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Hypertension being a multigenetic disease, the gene-gene interactions (epistasis) among the variants would consolidate global overview on gene-disease interactions.
Genetic variants in angiotensin converting enzyme (ACE), Angiotensin II receptor, type-1 (AT1R), angiotensinogen (AGT), aldosterone synthase (CYP11B2), endothelial nitric oxide synthase (NOS3), β2-adrenergic receptor (ADRB2), fat mass obesity associated gene (FTO) and guanine nucleotide binding protein, β-polypeptide 3 (GNB3) belonging to pathways like renin-angiotensinogen-aldosterone system (RAAS), kallikrein-kinin system (KKS), adrenergic receptor, nervous system and G protein coupled receptors family were screened using PCR-RFLP and SNaPshot methods in age- and -ethnicity matched case-control 1500 north-Indian subjects. The study was approved by Human ethics committee.
Gene-gene interactions revealed few best disease predicting models (p<0.01) such as the ACE I/D, AT1R 1166A/C and AGT –532C/T, –20A/C, –6G/A 235M/T; CYP11B2 -344T/C, Iw/Ic and NOS3 -922A/G, -786T/C, 4b/4a, 894G/T; FTO rs8050136C/A and GNB3 rs1129649T/C, 825C/T. The ORs (odds ratios) for CYP11B2 and NOS3 risk interacted-haplotypes (-344T/Ic) + (-922A/-786T/4a/894G) and (-344T/Ic) + (-922G/-786C/4a/894G) were 5.3 and 3.9, respectively (p≤0.04); whereas the OR for protective interacted-haplotypes (-344T/Iw) + (-922A/-786T/4b/894G) was 0.7 (p=0.03). Furthermore, stratification of interacted 4- and 5-locus models comprising polymorphisms of ADRB2 and NOS3 on the basis of increasing number of risk alleles demonstrated remarkable augmentation in the OR from 1.3 to 14.2 (p=0.508-4.51E-07) for hypertension susceptibility compared to respective individual gene models. Likewise stratification of 3-locus best model of FTO rs8050136C/A and GNB3 rs1129649T/C and 825C/T on the basis of interacted-genotypes comprising 1, 2, 3, 4 and 5 risk alleles correlated linearly with increased ORs from 1.9 to 11.6 for hypertension (p<0.01) compared to interacted-genotypes devoid of risk alleles. Of note, the genetic outcomes were further consolidated by significant varied clinical, biochemical parameters and expression levels, (p<0.05).
This study demonstrated the importance of non-linear interactions (epistasis) among the genes of several pathways in hypertension pathophysiology. A global cumulative consensus will immensely benefit the diagnosis and therapeutics.