Poster Presentation Lancefield International Symposium for Streptococci and Streptococcal Diseases 2025

Complement factor H and susceptibility to rheumatic heart disease (#244)

Tom Parks 1 2 , Richard Pouw 3 , Angela Kamp 3 , Monica Campos 1 , Gul Afshan 4 , Humera Javed 4 , Emma Ndagire 5 , Jafesi Pulle 5 6 , Andrea Beaton 7 , Emmy Okello 5 6 , Masood Sadiq 4 , On behalf of the Acute Rheumatic Fever Diagnostic Network (ARC) 7
  1. Imperial College London, London, United Kingdom
  2. University of Oxford, Oxford, UK
  3. Sanquin Institute, Amsterdam, The Netherlands
  4. University of Child Health Sciences, Lahore, Pakistan
  5. Uganda Heart Institute, Kampala, Uganda
  6. Makerere University, Kampala, Uganda
  7. Cincinnati Children's Hospital Medicial Center, Cincinnati, USA

Introduction: Large-scale genetic studies have implicated complement factor H (CFH) in rheumatic heart disease (RHD). Together with the neighbouring factor H-related proteins (FHRs), CFH plays a critical role in complement regulation and has been linked to several complement-mediated diseases. We therefore sought to define their relative contribution to the pathogenesis of acute rheumatic fever (ARF) and RHD, which remains uncertain.

Methods: We studied a cohort of 240 children or adults with ARF or RHD and 248 healthy or alternate diagnosis controls recruited in Pakistan, and a previously reported cohort of 49 children with ARF or RHD and 99 healthy or alternate diagnosis controls recruited in Uganda. We characterised host genetic variation using a combination of targeted and genome-wide genotyping in addition to short and long-read sequencing, and measured circulating CFH and FHRs using previously developed highly specific immunoassays.

Results: Across these studies, the CFH signal replicated, localising to a known deletion of CFHR3 and CFHR1 with minor allele frequency 30-33% that conferred a 1.2-fold lower risk of ARF and RHD combined (P<0.005). Additionally, this protective deletion was highly correlated with not only reduced circulating FHR3 and FHR1 (P<10-10), but also higher circulating CFH (P<10-5), even during the inflammatory state of ARF (Percentage change per copy of CFHR3/CFHR1 deletion: FHR3 -49.6%, 95% CI -35.2 to -63.9%, P<10-10; CFH +11.4%, 95% CI +6.6 to +16.2%, P<10-5). 

Conclusion: Genetic variation in the CFH locus drives risk of ARF and RHD by altering levels of key complement regulators, providing an invaluable new therapeutic target.