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Jessica Cooke Bailey, Puya Gharahkhani, Stuart W Tompson, Tomokazu Souma, Owen Siggs, Terri L Young, Angelo P Tanna, Louis R Pasquale, Susan E Quaggin, Stuart MacGregor, Jamie E Craig, Jonathan L Haines, Janey L. Wiggs; Association of ANGPT1 with Primary Open Angle Glaucoma. Invest. Ophthalmol. Vis. Sci. 2017;58(8):3822. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Primary open angle glaucoma (POAG), a major worldwide cause of blindness, is a genetically and clinically heterogeneous disease. Genetics play a significant role in POAG; however, the currently known 15 genomic regions associated with POAG risk account for only a fraction of disease heritability, suggesting that additional disease-related genes exist. Recently, TIE2 (TEK) loss of function mutations have been identified in congenital glaucoma families with age of disease onset varying from birth to adulthood (1). The purpose of this study is to examine POAG association for SNPs located in the genomic regions that include TIE2 and its ligand ANGPT1 as well as a related receptor ligand pair ANGPT2 and TIE1.1. Souma T et al. J Clin Invest. 2016 Jul 1;126(7):2575-87.
We accessed two POAG imputed datasets, the NEIGHBOR consortium’s 3,853 cases and 33,480 controls as well as the Australia (ANZRAG) 1,155 cases and 1,992 controls, each of which was analyzed via logistic regression controlling for age, gender and population specific eigenvectors and covariates. We assessed 2,302 SNPs located within the genomic regions corresponding to TIE1, TIE2, ANGPT1, and ANGPT2. Individual SNP results from each dataset were meta-analyzed using METAL.
We detected significant association (surpassing the multiple testing threshold for 2,302 SNPs of P=2.17x10-5) at 19 SNPs located in the genomic region around ANGPT1 (top SNP rs34597339[T], P = 3.24x10-6, OR = 0.81). Thirteen of these SNPs are located in a 15Kb promoter region (ENCODE) that includes an alternative transcription start site used by various cell types including umbilical vein endothelial cells (HUVEC). We did not observe significant association with POAG at SNPs located in the TIE1, TIE2, and ANGPT2 genomic regions (P> 2.17x10-5).
Prior studies have shown that ANGPT1 and TIE2 are necessary for development of Schlemm’s canal (2) and that loss of function mutations in TIE2 cause glaucoma with variable age of onset (1). The results from our study highlight SNPs located in the ANGPT1 genomic region as associated with POAG, which suggests that modulation of ANGPT1-TIE2 signaling may also contribute to the development of adult-onset glaucoma.2. Thomson BR, et al. J Clin Invest. 2014 Oct;124(10):4320-4.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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