PMID- 37410486
OWN - NLM
STAT- MEDLINE
DCOM- 20230818
LR  - 20230827
IS  - 2168-6173 (Electronic)
IS  - 2168-6165 (Print)
IS  - 2168-6165 (Linking)
VI  - 141
IP  - 8
DP  - 2023 Aug 1
TI  - Association of Risk Variants in the CFH Gene With Elevated Levels of Coagulation 
      and Complement Factors in Idiopathic Multifocal Choroiditis.
PG  - 737-745
LID - 10.1001/jamaophthalmol.2023.2557 [doi]
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 x 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 x 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 x 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.
FAU - de Groot, Evianne L
AU  - de Groot EL
AD  - Department of Ophthalmology, University Medical Center Utrecht, Utrecht 
      University, the Netherlands.
FAU - Ossewaarde-van Norel, Jeannette
AU  - Ossewaarde-van Norel J
AD  - Department of Ophthalmology, University Medical Center Utrecht, Utrecht 
      University, the Netherlands.
FAU - de Boer, Joke H
AU  - de Boer JH
AD  - Department of Ophthalmology, University Medical Center Utrecht, Utrecht 
      University, the Netherlands.
FAU - Hiddingh, Sanne
AU  - Hiddingh S
AD  - Center for Translational Immunology, University Medical Center Utrecht, Utrecht 
      University, Utrecht, the Netherlands.
FAU - Bakker, Bjorn
AU  - Bakker B
AD  - Department of Ophthalmology, Donders Institute for Brain, Cognition and 
      Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
FAU - van Huet, Ramon A C
AU  - van Huet RAC
AD  - Department of Ophthalmology, Donders Institute for Brain, Cognition and 
      Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
FAU - Ten Dam-van Loon, Ninette H
AU  - Ten Dam-van Loon NH
AD  - Department of Ophthalmology, University Medical Center Utrecht, Utrecht 
      University, the Netherlands.
FAU - Thiadens, Alberta A H J
AU  - Thiadens AAHJ
AD  - Department of Ophthalmology, Erasmus Medical Centre, Rotterdam, the Netherlands.
FAU - Meester-Smoor, Magda A
AU  - Meester-Smoor MA
AD  - Department of Ophthalmology, Erasmus Medical Centre, Rotterdam, the Netherlands.
FAU - de Jong-Hesse, Yvonne
AU  - de Jong-Hesse Y
AD  - Department of Ophthalmology, Amsterdam University Medical Centre, Amsterdam, the 
      Netherlands.
AD  - Department of Ophthalmology, Leiden University Medical Center, Leiden, the 
      Netherlands.
FAU - Los, Leonoor I
AU  - Los LI
AD  - Department of Ophthalmology, University Medical Center Groningen, University of 
      Groningen, Groningen, the Netherlands.
FAU - den Hollander, Anneke I
AU  - den Hollander AI
AD  - Department of Ophthalmology, Donders Institute for Brain, Cognition and 
      Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
AD  - AbbVie, Genomics Research Center, Cambridge, Massachusetts.
FAU - Boon, Camiel J F
AU  - Boon CJF
AD  - Department of Ophthalmology, Amsterdam University Medical Centre, Amsterdam, the 
      Netherlands.
AD  - Department of Ophthalmology, Leiden University Medical Center, Leiden, the 
      Netherlands.
FAU - Kiemeney, Lambertus A
AU  - Kiemeney LA
AD  - Department of Health Evidence, Radboud University Medical Centre, Nijmegen, the 
      Netherlands.
FAU - van Eijk, Kristel R
AU  - van Eijk KR
AD  - Department of Neurology, UMC Utrecht Brain Center, University Medical Center 
      Utrecht, Utrecht University, Utrecht, the Netherlands.
FAU - Bakker, Mark K
AU  - Bakker MK
AD  - Department of Neurology, UMC Utrecht Brain Center, University Medical Center 
      Utrecht, Utrecht University, Utrecht, the Netherlands.
FAU - Hoyng, Carel B
AU  - Hoyng CB
AD  - Department of Ophthalmology, Donders Institute for Brain, Cognition and 
      Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
FAU - Kuiper, Jonas J W
AU  - Kuiper JJW
AD  - Department of Ophthalmology, University Medical Center Utrecht, Utrecht 
      University, the Netherlands.
AD  - Center for Translational Immunology, University Medical Center Utrecht, Utrecht 
      University, Utrecht, the Netherlands.
LA  - eng
PT  - Comment
PT  - Journal Article
PL  - United States
TA  - JAMA Ophthalmol
JT  - JAMA ophthalmology
JID - 101589539
RN  - 80295-65-4 (Complement Factor H)
RN  - 0 (Proteins)
SB  - IM
CON - JAMA Ophthalmol. 2023 Aug 1;141(8):745-746. PMID: 37410484
MH  - Humans
MH  - Male
MH  - Female
MH  - Middle Aged
MH  - *Complement Factor H/genetics
MH  - Multifocal Choroiditis
MH  - Genome-Wide Association Study
MH  - Proteomics
MH  - Polymorphism, Single Nucleotide
MH  - *Choroiditis/diagnosis/genetics
MH  - Proteins/genetics
PMC - PMC10326733
COIS- Conflict of Interest Disclosures: Dr de Jong-Hesse reported speakers fees from 
      Novartis Pharma and grants from Bayer and Boehringer Ingelheim as principal 
      investigator in a randomized clinical trial outside the submitted work. Dr den 
      Hollander reported receiving personal fees from AbbVie outside the submitted 
      work. No other disclosures were reported.
EDAT- 2023/07/06 13:14
MHDA- 2023/08/18 06:42
PMCR- 2023/07/06
CRDT- 2023/07/06 11:34
PHST- 2023/08/18 06:42 [medline]
PHST- 2023/07/06 13:14 [pubmed]
PHST- 2023/07/06 11:34 [entrez]
PHST- 2023/07/06 00:00 [pmc-release]
AID - 2806492 [pii]
AID - eoi230036 [pii]
AID - 10.1001/jamaophthalmol.2023.2557 [doi]
PST - ppublish
SO  - JAMA Ophthalmol. 2023 Aug 1;141(8):737-745. doi: 
      10.1001/jamaophthalmol.2023.2557.