HTRA1 regulates angiogenesis through TGF-β family member GDF6.

Abstract

Genome-wide association study (GWAS) has identified genetic variants in the promoter region of the high temperature requirement factor A1 (HTRA1) gene associated with age-related macular degeneration (AMD). As a secreted serine protease, HTRA1 has been reported to interact with members of the transforming growth factor-beta (TGF-β) family and regulate their signaling pathways. Growth differentiation factor 6 (GDF6), a member of the TGF-β family, is involved in ectoderm patterning and eye development. Mutations in GDF6 have been associated with abnormal eye development that may result in microphthalmia and anophthalmia. In this report, we identified a single nucleotide polymorphism (SNP) rs6982567A/G near GDF6 gene that is significantly associated with AMD (p-value = 3.54E-8). We demonstrated that the GDF6 AMD risk allele (rs6982567 A) is associated with decreased expression of GDF6 and increased expression of HTRA1. Similarly, the HTRA1 AMD risk allele (rs10490924 T) is associated with decreased GDF6 and increased HTRA1 expression. We observed decreased vascular development in the retina and significant up-regulation of gdf6 gene in RPE layer, retinal and brain tissues from HTRA1 knockout (htra1-/-) mice as compared to the wild-type counterparts. We also showed enhanced SMAD signaling in htra1-/- mice. Our data suggests a critical role of HTRA1 in the regulation of angiogenesis via TGF-β signaling and identified GDF6 as a novel disease gene for AMD.