| BackgroundMetabolic syndrome(MetS)consists of a series of metabolic disorders related to the occurrence of cardiovascular disease(CVD).It is considered that rapid economic development and lifestyle changes contribute the prevalence of MetS in China.Recent survey revealed that the morbidity of MetS among Chinese population aged 20-70 years was up to 19.58%during 2016 to 2017,which impacted the health condition and living quality of residents of our country and increased the social economic burden.Genetic and environmental factors play a significant role in the incidence of MetS,while the pathogenesis of MetS is still unclear,resulting the deficiency of effective treatment measures.Recently,a large number of studies at home and abroad discovered genes associated with glycolipid metabolism were involved in the genesis and development of MetS.These results provided genetic guidlines to recognize susceptible population and take early preventions and treatments for MetS.MG53,located in human chromosome 16p11.2,encodes the synthesis of MG53 protein.MG53 is capable of suppressing the insulin signal pathway of skelete muscle to trigger insulin resistance,which is considered to be the critical foctor in pathogensis of MetS,as a consequence,we hypothesised that MG53 is one of the candidate genes of MetS.It is reported that there is a single nucleotide polymorphism(SNP)locus named rs7186832 on exon 3 of MG53 gene in Chinese Han population,which is likely to have an influence on the expression of MG53 and the SNP rs7186832 polymorphism of MG53 gene was associated with the risk of type 2 diabetes and impaired fasting glucose.However,whether there is association between SNP rs7186832 polymorphism of MG53 gene and MetS is still undefined.Individual response to treatments is affected by different genetic background.Therefore,it is meaningful to investigate the influence of SNP rs7186832 polymorphism of MG53 gene on efficacies of lifestyle interventions and drug therapy for MetS,which is beneficial to promote individual treatments for MetS.Objectives(1)To explore the association of SNP rs7186832 polymorphism of MG53 gene with the risk of MetS and its components;(2)To investigate the connection between SNP rs7186832 polymorphism of MG53 gene and longitudinal changes of MetS components during 5-year follow-up;(3)To evaluate the influence of SNP rs7186832 polymorphism of MG53 gene on the efficacies of lifestyle interventions and drug therapy for MetS.Study population and methodsParticipants in this study were Han Chinese recruited from Shandong Province from January to December of 2007.Totally 992 subjects with MetS and 1035 healthy controls were enrolled and 1003 subjects were involved in the 5-year follow-up study.The clinical data in 2007 and 2012 were collected for statistical analysis.According to NCBI HapMap database and previous literature,SNPs of MG53 gene located in non-intron region with minor allele frequency(MAF)>5%among Han Chinese in Beijing were selected,and SNP rs7186832 was determined in our study.SNP rs7186832 was genotyped by Sequenom MassARRAYY system containing several technique processes.Quantitative variables were expressed as mean± SD and compared by Student's t test or paired t test.Categorical variables were denoted by percentages and compared by Chi-square test.A one-way analysis of variance(ANOVA)was performed for more than two groups of data.Chi-square test for goodness-of-fit was adopted to calculate Hardy-Weinberg equilibrium for rs7186832.Multivariate logistic regression was performed to evaluate the association between the SNP genotype and risk factors of MetS and its components in different groups.The effects of SNP genotype on longitudinal variation of MetS components were evaluated by Multivariate logistic regression.The influence of SNP genotype on the efficacy of lifestyle interventions was analysied by Mann-Whitney U test.The relationship of SNP rs7186832 genotype with the efficacy of drugs was calculated by Multiple linear regression.SPSS ver.23.0 software was used for statistical analysis.Results(1)Comparison of clinical characteristics between control and MetS group in 2007:In the whole people,there was no statistical difference in male and age between control and MetS group(P>0.05).Compared with control group,BMI,WC,SBP,DBP,TG,TC,LDL-C and FPG increased significantly(P<0.001)in MetS group,while HDL-C and the proportion of somkers decreased(P<0.001).(2)Comparison of the frequencies of alleles and genotype between control and MetS group:The minor allele of SNP rs7186832 was C and MAF was 0.431.Genotype distributions in MetS group,control group and whole population all conformed to Hardy-Weinberg equilibrium.There is no difference in distribution of TT,TC and CC genotypes between control and MetS group(P=0.074).Compared with control group,the frequency of T allele decreased(79.1%vs.76.4%,P=0.037)and the frequency of C allele increased(20.9%vs.23.6%,P=0.037)in MetS group,indicating that C allele of SNP rs7186832 may be the risk factor of MetS.