Ultra-rare complement factor 8 coding variants in families with age-related macular degeneration

Lina Zelinger; Tammy M Martin; Jayshree Advani; Laura Campello; Milton A English; Alan Kwong; Claire Weber; Jennifer Maykoski; Yuri V Sergeev; Robert Fariss; Emily Y Chew; Michael L Klein; Anand Swaroop

doi:10.1016/j.isci.2023.106417

Ultra-rare complement factor 8 coding variants in families with age-related macular degeneration

iScience. 2023 Apr 3;26(4):106417. doi: 10.1016/j.isci.2023.106417. eCollection 2023 Apr 21.

Authors

Lina Zelinger¹, Tammy M Martin^{2

3}, Jayshree Advani¹, Laura Campello¹, Milton A English¹, Alan Kwong^{4

5}, Claire Weber⁶, Jennifer Maykoski², Yuri V Sergeev⁷, Robert Fariss⁸, Emily Y Chew⁶, Michael L Klein², Anand Swaroop¹

Affiliations

¹ Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
² Casey Eye Institute, Department of Ophthalmology, Oregon Health & Science University, Portland, OR, USA.
³ Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, OR, USA.
⁴ Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
⁵ 23andMe, Inc, Sunnyvale, CA, USA.
⁶ Division of Epidemiology and Clinical Applications, Clinical Trials Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
⁷ Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
⁸ Biological Imaging Core, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.

Abstract

Genome-wide association studies have uncovered 52 independent common and rare variants across 34 genetic loci, which influence susceptibility to age related macular degeneration (AMD). Of the 5 AMD-associated complement genes, complement factor H (CFH) and CFI exhibit a significant rare variant burden implicating a major contribution of the complement pathway to disease pathology. However, the efforts for developing AMD therapy have been challenging as of yet. Here, we report the identification of ultra-rare variants in complement factors 8A and 8B, two components of the terminal complement membrane attack complex (MAC), by whole exome sequencing of a cohort of AMD families. The identified C8 variants impact local interactions among proteins of C8 triplex in vitro, indicating their effect on MAC stability. Our results suggest that MAC, and not the early steps of the complement pathway, might be a more effective target for designing treatments for AMD.

Keywords: Genetics; Molecular Genetics; Molecular Structure; Molecular biology; Molecular interaction.

Grants and funding

UL1 TR002369/TR/NCATS NIH HHS/United States