Association Of Genetic Variations Of RPGRIP1L,FTO,IRXB Family And Their Interactions With Obesity Among Children And Adolescents

ObjectiveThis study aimed to analyze the association of RPGRIP1L,IRX5,IRX6genetic variations and environmental factors with obesity among children and adolescents;To explore the effects of gene-gene,gene-environment interactions among RPGRIP1L,FTO,IRX3,IRX5,IRX6 and environmental factors on childhood and adolescent obesity.MethodsBased on the Health Promotion Center for Primary and Middle Schools in Guangzhou,a total of 20076 students from primary school second grade,middle school first grade and high grade were examined among 39 primary and middle schools in Guangzhou City from June 2016 to June 2017.A case-control study was designed to include 1123 obese students as the case group.1246 normal-weight students were selected as the control group by school,gender and grade.When the association analysis was conducted,the case group were divided into general obesity and severe obesity.Epidemiological investigation was used to collect information on diet,exercise,etc.of the research subjects;A variety of bioinformatics tools and previous literature reports were used to screen for potential functional genetic variations;TaqMan Real-Time PCR was used to detect the genotypes.Unconditional logistic regression was used to analyze the association between environmental factors,single genetic variation and obesity;Genetic risk scores were used to analyze the association between cumulative effects of genetic variations and obesity;Random forest models and logistic regression were used to explore gene-gene,gene-environment interactions;Multiple corrections were made with false positive report probability or false discovery rate.ResultsAssociation analysis of environmental factors showed that good appetite?OR=2.25,95%CI=1.88-2.69?and the consumption of sugar-sweetened beverages?500ml/week?OR=1.40,95%CI=1.15-1.71?were risk factors for obesity;While eating rate?10 minutes/meal?OR=0.72,95%CI=0.54-0.95?,breakfast?3 times/week?OR=0.62,95%CI=0.41-0.94?,milk intake?3times/week?OR=0.74,95%CI=0.61-0.90?,medium and high intensity exercise time?1 hour/day?OR=0.77,95%CI=0.59-1.00?were protective factors for obesity.Single-variant association analysis showed that IRX6 rs79823687 AT genotype and dominant model increased the risk of obesity?AT:OR=1.30,95%CI=1.01-1.68;dominant model:OR=1.30,95%CI=1.01-1.67?,after multiple corrections,the results were statistically significant only when the prior probability=0.25 or 0.1.Random forest analysis showed,two models suggested IRX3 rs3751723,IRX6 rs9888978,FTO rs9939609,RPGRIP1L rs1421092,IRX6 rs59283668and FTO rs16952522;appetite,IRX3 rs3751723,IRX6 rs9888978,FTO rs9939609,RPGRIP1L rs6499632,RPGRIP1L rs1421092,IRX6 rs59283668?RPGRIP1L rs2302677,sugar-sweetened beverages intake,milk intake and RPGRIP1L rs4133017;there may be interactions between them,were key factors related to obesity.Association analysis between genetic risk score and obesity showed,the higher the score of GRS?IRX6 rs79823687+FTO rs16952522+rs9939609?,the greater the risk of obesity and severe obesity?severe obesity:OR=1.46,95%CI=1.24-1.72?;When GRS?RPGRIP1L_IRX5_IRX6?score is higher,the risk of severe obesity can be increased?OR=2.20,95%CI=1.10-4.39?.The results of gene-gene interactions showed that IRX3 rs3751723 and FTO rs9939609,FTO rs16952522 respectively had multiplicative and additive interactions associated with severe obesity(with FTO rs9939609:P_mult=0.043,P_add=0.027;with FTO rs16952522:P_mult=0.008,P_add=0.002).Results were still statistically significant after multiple corrections.The results of gene-environment interactions showed that IRX6rs79823687 and eating rate had multiplicative effect on severe obesity(P_mult=0.009),RPGRIP1L rs4133017 and appetite had multiplicative and additive interactions on severe obesity(P_mult=0.025,P_add=0.020),the cumulative effect of RPGRIP1L_IRX5_IRX6 genetic variation and milk intake had additive interactions with severe obesity(P_add=0.002).Results were still statistically significant after multiple corrections.ConclusionsThe interaction between IRX3 rs3751723 and FTO rs9939609,FTO rs16952522 respectively,the interaction between IRX6 rs79823687 and fast eating rate,the interaction between RPGRIP1L rs4133017 and good appetite could increase the risk of severe obesity among children and adolescents;More intake of milk could reduce the risk of severe obesity in individuals with high risk of RPGRIP1L_IRX5_IRX6;RPGRIP1L_FTO_IRX3_IRX5_IRX6 were genetic predisposition area for childhood and adolescent obesity and should be highly valued.