Studio dei tratti immunofenotipici e valutazione del loro contributo nell'insorgenza di patologie

The regulation of the immune response has been intensively studied for decades, however, the effect of the genetic factors affecting the immune cell levels is largely unknown. In order to better understand the immune system regulation and its involvement in diseases, we evaluated the quantitative variation of several leuckocyte populations in peripheral blood including monocytes, granulocytes, circulating dendritic cells and lymphocytes divided in NK, B and T cell subsets. Immunophenotypes, assessed by flow cytometry, were initially measured in 1,629 volunteers,belonging to the SardiNIA project, who have been genotipically characterized with the MetaboChip and ImmuoChip arrays. For each of the 272 assessed traits, we performed a sequenced-based GWAS approach with 8.2 million genotyped and imputed variants derived from the gene arrays and from a reference panel of 1,146 low pass whole-genome sequenced Sardinians. Our results showed that, on the average, the genetic component accounts for 40% (min 3% max 87%) of the phenotypic variation of the immune traits analyzed. Furthermore, we identified, and confirmed in a total of 2,870 volunteers, comprising 1,241 additional individuals, 23 independent signals at 13 loci (p-value<5.26x10-10). Among the associated loci, four of them (HLA, IL2RA, CIITA, ATXN2/SH2B3) are known to be associated with immune and non-immune diseases, indicating the relevance of this approach for identification of immune-related genetic factors in health and disease.