Key result
Haplotype I of the human AT1R gene, characterized by the -680T allele, is significantly associated with an increased risk of hypertension in Caucasian subjects.
Why the study?
Does haplotype I of the human AT1R gene increase blood pressure compared to haplotype II?
Case-Control (n=762)
Does haplotype I of the human AT1R gene increase blood pressure compared to haplotype II?
Haplotype I of the human AT1R gene is associated with hypertension in humans and causes increased blood pressure and oxidative stress in transgenic mice.
Does not support clinical genetic testing; leaves open causal validation of AT1R haplotype I effects in human hypertension.
The renin-angiotensin system plays an important role in the regulation of blood pressure via angiotensin II and the angiotensin II receptor type 1 (AT1R). Human AT1R gene promoter has four SNPs: T/A at -777, T/G at -680, A/C at -214, and A/G at -119, that are in linkage disequilibrium. Variants -777T, -680T, -214A, and -119A almost always occur together (named haplotype I), and variants -777A, -680G, -214C, and -119G almost always occur together (named haplotype II) in Caucasian subjects. Genomic DNA analyses, from 388 normotensive and 374 hypertensive subjects, link haplotype I of the human AT1R (hAT1R) gene with hypertension in Caucasians (p = 0.004, χ(2) = 8.46). Our results show increased basal promoter activity of the hAT1R gene in cells (H295R and A7r5) transfected with reporter construct containing haplotype I. We also show increased binding of the transcription factor, USF2, to oligonucleotide containing nucleoside -214A as opposed to -214C. Recombineering of a 166-kb bacterial artificial chromosome containing 68 kb of the 5'-flanking region, 45 kb of the coding sequence, and 53 kb of the 3'-flanking region of the hAT1R gene was employed to generate transgenic mice with either haplotype. We show that (a) hAT1R mRNA level is increased in the kidney and heart of transgenic mice containing haplotype I as compared with haplotype II; (b) USF2 binds more strongly to the chromatin obtained from the kidney of transgenic mice containing haplotype I as compared with haplotype II; and (c) blood pressure and oxidative stress are increased in transgenic mice containing haplotype I as compared with haplotype II.
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Jain et al. (2013) conducted a case-control in Hypertension (n=762). Haplotype I of the human AT1R gene (-680T allele) vs. Haplotype II (-680G allele) was evaluated on Association of the -680T allele with hypertension (p=0.004). Haplotype I of the human AT1R gene, characterized by the -680T allele, is significantly associated with an increased risk of hypertension in Caucasian subjects.
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