June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Risk variants in the CFH gene associate with elevated levels of coagulation and complement factors in idiopathic multifocal choroiditis
Author Affiliations & Notes
  • Evianne Laura de Groot
    Ophthalmology, University Medical Center Utrecht, Utrecht, Netherlands
  • Jeannette Ossewaarde-van Norel
    Ophthalmology, University Medical Center Utrecht, Utrecht, Netherlands
  • Joke H. de Boer
    Ophthalmology, University Medical Center Utrecht, Utrecht, Netherlands
  • Sanne Hiddingh
    Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Utrecht, Netherlands
  • Bjorn Bakker
    Ophthalmology, Radboud University Medical Center, Nijmegen, Netherlands
  • Ramon A.C. van Huet
    Ophthalmology, Radboud University Medical Center, Nijmegen, Netherlands
  • Ninette H. ten Dam-van Loon
    Ophthalmology, University Medical Center Utrecht, Utrecht, Netherlands
  • Alberta A H J Thiadens
    Ophthalmology, Erasmus MC, Rotterdam, Zuid-Holland, Netherlands
  • Magda A. Meester
    Ophthalmology, Erasmus MC, Rotterdam, Zuid-Holland, Netherlands
  • Yvonne de Jong-Hesse
    Ophthalmology, Leids Universitair Medisch Centrum, Leiden, Zuid-Holland, Netherlands
    Ophthalmology, Amsterdam Universitair Medische Centra, Duivendrecht, Noord-Holland, Netherlands
  • Leonoor I. Los
    Ophthalmology, University Medical Center Groningen, Groningen, Netherlands
  • Anneke I. den Hollander
    Ophthalmology, Radboud University Medical Center, Nijmegen, Netherlands
    AbbVie Genomics Research Center, Massachusetts, United States
  • Camiel J F Boon
    Ophthalmology, Amsterdam Universitair Medische Centra, Duivendrecht, Noord-Holland, Netherlands
    Ophthalmology, Leids Universitair Medisch Centrum, Leiden, Zuid-Holland, Netherlands
  • Kristel R. van Eijk
    Neurology, University Medical Center Utrecht, Utrecht, Utrecht, Netherlands
  • Carel C B Hoyng
    Ophthalmology, Radboud University Medical Center, Nijmegen, Netherlands
  • Jonas J.W. Kuiper
    Ophthalmology, University Medical Center Utrecht, Utrecht, Netherlands
    Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Utrecht, Netherlands
  • Footnotes
    Commercial Relationships   Evianne de Groot None; Jeannette Ossewaarde-van Norel None; Joke de Boer None; Sanne Hiddingh None; Bjorn Bakker None; Ramon van Huet None; Ninette ten Dam-van Loon None; Alberta Thiadens None; Magda Meester None; Yvonne de Jong-Hesse None; Leonoor Los None; Anneke den Hollander None; Camiel Boon None; Kristel van Eijk None; Carel Hoyng None; Jonas Kuiper None
  • Footnotes
    Support  Dr. F.P. Fischer Foundation, Foundation ‘Beheer het Schild’, ‘Landelijke Stichting voor Blinden en Slechtzienden (LSBS)’, ‘Rotterdamse Stichting Blindenbelangen (RBS)’, Foundation ‘Louise Rottinghuis’, ‘Oogfonds’. The Combined Ophthalmic Research Rotterdam Biobank (CORRBI) (Erasmus MC, Rotterdam) was financed by the Combined Ophthalmic Research Rotterdam Foundation. The sponsors or funding organizations had no role in the design or conduct of this research.
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 4528. doi:
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    • Get Citation

      Evianne Laura de Groot, Jeannette Ossewaarde-van Norel, Joke H. de Boer, Sanne Hiddingh, Bjorn Bakker, Ramon A.C. van Huet, Ninette H. ten Dam-van Loon, Alberta A H J Thiadens, Magda A. Meester, Yvonne de Jong-Hesse, Leonoor I. Los, Anneke I. den Hollander, Camiel J F Boon, Kristel R. van Eijk, Carel C B Hoyng, Jonas J.W. Kuiper; Risk variants in the CFH gene associate with elevated levels of coagulation and complement factors in idiopathic multifocal choroiditis. Invest. Ophthalmol. Vis. Sci. 2023;64(8):4528.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Idiopathic multifocal choroiditis (MFC) is poorly understood, hindering optimal treatment and monitoring of patients. The aim of this study was to identify genes and pathways involved in idiopathic MFC.

Methods : This was a multicenter study involving six Dutch universities and included 170 Dutch idiopathic MFC cases and 4267 controls (cohort 1), and 52 cases and 1292 controls (cohort 2). Idiopathic MFC was diagnosed according to the SUN working group guidelines for punctate inner choroidopathy and multifocal choroiditis with panuveitis. A genome-wide association study (GWAS) in cases and controls was performed to expose genetic variants associated with idiopathic MFC. Additionally, plasma samples from 87 treatment-free idiopathic MFC cases were subjected to targeted proteomics to explore if risk variants were associated with plasma protein concentrations in patients.

Results : The primary GWAS association mapped to the complement factor H (CFH) gene with genome-wide significance (lead variant the A allele of rs7535263; odds ratio (OR) [95% confidence interval (95%CI)] = 0.52 [0.41-0.64]; P= 9.3 × 10-9). There was no significant association with classical HLA alleles (lead classical allele; HLA-A*31:01, P = 0.002). The association with rs7535263 showed consistent direction of effect in an independent cohort of 52 cases and 1292 control samples (combined meta-analysis OR [95%CI] = 0.58 [0.38-0.77], P = 3.0 × 10−8). In proteomic analysis of 87 patients, the risk allele G of rs7535263 in the CFH gene was strongly associated with increased plasma concentrations of Factor H-related (FHR) proteins (e.g., FHR-2, likelihood ratio test, Padj = 1.1 × 10−3) and proteins involved in platelet activation and the complement cascade.

Conclusions : CFH gene variants increase systemic concentrations of key factors of the complement and coagulation cascades, thereby conferring susceptibility to idiopathic MFC. In conclusion, these results indicate that the complement and coagulation pathways are key targets for the treatment of idiopathic MFC.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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