Association Of PHACTR1 Gene Variation With Increased Pulse Pressure

Objective:Increased pulse pressure(PP)is an independent risk factor for cardiovascular and cerebrovascular diseases such as coronary heart disease and myocardial infarction,and is affected by genetic and various environmental factors.In this study,phosphatase and actin regulator 1(PHACTR1)gene was selected as the target gene to further study the relationship between PHACTR1 gene variation and increased PP in Chinese Han population,as well as the influence of the interaction with environmental factors on increased PP.The results can provide scientific basis for elucidating the change mechanism of PP,controlling the ideal PP and reducing the occurrence of cardiovascular and cerebrovascular diseases.Methods:This study was designed as a case-control study.The subjects were randomly selected from Qingdao community aged 30 and over and informed consent was obtained.PP≥65mmHg was defined as increased PP,30≤PP≤45mmHg and systolic/diastolic blood pressure≤120/80mmHg was defined as normal PP.PHACTR1gene rs475543,rs9472419,rs2026458,rs9349379,rs1223397,rs693758 and rs499818were selected as tag SNP.Logistic regression analysis was adopt to investigate the association between PHACTR1 gene variation and increased PP under five genetic models of codominant,additive,dominant,recessive and overdominant,which was expressed by odd ratio(OR)and 95%confidence interval(CI).Haplotype blocks were defined by linkage disequilibrium(LD)analysis,andχ~2 test was used to compare the distribution of haplotype frequencies between increased PP group and control group.By using the method of weighted gene score,taking theβcoefficient of each risk allele as the weight,PHACTR1 gene score of rs475543,rs9472419,rs2026458,rs9349379,rs1223397,rs693758 and rs499818 was calculated,to explore the association between the total genetic risk of PHACTR1 gene and increased PP.And the effect of the interaction between PHACTR1 gene score and environmental factors(such as age,obesity and dyslipidemia)on increased PP was assessed by multiplicative and additive interaction models.Dominance analysis method was used to explore the relative importance of PHACTR1 gene score and other factors on increased PP.Results:A total of 706 subjects were enrolled,including 347 patients with increased PP(case group)and 359 subjects with normal PP(control group).1.Association between single SNP of PHACTR1 gene and increased PP After adjusting for age,gender,obesity,dyslipidemia,diabetes,drinking status and recreational activity,(1)rs9349379:under codominant model(AA vs GG),compared with GG genotype,individuals with AA genotype had an increased risk of increased PP(OR=2.255,95%CI:1.132-4.492);under additive model(AA vs GA vs GG),the SNP was related to increased PP(OR=1.368,95%CI:1.049-1.783);under recessive model[AA vs(GA+GG)],compared with(GA+GG)genotype,individuals with AA genotype had an increased risk of increased PP(OR=2.062,95%CI:1.051-4.045),all the associations were statistically significant(P<0.05);under codominant(GA vs GG),dominant[(GA+AA)vs GG]and overdominant[GA vs(GG+AA)]models,there was no significant correlation between the SNP and increased PP(P>0.05).(2)rs499818:under codominant model(AA vs GG),compared with GG genotype,individuals with AA genotype had an increased risk of increased PP(OR=3.483,95%CI:1.044-11.613);under recessive model[AA vs(GG+GA)],compared with(GG+GA)genotype,individuals with AA genotype had an increased risk of increased PP(OR=3.716,95%CI:1.119-12.339),all the associations were statistically significant(P<0.05);under codominant(GA vs GG),additive(AA vs GA vs GG),dominant[(GA+AA)vs GG]and overdominant[GA vs(GG+AA)]models,there was no significant correlation between the SNP and increased PP(P>0.05).(3)rs475543,rs9472419,rs2026458,rs1223397 and rs693758:under the five genetic models of codominant,additive,dominant,recessive and overdominant,there was no significant correlation between the five SNP and increased PP(P>0.05).According to the Akaike information criterion(AIC),the optimal genetic models of rs9349379 and rs499818 were codominant.2.Haplotype analysis According to Haploview software,a haplotype block was defined,covering rs475543 and rs9472419.The haplotypes with a total frequency≥5%were composed of GC,GT and AC.The frequencies of GC,GT and AC haplotypes were0.568,0.321 and 0.111 in increased PP group and 0.547,0.347 and 0.106 in normal PP group,respectively.There was no significant difference in the frequency distribution of GC,GT and AC haplotypes between the groups(χ~2=0.594,1.029,0.095,P>0.05).3.Association between PHACTR1 gene score and increased PP After adjusting for age,gender,obesity,dyslipidemia,diabetes,drinking status and recreational activity,the association between PHACTR1 gene score and increased PP was statistically significant(OR=1.702,95%CI:1.055-2.746,P=0.029),indicating that the higher the PHACTR1 gene score,the higher the risk of increased PP.4.Interaction of PHACTR1 gene score and age,obesity and dyslipidemia on increased PP(1)multivariate multiplicative interaction models showed that there might be no multiplicative interaction between PHACTR1 gene score and age,obesity and dyslipidemia(P>0.05);(2)multivariate additive interaction model indicated that in the interaction analysis of PHACTR1 gene score and age,relative excess risk due to interaction(RERI)=0.738,95%CI:0.004-17.772,attributable proportion due to interaction(AP)=0.031,95%CI:0.003-0.067,synergy index(S)=1.033,95%CI:1.001-1.072,indicating that there might be positive additive interaction between PHACTR1 gene score and age on increased PP.It was suggested that the effect of PHACTR1 gene variation on increased PP increased with age.There might be no additive interaction between PHACTR1 gene score and obesity or dyslipidemia.5.Dominance analysis The relative important predictor for increased PP was diabetes(34.41%),obesity(34.33%),recreational activity(10.83%),drinking status(6.30%),dyslipidemia(4.57%),PHACTR1 gene score(3.95%),age(3.51%)and gender(2.10%)according to the standardized dominance weight.Conclusion:PHACTR1 gene rs9349379 and rs499818 affect the genetic susceptibility to increased PP,suggesting that PHACTR1 gene variation was related to increased PP.PHACTR1 gene score was associated with increased PP.The higher the score,the higher the risk of increased PP.There was positive additive interaction between PHACTR1 gene score and age on increased PP,suggesting that the effect of PHACTR1gene variation on increased PP increased with age.In addition,compared with other factors,diabetes and obesity were the main factors that affect increased PP.