Genetic Variants in the Leptin, Leptin Receptor and FTO Genes in Obese Pakistani Population

Abstract

Obesity is a global public health problem of 21 st century. Recent surveys show that the incidence of obesity has reached epidemic proportions in the world and its rate is increasing both in children and adults. It is a multi-factorial and heterogeneous condition due to complex interaction between genetic, behavioral and environmental factors. Recent reports suggest that the genetic factors play an important role in the development of obesity. A number of genetic variants in different genes have been reported to be associated with obesity in various populations. The current study was carried out to gain an insight into the role of fat mass and obesity associated gene (FTO), leptin receptor (LEPR) and leptin (LEP) gene variants in the pathophysiology of obesity in local population. A total of 394 subjects (obese=239, BMI ≥30Kg/m 2 or 95 th percentile and non-obese=155, BMI<25Kg/m 2 or 5 th -85 th percentile) between 5-45yrs of age were analyzed for Q223R, G2548A and rs9939609 variants of LEPR, LEP and FTO genes respectively, and their association with anthropometric and metabolic parameters was determined. Body weight, height, waist and hip circumference and blood pressure (BP) were measured, BMI and Waist Hip Ratio (WHR) were determined. Fasting blood glucose (FBG), insulin, leptin and leptin receptors were measured in duplicate using ELISA and HOMA-IR was calculated. DNA was extracted from the whole blood; genotyping of the polymorphisms were carried out by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Data were analyzed using SPSS version 17; parameters were compared using t-test, one way ANOVA, Tukey post hoc test, Pearson test, Chi-square test, general linear model (GLM) multivariate analysis and Hardy Weinberg equilibrium test. In the present study LEP G2548A polymorphism was found to be associated with obesity in female children and adolescents (≤18years of age). Female children and adolescents carrying G allele of G2548A polymorphism were found to have 2.23 times increased risk of obesity in (95% CI=1.07–4.63). G allele of G2548A polymorphism was found to be associated with increased body weight, height, BMI, hip circumference, WHR, HOMA-IR, plasma insulin and leptin levels. No significant difference was found in genotype and allele frequencies of LEPR Q223R polymorphism between obese and non obese subjects. No association of LEPR Q223R polymorphism was observed with any of the anthropometric and metabolic traits related to obesity. FTO rs9939609 variant was found to be associated with obesity in adult females (>18years of age). Women carrying A allele of this polymorphism were found to have 2.81 times increased risk of obesity (95% CI=1.31-6.04). A allele was found to be xiiiassociated with increase in body weight, BMI, waist and hip circumference, WHR, BP, FBG, HOMA-IR, plasma insulin and leptin levels and decrease in leptin receptor levels. LEP (G2548A) variant is an important predictor for increased plasma leptin and BMI among female children and adolescents. FTO (rs9939609) variant is associated with BMI and risk of obesity in adult females, carrier of A allele had higher FBG, HOMA-IR and leptin levels independent of BMI.