Association Of ?-adducin Gene With Essential Hypertension

Objective?This study aimed to identify the susceptibility loci of ?-adducin (ADD1) gene foressential hypertension (EH) and explore the gene-environmental interaction on EH. Additionally,the goal of the study is also to explore whether the promoter DNA methylation of ADD1gene isassociated with EH. Thereby, we can deeply understand the etiology of EH, and it can contribute toprovide the evidence for prevention and drug development of EH in Ningbo Han population.Methods?1. This case-control study comprised a total of2040unrelated participants (1020cases and1020controls) collected from Ningbo Han population. The gender and age of controlswere well matched with EH cases The baseline data of participants such as personal information,height, weight, drinking status, smoking status and the history of disease was obtained via thequestionnaire. And the data of TG, TC, blood glucose and HDL was extracted from the medicalexamination. DNA was extracted by Blood genomic DNA Extraction Kit. The tagSNPpolymorphisms of ADD1gene were detected by Tm-shift genotyping method.2. We selected33cases and33controls on the basis of the first stage sample to explore theassociation of ADD1promoter DNA methylation with EH. The DNA methylation levels of ADD1gene promoter were measured by pyrosequencing technology. Multifactor DimensionalityReduction (MDR) method was used to examine the interaction of gene-environment.Results?1. Our results showed that triglycerides (TG), body mass index (BMI) and drinkingstatus were significantly associated with EH (all P <0.05). The EH risk of high TG level was1.537times of the normals. And the EH risk of overweight people was1.235times of normalweight. Additionally, the EH risk of drinking was7.151times of non-drinking.2. The results showed the genotype and allele frequency of rs3755885, rs2071694, rs4963andrs3775067were not significantly different between cases and controls (all P>0.05). But we foundthe rs4961-T allele was associated with EH in females, and the EH risk of rs4961-T allele was79%of rs4961-G allele. Additionally, the genetic tests under dominant/recessive inheritance modelshowed that the EH risk of rs4961-GT+TT genotype was significantly different with rs4961-GG genotype in males, and the EH risk of rs4961-GT+TT was only67%of rs4961-GG. And the EHrisk in females will gradually decrease along with the change of rs4961-GG, GT, TT genotype.3. The haplotype analysis of ADD1gene tagSNP showed there were linkage disequilibriumblock among rs3755885(C/G), rs3775067(C/T), rs4961(G/T) and rs4963(C/G). The haplotypeGCTG was the protective factor of EH (OR=0.86,95%CI=0.76-0.97), but the haplotypes GTGC(OR=1.47,95%CI=1.20-1.79?and GCGG (OR=3.08,95%CI=1.93-4.90) were the riskfactors of EH.4. The results of MDR suggested that there were interactions among BMI, HDL and drinkingstatus in the etiology of EH, but no gene-environment interactions was found.5. In the second stage of study, we found DNA methylation levels were closely correlatedamong CpG2-5(r>0.80, P <0.01).6. ADD1promoter DNA methylation was significantly different between males and females,the results showed that CpG1DNA methylation levels (Women versus Men (%)?10.58±2.63versus9.25±1.40?P=0.016) and CpG2-5DNA methylation levels (Women versus Men (%)?31.16±5.58versus27.17±7.56?P=0.021) were significantly higher in females than males.Additionally, ADD1methylation levels were significantly higher in pre-menopausal (?50years)women than post-menopausal (>50years) women (CpG1: P=0.006; CpG2-5: P=0.034).7. The results also showed there were significantly association of ALT (EH versus Non-EH?18.7±11.2versus10.8±5.2?P=0.012) and AST (EH versus Non-EH?23.4±5.6versus18.7±3.6?P=0.008) with EH in females, and the increased ALT and AST levels maybe the risk ofEH.8. The study results found that the association of ADD1promoter DNA methylation with EHwas significantly different between males and females. The results showed ADD1CpG1andCpG2-5methylation levels were associated with EH in females (P=0.042) and males (P=0.008),respectively.Conclusion?1. TG, BMI and drinking were the major risk factors of EH in Ningbo Hanpopulation.2. The tagSNP rs4961was associated with EH in females, and the EH risk of rs4961-T allelewas only79%of rs4961-G allele.3. There were linkage disequilibrium block among rs3755885(C/G), rs3775067(C/T), rs4961(G/T) and rs4963(C/G). And the haplotype GCTG was the protective factor of EH, but thehaplotypes GTGC and GCGG were the risk factors of EH. 4. There were significantly association of ALT and AST with EH in females, and theincreased ALT and AST levels maybe the risk of EH.5. ADD1promoter DNA methylation was significantly different between males and females,and the DNA methylation levels were significantly higher in females than males. Additionally, theassociation of ADD1promoter DNA methylation with EH was significantly different betweenmales and females. Moreover, the ADD1CpG1and CpG2-5methylation levels were associatedwith EH in females and males, respectively.