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Activating transcription factor 1 (ATF1) may be involved in essential hypertension (EH) by induction of NADPH oxidase 1 (NOX1) and radical oxygen species (ROSs) production. Abnormal expression of ATF1 was found in EH in previous microarray analysis. Here we tested whether a single nucleotide polymorphism (SNP) located in the 3′-untranslated region (3′UTR) of ATF1 was associated with EH susceptibility by affecting microRNA (miRNA) binding. In silico analysis indicated that rs11169571 (T > C) was a candidate SNP to modulate miRNA: ATF1 mRNA complex, with the greatest changed energy for hsa-miR-1283, and the luciferase reporter analysis showed that miR-1283 inhibited the activity of the reporter vector carrying –T allele, but not the –C allele. In addition, inhibition of miR-1283 in HA-VSMCs enhanced the expression of ATF1 mRNA as well as the ROS levels. Further case-control study showed that rs11169571 was significantly associated with increased risk of EH. Finally, we observed an increased ATF1 protein level in peripheral blood of EH patients with CC carriers compared to TT carriers of rs11169571, with an intermediate ATF1 level in TC carriers. These results suggested that rs11169571 of ATF1 gene may be associated with EH, and the SNP-modified posttranscriptional gene regulation by miRNAs could be a potentially pathogenetic mechanism of EH. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum aminopeptidase 1 (ERAP1) may be involved in blood pressure regulation by inactivation of angiotensin II and generation of bradykinin. Our previous study with cDNA microarray indicated that the expression of ERAP1 is down-regulated in essential hypertension (EH) patients. Since the 3′untranslated region (3′UTR) is known to play an important role in the post-transcriptional regulation by influencing the stability and translation process of mRNA, the present study aims to identify single nucleotide polymorphisms (SNPs) in the 3′UTR of ERAP1 gene in a case–control study among the Northeastern Han Chinese through PCR-sequencing, and analyze the association with EH. Our results further verified the lower expression level of ERAP1 in the peripheral blood cells in patients with EH (917.12 ± 517.57 vs. 1506.59 ± 1214.09 pg/mL, P = 0.011). Four SNPs, 3′UTR-761G>A, 3′UTR-787C>T, 3′UTR-1008A>C and 3′UTR-1055A>G, were identified in the 3′UTR of ERAP1 . 3′UTR-1008A>C and 3′UTR-1055A>G were in almost complete linkage disequilibrium. Association analysis showed that the genotypic and allelic frequencies of 3′UTR-1008A>C and 3′UTR-1055A>G were significantly different between EH and the control groups. Logistic regression and haplotypic analysis indicated that alleles of E20-1037C and E20-1084G as well as haplotype of C-G were the risk factors of EH (P < 0.05). Subgroup analysis performed by age suggested that the frequencies of genotype and allele of 3′UTR-1008A>C and 3′UTR-1055A>G as well as the haplotypes C-G and A-A were significantly different between EH and the control in the younger group (< 50), but not in the older group (≥ 50). Younger population with the 3′UTR-1008CC and/or 3′UTR-1055GG genotypes also tended to have higher blood pressure, especially the diastolic blood pressure. In conclusion, the 3′UTR-1008A>C and 3′UTR-1055A>G polymorphisms of ERAP1 gene were associated with EH, especially in the younger population, and the haplotype C-G could be the independent marker of EH. [ABSTRACT FROM AUTHOR]