Association Of GPCR Signaling Pathway Gene Variation With Obesity

Objective:Obesity is a worldwide epidemic.As a complex disease with multifactorical pathology,obesity is affected by both genetic factors and environmental factors,in which genetic factors play an important role.Recently,our body mass index(BMI)-waist-hip ratio(WHR)bivariate genome wide association study(GWAS)found that G protein-coupled receptor(GPCR)signaling pathway genes were associated with obesity in Northern Han Chinese adults.In this study,we aimed to further estimate the association of GPCR signaling pathway gene variation with obesity,and to examine the interaction between gene variants and environment factors in Shandong Han adults.The results will help to identify the underlying pathogenesis of obesity and provide a theoretical basis for the control of obesity.Methods:The study was designed as a case-control study based on community population in Jiaozhou city,Qingdao.Inclusion criteria:(1)ethnic Han permanent residents of Shandong nationality without blood relationship;(2)for obesity subjects,BMI≥28 kg/m2 and WHR≥0.85 for women and≥0.9 in men and for controls,BMI 18.5≤BMI<24 kg/m2 and WHR<0.85 for women and<0.9 for men.Exclusion criteria:people with a history of physical disabilities,severe mental disease,or other major diseases(such as heart failure,kidney failure,cancer,aplastic anemia,etc.);pregnant and lactating women;people who had taken weight-loss drugs in the past year.According to the candidate gene selection method,5 GPCR signaling pathway genes(GLP-1R,GPR55,DGKB,HRH2,CCK)from the previous BMI-WHR bivariate GWAS results were selected.According to the single nucleotide polymorphisms(SNPs)selection method,55 SNPs in 5 genes were selected.Logistic regression analysis was used to explore the relationship between genotype and obesity under five genetic models,including codominant,additive,dominant,recessive and overdominan model.Weighted genetic score method was employed to calculated GPCR signaling pathway gene score.Logistic regression analysis was used to investigate the association of gene scores with obesity,and multiplicative and additive model interaction analysis was used to evaluate the interaction between gene scores and environmental factors(smoking,alcohol drinking,leisure physical activity)on obesity.Results:After screening,301 cases and 307 controls were included in the study.1.Association of single SNP of GPCR signaling pathway gene with obesity(1)GLP-1R rs1820:under codominant model(TT vs AT),compared with TT genotype,people with AT genotype had a lower possibility to be portly(OR=0.476,95%CI:0.288-0.787);under additive model(TT vs AT vs AA),OR=0.487,95%CI:0.305-0.777;under domiant model[TT vs(AT+AA)],compared with TT genotype,people with(AT+AA)genotype had a lower possibility to be portly(OR=0.467,95%CI:0.285-0.764);under overdomiant model[(TT+AA)vs AT],compared with(TT+AA)genotype,people with AT genotype had a lower possibility to be portly(OR=0.480,95%CI:0.290-0.793).After adjusting for age,gender,smoking,acohol drinking,and leisure physical activity,the correlations between rs1820 and obesity were still statistically significant.(2)GLP-1R rs4714211:under additive model(AA vs AG vs GG),the SNP was associated with obesity(OR=0.790,95%CI:0.628-0.994).In multivariate logistic regression analysis,the association between this SNP and obesity was no longer statistically significant(P>0.05).(3)DGKB rs976760:under codominant model(TT vs CC),compared with TT genotype,people with CC genotype had a lower possibility to be portly(OR=0.596,95%CI:0.361-0.984);under recessive model[(TT+CT)vs CC],compared with(TT+CT)genotype,people with CC genotype had a lower possibility to be portly(OR=0.592,95%CI:0.375-0.934).In multivariate logistic regression analysis,the association between this SNP and obesity was no longer statistically significant(P>0.05).(4)GPR55 rs1992188:under codominant model(GG vs TT),compared with GG genotype,people with TT genotype had a higher possibility to be portly(OR=2.361,95%CI:1.083-5.149);under additive model(GG vs GT vs TT),(OR=1.334,95%CI:1.015-1.752;under recessive model[(GG+GT)vs TT],compared with(TT+CT)genotype,people with TT genotype had a higher possibility to be portly(OR=2.220,95%CI:1.027-4.797).In multivariate logistic regression analysis,the association between this SNP and obesity was no longer statistically significant(P>0.05).(5)CCK rs8192473:multivariate logistic regression analysis of additive model(CC vs TC vs TT)showed that SNP was associated with obesity(OR=1.510,95%CI:1.034-2.204).2.Association of GPCRsignaling pathway gene scores with obesity Univariate logistic regression results showed that GLP-1R(OR=0.740,95%CI:0.601-0.942)and DGKB(OR=0.751,95%CI:0.624-0.903)gene score were negatively associated with obesity.After adjusting for confounding factors,the correlations between DGKB gene score and obesity were still statistically significant(OR=0.785,95%CI:0.642-0.960).In multivariate logistic regression analysis,CCK gene score was positively associated with obesity(OR=1.526,95%CI:1.101-2.115).The total gene score of GPCR signaling pathway was significantly correlated with obesity,and the results were statistically significant before and after adjusting confounding factors(crude(OR=1.240,95%CI:1.090-1.411;adjusted OR=1.238,95%CI:1.074-1.427).3.Interaction of GPCR signaling pathway gene score and environmental factors on obesity(1)multiplicative interaction:after adjusting for confounding factors,the OR and 95%CI of the GLP-1R gene score-smoking product term on a multiplicative scale were OR=1.773,95%CI:1.059-2.970,P=0.029,indicating a positive multipulicative interaction between GLP-1R gene score and smoking.Stratified analysis showed that among non-smokers,people with higher the GLP-1R gene score had a lower possibility to be portly(adjusted OR=0.707,95%CI:0.538-0.930).There was no multiplicative interaction between other gene scores and smoking(Pinteraction>0.05).No multiplicative interaction between GPCR signaling pathway gene scores and alcohol drinking or physical activity(Pinteraction>0.05).(2)additive interaction:after adjusting confounding factors,the relative excess risk due to interaction(RERI)and attributable proportion due to interaction(AP)between GLP-1R gene score and smoking were 0.425(95%CI:0.069-1.467)and 0.458(95%CI:0.053-0.783),respectively.The 95%CI of RERI and AP were greater than 0,indicating a positive additive interaction between GLP-1R gene score and smoking.There was no additive interaction between other gene scores and smoking.No additive interaction between GPCR signaling pathway gene scores and alcohol drinking or physical activity.Conclusion:GPCR signaling pathway gene variations were associated with obesity in Shandong Han adults.Smoking modified the genetic susceptibility to obesity.These findings could help to identify people at high risk of obesity,and thus to develop more professional and personalized obesity treatment.