Associations Between The Single Nucleotide Polymorphisms Of PIK3CG And Increased Pulse Pressure

Objective:Pulse pressure(PP)is an important indicator of arterial elasticity,which is related to various environmental and genetic factors.Increased PP is an independent risk factor for cardiovascular and cerebrovascular diseases such as coronary heart disease,heart failure,myocardial infarction and stroke.In this study,Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma(PIK3CG)gene was used as the target gene to investigate the association between the single nucleotide polymorphism(SNP)of PIK3CG gene and increased PP in Chinese Han population.The results are helpful to reveal the mechanism of PP change at the gene level,and provide scientific basis for controlling PP level and preventing cardiovascular and cerebrovascular diseases.Methods:In this study,the community population aged 30 and above in Qingdao were selected as the research object,and a case-control study design was adopted.The PIK3CG gene located on chromosome 7(7q22.3)was selected as target gene,and rs12667819,rs1129293,rs17398575,rs17477177 Rs17847825 rs2230460 rs28763991 rs3173908 and rs4727666 were selected as tag SNP.Subjects with PP≥65mm Hg were treated as case group(increased PP group),and subjects with 30mm Hg≤PP≤45mm Hg and normal blood pressure(systolic/diastolic≤120/80mm Hg)were treated as normal control group(normal PP group).Logistic regression analysis was used to investigate the association between the single nucleotide polymorphisms of PIK3CG gene and the increase of PP under five genetic models(codominant,additive,dominant,recessive and overdominant models).and the best genetic model for each genetic locus was determined by Akaike information criterion(AIC);Weighted gene score method was used to calculate PIK3CG gene score of rs12667819,rs1129293,rs17398575,rs17477177,rs17847825,rs2230460,rs28763991,rs3173908 and rs4727666,and explore the association between PIK3CG gene score and increased PP;Multiplication and additive models were used to analyze the effects of the interaction between PIK3CG gene score and age,obesity and hyperlipidemia on PP increase;The relative effects of age,sex,obesity,education level,hyperlipidemia,diabetes,smoking status,alcohol consumption status,leisure physical activity and gene scores on PP increase were compared by dominance analysis.Results:1.Basic information of case group and control group A total of 718 subjects were included in this study,including 367 patients in the control group(normal PP group)and 351 patients in the case group(increased PP group).The differences in age(t=-3.614,P<0.05),obesity(χ~2=53.844,P<0.05),education level(χ~2=35.071,P<0.05),hyperlipidemia(χ~2=16.633,P<0.001),diabetes(χ~2=57.167,P<0.05),alcohol status(χ~2=7.706,P<0.05)and recreational physical activity(χ~2=10.103,P<0.05)between the case and control group were statistically significant.There was no significant difference in gender(χ~2=0.008,P>0.05)and smoking status(χ~2=0.450,P>0.05)between the two groups.2.Association between various SNP locus of PIK3CG gene and increased PP After adjusting for age,gender,obesity,education level,hyperlipidemia,diabetes,smoking status,alcohol consumption status,and leisure physical activity,the results of multivariate Logistic regression analysis showed that(1)rs17398575 locus:In the additive model,rs17398575was associated with increased PP(GG vs GA vs AA,OR=1.40,95%CI:1.01-1.95,P<0.05);In codominance(GA vs GG;AA vs GG),dominant[(GA+AA)vs GG],recessive[AA vs(GG+GA)]and overdominant[(GG+AA)vs GA]models showed no significant association between rs17398575 locus and PP increase(P>0.05).(2)(2)rs17477177 locus:in the codominant model of rs17477177 locus,compared with TT genotype,carriers of CC genotype had an increased risk of PP(CC vs TT,OR=3.07,95%CI:1.06-8.83,P<0.05);In the additive model,rs17477177 locus variation was associated with increased PP(TT vs CT vs CC,OR=1.46,95%CI:1.05-2.03,P<0.05);In recessive model,compared with individuals with(TT+CT)genotype,individuals with CC genotype had an increased likelihood of increased PP[CC VS(TT+CT),OR=2.89,95%CI:1.01-8.29,P<0.05];In dominant[(CT+CC)vs TT]and superdominant[(CC+TT)vs CT]models,no statistically significant was found between rs17477177 locus and increased PP(P>0.05).(3)In codominant,additive,dominant,recessive and overdominant genetic models,rs12667819,rs1129293,rs17847825,rs2230460,rs28763991,rs3173908 and rs4727666 loci,no significant association was found between the nine SNP and increased PP(P>0.05).According to AIC,the optimal genetic model for rs17398575 and rs17477177 loci was additive model.3.The association between haplotypes of SNP loci of PIK3CG gene and increased PP Two haplotype domains were defined by using Haploview 4.2 software for linkage disequilibrium analysis,rs17398575 and rs17477177 are located in block 1;rs4727666,rs17847825,rs1129293,rs28763991,rs2230460 and rs3173908 are in haplotype block 2.The results of haplotype analysis showed that there was no statistically significant difference in the haplotype frequency distribution between the increased PP group and the normal PP group(P>0.05).4.Correlation between SNP locus of PIK3CG gene and increased PP Univariate logistic regression analysis showed that PIK3CG gene score(OR=1.78,95%CI:1.02-3.12,P=0.043)was positively correlated with increased PP.After adjusting for age,sex,obesity,education level,hyperlipidemia,diabetes,smoking status,alcohol status,and recreational physical activity,the positive correlation between PIK3CG gene score(OR=2.22,95%CI:1.19-4.16,P=0.013)was still positively associated with increased PP.5.Interaction of PIK3CG gene score and environmental factors(such as age,obesity and dyslipidemia)on increased PP Analysis of the interaction between the weighted gene fraction of each PIK3CG SNP and environmental factors(such as age,obesity,hyperlipidemia)showed that there was no statistical significance in both multiplication and additive models(P>0.05).6.Dominance analysis According to the weight of standardized advantage,the influencing factors of increased PP were obesity(30.20%),diabetes(28.98%),education level(18.73%),hyperlipidemia(5.59%),drinking status(4.81%),leisure physical activity(4.27%),PIK3CG gene score(3.28%),age(3.16%),sex(0.57%)and smoking status(0.42%).Conclusion:(1)PIK3CG gene rs17398575 and rs17477177 affect the genetic susceptibility to increased PP,suggesting that PIK3CG gene variation was related to increased PP.No association were found between rs12667819,rs1129293,rs17847825,rs2230460,rs28763991,rs3173908 and rs4727666 locus and increased PP under five genetic models;(2)PIK3CG gene score was associated with increased PP.The higher the score,the higher the risk of increased PP;(3)Compared with other factors,obesity and diabetes were the main factors that affect increased PP;(4)No interaction was found between PIK3CG gene score and age,obesity and hyperlipidemia on increased PP.