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Gibson, Kristen

University of British Columbia

Chronic primary systemic vasculitis (PSV) describes a diverse group of debilitating and potentially life-threatening diseases, characterized by inflammation of blood vessels within various organs such as the kidneys, lungs, brain, eyes, and skin. Subtypes of the small- to medium-sized vessel vasculitides are particularly challenging to classify due to many overlapping clinical symptoms. Their differentiation is important, however, as there is evidence that different subtypes benefit from different treatment approaches. The rarity of vasculitis in children has limited pediatric-specific PSV studies and the clinical approach to pediatric PSV is adapted primarily from adult studies. Not surprisingly, adult-derived classification criteria are imperfect for children and consequently, fail to classify up to two thirds of children with small- to medium-vessel PSV. The objective of this dissertation is to identify genetic markers and select, circulating biomarkers to better our understanding and clinical approach to managing the disease and to improve outcomes of children with chronic PSV. Using biological samples and clinical metadata from a worldwide cohort of children with chronic PSV, this dissertation reports (1) genetic associations specific to pediatric autoimmune vasculitis through employing a genome-wide association study; (2) a high prevalence of autoantibodies to lysosome associated membrane protein-2 in pediatric PSV that correlate to vasculitis-associated kidney dysfunction; and (3) the identification of nine patients, originally diagnosed with chronic PSV, harbouring novel and/or rare variants in adenosine deaminase 2 (ADA2) – these genetic data alongside having abrogated ADA2 enzyme activity have led to their reclassification as having a new monogenic form of vasculitis, deficiency of adenosine deaminase 2. This dissertation reports the first large-scale genotype and biomarker study of primary vasculitis focusing solely on pediatric cases. Improved classification is critical for timely therapeutic intervention, for identification of appropriately classified children for clinical trials, and for research, all of which will improve our understanding of the disease and the quality of life of children suffering from chronic PSV.

Text

2023-09-06

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/85811

Medical Genetics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/