Association Between ADAMTS8 Gene Polymorphism And Elevated Pulse Pressure

Objective: In this study,the ADAM metallopeptidase with thrombospondin type 1 motif 8(ADAMTS8)gene was used as the target gene.To explore the association between ADAMTS8 gene variation and elevated pulse pressure,the research results can provide scientific basis for controlling ideal pulse pressure,preventing and reducing the occurrence of cardiovascular and cerebrovascular diseases.Methods: In this study,with Qingdao community residents aged 30 years and older,stratified random sampling was performed,and a case-control study design method was used.We select rs2131535,rs2242312,rs2291348,rs35468629 and rs7927048 of ADAMTS8 gene as label SNP.Pulse pressure ≥65mm Hg was defined as high pulse pressure group,30 mm Hg≤ pulse pressure ≤45mm Hg and systolic/diastolic blood pressure ≤120/80 mm Hg were defined as normal pulse pressure group.Chi-square test was used to compare the frequency distribution of alleles and genotypes of the five SNPs between the two groups.Logistic regression method was used to calculate the odds ratio of rs2131535,rs2242312,rs2291348,rs35468629 and rs7927048 in the five genetic models of codominant,additive,dominant,recessive and overdominant and 95% Confidence Interval(CI),and evaluate the association between ADAMTS8 gene and elevated pulse pressure.The haplotype domain was defined by linkage disequilibrium analysis,and the distribution of haplotype frequency between the elevated pulse pressure group and the control group was compared by χ2 test.Weighted gene scores were calculated for rs2131535,rs2242312,rs2291348,rs35468629 and rs7927048 to further explore the association between total genetic variation of ADAMTS8 gene and elevated pulse pressure.The effects of the interaction between ADAMTS8 gene score and environmental factors on elevated pulse pressure were investigated by multiplying and adding interaction models.Dominance analysis was used to explore the contribution of influencing factors to elevated pulse pressure.Results: A total of 768 subjects were included in this study,including 377 in the high pulse pressure group and 391 in the control group.1.Analysis of the basic characteristics of the research objects The difference in the distribution of Age(t=-3.341,P < 0.05),obesity(χ2=64.438,P < 0.05),education level(χ2=33.016,P < 0.05),monthly income(χ2=18.623,P < 0.05),leisure physical activity(χ2=6.894,P < 0.05),diabetes mellitus(χ2=56.546,P < 0.05),hyperlipidemia(χ2=18.497,P < 0.05)and alcohol consumption(χ2=10.680,P < 0.05)were statistically significant between the groups.There was no statistically significant difference in the distribution between gender(χ2=0.006,P> 0.05)and smoking status(χ2=0.003,P> 0.05).2.Hardy-Weinberg Equilibrium Hardy-Weinberg Equilibrium test was performed on 5 SNPs of ADAMTS8 gene in control pulse pressure group,except rs35468629,the others were consistent with Hardy-Weinberg equilibrium.3.Comparison of genotype and allele frequency distribution of five SNPs of ADAMTS8 gene between the two groups The genotype frequency of rs2131535 、rs2242312 、 rs2291348 、 rs35468629 and rs7927048 of ADAMTS8 gene showed no statistically significant difference between the group with elevated pulse pressure and the control pulse pressure group(χ2=2.980,0.959,1.103,4.855,0.732,P>0.05).Allele frequency distribution of five SNPs of ADAMTS8 gene was compared between the two groups,rs7927048(χ2=4.075,P < 0.05)was statistically significantly different between the two groups,rs2131535(χ2=2.919,P>0.05)、rs2242312(χ2=0.175,P>0.05)、rs2291348(χ2=1.069,P>0.05)and rs35468629(χ2=4.075,P>0.05)were no statistically significant difference in the distribution between the two groups(χ2=2.919,0.175,1.069,4.796,P>0.05).4.Association between SNPs locus of ADAMTS8 gene and elevated pulse pressure After adjusting for age,sex,obesity,education level,monthly