EH is the most common cardiovascular disease. Genetic biomarkers has a significant role in identifying patients at a high susceptibility to EH. Data from our current study showed that the P2Y2R rs4382936 polymorphisms were associated with an increased EH susceptibility. Furthermore, four P2Y2R haplotypes combined by rs1783596-rs4382936-rs10898909, i.e., CAA, CAG, TAA and TAG, were susceptible haplotypes for EH, whereas haplotype CCG was a protective haplotype for EH. These results supported that P2Y2R rs4382936 and its estimated haplotypes may contribute to the identification of postmenopausal women at a high susceptibility to EH.
It has been shown that the P2Y2R signaling is correlated with endothelial function, which regulates blood pressure by controlling the effects of an endothelium-related vasoconstrictive factor, nucleotide uridine adenosine tetraphosphate (Up4A) [38]. The activation of P2Y2R was also reported to mediate the proliferation of vascular SMCs and vascular hyperplasia that were closely relevant to EH [27, 28]. Moreover, P2Y2R may be involved in hypertension through the regulation of renal reabsorption of Na+ and fluid [30]. The purinergic system was suggested to regulate blood pressure in parallel with the sympathetic and renin-angiotensin-aldosterone system (RAAS) [39]. Consequently, genetic variation in the P2Y2R gene may have a role in regulating hypertension and cardiovascular disease. Indeed, the clinical relevance of P2Y2R polymorphisms with diseases including hypertension and cardiovascular disease has attracted much interest in recent years [34, 35].
To the best of our knowledge, this is the first study to examine the association between P2Y2R genetic variants and EH risk in Chinese. We identified P2Y2R rs4382936A was correlated with EH risk in Han Chinese women. Moreover, we found the subjects with four P2Y2R haplotypes combined by rs1783596-rs4382936-rs10898909, i.e., CAA, CAG, TAA and TAG, had an increased risk to EH while the carriers with CCG haplotype had a low risk to EH. Although the functional influences of the P2Y2R rs4382936 genetic polymorphism in the 3’-UTR region were not fully understood, it has been suggested that the genetic polymorphisms in the 3’-UTR region may affect the translation initiation, mRNA stability, and subcellular localization [40]. In addition, there was also mounting evidence supporting that genetic variation in the 3’-UTR region influenced gene expression via disturbing the binding of miRNA to the target gene [41, 42].
However, our result regarding to the association of P2Y2R rs4382936 polymorphisms with EH was inconsistent with that of Wang et al. [34]. Their study did not detect the significant association between rs4382936 and blood pressure or EH in a Japanese-based population; This discrepancy is probably due to several inter-study differences. Firstly, these two studies involved populations with different genetic backgrounds. Our study identified the frequency of rs4382936A as 36% or so in Chinese, which is higher than that in Japanese (about 27%). Thus, the difference in allele frequencies between Chinese and Japanese may affect the association between rs4382936 and EH risk. Secondly, the different characteristics of subjects between the two studies may also account for the disparate results. For example, the mean age of enrolled women was about 50 years old in the study of Wang et al. [34]; our subjects were postmenopausal women with a mean age of nearly 60 years old.
Many efforts have been devoured in delineating the genetic contributions underlying EH [43, 44]. According to the common variant-common disease hypothesis, several GWASs have discovered many loci associated with EH in various populations [43, 44]. These studies suggested a large number of common genetic variants in various genes may contribute to the pathogenesis of EH. Nonetheless, these common variations can only explain a relatively limited amount of genetic variations underlying EH [45]. Thus, the majority of genetic variations in EH are still undetermined. Accordingly, based on prior knowledge about the possible signaling pathways associated with the etiology of EH, the candidate gene approach shows superiority in identifying potential genes associated with EH. Therefore, considering the importance of P2Y2R in regulating vascular function and Na+ and fluid reabsorption, we carried out this association study which provided evidence for the correlation between P2Y2R gene and EH in a population of Chinese women.
Given the limitations of this study, the sample size was relatively small, which may not represent the entire population. The frequencies of genotypes between controls and cases were in HWE, indicating that the participant selection was random, and the study power reached 88.31% (two-sided test, α = 0.05), with a 14.65 OR for rs4382936-AA genotype. Secondly, our study only included Han Chinese. Since different ethnic groups have different genetic backgrounds, the impacts of the P2Y2R genetic variants could be disparate on other populations. Therefore, the findings of this Chinese population-based study may not be generalized to non-Chinese populations. Thirdly, it is still possible that there are functional mutations in the P2Y2R gene or in neighboring genes that are in LD with the P2Y2R rs4944832 polymorphism. Fourthly, other genes have been demonstrated to be associated with EH [8, 44]. Interactions can exist among P2Y2R and these genes. Thus, joint consideration of the gene-gene interaction may help us better realize the underlying genetic regulation of EH. Last but not least, a gender-specific effect of P2Y2R polymorphism on EH susceptibility has been shown in Japanese [34]. In this follow-up study, only women were involved into our analysis. Further study by involving the subjects of men may be helpful for clarifying whether there exists a gender-specific association between P2Y2R polymorphism and EH susceptibility in Chinese population.
Together, our findings confirmed that rs4382936 and its estimated haplotypes of P2Y2R gene were correlated with EH susceptibility in a group of Chinese postmenopausal women. To support our results and pursue further research, more large-cohort-based studies involving different ethnic populations are needed in the future. Our results may provide new evidence for applying P2X2R genetic polymorphisms as useful markers in clinic screening or monitoring potential EH cases.