Estudos de associação entre genótipos e níveis de mediadores inflamatórios na população brasileira miscigenada

Abstract

Genome-wide association studies (GWAS) have proven effective in identifying the genetic basis of various phenotypes, such as blood pressure, blood glucose, and — in the present case — serum concentrations of inflammatory mediators. GWAS performs a scan across the genome to test whether specific positions (loci) are associated with the phenotype of interest. Inflammatory mediators, in turn, play a central role in regulating the immune response and serve as important biomarkers of health, disease, and risk for chronic conditions. Their serum concentrations represent complex, multifactorial phenotypes in which genetic factors directly influence interindividual variability in expression. Elucidating genes and genetic variants that affect biochemical pathways related to expression is therefore crucial to understanding the underlying molecular mechanisms. To this end, genetic data from 1,442 members of the Bambuí Aging Cohort were analyzed to investigate genotype–phenotype associations. Seven inflammatory mediators were considered in the study: the chemokines CCL2, CCL5, CXCL8, CXCL9 and CXCL10, as well as the interleukin IL-6 and C-reactive protein (CRP). Thirteen loci located on chromosome 1, region 1q23, showed significant association, surpassing the established significance threshold (p < 5×10⁻⁸). All the genetic variants were associated with serum concentrations of the chemokine CCL2, with rs12075 showing the smallest test statistic (p = 4.18E - 20). The polymorphism rs12075 corresponds to a nucleotide substitution in the ACKR1 gene, resulting in a missense change. This gene encodes a membrane protein that functions as an atypical receptor, modulating the bioavailability of multiple chemokines, including CCL2. The findings are biologically coherent and consistent with previous evidence of association at this locus. However, among the variants associated with serum CCL2 concentrations, eight have no previously described phenotype associations and thus represent promising targets for future investigation. This study is the first to report, in the Brazilian population, an association between serum CCL2 concentrations and variants in the ACKR1 gene.