Universität zu Köln

Schellevis, Rosa L., van Dijk, Elon H. C., Breukink, Myrte B., Altay, Lebuz, Bakker, Bjorn, Koeleman, Bobby P. C., Kiemeney, Lambertus A. ORCID: 0000-0002-2368-1326, Swinkels, Dorine W., Keunen, Jan E. E., Fauser, Sascha, Hoyng, Carel B., den Hollander, Anneke, I, Boon, Camiel J. F. and de Jong, Eiko K. (2018). Role of the Complement System in Chronic Central Serous Chorioretinopathy A Genome-Wide Association Study. JAMA Ophthalmol., 136 (10). S. 1128 - 1137. CHICAGO: AMER MEDICAL ASSOC. ISSN 2168-6173

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Abstract

IMPORTANCE To date, several targeted genetic studies on chronic central serous chorioretinopathy (cCSC) have been performed; however, unbiased genome-wide studies into the genetics of cCSC have not been reported. To discover new genetic loci associated with cCSC and to better understand the causative mechanism of this disease, we performed a genome-wide association study (GWAS) on patients with cCSC. OBJECTIVE To discover new genetic loci and pathways associated with cCSC and to predict the association of genetic variants with gene expression in patients with cCSC. DESIGN, SETTING, AND PARTICIPANTS This case-control GWAS was completed in the general community, 3 referral university medical centers, and outpatient care on Europeans individuals with cCSC and population-based control participants. Genotype data was collected from May 2013 to August 2017, and data analysis occurred from August 2017 to November 2017. MAIN OUTCOMES AND MEASURES Associations of single-nucleotide polymorphisms, haplotypes, genetic pathways, and predicted gene expression with cCSC. RESULTS A total of 521 patients with cCSC (median age, 51 years; interquartile range [IQR], 44-59 years; 420 [80.6%] male) and 3577 European population-based control participants (median age, 52 years; IQR. 37-71 years; 1630 [45.6%] male) were included. One locus on chromosome 1 at the complement factor H (CFH) gene reached genome-wide significance and was associated with an increased risk of cCSC (rs1329428; odds ratio [OR], 1.57 [95% CI, 1.38-1.80]; P = 3.12 x 10(-11)). The CFH haplotypes H1 and H3 were protective for cCSC (HI: OR, 0.64 [95% CI, 0.53-0.77]; P = 2.18 x 10(-6); H3: OR, 0.54 [95% CI, 0.42-0.70]; P = 2.49 x 10(-6)), whereas haplotypes H2, H4, H5, and the aggregate of rare CFH haplotypes conferred increased risk (H2: OR, 1.57 [95% CI, 1.30-1.89]; P = 2.18 x 10(-6); H4: OR, 1.43 [95% CI, 1.13-1.80]; P = 2.49 x 10(-3); HS: OR, 1.80 [95% Cl, 1.36-2.39]; P = 4.61 x 10(-5); rare haplotypes: OR, 1.99 [95% CI, 1.43-2.77]; P = 4.59 x 10(-5)). Pathway analyses showed involvement of the complement cascade and alternative open reading frame (ARF) pathway in cCSC. Using PrediXcan, we identified changes in predicted expression of complement genes CFH, complement factor H related 1(CFHR1), complement factor related 4 (CFHR4), and membrane cofactor protein (MCP/CD46), Additionally, the potassium sodium-activated channel subfamily T member 2 (KCNT2) and tumor necrosis factor receptor superfamily member 10a (TNFRSF10A) genes were differentially expressed in patients with cCSC. CONCLUSIONS AND RELEVANCE In this GWAS on cCSC, we identified a locus on chromosome 1 at the CFH gene that was significantly associated with cCSC, and we report protective and risk-conferring haplotypes in this gene. Pathway analyses were enriched for complement genes, and gene expression analysis suggests a role for CFH, CFHR1, CFHR4, CD46, KCNT2, and TNFRSF70A in the disease. Taken together, these results underscore the potential importance of the complement pathway in the causative mechanisms of cCSC.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Schellevis, Rosa L. UNSPECIFIED UNSPECIFIED UNSPECIFIED van Dijk, Elon H. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Breukink, Myrte B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Altay, Lebuz UNSPECIFIED UNSPECIFIED UNSPECIFIED Bakker, Bjorn UNSPECIFIED UNSPECIFIED UNSPECIFIED Koeleman, Bobby P. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kiemeney, Lambertus A. UNSPECIFIED orcid.org/0000-0002-2368-1326 UNSPECIFIED Swinkels, Dorine W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Keunen, Jan E. E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fauser, Sascha UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoyng, Carel B. UNSPECIFIED UNSPECIFIED UNSPECIFIED den Hollander, Anneke, I UNSPECIFIED UNSPECIFIED UNSPECIFIED Boon, Camiel J. F. UNSPECIFIED UNSPECIFIED UNSPECIFIED de Jong, Eiko K. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-171117
DOI:	10.1001/jamaophthalmol.2018.3190
Journal or Publication Title:	JAMA Ophthalmol.
Volume:	136
Number:	10
Page Range:	S. 1128 - 1137
Date:	2018
Publisher:	AMER MEDICAL ASSOC
Place of Publication:	CHICAGO
ISSN:	2168-6173
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language FACTOR-H; GENETIC-VARIANTS; RISK-FACTORS; CD46; GWAS Multiple languages Ophthalmology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/17111