Association Analysis Of The Variants In Genes Of The Leptin-melanocortin Pathway With Obesity Risk In Children And Adolescents

Objectives1.To analysis the association between eating and lifestyle behavior with obesity in children and adolescents;2.To evaluate the association of the variants in genes(LEP,LEPR,POMC,NPY,MC3 R and MC4R)of the Leptin-Melanocortin pathway with obesity risk in children and adolescents;3.To explore the potential gene-gene or gene-environment interactions in the-correlation to obesity in children and adolescents.MethodsA frequency-matched case-control study was conducted based on the regular physical monitoring for primary and middle school students in Guangzhou.Between June 2016 and June 2017,1123 obesity were enrolled.1231 normal weight children,frequency-matched to the obesity on school,grade and gender,were selected at the same time.We selected 12 potential functional variants(LEP rs1349419 and rs2167270,LEPR rs11208659,rs1137100 and rs1137101,POMC rs6713532,NPY rs16141,MC3 R rs6127698 and rs3746619,MC4 R rs17782313,rs12970134 and rs8087522)in genes of the Leptin-Melanocortin pathway,using bioinformatical approache.The multivariable logistic regression was used to evaluate the association between the eating and lifestyle behaviors,variants and obesity risk in children and adolescents.Also calculated false positive report probabilities(FPRP)for multiple hypothesis testing.Simple genetic risk score(GRS)were used to evaluate the combined effect of variants on the risk of obesity.Classification and regression tree(CART)method was used to analyse multivariable genegene or gene-environment interactions.Further,based on the crossover analysis,the relative excess risk due to interaction(RERI)and the attributable proportion of interaction(API)indices were used to measure the additive interaction between two factors,and the interaction of OR index(IOR)was applied to assess the multiplicative interaction.Results1.Good appetite(OR=2.23,95% CI=1.88~2.64),eating time <10min(OR=1.46,95% CI=1.11~1.93),and screen time ?2 h/d(OR=1.24,95% CI= 1.03~1.50)were showed to associated with the increased risk of obesity in children and adolescent.2.On the FPRP<0.50 standard,MC4 R rs17782313 was significantly associated with obesity in children and adolescents after adjusting for grade,gender,appetite,eating time and screen time.MC4 R rs17782313 CT genotype had an OR of 1.37(95% CI=1.13~1.65,FPRP=0.010)compared with the CC genotype.Analysis with pooled rs17782313 CT and TT genotypes had an OR of 1.37(95% CI=1.15~1.64,FPRP=0.006)compared with the CC genotype,suggesting a dominant effect of rs17782313.Further,the rs17782313 was associated with increased risk of obesity in additive model(OR=1.29,95%CI= 1.11~1.50,FPRP=0.009).MC4 R rs12970134 AG genotype had an OR of 1.23(95% CI=1.02~1.49,FPRP=0.240)compared with the GG genotype.MC4 R rs12970134 was significant associated with increased risk of obesity in dominant and additive models(OR=1.27,95% CI=1.06~1.52,FPRP=0.078;OR=1.27,95% CI=1.07~1.45,FPRP=0.004).The C allele at MC4 R rs17782313 and A allele at MC4 R rs12970134 were positively associated with the risk of obesity in children and adolescent respectively(OR=1.30,95% CI= 1.11~1.51,FPRP=0.005;OR=1.25,95% CI=1.07~ 1.46,FPRP=0.042).CAG haplotype constructed by MC4 R rs17782313,rs12970134 and rs8087522 was associated with the risk of obesity(OR=1.35,95% CI=1.13~1.62,FPRP= 0.013).3.In completed Leptin-Melanocortin pathway,compared with children whose GRSs 5~8,children with GRSs 16~19 had higher risk for obesity with an OR 2.19(95% CI=1.26~3.79).In negative feedback regulation pathway with POMC variant,compared with children whose GRSs 5~7,children with GRSs 14~17 had higher risk for obesity with an OR 2.19(95% CI=1.38~3.48).In positive feedback regulation pathway with NPY variant,compared with children whose GRSs 5~7,children with GRSs 15~18 had higher risk for obesity with an OR 2.28(95% CI=1.21~4.29).4.In gene-gene interaction analysis,CART suggested that the interaction among MC4 R rs17782313,POMC rs6713532,LEPR rs1137101 and MC4 R rs12970134 may affect obesity in children and adolescents.On the FPRP<0.50 standard,based on crossover analysis,significant additive interaction was found between MC4 R rs17782313 and LEPR rs1137101(RERI=0.77,95% CI=0.05~1.50,FPRP=0.332;API=0.39,95% CI=0.13~0.65,FPRP=0.044).Similarly,significant additive interaction was found between MC4 R rs12970134 and LEPR rs1137101(RERI=0.70,95% CI=0.03~1.38,FPRP= 0.367;API=0.38,95% CI=0.11~0.65,FPRP=0.065).5.In gene-environment interaction analysis,CART suggested that the interaction among appetite,physical exercise and LEPR rs1137100 may affect obesity in children and adolescents.On the FPRP<0.50 standard,significant additive interaction was found between appetite and LEPR rs1137100(RERI= 0.79,95% CI=0.12~1.48,FPRP=0.257;API=0.30,95% CI=0.09~0.50,FPRP= 0.070).Conclusions1.Good appetite,eating fast and high screen time are the risk factors for obesity in children and adolescents;2.MC4 R rs17782313 and rs12970134 are the most important genetic variants in Leptin-Melanocortin pathway for susceptibility to obesity;3.Combined effect of the genetic variants in Leptin-Melanocortin pathway are associated with obesity in children and adolescents;4.MC4 R rs17782313 and rs12970134 respectively coordinates with rs1137101 in LEPR on obesity.Furthermore,LEPR rs1137100 coordinates with appetite for obesity in children and adolescents.