Protective effects of a HTRA1 insertion-deletion variant against age-related macular degeneration

Abstract

Purpose : Common polymorphisms are prone to show stronger association with diseases than rare variants because of higher minor allele frequencies. In contract, rare variants in coding regions could be more related to the functions of the proteins. In this study, we investigated the genetic association and biological functions of our previously identified HTRA1 insertion-deletion (indel) variant (c.34delCinsTCCT).

Methods : Two Chinese exudative AMD cohorts with totally 963 subjects were recruited for the genetic association study. Wildtype HTRA1 and variant were cloned and expressed in retinal pigment epithelial (RPE) cells, followed by the characterization of their biological functions.

Results : Genetic analysis verified the higher prevalence of c.34delCinsTCCT allele in control subjects than in AMD patients (p = 8.33 x 10^-5, odds ratio = 0.226). This protective effect was validated as the haplotype of the c.34delCinsTCCT allele existed independent of the risk haplotype (p = 6.23 x 10^-5). In vitro studies showed that recombinant HTRA1 c.34delCinsTCCT variant protein was more localized in the endoplasmic reticulum of RPE cells compared to the wildtype protein, and its secretion was delayed. Moreover, ARPE-19 cells expressing HTRA1 c.34delCinsTCCT variant had higher cell viability, lower cell apoptosis and were less responsive to anoikis, supporting its protective role.

Conclusions : Our results revealed a protective HTRA1 variant against HTRA1-induced RPE cell death, indicating its involvement in AMD pathogenesis.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.