Universität zu Köln

Grassmann, Felix ORCID: 0000-0003-1390-7528, Harsch, Sebastian, Brandl, Caroline ORCID: 0000-0001-8223-6137, Kiel, Christina ORCID: 0000-0003-3154-4847, Nuernberg, Peter, Toliat, Mohammad R., Fleckenstein, Monika, Pfau, Maximilian, Schmitz-Valckenberg, Steffen, Holz, Frank G., Chew, Emily Y., Swaroop, Anand, Ratnapriya, Rinki ORCID: 0000-0002-0469-4631, Klein, Michael L., Mulyukov, Zufar, Zamiri, Parisa and Weber, Bernhard H. F. (2019). Assessment of Novel Genome-Wide Significant Gene Loci and Lesion Growth in Geographic Atrophy Secondary to Age-Related Macular Degeneration. JAMA Ophthalmol., 137 (8). S. 867 - 877. CHICAGO: AMER MEDICAL ASSOC. ISSN 2168-6173

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Abstract

Importance Age-related macular degeneration (AMD) is a common threat to vision loss in individuals older than 50 years. While neovascular complications in AMD are treatable, there is currently no therapy for geographic atrophy secondary to AMD. Geographic atrophy lesion progression over time shows considerable interindividual variability, but little is known about prognostic factors. Objective To elucidate the contribution of common genetic variants to geographic atrophy lesion growth. Design, Setting, and Participants This pooled analysis combined 4 independent studies: the Fundus Autofluorescence Imaging in Age-Related Macular Degeneration (FAM) study, the Directional Spread in Geographic Atrophy (DSGA) study, the Age-Related Eye Disease Study (AREDS), and the Geographic Atrophy Treatment Evaluation (GATE) study. Each provided data for geographic atrophy lesion growth in specific designs. Patients with geographic atrophy secondary to AMD were recruited to these studies. Genotypes were retrieved through the database of Genotypes and Phenotypes (for AREDS) or generated at the Cologne Center for Genomics (for FAM, DSGA, and GATE). Main Outcomes The correlation between square root-transformed geographic atrophy growth rate and 7596219 genetic variants passing quality control was estimated using linear regression. The calculations were adjusted for known factors influencing geographic atrophy growth, such as the presence of bilateral geographic atrophy as well as the number of lesion spots and follow-up times. Main Outcomes and Measures Slopes per allele, 95% CIs, and P values of genetic variants correlated with geographic atrophy lesion growth. Results A total of 935 patients (mean [SD] age, 74.7 [7.8] years; 547 female participants [59.0%]) were included. Two gene loci with conservative genome-wide significance were identified. Each minor allele of the genome-wide associated variants increased the geographic atrophy growth rate by a mean of about 15% or 0.05 mm per year. Gene prioritization within each locus suggests the protein arginine methyltransferase 6 gene (PRMT6; chromosome 1; slope, 0.046 [95% CI, 0.026-0.066]; P=4.09x10(-8)) and the lanosterol synthase gene (LSS; chromosome 21; slope, 0.105 [95% CI, 0.068-0.143]; P=4.07x10(-7)) as the most likely progression-associated genes. Conclusions and Relevance These data provide further insight into the genetic architecture of geographic atrophy lesion growth. Geographic atrophy is a clinical outcome with a high medical need for effective therapy. The genes PRMT6 and LSS are promising candidates for future studies aimed at understanding functional aspects of geographic atrophy progression and also for designing novel and targeted treatment options.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Grassmann, Felix UNSPECIFIED orcid.org/0000-0003-1390-7528 UNSPECIFIED Harsch, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Brandl, Caroline UNSPECIFIED orcid.org/0000-0001-8223-6137 UNSPECIFIED Kiel, Christina UNSPECIFIED orcid.org/0000-0003-3154-4847 UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Toliat, Mohammad R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fleckenstein, Monika UNSPECIFIED UNSPECIFIED UNSPECIFIED Pfau, Maximilian UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmitz-Valckenberg, Steffen UNSPECIFIED UNSPECIFIED UNSPECIFIED Holz, Frank G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Chew, Emily Y. UNSPECIFIED UNSPECIFIED UNSPECIFIED Swaroop, Anand UNSPECIFIED UNSPECIFIED UNSPECIFIED Ratnapriya, Rinki UNSPECIFIED orcid.org/0000-0002-0469-4631 UNSPECIFIED Klein, Michael L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mulyukov, Zufar UNSPECIFIED UNSPECIFIED UNSPECIFIED Zamiri, Parisa UNSPECIFIED UNSPECIFIED UNSPECIFIED Weber, Bernhard H. F. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-145759
DOI:	10.1001/jamaophthalmol.2019.1318
Journal or Publication Title:	JAMA Ophthalmol.
Volume:	137
Number:	8
Page Range:	S. 867 - 877
Date:	2019
Publisher:	AMER MEDICAL ASSOC
Place of Publication:	CHICAGO
ISSN:	2168-6173
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NATURAL-HISTORY; EYE DISEASE; ASSOCIATION; EXPRESSION; DISCOVERY; DATABASE; RARE; AREA Multiple languages Ophthalmology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/14575