Strong Association of a Renin Intronic Dimorphism with Essential Hypertension

Abstract

The objectives of this project were two-fold: to identify the genetic mutation that has been detected as an MboI dimorphism in intron 9 of the human renin (REN) gene and to confirm a previously reported, putative association between the REN MboI dimorphism and clinical diagnosis of essential hypertension (EHT) in a population of Gulf Arabs from the United Arab Emirates. Sequencing of the MboI dimorphic site was carried out on DNA of randomly chosen cases and controls. A retrospective case-control study was carried out in 689 unrelated subjects (326 first-time, clinically diagnosed hypertensives and 363 age- and gender-matched normotensive subjects), selected from the resident population of the Abu Dhabi Emirate. A polymerase chain reaction/MboI-RFLP based method was employed to compare genotype and allele distributions. Nucleotide sequences at the MboI site of the cut and uncut alleles were determined to be GATC and GGTC, respectively. This A>G mutation is located 10,631 base pairs (bp) 3' to the start of the REN gene, and 79 bp 3' to the end of exon 9. The genotype distributions of the REN 10631A>G dimorphism were found to be significantly different between hypertensive and normotensive subjects (x2= 42.29, df=2, p<0.001). Frequencies of A alleles were 0.54 in EHT vs. 0.37 in normotensive subjects, which is even more demarcated than what was found previously. The frequency of AA genotypes was higher in the hypertensive group than in the normotensive group (34.7% vs. 14.0%). The quantification of the association of A alleles with increased risk of EHT was assessed with corresponding odds ratios (OR), which gave the following values: OR of GG vs. AG genotypes, 1.3 (95% confidence interval [CI]: 0.90-1.88); OR of GG vs. AA, 3.75 (95% CI: 2.41-5.86). In conclusion, REN 10631A alleles are significantly associated with EHT in the Emirati population. This has now been found in two different and therefore independent sample populations from the Abu Dhabi Emirate. Moreover, this genetic effect seems to be acting in a recessive fashion. Hence, either the REN gene itself, or another gene that is in linkage disequilibrium with REN 10631A>G, is implicated in the pathogenesis of EHT in Emirati.