Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 287, Issue 2, Pages 1520-1526Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.275990
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Funding
- NEI
- National Basic Research Program of China [2011CB510200]
- Chinese National 985 Project
- Veterans Affairs Merit Award
- Research to Prevent Blindness
- BWF
- National Natural Science Foundation of China [81025006]
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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-beta) family and regulate their signaling pathways. Growth differentiation factor 6 (GDF6), a member of the TGF-beta 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) rs6982567 A/G near the GDF6 gene that is significantly associated withAMD(p value = 3.54 x 10(-8)). We demonstrated that the GDF6 AMD risk allele (rs6982567 A) is associated with decreased expression of the 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 the RPE layer, retinal and brain tissues in HTRA1 knock-out (htra1(-/-)) mice as compared with the wild-type counterparts. Furthermore, we showed enhanced SMAD signaling in htra1(-/-) mice. Our data suggests a critical role of HTRA1 in the regulation of angiogenesis via TGF-beta signaling and identified GDF6 as a novel disease gene for AMD.
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