Risk and protection of different rare protein-coding variants of complement component C4A in age-related macular degeneration

Johanna M Seddon; Dikha De; William Casazza; Shun-Yun Cheng; Claudio Punzo; Mark Daly; Danlei Zhou; Samantha L Coss; John P Atkinson; Chack-Yung Yu

doi:10.3389/fgene.2023.1274743

Risk and protection of different rare protein-coding variants of complement component C4A in age-related macular degeneration

Front Genet. 2024 Jan 29:14:1274743. doi: 10.3389/fgene.2023.1274743. eCollection 2023.

Authors

Affiliations

¹ Department of Ophthalmology and Visual Sciences, University of Massachusetts Chan Medical School, Worcester, MA, United States.
² Broad Institute of MIT and Harvard, Cambridge, MA, United States.
³ Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, United States.
⁴ Department of Internal Medicine, Division of Rheumatology, Washington University School of Medicine, Saint Louis, MO, United States.

Abstract

Introduction: Age-related macular degeneration (AMD) is the leading cause of central vision loss in the elderly. One-third of the genetic contribution to this disease remains unexplained. Methods: We analyzed targeted sequencing data from two independent cohorts (4,245 cases, 1,668 controls) which included genomic regions of known AMD loci in 49 genes. Results: At a false discovery rate of <0.01, we identified 11 low-frequency AMD variants (minor allele frequency <0.05). Two of those variants were present in the complement C4A gene, including the replacement of the residues that contribute to the Rodgers-1/Chido-1 blood group antigens: [VDLL1207-1210ADLR (V1207A)] with discovery odds ratio (OR) = 1.7 (p = 3.2 × 10^-5) which was replicated in the UK Biobank dataset (3,294 cases, 200,086 controls, OR = 1.52, p = 0.037). A novel variant associated with reduced risk for AMD in our discovery cohort was P1120T, one of the four C4A-isotypic residues. Gene-based tests yielded aggregate effects of nonsynonymous variants in 10 genes including C4A, which were associated with increased risk of AMD. In human eye tissues, immunostaining demonstrated C4A protein accumulation in and around endothelial cells of retinal and choroidal vasculature, and total C4 in soft drusen. Conclusion: Our results indicate that C4A protein in the complement activation pathways may play a role in the pathogenesis of AMD.

Keywords: C4A, C4B; age-related macular degeneration; complement proteins; complement system; genetic associations; targeted sequencing.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. Supported by NIH R01-EY011309, R01-EY028602, R01-AR073311, American Macular Degeneration Foundation, Northampton, MA, Macular Degeneration Research Fund, University of Massachusetts Chan Medical School, Department of Ophthalmology and Visual Sciences, Worcester, MA. Targeted sequencing for ARTS study supported by an anonymous donor to AMD Research Fund (JMS). Sequencing for MMAP supported by U54-HG003079, National Human Genome Research Institute, NIH.