AMD, a retinal angiogenic disease associated with VEGF, affects approximately 50 million elderly people worldwide.
15 We previously identified an association of exudative AMD with a single nucleotide polymorphism, rs11200638, in the promoter region of the high-temperature requirement factor A1 (
HTRA1) gene.
16 –18 HtrA1 belongs to the evolutionarily conserved HtrA family of chymotrypsin-like serine protease, which exhibits temperature-dependent proteolytic and molecular chaperone activities.
19,20 It carries a N-terminal secretory signal peptide, a mac25-like domain, and a C-terminal HtrA (proteolytic and PDZ) domain.
21,22 Human
HTRA1 was identified as a differentially expressed gene in SV40-transformed fibroblasts
21 and osteoarthritic cartilage.
22 Downregulation of
HTRA1 was detected in 11–63% cancer samples from different tissues.
23,24 In HtrA1-overexpressed cancer cell lines there was enhanced cell apoptosis and reduced cell proliferation.
23,24 In contrast to cancer, upregulation of HtrA1 occurs in placentation,
25 arthritis,
22,26 Alzheimer's disease,
27 and Duchenne muscular dystrophy.
28 HTRA1 mRNA and protein expressions were elevated in the lymphocytes and retinal pigment epithelium (RPE) of AMD patients carrying the risk-associated allele.
17 HtrA1 is also present in drusen, abnormal RPE, and choroidal neovascularization lesion, with elevated expressions in AMD eyes.
17,29 –31 HtrA1 also inhibits TGFβ signaling and degrades extracellular matrix proteins.
26,32,33 These findings provide evidence for a contributory role of HtrA1 on AMD pathogenesis.