ANGPTL7, a therapeutic target for increased intraocular pressure and glaucoma

Abstract

Glaucoma is a leading cause of blindness. Current glaucoma medications work by lowering intraocular pressure (IOP), a risk factor for glaucoma, but most treatments do not directly target the pathological changes leading to increased IOP, which can manifest as medication resistance as disease progresses. To identify physiological modulators of IOP, we performed genome- and exome-wide association analysis in >129,000 individuals with IOP measurements and extended these findings to an analysis of glaucoma risk. We report the identification and functional characterization of rare coding variants (including loss-of-function variants) in ANGPTL7 associated with reduction in IOP and glaucoma protection. We validated the human genetics findings in mice by establishing that Angptl7 knockout mice have lower (~2 mmHg) basal IOP compared to wild-type, with a trend towards lower IOP also in heterozygotes. Conversely, increasing murine Angptl7 levels via injection into mouse eyes increases the IOP. We also show that acute Angptl7 silencing in adult mice lowers the IOP (~2–4 mmHg), reproducing the observations in knockout mice. Collectively, our data suggest that ANGPTL7 is important for IOP homeostasis and is amenable to therapeutic modulation to help maintain a healthy IOP that can prevent onset or slow the progression of glaucoma.

A deep catalog of protein-coding variation in 985,830 individuals

“…Interestingly, T2D, metabolic disorder risks and immune system disorders has been previously hypothesized to be a target of natural selection in humans because of adaptations to metabolism, energy production, and pathogens 51,56–58 . Some of the notable association signals of genes with variants having high Fst identified in Biobank of Japan data that fit this hypothesis include PAX4 (p=6.3 x 10 - 90 ; T2D), GP2 (p=1.33×10 - 14 ; T2D), GLP1R (p= 6.10×10 - 14 ; T2D), ATXN2 (p=1.09×10 - 11 ; chronic obstructive pulmonary disease), 6p21.32 ( BTNL2 , NOTCH4 ; p<2.89×10 - 54 ; rheumatoid arthritis) and NLRP10 (p=2.39×10 - 35 ; atopic dermatitis) (Supplementary Table 7.4). We also observed significant association of high-Fst variants in IFRD2 (p=2.72 x 10 - 21 ; reticulocyte count), MFSD2B (p=1.75 x 10 - 12 ; HbA1C), USP40 (p=1.05 x 10 - 10 ; total bilirubin) in UKB-Africans summary statistics.…”

“…Anti-PCSK9 drug therapy is an example of human-genetics-guided drug development based on the observation that loss of PCSK9 function is associated with lower cholesterol levels 9 . Large-scale exome sequencing studies identified rare variants in several genes associated with protective traits, notably, ANGPTL3 for coronary artery disease, GPR75 for obesity, CIDEB for liver disease, MAP3K15 for diabetes, and ANGPTL7 for intraocular pressure 8,[10][11][12][13][14] . Thus, exome sequencing efforts have led to the discovery of functionally important rare variants and genes.…”

Genome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease susceptibility and age-of-onset

“…In addition, thyroid function within the euthyroid range is associated with adverse outcomes (18) and thus TSH-associated variants that have not yet been overtly associated with thyroid disease remain highly relevant. GWAS of other quantitative traits -including those on the UK Biobank biomarker panel -have highlighted a number of targets leading to active drug development for related diseases (3)(4)(5). However, TSH has not yet been measured in UK Biobank samples.…”

“…Genome-wide association studies (GWAS) of quantitative traits have been particularly powerful and successful in identifying new drug targets (3)(4)(5). Most genetic associations for thyroid disorders were discovered in GWAS of thyroid-stimulating hormone (TSH) levels, a sensitive marker of thyroid function which is suppressed when levels of thyroxine (T 4 ) and triiodothyronine (T 3 ) are high and elevated when T 4 and T 3 levels are low.…”

ANGPTL7 and Its Role in IOP and Glaucoma

“…In line with these observations, ANGPTL7 is highly expressed in TM cells, the prominent cell type in the conventional outflow tract. 4 – 6 Variants that destabilize ANGPTL7 and decrease the secretion of ANGPTL7 are associated with reduced IOP, 7 and increased levels of secreted ANGPTL7 have been found in the aqueous humor of human patients with glaucoma compared to controls. 8 In addition, ANGPTL7 gene expression has been shown to increase in response to stressors associated with glaucoma pathobiology, including the glucocorticoid dexamethasone (Dex) and transforming growth factor-β.…”