Chromosome 10q26–driven age-related macular degeneration is associated with reduced levels of <i>HTRA1</i> in human retinal pigment epithelium
Brandi L. Williams, Nathan A. Seager, Jamie Gardiner, Chris Pappas, Monica C. Cronin, Cristina Amat Di San Filippo, Robert A. Anstadt, Jin Liu, Marc Toso, Lisa Nichols, Timothy J. Parnell, Jacqueline R Eve, Sven Heinz, Michael G.B. Hayes, Paul L. Bartel, Moussa A. Zouache, Burt T. Richards, Gregory S. Hageman
Abstract
Significance The chromosome 10q26 locus is the genetic region most strongly associated with elevated risk of age-related macular degeneration (AMD), but the underlying genetic defects initiating disease are unresolved. Using human-derived eye tissues, we demonstrate that mRNA encoding the serine protease, HTRA1, is reduced in the retinal pigment epithelium (RPE) of donors with risk-associated variants that disrupt a cis-regulatory element within the 10q26 locus. Consequentially, there is diminished HtrA1 protein within the RPE–Bruch’s membrane interface, the primary site of AMD initiation, with age. This indicates that HtrA1 functions to maintain the integrity of this interface during the aging process and that HtrA1 levels are impaired by chromosome 10q26 risk-associated variants. HtrA1 augmentation may be a viable therapeutic option for AMD.