gms | German Medical Science

Genome-wide association studies (GWAS) have shown that one or more single nucleotide polymorphisms (SNPs) and/or an insertion/deletion within the chromosome 10q26 locus (Chr10) significantly increase(s) risk for developing age-related macular degeneration (AMD). Genes within this locus include age-related maculopathy susceptibility 2 (ARMS2) and high-temperature requirement A serine peptidase 1 (HTRA1). Using multiple methodologies, we show that HTRA1 mRNA expression is specifically reduced in retinal pigment epithelium (RPE) of human donors with Chr10 risk relative to non-risk donors but is not reduced in the retinas of these same donors, indicating an RPE-specific HTRA1 eQTL effect. Importantly, HTRA1 mRNA in the RPE-choroid from Chr10 risk donors without clinically detectable AMD is low relative to non-risk donors and levels remain low even after disease onset. By comparison, HTRA1 mRNA is higher in non-risk donors, both before and after AMD disease onset. Using two independent and validated HtrA1 ELISAs, we demonstrate that levels of HtrA1 protein in human serum, vitreous and retina are unaffected by Chr10 SNPs or AMD status. In contrast, HtrA1 protein levels increase with age in RPE-choroid tissue from Chr10 non-risk donors and this age-dependent increase is absent in donors with homozygous Chr10 risk. Together, these data indicate that altered expression of HtrA1 in RPE tissue from Chr10 risk donors is an early event that precedes disease onset and is a contributing factor to disease initiation and/or progression. It implies that HtrA1 is important for maintaining a healthy RPE-Bruch’s membrane interface during the aging process and that decreased HtrA1 protein, specifically in RPE tissue, contributes to increased risk for AMD pathogenesis.