(3)Comparison of the frequency of alleles and genotype between normal and abnormal groups of MetS components:According to the diagnostic criterias of MetS component,the overall sample was divided into the normal WC group and the high WC group,the normal BP group and the hypertension group,the normal TG group and the high TG group,the normal HDL-C group and the low HDL-C group and the normal FPG group and the high FPG group.The difference in distribution of TT,TC and CC genotypes between participants with normal BP and raised BP was statistically significant(Normal BP:TT 61.2%,TC 34.8?,CC 4.1%;Hypertension:TT 61.2%,TC 32.0%,CC 6.8%,P=0.018).There is no difference in frequencies of T and C alleles between normal BP group and hypertension group(P=0.096).The distribution of TT,TC and CC genotypes showed a statistically significant difference between participants with normal FPG and raised FPG(Normal FPG:TT 62.6%,TC 32.1%,CC 5.2%;High FPG:TT 56.5%,TC 36.9%,CC 6.7%,P=0.047).In the high FPG group,the frequency of C allele increased(21.3%vs.25.2%,P=0.013)and the frequency of T allele decreased(78.7%vs.74.8%,P=0.013).The distribution of genotypes and alleles in the increased WC group,the elevated TG group and the decreased HDL-C group were not significantly different from those in corresponding normal groups.These results indicated that C allele of SNP rs7186832 was likely to be associated with hypertension and increased FPG.(4)The influence of SNP rs7186832 polymorphism on the risks of MetS and its components:In the whole population,CC genotype increased the risk of MetS(OR=1.525,95%CI:1.025-2.267,P=0.037)in co-dominant genetic model.In dominant genetic model,C allele carriers was at a higher risk of increased WC(OR=1.427,95%CI:1.032-1.973,P=0.032)and FPG(OR=1.283,95%CI:1.013-1.624,P=0.039).In recessive genetic model,CC genotype was the indepentdent risk factor of MetS(OR=1.493,95%CI:1.010-2.208,P=0.044).Among subjects with MetS,CC genotype was at a higher risk of increased FPG in co-dominant genetic model(OR=1.337,95%CI:1.006-1.778,P=0.046).The polymorphism of rs7186832 was irrelevant to hypertension,elevated TG and decreased HDL-C.These results showed that CC genotype of SNP rs7186832 was the independent risk factor for MetS and C allele was the independent predictor of increased WC and increased FPG.(5)The association of SNP rs7186832 polymorphism with longitudinal change of MetS components in participants without drug therapy of MetS:At the end of 5-year follow-up,there were 319 participants without drug therapy of MetS.Compared with the data in 2007,BMI,WC,HDL-C and LDL-C were reduced significantly(P<0.001)at the end of follow-up and the decreased DBP(P<0.05)was observed as well,while SBP increased(P<0.001).Among participants received no drug therapy of MetS,CC genotype was associated with a lower risk of elevated TG(OR=0.309,95%CI:0.097-0.977,P=0.046)in dominant genetic model.In recessive genetic model,CC genotype decreased the risk of elevated TG(OR=0.308,95%CI:0.099-0.964,P=0.043).The polymorphism of rs7186832 had no influence on the exacerbation of other MetS components.These results indicated CC genotype of SNP rs7186832 was the protective factor for elevated TG.(6)The influence of SNP rs7186832 polymorphism on the efficacies of lifestyle modifications and drug therapy:The efficacy of lifestyle interventions was showed by the variation of the number of MetS components.Among people under weight control,the reduction of the number of MetS components in C allele carriers was less than TT genotype carriers(P=0.014).Among peopole with regular exercise,the reduction of the number of MetS components in C allele carriers was less than TT genotype carriers(P=0.043).Neither in population with salt intake restriction or population under diet control,there was no significant difference in the changes of the number of MetS components between C allele carriers and TT genotype carriers.In participants with statin theropy during follow-up,C allele of SNP rs7186832 attenuated the degree of statins on lowering TC(?=0.330,P=0.007)and LDL-C(?=0.288,P=0.041)in co-dominant model.In dominant model,C allele attenuated the degree of statins on lowering LDL-C(?=0.268,P=0.030).In recessive model,C allele weakened the degree of statins on lowering TC(?=0.253,P=0.036)and LDL-C(?=0.275,P=0.042).The polymorphism of rs7186832 had no influence on the efficacy of antihypertensive drugs and metformin.The results suggested that C allele of SNP rs7186832 suppressed the efficacy of weight control and exercise,as well as the efficacy of statins on lowering TC and LDL-C.Conclusions(1)In Shandong Han population of China,CC genotype carriers of SNP rs7186832 of MG53 gene were susceptible to MetS.C allele carriers were at a higher risk to suffer from abdominal obesity and hyperglycemia.(2)CC genotype carriers of SNP rs7186832 were less likely to develop elevated TG.(3)C allele carriers of SNP rs7186832 acquired less benefit from weight control and exercise to improve MetS.(4)For C allele carriers of SNP rs7186832,the efficacy of statins on lowering TC and LDL-C was poorer. |
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