Lobina, Monia (2016) Ricerca delle varianti genetiche implicate nella regolazione dei livelli delle immunoglobuline e comprensione dei meccanismi biologici nell’eziopatogenesi delle patologie autoimmuni tra cui la Sclerosi Multipla. Doctoral Thesis.
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Aim: The genetic analysis of immunoglobulin levels and their subclasses were performed both to detect the genetic variants influencing their inter-individual variation and to define the immunoglobulin-related biological pathways involved in autoimmune disease physiopathology.
Methods: Levels of IgA, IgM and IgG and IgG1, IgG2, IgG3 and IgG4 subclasses were quantified in 3000 sera of deeply genotyped individuals belonging to the ProgeNIA cohort. Furthermore, on a subset of 1842 individuals, the level of soluble BAFF (sBAFF) was evaluated by E.L.I.S.A and in parallel, a greater amount of individuals from the same cohort were extensively immunophenotyped. We performed a sequencing-based GWAS for each inverse-normalized assessed trait corrected for age and gender as covariates, by analyzing 23 million SNPs and 3 million INDELs assembled through the integration of genotypes from four genotyping arrays, and markers imputed using a reference panel from 3514 fully sequenced Sardinian individuals. The associated variants were systematically checked for coincidence with disease associated variants.
Results: Among the diverse association signals, we identified, at TNFSF13B locus, a coincident association between sBAFF, IgA, IgM, IgG subclasses, B cell levels and Multiple Sclerosis (MS) disease.
Conclusion: Our results indicate a central role for TNFSF13B and its protein product sBAFF in the pathogenesis of MS and suggest possible new pathway-specific therapeutic approaches to the disease.
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