Abstract Introduction Essential Hypertension (EH) is a multifactorial disorder resulting from environmental and genetic factors and a primary factor for morbidity and mortality worldwide. A genetic variant in the ZC3HC1 gene, resulting in an arginine-to-histidine at the 363 position of the NIPA protein, has been associated with coronary artery disease (CAD). Still, its relationship with EH remains less clear. Aim Investigate whether ZC3HC1 rs11556924 CT was associated with EH in a Portuguese population without apparent CAD. Methods A prospective study included 1421 participants from our Research Center dataset on a normal Portuguese population without apparent CAD. Participants were followed during an extended period (average 7.3±6.0 years), and all demographic, biochemical, CV risk factors and clinical data were collected. ZC3HC1 rs11556924 was genotyped by TaqMan assays real-time polymerase chain reaction (PCR). The allelic and genotypic frequency distributions were estimated, and the Hardy-Weinberg equilibrium was tested. Data were displayed as absolute numbers, as well as means and standard deviations (SD). The Student's t-test compared numerical variables, and the Chi-square was analyzed categorically. Multivariate logistic regression adjusted to confounders was performed. Statistical significance was defined as p0.05, and all analyses were performed using SPSS statistical software vs 25.0. Results The population was in the Hardy-Weinberg equilibrium either in the group with EH (p=0.438) or without EH (p=0.768). In the overall population, the frequencies of the CC, CT, and minor TT genotypes were, respectively, 38.4%, 48.2% and 13.4% in the EH group and 43.9%, 45.1% and 11.0% in the non-EH group (p=0.074). In bivariate analysis, the dominant model (TT+TC vs CC) presented an OR=1.255; p=0.031 and the recessive model (TT vs TC+CC) had an OR=1.249; p=0.162. The dominant model was also risk against EH in the non-smoking population, with statistical significance (p=0.016). In this population (non-smoking), after multivariate logistic regression adjusted for all other co-variables, ZC3HC1 also remained in the equation, with an OR=1.376 (CI: 1.047-1.809; p=0.022). Conclusion ZC3HC1 rs11556924 was shown to be a risk factor for EH. However, this variant may no longer be independently significant in the general population. Meanwhile, in non-smokers, this variant increases EH risk in either bivariate or multivariate models. Smoking, through vascular damage or inflammation pathways, can act as a confounder or modifier of EH in the general population. Removing smokers may reduce noise, unmasking the proper relationship between the variant and hypertension.
Olim et al. (Sat,) studied this question.