Universität zu Köln

Acar, Ilhan E., Lores-Motta, Laura, Colijn, Johanna M., Meester-Smoor, Magda A., Verzijden, Timo, Cougnard-Gregoire, Audrey, Ajana, Soufiane, Merle, Benedicte M. J., de Breuk, Anita, Heesterbeek, Thomas J., van den Akker, Erik, Daha, Mohamed R., Claes, Birte, Pauleikhoff, Daniel, Hense, Hans-Werner, van Duijn, Cornelia M., Fauser, Sascha, Hoyng, Carel B., Delcourt, Cecile ORCID: 0000-0002-2099-0481, Klaver, Caroline C. W., Galesloot, Tessel E. and den Hollander, Anneke, I (2020). Integrating Metabolomics, Genomics, and Disease Pathways in Age-Related Macular Degeneration The EYE-RISK Consortium. Ophthalmology, 127 (12). S. 1693 - 1710. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1549-4713

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Abstract

Purpose: The current study aimed to identify metabolites associated with age-related macular degeneration (AMD) by performing the largest metabolome association analysis in AMD to date, as well as aiming to determine the effect of AMD-associated genetic variants on metabolite levels and investigate associations between the identified metabolites and activity of the complement system, one of the main AMD-associated disease pathways. Design: Case-control association analysis of metabolomics data. Participants: Five European cohorts consisting of 2267 AMD patients and 4266 control participants. Methods: Metabolomics was performed using a high-throughput proton nuclear magnetic resonance metabolomics platform, which allows quantification of 146 metabolite measurements and 79 derivative values. MetabolomeeAMD associations were studied using univariate logistic regression analyses. The effect of 52 AMD-associated genetic variants on the identified metabolites was investigated using linear regression. In addition, associations between the identified metabolites and activity of the complement pathway (defined by the C3d-to-C3 ratio) were investigated using linear regression. Main Outcome Measures: Metabolites associated with AMD. Results: We identified 60 metabolites that were associated significantly with AMD, including increased levels of large and extra-large high- density lipoprotein (HDL) subclasses and decreased levels of very low-density lipoprotein (VLDL), amino acids, and citrate. Of 52 AMD-associated genetic variants, 7 variants were associated significantly with 34 of the identified metabolites. The strongest associations were identified for genetic variants located in or near genes involved in lipid metabolism (ABCA1, CETP, APOE, and LIPC) with metabolites belonging to the large and extra-large HDL subclasses. Also, 57 of 60 metabolites were associated significantly with complement activation levels, independent of AMD status. Increased large and extra-large HDL levels and decreased VLDL and amino acid levels were associated with increased complement activation. Conclusions: Lipoprotein levels were associated with AMD-associated genetic variants, whereas decreased essential amino acids may point to nutritional deficiencies in AMD. We observed strong associations between the vast majority of the AMD-associated metabolites and systemic complement activation levels, independent of AMD status. This may indicate biological interactions between the main AMD disease pathways and suggests that multiple pathways may need to be targeted simultaneously for successful treatment of AMD. (C) 2020 by the American Academy of Ophthalmology. This is an open access article under the CC BY-NC-ND license

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Acar, Ilhan E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lores-Motta, Laura UNSPECIFIED UNSPECIFIED UNSPECIFIED Colijn, Johanna M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Meester-Smoor, Magda A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Verzijden, Timo UNSPECIFIED UNSPECIFIED UNSPECIFIED Cougnard-Gregoire, Audrey UNSPECIFIED UNSPECIFIED UNSPECIFIED Ajana, Soufiane UNSPECIFIED UNSPECIFIED UNSPECIFIED Merle, Benedicte M. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED de Breuk, Anita UNSPECIFIED UNSPECIFIED UNSPECIFIED Heesterbeek, Thomas J. UNSPECIFIED UNSPECIFIED UNSPECIFIED van den Akker, Erik UNSPECIFIED UNSPECIFIED UNSPECIFIED Daha, Mohamed R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Claes, Birte UNSPECIFIED UNSPECIFIED UNSPECIFIED Pauleikhoff, Daniel UNSPECIFIED UNSPECIFIED UNSPECIFIED Hense, Hans-Werner UNSPECIFIED UNSPECIFIED UNSPECIFIED van Duijn, Cornelia M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fauser, Sascha UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoyng, Carel B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Delcourt, Cecile UNSPECIFIED orcid.org/0000-0002-2099-0481 UNSPECIFIED Klaver, Caroline C. W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Galesloot, Tessel E. UNSPECIFIED UNSPECIFIED UNSPECIFIED den Hollander, Anneke, I UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-309470
DOI:	10.1016/j.ophtha.2020.06.020
Journal or Publication Title:	Ophthalmology
Volume:	127
Number:	12
Page Range:	S. 1693 - 1710
Date:	2020
Publisher:	ELSEVIER SCIENCE INC
Place of Publication:	NEW YORK
ISSN:	1549-4713
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CHAIN AMINO-ACIDS; COMPLEMENT ACTIVATION; WIDE ASSOCIATION; MACULOPATHY; REVEALS; SMOKING; DRUSEN; PANEL; LOCI; RARE Multiple languages Ophthalmology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/30947