Association of Risk Variants in the CFH Gene With Elevated Levels of Coagulation and Complement Factors in Idiopathic Multifocal Choroiditis (2025)

de Groot, E. L., Ossewaarde-van Norel, J., de Boer, J. H., Hiddingh, S., Bakker, B., van Huet, R. A. C., ten Dam-van Loon, N. H., Thiadens, A. A. H. J., Meester-Smoor, M. A., de Jong-Hesse, Y., Los, L. I., den Hollander, A. I., Boon, C. J. F., Kiemeney, L. A., van Eijk, K. R., Bakker, M. K., Hoyng, C. B., & Kuiper, J. J. W. (2023). Association of Risk Variants in the CFH Gene With Elevated Levels of Coagulation and Complement Factors in Idiopathic Multifocal Choroiditis. JAMA ophthalmology, 141(8), 737-745. https://doi.org/10.1001/jamaophthalmol.2023.2557

de Groot, Evianne L. ; Ossewaarde-van Norel, Jeannette ; de Boer, Joke H. et al. / Association of Risk Variants in the CFH Gene With Elevated Levels of Coagulation and Complement Factors in Idiopathic Multifocal Choroiditis. In: JAMA ophthalmology. 2023 ; Vol. 141, No. 8. pp. 737-745.

@article{26f4dd8788a24739a608ef229c8775df,

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

abstract = "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.",

author = "{de Groot}, {Evianne L.} and {Ossewaarde-van Norel}, Jeannette and {de Boer}, {Joke H.} and Sanne Hiddingh and Bjorn Bakker and {van Huet}, {Ramon A. C.} and {ten Dam-van Loon}, {Ninette H.} and Thiadens, {Alberta A. H. J.} and Meester-Smoor, {Magda A.} and {de Jong-Hesse}, Yvonne and Los, {Leonoor I.} and {den Hollander}, {Anneke I.} and Boon, {Camiel J. F.} and Kiemeney, {Lambertus A.} and {van Eijk}, {Kristel R.} and Bakker, {Mark K.} and Hoyng, {Carel B.} and Kuiper, {Jonas J. W.}",

note = "Publisher Copyright: {\textcopyright} 2023 American Medical Association. All rights reserved.",

year = "2023",

month = aug,

day = "17",

doi = "https://doi.org/10.1001/jamaophthalmol.2023.2557",

language = "English",

volume = "141",

pages = "737--745",

journal = "JAMA ophthalmology",

issn = "2168-6165",

publisher = "American Medical Association",

number = "8",

}

de Groot, EL, Ossewaarde-van Norel, J, de Boer, JH, Hiddingh, S, Bakker, B, van Huet, RAC, ten Dam-van Loon, NH, Thiadens, AAHJ, Meester-Smoor, MA, de Jong-Hesse, Y, Los, LI, den Hollander, AI, Boon, CJF, Kiemeney, LA, van Eijk, KR, Bakker, MK, Hoyng, CB & Kuiper, JJW 2023, 'Association of Risk Variants in the CFH Gene With Elevated Levels of Coagulation and Complement Factors in Idiopathic Multifocal Choroiditis', JAMA ophthalmology, vol. 141, no. 8, pp. 737-745. https://doi.org/10.1001/jamaophthalmol.2023.2557

Association of Risk Variants in the CFH Gene With Elevated Levels of Coagulation and Complement Factors in Idiopathic Multifocal Choroiditis. / de Groot, Evianne L.; Ossewaarde-van Norel, Jeannette; de Boer, Joke H. et al.
In: JAMA ophthalmology, Vol. 141, No. 8, 17.08.2023, p. 737-745.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Association of Risk Variants in the CFH Gene With Elevated Levels of Coagulation and Complement Factors in Idiopathic Multifocal Choroiditis

AU - de Groot, Evianne L.

AU - Ossewaarde-van Norel, Jeannette

AU - de Boer, Joke H.

AU - Hiddingh, Sanne

AU - Bakker, Bjorn

AU - van Huet, Ramon A. C.

AU - ten Dam-van Loon, Ninette H.

AU - Thiadens, Alberta A. H. J.

AU - Meester-Smoor, Magda A.

AU - de Jong-Hesse, Yvonne

AU - Los, Leonoor I.

AU - den Hollander, Anneke I.

AU - Boon, Camiel J. F.

AU - Kiemeney, Lambertus A.

AU - van Eijk, Kristel R.

AU - Bakker, Mark K.

AU - Hoyng, Carel B.

AU - Kuiper, Jonas J. W.

N1 - Publisher Copyright: © 2023 American Medical Association. All rights reserved.

PY - 2023/8/17

Y1 - 2023/8/17

N2 - 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.

AB - 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.

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U2 - https://doi.org/10.1001/jamaophthalmol.2023.2557

DO - https://doi.org/10.1001/jamaophthalmol.2023.2557

M3 - Article

C2 - 37410486

SN - 2168-6165

VL - 141

SP - 737

EP - 745

JO - JAMA ophthalmology

JF - JAMA ophthalmology

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ER -

de Groot EL, Ossewaarde-van Norel J, de Boer JH, Hiddingh S, Bakker B, van Huet RAC et al. Association of Risk Variants in the CFH Gene With Elevated Levels of Coagulation and Complement Factors in Idiopathic Multifocal Choroiditis. JAMA ophthalmology. 2023 Aug 17;141(8):737-745. doi: https://doi.org/10.1001/jamaophthalmol.2023.2557