Universität zu Köln

Geerlings, Maartje J., Kremlitzka, Mariann, Bakker, Bjorn, Nilsson, Sara C., Saksens, Nicole T., Lechanteur, Yara T., Pauper, Marc ORCID: 0000-0001-6274-9891, Corominas, Jordi, Fauser, Sascha, Hoyng, Carel B., Blom, Anna M., de Jong, Eiko K. and den Hollander, Anneke I. (2017). The Functional Effect of Rare Variants in Complement Genes on C3b Degradation in Patients With Age-Related Macular Degeneration. JAMA Ophthalmol., 135 (1). S. 39 - 47. CHICAGO: AMER MEDICAL ASSOC. ISSN 2168-6173

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Abstract

IMPORTANCE In age-related macular degeneration (AMD), rare variants in the complement system have been described, but their functional consequences remain largely unexplored. OBJECTIVES To identify new rare variants in complement genes and determine the functional effect of identified variants on complement levels and complement regulation in serum samples from carriers and noncarriers. DESIGN, SETTING, AND PARTICIPANTS This study evaluated affected (n = 114) and unaffected (n = 60) members of 22 families with AMD and a case-control cohort consisting of 1831 unrelated patients with AMD and 1367 control individuals from the European Genetic Database from March 29, 2006, to April 26, 2013, in Nijmegen, the Netherlands, and Cologne, Germany. Exome sequencing data of families were filtered for rare variants in the complement factor H (CFH), complement factor I (CFI), complement C9 (C9), and complement C3 (C3) genes. The case-control cohort was genotyped with allele-specific assays. Serum samples were obtained from carriers of identified variants (n = 177) and age-matched noncarriers (n = 157). Serum concentrations of factor H (FH), factor I (FI), C9, and C3 were measured, and C3b degradation ability was determined. MAIN OUTCOMES AND MEASURES Association of rare variants in the CFH, CFI, C9, and C3 genes with AMD, serum levels of corresponding proteins, and C3b degradation ability of CFH and CFI variant carriers. RESULTS The 1831 unrelated patients with AMD had a mean (SD) age of 75.0 (9.4) years, and 60.5% were female. The 1367 unrelated control participants had a mean (SD) age of 70.4 (7.0), and 58.7% were female. All individuals were of European descent. Rare variants in CFH, CFI, C9, and C3 contributed to an increased risk of developing AMD (odds ratio, 2.04; 95% CI, 1.47-2.82; P <.001). CFI carriers had decreased median FI serum levels (18.2 mu g/mL in Gly119Arg carriers and 16.2 mu g/mL in Leu131Arg carriers vs 27.2 and 30.4 mu g/mL in noncarrier cases and controls, respectively; both P <.001). Elevated C9 levels were observed in Pro167Ser carriers (10.7 mu g/mL vs 6.6 and 6.1 mu g/mL in noncarrier cases and controls, respectively; P <.001). The median FH serum levels were 299.4 mu g/mL for CFH Arg175Gln and 266.3 mu g/mL for CFH Ser193Leu carriers vs 302.4 and 283.0 mu g/mL for noncarrier cases and controls, respectively. The median C3 serum levels were 943.2 mu g/mL for C3 Arg161Trp and 946.7 mu g/mL for C3 Lys155Gln carriers vs 874.0 and 946.7 mu g/mL for noncarrier cases and controls, respectively. The FH and FI levels correlated with C3b degradation in noncarriers (R2 = 0.35 and R2 = 0.31, respectively; both P <.001). CONCLUSIONS AND RELEVANCE Reduced serum levels were associated with C3b degradation in carriers of CFI but not CFH variants, suggesting that CFH variants affect functional activity of FH rather than serum levels. Carriers of CFH (Arg175Gln and Ser193Leu) and CFI (Gly119Arg and Leu131Arg) variants have an impaired ability to regulate complement activation and may benefit more from complement-inhibiting therapy than patients with AMD in general.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Geerlings, Maartje J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kremlitzka, Mariann UNSPECIFIED UNSPECIFIED UNSPECIFIED Bakker, Bjorn UNSPECIFIED UNSPECIFIED UNSPECIFIED Nilsson, Sara C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Saksens, Nicole T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lechanteur, Yara T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pauper, Marc UNSPECIFIED orcid.org/0000-0001-6274-9891 UNSPECIFIED Corominas, Jordi UNSPECIFIED UNSPECIFIED UNSPECIFIED Fauser, Sascha UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoyng, Carel B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Blom, Anna M. UNSPECIFIED UNSPECIFIED UNSPECIFIED de Jong, Eiko K. UNSPECIFIED UNSPECIFIED UNSPECIFIED den Hollander, Anneke I. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-247061
DOI:	10.1001/jamaophthalmol.2016.4604
Journal or Publication Title:	JAMA Ophthalmol.
Volume:	135
Number:	1
Page Range:	S. 39 - 47
Date:	2017
Publisher:	AMER MEDICAL ASSOC
Place of Publication:	CHICAGO
ISSN:	2168-6173
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HEMOLYTIC-UREMIC SYNDROME; FACTOR-I; FACTOR-H; HIGH-RISK; CFI GENE; MUTATION; ASSOCIATION; CONFERS Multiple languages Ophthalmology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/24706