Association Of Olfactory Signaling Pathway Gene Polymorphism With Obesity

Background:Obesity is a chronic complex disease that is influenced by both genetic and environmental factors,with genetic factors occupying an important position.Evidence from twin and family studies have indicated that the heritability of obesity related traits is as high as 40%-70%.Our previous bivariate genome-wide association study(GWAS)on body mass index(BMI)-waist hip ratio(WHR)in dizygotic twins found that the olfactory singnaling pathway genes were related to obesity in Northern Han Chinese.Accordingly,the purpose of this study was to confirm the connection between genetic polymorphism in olfactory signaling pathway and obesity in populations with the same genetic background,and to explore the impact of gene-gene interactions on obesity.The research results will be helpful to identify the genetic mechanisms underlying obesity and give a theoretical framework for the prevention and management of obesity.Methods:During the 2019-2021,a case-control study was performed based on community population,in Jiaozhou city,Qingdao.According to the inclusion and exclusion criteria,301 obesity individuals(BMI≥28 kg/m~2 and WHR≥0.85 for women and≥0.9 for men)were included in the case group and 307 individuals with normal BMI and WHR(18.5≤BMI<24 kg/m~2 and WHR<0.85 for women and<0.9 for men)were included in the control group.Seven olfactory signaling pathway genes(OR2AK2,OR2L8,OR4D1,OR52K1,OR52K2,CALML3 and CLCA2)from the previous bivariate GWAS results were selected for research.Based on the selection principle of single nucleotide polymorphisms(SNPs),29 SNPs were selected from these 7 genes.The univariate and multivariate logistic regression analysis were employed to examine the link between genotype and obesity after constructing five genetic models,including codominant,additive,dominant,recessive and overdominan.Through linkage disequilibrium(LD)and haplotype analysis,we examined whether there was a strong LD relationship between SNPs,and constructed haplotype domains to explore the association between each haplotype and obesity.The weighted genetic score of each gene and the pathway were calculated.The relationship between gene scores and obesity was investigated utilizing logistic regression analysis.To address the issue of multiple tests in logistic regression analysis,the Benjamini-Hochberg false discovery rate(FDR)was used for correction.Classification and regression tree(CART)analysis was conducted to investigate the possible influence of gene-gene interactions in olfactory signaling pathway on obesity.Results:1.Association of single SNP of olfactory signaling pathway gene with obesity:After correcting with Benjamini-Hochberg’s false discovery rate(FDR),in the multivariate logistic regression model using age,sex,smoking,drinking and physical activity as adjusting variables,(1)the rs8071251,rs7218964 and rs1075009 of OR4D1 can increase the risk of obesity under three genetic models of codominance,dominance and overdominan(OR:1.675-1.869,P:0.003-0.006,FDR:0.028-0.042).The rs9908511 had a correlation with a higher risk of obesity under two genetic models of dominance and overdominan(OR:1.648-1.714,P:0.008-0.011,FDR:0.039-0.042).(2)The rs4468345of OR52K1 can increase the risk of obesity under two genetic models of dominance and overdominan(OR:1.827-1.907,P:0.008-0.011,FDR:0.039-0.042).(3)The rs1131482of the CALML3 was associated with a lower risk of obesity in codominant,dominant and overdominan models(OR:0.546-0.625,P:0.002-0.009,FDR:0.034-0.042).The rs2231413 and rs1142825 can reduce the risk of obesity in the dominant(OR:0.581-0.620,P:0.005-0.010,FDR:0.034-0.039)model.2.Analysis of linkage disequilibrium(LD)and haplotype of olfactory signaling pathway genes:(1)There were two groups of strong LD in six SNPs of the CALML3 gene on chromosome 10,between rs2231413 and rs1142825,and between rs4589189,rs4589188.A haplotype region was constructed.After 1000 substitution tests,the distribution frequency of GAGG haplotypes between the obesity group and the control group differed significantly(X~2=10.308,P=0.005).(2)There was a group of strong LD in four SNPs of OR4D1 on chromosome 17,between rs1075009,rs9908511,rs8071251 and rs7218964.These four SNPs constructed a haplotype region.After 1000 substitution tests,the distribution difference of ACAA haplotypes(X~2=6.958,P=0.026)between the two groups was statistically significant.3.Correlation of olfactory signaling pathway gene score and obesity:After FDR correction,univariate logistic regression showed that OR4D1 gene score was positively linked with obesity(OR=1.592,95%CI=1.155-2.193,FDR=0.014),while CALML3 gene score was negatively correlated with obesity(OR=0.560,95%CI=0.393-0.796,FDR=0.007).The results were significant even after adjusting for covariates(OR4D1:OR=1.546,95%CI=1.094-2.185,FDR=0.049;CALML3:OR=0.596,95%CI=0.407-0.875,FDR=0.049).In addition,in multivariate logistic regression analysis,after FDR correction,OR52K1 gene score was positively correlated with obesity(OR=1.441,95%CI=1.058-1.964,FDR=0.049).The total gene score for all the SNPs in the olfactory pathway was significantly correlated with obesity in both univariate(OR=0.660,95%CI=0.555-0.785,P<0.001)and multivariate(OR=0.674,95%CI=0.560-0.811,P<0.001)logistic regression.4.The effect of gene-gene interaction on obesity in olfactory signaling pathways:CART analysis results indicated that the interaction between OR4D1 rs1075009,OR52K1rs4468345 and OR2AK2 rs10788748 was associated with obesity in adults.Compared to the individuals with the OR4D1rs1075009(GG)-OR52K1rs4468345(AA/GG)-OR2AK2rs10788748(CC/TT)genotype,individuals with the OR4D1rs1075009(GA/AA)-CALML3rs2231413(GG)genotype had the highest risk of obesity(OR=6.936,95%CI=3.072-15.660,P<0.001).Conclusion:Genetic polymorphism in the olfactory signaling pathway were associated with obesity in Northern Han Chinese.The interaction between olfactory pathway genes affected the risk of obesity.Our research results deeply revealed the relationship between genotype and obesity phenotype,helping to identify high-risk groups of obesity,and supplying a theoretical framework for formulating targeted obesity management plans.