High temperature requirement factor A1 (HTRA1) gene regulates angiogenesis through transforming growth factor-β family member growth differentiation factor 6

J Biol Chem. 2012 Jan 6;287(2):1520-6. doi: 10.1074/jbc.M111.275990. Epub 2011 Nov 2.

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-β (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) rs6982567 A/G near the GDF6 gene that is significantly associated with AMD (p value = 3.54 × 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-β signaling and identified GDF6 as a novel disease gene for AMD.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged
  • Alleles
  • Animals
  • Cohort Studies
  • Female
  • Gene Expression Regulation / genetics
  • Growth Differentiation Factor 6 / biosynthesis*
  • Growth Differentiation Factor 6 / genetics
  • High-Temperature Requirement A Serine Peptidase 1
  • Humans
  • Macular Degeneration / genetics
  • Macular Degeneration / metabolism*
  • Macular Degeneration / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism*
  • Neovascularization, Pathologic / pathology
  • Polymorphism, Single Nucleotide*
  • Retina / metabolism
  • Retina / pathology
  • Risk Factors
  • Serine Endopeptidases / biosynthesis*
  • Serine Endopeptidases / genetics
  • Signal Transduction / genetics
  • Smad Proteins / genetics
  • Smad Proteins / metabolism

Substances

  • GDF6 protein, human
  • Gdf6 protein, mouse
  • Growth Differentiation Factor 6
  • Smad Proteins
  • High-Temperature Requirement A Serine Peptidase 1
  • HTRA1 protein, human
  • HtrA1 protein, mouse
  • Serine Endopeptidases