Precision Medicine in Obesity: Revealing the Role of SPON2 in Inflammation Through Gwas Analysis in Admixture Brazilian Population.

Abstract

Introduction: Obesity is recognized as a chronic condition with a multifactorial etiology, marked by persistent systemic low-level inflammation. Objectives: This study aims to explore and evaluate the role of genetic factors in predisposition to obesity within a diverse, mixed-race population. Methods: We conducted a Genome-Wide Association Study (GWAS) involving 1,036 individuals, comprising 333 eutrophic and 703 people with overweight, to pinpoint genetic variants linked to obesity. Genotyping was carried out using the MEGA chip by Illumina. Following this, imputation was performed using the CAAPA reference panel. We conducted in silico analyses using different platforms. Additionally, in a subset of 657 participants, we quantified levels of 11 cytokines (Eotaxin, IFNγ, IL-10, IL-6, IL-12, IL-13, IL-17A, IL-1β, IL-5, IL-8, and TNFα) in peripheral blood. We examined their relationship with the genotypes of the variants identified in the GWAS study. Results: We identified thirty-five variants that exhibited suggestive associations (5 x 10^-8 < p-value < 1 x 10^-5) with weight excess. Chromosome 4 harbored the main genes linked to this outcome (SPON2, RNF212, COL4A3, TMED11P and PCSK2) expressed in adipose tissue. Furthermore, we found a variant within the ZZEF1 gene on chromosome 17. Notably, variants such as rs10014526-T and rs77703123-T, in TMED11P displayed high linkage disequilibrium (LD) with variants in SPON2, rs75448245-G, rs11538062-T and rs75654334-T and in COL4A3, rs13419630-A, all negatively associated with the outcome. In contrast, the rs781851-G variant, in the ZZEF1 gene showed a positive association with the outcome. These polymorphic alleles were associated with variations in serum levels of the cytokines IL-6, IL-10, and IL-12. Conclusions: Our study implies that candidate genes linked to weight excess, notably SPON2, are connected to a perturbed immune pathway that underlies the characteristic inflammation seen in obesity. These novel uncovered associations in our study could potentially advance the field of precision medicine to treat obesity.