Association study of leptin receptor polymorphisms in women with obesity and their impact on protein domains: a case-control study and in silico analyses

Leptin receptor (LEPR) is a member of the class I cytokine receptor family that receives and transmits leptin signals. It is primarily involved in the regulation of energy expenditure and food intake. This study aimed to evaluate the association of LEPR gene polymorphisms, Lys109Arg, Gln223Arg and Lys656Asn, with obesity in Moroccan women and to explore the structural and functional consequences of these SNPs. The variants were genotyped using the Sanger sequencing method. The three-dimensional structures of LEPR extracellular domains were determined using a template-based tertiary structure modeling web server and the protein variants were generated using in silico mutagenesis. The amino acids conservation analysis in the variants region was performed based on a protein's evolutionary profile. The molecular dynamics simulations of the wild-types and variants N-terminal, cytokine receptor homology I and fibronectin type III domains of LEPR protein were performed to investigate their impact on the domain structures. We identified that only Lys656Asn polymorphism is associated with obesity in Moroccan women (P = 0.024). In silico analyses revealed that Lys109, Gln223 and Lys656 are exposed residues and their substitution leads to changes in protein structure through loss or gain of hydrogen bonds and hydrophobic interactions. Lys656Asn increases the stability and decreased flexibility of the fibronectin type III domain. Lys109Arg highly decreases the stability and increases flexibility and the overall dimension of N-terminal and cytokine receptor homology I domains. Gln223Arg increases the stability and the compaction level of these domains. These results provide insight into the involvement of LEPR variants in obesity development. Communicated by Ramaswamy H. Sarma