Impact of interactions between risk alleles on clinical endpoints in hypertension.

ABSTRACT: OBJECTIVE:Impairment of the renin-angiotensinogen-aldosterone system (RAAS), one of the characteristics of essential hypertension (EH), imbalances vascular homeostasis. Despite inconsistent reports on individual single nucleotide polymorphisms (SNPs) as a major predictor of EH, interactions among RAAS genetic variants are rarely investigated. METHODS:Using SNP markers, we studied potential interactions between angiotensin 1 converting enzyme (ACE), angiotensinogen (AGT), angiotensin II-type 1 receptor (AGTR1), and ? adducin (ADD1) variants and their correlation with clinical endpoints in 545 individuals with hypertension and 400 age- and ethnicity-matched unrelated controls. Generalised multifactor dimensionality reduction (GMDR) analysis identified the models for genotype interaction. RESULTS:Although the results on single genes were significant, gene-gene interactions were more reliable and promising as markers in predisposing hypertension. The best models to represent association of multi-locus interactions with augmented hypertension susceptibility were: (a) within gene 4-locus model comprised of AGT SNPs -217G/A, -20A/C, -6G/A and 235M/T (p=0.022, OR 6.1); and (b) between genes 5-locus model comprised of AGT -217G/A, -20A/C, -6G/A, 235M/T and ACE I/D (p=0.05, OR 4.6). Stratification of 4- and 5-locus GMDR models on the basis of risk alleles from ?1 to ?7 increased the ORs from 2.8 to 36.1 and from 0.9 to 16.1, respectively. Moreover, compared to ?1 risk alleles the ?7 interacting risk alleles in both 4- and 5-locus models showed an increment of 14.2% and 11.1% in systolic blood pressure, 7.7% and 1.1% in diastolic blood pressure, and 10.5% and 5.1% in mean arterial pressure, respectively, in patients. CONCLUSIONS:Interactions among the genetic loci of RAAS components may be used as a predictor for susceptibility to hypertension.

SUBMITTER: Kohli S 

PROVIDER: S-EPMC4898629 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature