Article Text

PDF
Impact of interactions between risk alleles on clinical endpoints in hypertension
  1. Samantha Kohli1,2,
  2. Rahul Kumar1,3,
  3. Mohit Gupta4,
  4. Sanjay Tyagi4,
  5. M A Qadar Pasha1,2
  1. 1Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, New Delhi, Delhi, India
  2. 2Academy of Scientific and Innovative Research, New Delhi, Delhi, India
  3. 3Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado, Denver, USA
  4. 4Department of Cardiology, G.B. Pant Hospital, New Delhi, Delhi, India
  1. Correspondence to Dr Rahul Kumar, CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi-110 007, India; rahuligib{at}gmail.com and Dr M A Qadar Pasha, CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi-110 007, India; qpasha{at}igib.res.in

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 α 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.

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.