The Genetics of Inflammation

Autoimmune diseases are highly heterogeneous.

Heterogeneity is not limited to the clinical presentation, but also to differences in the molecular and cellular mechanisms affecting tissues, reflected as a lack of effective response to treatment.

All genome-wide association studies (GWAS) for complex diseases have been done based on clinical phenotypes.We grouped patients using an unsupervised clustering method of transcriptome and methylome data. We identified 3 pathological clusters of patients: 1) inflammatory; 2) lymphoid, and 3) interferon.

Genetically, the interferon cluster had a unique association to the HLA class II, and the inflammatory cluster revealed a novel genetic association in chromosome 9p21.2 (2,17 x 10-10, OR = 3,17, CI 2.28-4.40) shared between autoimmunity and covid-19.

The associated locus, in linkage disequilibrium with 5 genes and eQTLs that modulated their expression in various tissues and cells. Also, the risk alleles were associated with levels of CCL17 produced by M2 macrophages.

Our aims are: 1)Identify the causal variants and the regulation of the chr. 9 locus in myeloid cells; 2) Determine the spatial organization and intercellular interactions of the chr 9 genes in inflamed tissues; and 3) Define if and how in vitro and in vivo disruption of any of the chr 9 genes alters the structure of the tissues and the macrophage polarization during inflammatory processes.Only through precision medicine strategies could we identify this locus.