The Association Study Of Ion-Channel Gene SLC12A3Variants With Essential Hypertension Of Mongolian Population In The Inner Mongolia Region

Objective: Essential hypertension (EH) is one of the most common cardiovasculardiseases threatening human health. The pathogenesis of EH stems from a complexinteraction between environmental and genetic factors. Identifying the related genesand risk factors of EH is of great significance for the prevention and treatment of EH.Using epidemiological investigation combined with genetic study, we aimed to findthe variants affecting blood pressure traits of Mongolian population in InnerMongolia regions, clarify the underlying molecular mechanisms of essentialhypertension, especially the molecular mechanisms of Mongolian hypertension in theInner Mongolia region, further narrow these regions to identify the causal gene(s),and provide scientific basises for the prevention and treatment of local Mongolianhypertention.Methods:1. Epidemiological researches were carried out by cross-sectional survey for fourtimes. Totally,908blood samples were collected from three villages and involvedin Dongwuzhumuxin county (including three investigation townships of Wulagai,Baolage and Bayanhuobuer), the Xianghuang county of Xilin Gol League in InnerMongolia Autonomous Region. After excluding the subjects with coronary heartdisease, stroke, the kidney disease, the other related disease as well as the subjects having the relative relationship,754subjects were ultimately selected in our study,including508unrelated Mongolian essential hypertension patients and246unrelated Mongolian normotensive subjects.2. TagSNPs were identified from the Chinese HapMap database based on pairwiser2≥0.5and minor allele frequency (MAF)≥0.05, and15tagSNPs were selectedaccording to the block of LD in our study, including rs4784733、rs2304478、rs13306673、rs2289119、rs8043560、rs2304483、rs5803、rs7187932、rs6499858、rs11644728、rs8049280、rs7204044、rs2010501、rs2399594and rs711746.Genotyping was performed using the PCR/ligase detection reaction assay.3. The basic clinical data of hypertensive and normotensive subjects were assessedby ANOVA (SPSS13.0software). The association study of single SNPs, theanalysis of LD and haplotype in selected SNPs were performed byUNPHASED3.0.13software and Haploview4.0software. We researched theassociation of15single selected SNPs of SLC12A3and their haplotypes withessential hypertension. We also analyzed the association of15single selectedSNPs of SLC12A3with the other blood traits SBP and DBP. G power softwarewas used to assess the statistical power of our study.Results:1. The analysis of basic clinical data showed that there are significant differences insex, average age, BMI, waistline, hipline, SBP, DBP and TG betweenhypertensive and normotensive subjects of Mongolian population. Compared tonormotensive group, the cases are higher in average age, BMI, waistline, hipline,SBP, DBP and TG （P<0.01）. However, there are no significant differences infasting blood glucose, heart beat, HDL-C, LDL-C and TC between the twogroups（P>0.05）. In the habits of life, drinking showed statistical difference（P<0.01）, however smoking didn’t showed statistically significant differences between the two groups （P>0.05）, suggesting that drinking may play animportant role in the development of Mongolian hypertension.2. The association study of single SNPs showed that three SNPs of SLC12A3geneare significantly associated with the traits of blood pressure respectively:rs2399594(HTN，p=0.030；SBP，P=0.029；DBP，P=0.050），rs7187932（HTN，p=0.048）and rs2304478（SBP，P=0.028）.3. LD analysis showed that11SNPs of SLC12A3gene composed three high LDblocks: block1（rs4784733, rs2304478and rs13306673）, block2（rs8043560,rs2304483, rs5803, rs7187932, rs6499858and rs11644728） and block3（rs2399594and rs711746）; Therefore we further performed a haplotypeanalysis.4. The results of Haplotype analysis showed that the GG haplotype of block3issignificantly associated with hypertension (P=0.029), suggesting it is likely to bea genetic risk factor of Mongolian hypertension.Conclusion:1. In Mongolian population, there are significant differences in sex, average age,BMI, waistline, hipline, SBP, DBP and TG between hypertensive andnormotensive groups. Compared to normotensive subjects, the cases are higher inaverage age, BMI, waistline, hipline, SBP, DBP and TG. In the habits of life,drinking showed statistical difference, suggesting that drinking may play animportant role in the development of Mongolian hypertension.2. Three SNPs of SLC12A3gene are significantly associated with blood pressuretraits respectively: rs2399594(HTN, SBP and DBP），rs7187932（HTN）andrs2304478（SBP）.3. A haplotype GG of the block3(rs2399594and rs711746) is significantly associatedwith hypertension, suggesting it is likely to be a genetic risk factor of Mongolian hypertension.