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Autoimmunity Insights Gleaned From GWAS of Immune Cell Traits

NEW YORK – A team from Italy, the UK, and the US has uncovered immune cell-related genetic variants that appear to impact autoimmune conditions and responses using a new genome-wide association study of immune cell traits.

 "To overcome previous limitations, we have performed a new GWAS with almost three times the number of immune cell traits and more than double the number of individuals previously studied," senior author Francesco Cucca, a geneticist and biomedical scientist affiliated with Italy's National Research Council and the University of Sassari, and his co-authors wrote in a paper published in Nature Genetics on Monday.

In their study, the researchers outlined efforts to identify yet-overlooked immune trait associations using genotyping profiles and imputation to search for variants influencing 731 immune cell counts or traits — assessed by flow cytometry-based cell sorting, cell surface markers, and other methods — in more than 3,500 Italian individuals from Sardinia participating in a longitudinal study.

Based on data at around 22 million variants in the Sardinian group, which included members of the same families, the team tracked down 122 SNPs at 52 new and 17 known loci with independent ties to 459 different immune cell traits. This set included variants at three dozen loci that had been linked to autoimmune conditions and other diseases in the past.

With the help of follow-up validation, fine-mapping, expression quantitative trait locus, protein quantitative trait locus (pQTL), and selection analyses, the investigators got a better look at some of the genetics behind immune cell traits and immune regulation that may influence conditions such as Kawasaki disease, multiple sclerosis, inflammatory bowel disease, type 1 diabetes, rheumatoid arthritis, or asthma.

"The enhanced power of the study increased considerably the number of reported associations with immune cell traits and coincident associations with disease risk, revealing numerous potential druggable protein targets for autoimmune diseases," they reported, noting that the results so far point to complex immune cell regulation "with highly selective effects on autoimmune disease risk at the cell-subtype level."

Building out from those results, the team explored the possibility of using pQTLs identified in certain immune cell types in the study to focus on investigational or approved drugs that are likely to be active against specific autoimmune conditions. In systemic lupus erythematosus, for example, the GWAS highlighted protective variants at two sites linked to lower-than-usual levels of plasmacytoid dendritic cells, hinting that treatments that can directly or indirectly dial down those cells may be beneficial.

Even so, the broader genetic susceptibility signatures found across autoimmune conditions suggested that it may be even more beneficial to target more than one protein or pathway, depending on the immune cell subtypes at play in each disease.

"[I]n contrast to classical autoimmune disease treatments directed against individual protein targets, future therapies of greater efficacy and safety may more usefully co-target two or more proteins to discriminate a particular cell subtype or could be based on the targeted delivery of a drug to a specific cell type — for example, by poly-specific monoclonal antibodies or other carriers for small molecules," the authors concluded.