Association of Risk Variants in the CFH Gene With Elevated Levels of Coagulation and Complement Factors in Idiopathic Multifocal Choroiditis

Importance Idiopathic multifocal choroiditis (MFC) is poorly understood, thereby hindering optimal treatment and monitoring of patients. Objective To identify the genes and pathways associated with idiopathic MFC. Design, Setting, and Participants This was a case-control genome-wide association study (GWAS) and protein study of blood plasma samples conducted from March 2006 to February 2022. This was a multicenter study involving 6 Dutch universities. Participants were grouped into 2 cohorts: cohort 1 consisted of Dutch patients with idiopathic MFC and controls, and cohort 2 consisted of patients with MFC and controls. Plasma samples from patients with idiopathic MFC who had not received treatment were subjected to targeted proteomics. Idiopathic MFC was diagnosed according to the Standardization of Uveitis Nomenclature (SUN) Working Group guidelines for punctate inner choroidopathy and multifocal choroiditis with panuveitis. Data were analyzed from July 2021 to October 2022. Main outcomes and measures Genetic variants associated with idiopathic MFC and risk variants associated with plasma protein concentrations in patients. Results This study included a total of 4437 participants in cohort 1 (170 [3.8%] Dutch patients with idiopathic MFC and 4267 [96.2%] controls; mean [SD] age, 55 [18] years; 2443 female [55%]) and 1344 participants in cohort 2 (52 [3.9%] patients with MFC and 1292 [96.1%] controls; 737 male [55%]). The primary GWAS association mapped to the CFH gene with genome-wide significance (lead variant the A allele of rs7535263; odds ratio [OR], 0.52; 95% CI, 0.41-0.64; P = 9.3 × 10-9). There was no genome-wide significant association with classical human leukocyte antigen (HLA) alleles (lead classical allele, HLA-A*31:01; P = .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, 0.58; 95% CI, 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 (eg, FHR-2, likelihood ratio test, adjusted P = 1.1 × 10-3) and proteins involved in platelet activation and the complement cascade. Conclusions and relevance Results suggest that CFH gene variants increase systemic concentrations of key factors of the complement and coagulation cascades, thereby conferring susceptibility to idiopathic MFC. These findings suggest that the complement and coagulation pathways may be key targets for the treatment of idiopathic MFC.

[1]  Andrew P. Voigt,et al.  Systems genomics in age-related macular degeneration , 2022, Experimental eye research.

[2]  T. Renné,et al.  Elevated plasma Complement Factor H Regulating Protein 5 is associated with venous thromboembolism and COVID-19 severity , 2022, medRxiv.

[3]  Ewout J. N. Groen,et al.  Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology , 2021, Nature Genetics.

[4]  S. Haitjema,et al.  Central Multifocal Choroiditis: Platelet Granularity as a Potential Marker for Treatment With Steroid-Sparing Immunomodulatory Therapy , 2021, Frontiers in Ophthalmology.

[5]  J. Lamb,et al.  A proteogenomic signature of age-related macular degeneration in blood , 2021, Nature Communications.

[6]  V. Zuber,et al.  Beyond factor H: The impact of genetic-risk variants for age-related macular degeneration on circulating factor-H-like 1 and factor-H-related protein concentrations , 2021, American journal of human genetics.

[7]  A. D. den Hollander,et al.  Common haplotypes at the CFH locus and low-frequency variants in CFHR2 and CFHR5 associate with systemic FHR concentrations and age-related macular degeneration , 2021, American journal of human genetics.

[8]  Y. Sepah,et al.  Distinct Patterns of Choroidal Lesions in Punctate Inner Choroidopathy and Multifocal Choroiditis Determined by Heatmap Analysis , 2021, Ocular immunology and inflammation.

[9]  B. Trusko,et al.  Classification criteria for punctate inner choroiditis. , 2021, American journal of ophthalmology.

[10]  B. Trusko,et al.  Classification criteria for multifocal choroiditis with panuveitis. , 2021, American journal of ophthalmology.

[11]  O. McCarty,et al.  Cross-Talk between the Complement Pathway and the Contact Activation System of Coagulation: Activated Factor XI Neutralizes Complement Factor H , 2021, The Journal of Immunology.

[12]  Ewout J. N. Groen,et al.  Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology , 2021, Nature Genetics.

[13]  J. D. de Boer,et al.  The efficacy of adalimumab in treating patients with central multifocal choroiditis , 2020, American journal of ophthalmology case reports.

[14]  B. Joondeph,et al.  C5 Inhibitor Avacincaptad Pegol for Geographic Atrophy Due to Age-Related Macular Degeneration: A Randomized Pivotal Phase 2/3 Trial. , 2020, Ophthalmology.

[15]  N. H. ten Dam-van Loon,et al.  The efficacy of corticosteroid‐sparing immunomodulatory therapy in treating patients with central multifocal choroiditis , 2020, Acta ophthalmologica.

[16]  S. Sivaprasad,et al.  Central serous chorioretinopathy: An update on risk factors, pathophysiology and imaging modalities , 2020, Progress in Retinal and Eye Research.

