Significance of AGT haplotypes and genotypes-combinations versus single nucleotide polymorphisms in hyprtension: togetherness does matter

Renin-angiotensin system gene polymorphisms are associated with essential hypertension; angiotensinogen (AGT) gene variants are considered potential genetic risk factors. The aim of this study was to investigate the contribution of the G-6A, T174M, M235T polymorphisms, respective genotypic interactions and haplotypes towards essential hypertension. Methods In a case-control design, 810 consecutive ethnically-matched unrelated subjects comprising 450 hypertensives and 360 controls were recruited. Genotyping by PCR-RFLP, genotypes-combination and haplotype analyses were performed. Results The G-6A and M235T polymorphisms differed significantly (P = 0,007, OR=1.9,95% CI =1.2-2.9; P<0.0001, OR =3.7.95% CI =2.3-5.7, respectively), wherein the-6A and 235T mutant alleles were over-represented in hypertensives (P < 0.0001, cach). The genotypes combinations of the three polymorphisms having 6 wild-type alleles versus the remaining resulted in odds ratio of 2.4 (P < 0.0001), further as the number of mutant alleles in a combination increased, the systolic, diastolic and mean blood pressure increased. The overall likelihood of haplotypes profile difference between the two groups was highly significant (P < 0.0001). Overrepresentation of the haplotypes viz., A/1741, 174T/235T, A/235T, A/174T/235T in hypertensives, and G/174T, 174T/235M, G/235M, G/174T/235M in controls, was identified as risk and protective haplotypes (P<0.0001. each). respectively. Conclusion The-6A and 235T alleles and respective homozygous genotypes were independently associated with hypertension susceptibility. The interaction of 174T-allele with M235T and G-6A polymorphisms in combinations or haplotypes emerged significant. The 3-locus haplotypes were distinct by the prevalence of 235T-allele in hypertensives and 235M-allele in controls.

Keywords:

hypertension , AGT. polymorphisms , haplotypes , genotypes combination