Genetic approaches to complex immune disease: dissecting vasculitis with GWAS, and primary immunodeficiency with cohort-based whole genome sequencing.

Dr. Ken Smith

Professor of Medicine

Head of Department of Medicine

University of Cambridge

Modern genetics is allowing us to gain insight into complex human diseases. This talk will outline two approaches.

1. ANCA-associated vasculitis is comprised of three clinical syndromes (granulomatosis with polyangiitis (GPA, formerly Wegener’s granulomatosis), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss). A series of genome-wide association studies by the European Vasculitis Genetics consortium has defined the genetic underpinning of these diseases, uncovering new pathogenic pathways and suggested that AAV syndromes should be reclassified along genetic lines, providing practical diagnostic criteria better aligned to patient phenotype, outcomes and treatment responses.

2. Primary immunodeficiency (PID) is characterised by recurrent and often life-threatening infections, autoimmunity and cancer; it presents major diagnostic and therapeutic challenges. Most patients present in adulthood with no apparent family history and a variable clinical phenotype. Consequently, in sporadic PID genetic diagnosis is difficult. We performed whole genome sequencing (WGS) of a PID cohort of 1,318 subjects, and used a Bayesian approach (BeviMed) to identify multiple potential new disease-associated genes, and to reveal deletions in regulatory regions which contribute to disease causation. Finally, a genome-wide association study (GWAS) identified novel PID-associated loci and uncovered evidence for co-localisation of, and interplay between, novel high penetrance monogenic variants and common variants. This approach begins to explain the contribution of common variants to variable penetrance and phenotypic complexity in PID, and can increase diagnostic yield while deepening our understanding of the key pathways determining variation in human immune responsiveness.

Time: 14:00-15:30, March 7th (Thursday)

Venue: Room D326, Medical Science Building

Host: Dr. Chen Dong