[17]  A. D. den Hollander,et al.  Increased circulating levels of Factor H-Related Protein 4 are strongly associated with age-related macular degeneration , 2020, Nature Communications.

[18]  R. Niederer,et al.  Differentiating Multifocal Choroiditis and Punctate Inner Choroidopathy: A Cluster Analysis Approach. , 2020, American journal of ophthalmology.

[19]  Philip J Rosenfeld,et al.  Complement C3 Inhibitor Pegcetacoplan for Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Randomized Phase 2 Trial. , 2020, Ophthalmology.

[20]  Q. Tan,et al.  Myopia genetics in genome-wide association and post-genome-wide association study era. , 2019, International journal of ophthalmology.

[21]  B. Nilsson,et al.  The Human Platelet as an Innate Immune Cell: Interactions Between Activated Platelets and the Complement System , 2019, Front. Immunol..

[22]  C. Klaver,et al.  IMI – Myopia Genetics Report , 2019, Investigative ophthalmology & visual science.

[23]  L. Kiemeney,et al.  Role of the Complement System in Chronic Central Serous Chorioretinopathy: A Genome-Wide Association Study , 2018, JAMA ophthalmology.

[24]  Stephen Burgess,et al.  Genomic atlas of the human plasma proteome , 2018, Nature.

[25]  Lars G Fritsche,et al.  Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies , 2017, Nature Genetics.

[26]  Y. Wang,et al.  Murine systemic thrombophilia and hemolytic uremic syndrome from a factor H point mutation. , 2017, Blood.

[27]  P. Keane,et al.  Punctate inner choroidopathy: A review , 2016 .

[28]  L. Kiemeney,et al.  Cohort Profile Cohort Profile : The Nijmegen Biomedical Study ( NBS ) , 2017 .

[29]  L. Yannuzzi,et al.  Idiopathic Multifocal Choroiditis , 2016, Journal of ophthalmic & vision research.

[30]  Yara T. E. Lechanteur,et al.  Nature Genetics Advance Online Publication , 2022 .

[31]  D. Jabs,et al.  Success with single-agent immunosuppression for multifocal choroidopathies. , 2014, American journal of ophthalmology.

[32]  Q. Nguyen,et al.  CLINICAL FEATURES AND INCIDENCE RATE OF OCULAR COMPLICATIONS IN PUNCTATE INNER CHOROIDOPATHY , 2014, Retina.

[33]  J. Slakter,et al.  MULTIFOCAL CHOROIDITIS WITHOUT PANUVEITIS: Clinical Characteristics and Progression , 2014, Retina.

[34]  A. Hartmann,et al.  Human Factor H-Related Protein 2 (CFHR2) Regulates Complement Activation , 2013, PloS one.

[35]  K. Freund,et al.  REDEFINING MULTIFOCAL CHOROIDITIS AND PANUVEITIS AND PUNCTATE INNER CHOROIDOPATHY THROUGH MULTIMODAL IMAGING , 2013, Retina.

[36]  Claire L. Simpson,et al.  Large scale international replication and meta-analysis study confirms association of the 15q14 locus with myopia. The CREAM consortium , 2012, Human Genetics.

[37]  A. Uitterlinden,et al.  Large scale international replication and meta-analysis study confirms association of the 15q14 locus with myopia. The CREAM consortium , 2012, Human Genetics.

[38]  Guangchuang Yu,et al.  clusterProfiler: an R package for comparing biological themes among gene clusters. , 2012, Omics : a journal of integrative biology.

[39]  Q. Nguyen,et al.  Mycophenolate Mofetil and Fundus Autofluorescence in the Management of Recurrent Punctate Inner Choroidopathy , 2011, Ocular immunology and inflammation.

[40]  J. Forrester,et al.  Punctate inner choroidopathy and multifocal choroiditis with panuveitis share haplotypic associations with IL10 and TNF loci. , 2011, Investigative ophthalmology & visual science.

[41]  T. Spector,et al.  A genome-wide association study for myopia and refractive error identifies a susceptibility locus at 15q25 , 2010, Nature Genetics.

[42]  A. Hofman,et al.  A genome-wide association study identifies a susceptibility locus for refractive errors and myopia at 15q14 , 2010, Nature Genetics.

[43]  L. Yannuzzi,et al.  Analysis of major alleles associated with age-related macular degeneration in patients with multifocal choroiditis: strong association with complement factor H. , 2008, Archives of ophthalmology.

[44]  D. Jabs,et al.  MULTIFOCAL CHOROIDITIS WITH PANUVEITIS AND PUNCTATE INNER CHOROIDOPATHY: Comparison of Clinical Characteristics at Presentation , 2007, Retina.

[45]  D. Jabs,et al.  Multifocal choroiditis with panuveitis incidence of ocular complications and of loss of visual acuity. , 2006, Ophthalmology.

[46]  PEA – a high-multiplex immunoassay technology with qPCR or NGS readout , 2020 .

[47]  A. Bird,et al.  Idiopathic multifocal choroiditis: a comment on present and past nomenclature. , 2013, Retina.