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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

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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Abstract

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.

Item Type:Doctoral Thesis
ID Code:11094
Contributors:Cucca, Francesco
Publisher:Universita' degli studi di Sassari
Uncontrolled Keywords:Genetic variants, immunoglobulin, multiple sclerosis, Sardinia
Varianti genetiche, immunoglobine, sclerosi multipla
Subjects:Area 06 - Scienze mediche > MED/03 Genetica medica
Divisions:001 Università di Sassari > 01-a Nuovi Dipartimenti dal 2012 > Scienze Biomediche
Cicli, scuole e corsi:Ciclo 28 > Scienze biomediche > Genetica medica, malattie metaboliche e nutrigenomica
Deposited On:03 May 2016 09:53

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