead to increase its expression and modulate the alternative splicing.

Aim: To study the frequency of a novel SNP rs836478 (intron3, C>T) and two previously described SNP rs10951982 (intron 1, G> A) and SNP rs140559382 (exon 3, A>G) in RAC1 gene, and also perform association studies with clinical and biochemical parameters in a Chilean pediatric cohort.

Subjects and Methods:  We studied 200 normotensive (NT) children (4-18 years old) [NT with hypertensive parents (NH), and NT with NT parents (NN) (n=100 each)]. We measured inflammation variables (hsRCP, IL-6, IL-8, TNF-a); endothelial damage (PAI-I, MMP9 and MMP2) and oxidative stress (malondialdehyde). We designed primers to amplify the intron 1 and exon-intron 3 boundary region of RAC1 gene. Every SNP was genotyped by PCR-HRM. Data were expressed as interquartile range [Q1-Q3] and statistical comparisons by Kruskal-Wallis with Dunn's, X2, and odds ratio (OR) with Prism v5.0 software.

Results: We found a novel SNP rs836478 (intron3, C>T) located 18 bp downstream of the SNP rs14059382. This novel SNP showed differences in genotypic (X2=15.21, 2; p 0.0005) and allelic (X2=5.49, 1; p 0.01) frequencies in NH vs. NN, where in NH the 26% of patients carrying the T allele have increased risk of having hypertension [OR = 1.74, 95% CI 1.09-2.76]. NH subjects with TT genotype showed also higher MMP9 values (1.6 [1.6-2.3] vs. 2.3 [1.6-3.2] AU; p 0.015) and lower IL-6 levels (12.1 [8.2-14.7] vs. 8.8 [7.0-11.8] pg/ml; p 0.025) compared to native CC genotype. The SNP rs10951982 not showed any significant difference in allele frequency distribution (NH vs. NN, X2 =0.22, 1; p 0.63). Here, NN subjects with GA genotype showed lower diastolic BP indexes relative to native GG genotype (1.08 [1.0-1.2] vs. 0.99 [0.94-1.1] p 0.015). The SNP rs14059382 was not found in our cohort.

Conclusion: We report a novel SNP located in intron 3 of RAC1 gene (rs836478) showing differences in genotype and allelic frequencies. This SNP in RAC1 gene could contribute to increase the Rac1 expression, and secondarily affect some inflammation parameters (i.e. MMP9 and IL-6) in pediatric subjects with a hypertensive genetic background.

Nothing to Disclose: AT, CAC, AV, CC, CV, FA, SS, LG, SL, CAF, CFL, AM, RB, MA, HG, CEF

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm