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<p>Genetic and epigenetic alterations have been shown to influence the global burden of obesity significantly. Single-nucleotide polymorphisms (SNPs), including both coding and non-coding amino acid changes, are the key regulators of the protein structural and functional modifications. The current computational study utilizes in silico techniques focused on the screening and identification of the most pathogenic missense SNPs of the selected candidate genes of the leptin-melanocortin and adiponectin signaling pathways, and validating their significance in accelerating obesity. Gene-network analysis was created using the STRING database to identify the genes involved in the targeted pathways. A total of 4228 missense SNPs from 12 candidate genes were extracted from the NCBI database, followed by pathogenicity prediction using seven servers: SIFT, PANTHER, Meta-SNP, PhD-SNP, PredictSNP, PolyPhen-2, and SNAP2. The shortlisted variants (n = 458) were analyzed for structural stability using DynaMut, iMutant, INPS3D, MuPro, and iStable, followed by functional stability analysis (n = 153) using Mut-Pred2 and Project HOPE. Seven variants, viz. <i>ADIPOQ</i> (rs182223755), <i>ADIPOR1</i> (rs766267373), <i>ADIPOR2</i> (rs775795062), <i>PPARG</i> (rs777103332), <i>PRKAA2</i> (rs2100428068), and <i>AGRP</i> (rs767874407 and rs1392000625) were predicted in the study to be the most pathogenic among the twelve screened highest pathogenic variants, resulting in altered protein functionality but not reported to be significant in any population so far. Rather, the variants of <i>LEP</i> (rs28954113) and <i>POMC</i> (rs150343979, rs28932472, and rs149540566) frequently present in African and European populations, gained more significance. rs1801282 (<i>PPARG</i>) with reported clinical significance was observed in the obese male case study in our urban Indian study population. The observed variants were minimally pathogenic, with moderate VEP impact and a low CADD PHRED score. Epigenetic modifications, including promoter DNA methylation, HAT-HDAC activities, and histone acetylation, were largely responsible for the manifestation of obesity in our population. Therapeutic strategies, including precision medicine formulated based on early pathogenicity predictions derived from in silico analyses and in vivo-in vitro validation, may open a new frontier in evidence-based policy-making, ultimately contributing to more effective control of disease prevalence. This article aligns with SDG—3 (Good Health and Well-Being) of the UN Agenda for Sustainable Development.</p>

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Predictive analysis of the leptin-melanocortin and adiponectin signaling pathways in obesity through in silico techniques

  • 期刊论文

  • 发表日期：

    2026年4月2日

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  • Sunandini Ghosh,
  • Shrinjana Dhar,
  • Ushasi Roy,
  • Sayan Mondal,
  • Pritha Bhattacharjee

摘要

Genetic and epigenetic alterations have been shown to influence the global burden of obesity significantly. Single-nucleotide polymorphisms (SNPs), including both coding and non-coding amino acid changes, are the key regulators of the protein structural and functional modifications. The current computational study utilizes in silico techniques focused on the screening and identification of the most pathogenic missense SNPs of the selected candidate genes of the leptin-melanocortin and adiponectin signaling pathways, and validating their significance in accelerating obesity. Gene-network analysis was created using the STRING database to identify the genes involved in the targeted pathways. A total of 4228 missense SNPs from 12 candidate genes were extracted from the NCBI database, followed by pathogenicity prediction using seven servers: SIFT, PANTHER, Meta-SNP, PhD-SNP, PredictSNP, PolyPhen-2, and SNAP2. The shortlisted variants (n = 458) were analyzed for structural stability using DynaMut, iMutant, INPS3D, MuPro, and iStable, followed by functional stability analysis (n = 153) using Mut-Pred2 and Project HOPE. Seven variants, viz. ADIPOQ (rs182223755), ADIPOR1 (rs766267373), ADIPOR2 (rs775795062), PPARG (rs777103332), PRKAA2 (rs2100428068), and AGRP (rs767874407 and rs1392000625) were predicted in the study to be the most pathogenic among the twelve screened highest pathogenic variants, resulting in altered protein functionality but not reported to be significant in any population so far. Rather, the variants of LEP (rs28954113) and POMC (rs150343979, rs28932472, and rs149540566) frequently present in African and European populations, gained more significance. rs1801282 (PPARG) with reported clinical significance was observed in the obese male case study in our urban Indian study population. The observed variants were minimally pathogenic, with moderate VEP impact and a low CADD PHRED score. Epigenetic modifications, including promoter DNA methylation, HAT-HDAC activities, and histone acetylation, were largely responsible for the manifestation of obesity in our population. Therapeutic strategies, including precision medicine formulated based on early pathogenicity predictions derived from in silico analyses and in vivo-in vitro validation, may open a new frontier in evidence-based policy-making, ultimately contributing to more effective control of disease prevalence. This article aligns with SDG—3 (Good Health and Well-Being) of the UN Agenda for Sustainable Development.