Ongoing controversies and recent insights of the ARMS2-HTRA1 locus in age-related macular degeneration

Adam May; Fei Su; Brian Dinh; Rachael Ehlen; Christina Tran; Harini Adivikolanu; Peter X Shaw

doi:10.1016/j.exer.2021.108605

Ongoing controversies and recent insights of the ARMS2-HTRA1 locus in age-related macular degeneration

Exp Eye Res. 2021 Sep:210:108605. doi: 10.1016/j.exer.2021.108605. Epub 2021 Apr 28.

Authors

Adam May¹, Fei Su², Brian Dinh³, Rachael Ehlen⁴, Christina Tran⁵, Harini Adivikolanu⁶, Peter X Shaw⁷

Affiliations

¹ Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California, San Diego, 9415 Campus Point Drive, La Jolla, CA 92093-0946, USA; Altman Clinical and Translational Research Institute, University of California, San Diego, 9452 Medical Center Drive, La Jolla, CA 92093-0990, USA. Electronic address: [email protected].
² Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California, San Diego, 9415 Campus Point Drive, La Jolla, CA 92093-0946, USA; Altman Clinical and Translational Research Institute, University of California, San Diego, 9452 Medical Center Drive, La Jolla, CA 92093-0990, USA. Electronic address: [email protected].
³ Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California, San Diego, 9415 Campus Point Drive, La Jolla, CA 92093-0946, USA; Altman Clinical and Translational Research Institute, University of California, San Diego, 9452 Medical Center Drive, La Jolla, CA 92093-0990, USA. Electronic address: [email protected].
⁴ Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California, San Diego, 9415 Campus Point Drive, La Jolla, CA 92093-0946, USA; Altman Clinical and Translational Research Institute, University of California, San Diego, 9452 Medical Center Drive, La Jolla, CA 92093-0990, USA. Electronic address: [email protected].
⁵ Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California, San Diego, 9415 Campus Point Drive, La Jolla, CA 92093-0946, USA; Altman Clinical and Translational Research Institute, University of California, San Diego, 9452 Medical Center Drive, La Jolla, CA 92093-0990, USA. Electronic address: [email protected].
⁶ Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California, San Diego, 9415 Campus Point Drive, La Jolla, CA 92093-0946, USA; Altman Clinical and Translational Research Institute, University of California, San Diego, 9452 Medical Center Drive, La Jolla, CA 92093-0990, USA. Electronic address: [email protected].
⁷ Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California, San Diego, 9415 Campus Point Drive, La Jolla, CA 92093-0946, USA; Altman Clinical and Translational Research Institute, University of California, San Diego, 9452 Medical Center Drive, La Jolla, CA 92093-0990, USA. Electronic address: [email protected].

PMID: 33930395
DOI: 10.1016/j.exer.2021.108605

Abstract

Age-related macular degeneration (AMD) is the most common cause of central vision loss among elderly populations in industrialized countries. Genome-wide association studies have consistently associated two genomic loci with progression to late-stage AMD: the complement factor H (CFH) locus on chromosome 1q31 and the age-related maculopathy susceptibility 2-HtrA serine peptidase 1 (ARMS2-HTRA1) locus on chromosome 10q26. While the CFH risk variant has been shown to alter complement activity, the ARMS2-HTRA1 risk haplotype remains enigmatic due to high linkage disequilibrium and inconsistent functional findings spanning two genes that are plausibly causative for AMD risk. In this review, we detail the genetic and functional evidence used to support either ARMS2 or HTRA1 as the causal gene for AMD risk, emphasizing both the historical development and the current understanding of the ARMS2-HTRA1 locus in AMD pathogenesis. We conclude by summarizing the evidence in favor of HTRA1 and present our hypothesis whereby HTRA1-derived ECM fragments mediate AMD pathogenesis.

Keywords: ARMS2-HTRA1 gene locus; Age-related macular degeneration; Complement system; Extracellular matrix; Linkage disequilibrium; TGF-Beta signaling.

Publication types

Research Support, N.I.H., Extramural
Review

MeSH terms

Chromosomes, Human, Pair 10 / genetics
Genetic Loci
Genome-Wide Association Study
Haplotypes
High-Temperature Requirement A Serine Peptidase 1 / genetics*
Humans
Linkage Disequilibrium
Macular Degeneration / genetics*
Proteins / genetics*

Substances

ARMS2 protein, human
Proteins
High-Temperature Requirement A Serine Peptidase 1
HTRA1 protein, human

Grants and funding

P30 EY022589/EY/NEI NIH HHS/United States