income,leisure physical activity,diabetes,hyperlipidemia,smoking and drinking,multivariate logistic regression analysis showed that:(1)rs2131535 Under the codominant model(AG vs AA,OR=1.58,95%CI: 1.06-2.38,P<0.05),dominant model [(AG+GG)vs AA,OR=1.43,95CI:1.01-2.03,P<0.05)] and additive model(AA vs AG vs GG,OR=1.39,95%CI: 1.02-1.90,P<0.05),the locus variation was statistically significantly associated with elevated pulse pressure.Under codominant(GG vs AA,OR=2.07,95%CI: 0.80-5.33),recessive [GG vs(AA+AG),OR=1.85,95%CI:0.73-4.72] and overdominant model [AG vs(AA+GG),OR=1.31,95%CI:0.91-1.88],there was no significant correlation between this locus and elevated pulse pressure(P > 0.05).(2)rs35468629 Under the codominant model(CG vs CC,OR=1.60,95%CI: 1.01-2.53,P<0.05)and additive model(CC vs CG vs GG,OR=1.69,95%CI: 1.07-2.66,P<0.05)the locus variation was statistically significantly associated with elevated pulse pressure.Under dominant model [(CG+GG)vs CC,OR=1.25,95%CI:0.73-2.15] and overdominant model [CG vs(CC+GG),OR=1.14,95%CI: 0.67-1.94],there was no significant correlation between this locus and elevated pulse pressure(P > 0.05).(3)rs2242312、rs2291348 and rs7927048 Under the five models of codominant,additive,dominant,recessive and overdominant,there was no statistically significant association between these locus and increased pulse pressure.5.Linkage disequilibrium and haplotype analysis A haplotype domain was defined in this study,which was covered by rs2242312 and rs2131535.Results of haplotype analysis showed that there was no statistically significant difference in haplotype frequency distribution between the control group and the group with elevated pulse pressure(χ2=1.12,2.889,0.178,P > 0.05).6.Association of ADAMTS8 gene score with elevated pulse pressure Univariate logistic regression analysis showed that ADAMTS8 gene score was significantly associated with elevated pulse pressure(OR=2.18,95%CI: 1.22-3.19,P<0.05).After adjusting for age,sex,obesity,education level,monthly income,leisure physical activity,diabetes,hyperlipidemia,smoking status,and alcohol consumption,the association between gene score and elevated pulse pressure remained statistically significant(OR=2.18,95%CI:1.07-4.45,P<0.05).7.Analysis of the influence of the interaction between ADAMTS8 gene score and age,sex,obesity and hyperlipidemia on elevated pulse pressure After adjusting for all of the covariates,There was no multiplicative interaction between ADAMTS8 gene score and age,sex,obesity or hyperlipidemia(P >0.05).There was an additive interaction between the ADAMTS8 gene score and the sex(RERI=0.57,95%CI:0.42-12.37;AP=1.32,95%CI:0.04-116.89),statistically significant,and a positive additive interaction.The additive interaction of gene score with age,obesity,and hyperlipidemia was not significant.8.Dominance analysis The results of the dominance analysis showed that the importance of elevated pulse pressure was obesity(29.98%),diabetes(24.63%),education level(14.45%),drinking status(10.11%),income level(6.09%),hyperlipidemia(5.56%),age(3.06%),genetic score(2.94%),physical activity(2.14%),gender(1.01%),smoking status(0.01%).Conclusion:(1)The rs2131535 and rs35468629 variation of ADAMTS8 was associated with elevated pulse pressure,rs2242312,rs2291348 and rs7927048 were not found to be associated with elevated pulse pressure;(2)Total genetic variants at the rs2131535,rs2242312,rs2291348,rs35468629,and rs7927048 of the ADAMTS8 gene,were associated with elevated pulse pressure,the higher the weighted gene score for the five locus,the higher the risk of elevated pulse pressure;(3)Compared with other factors included in this study,diabetes and obesity were the main factors affecting elevated pulse pressure;(4)There may be additive interaction between ADAMTS8 gene score and gender,ADAMTS8 gene variation increases the risk of elevated pulse pressure in females compared with males.