Glaucoma is a group of eye diseases which result in damage to the optic nerve and may cause vision loss if not treated early enough. Higher than normal Intraocular pressure (IOP) is a known risk factor for glaucoma. Although genome-wide association studies (GWAS) have been performed previously, the functional consequences of the found associations have not been clear.
A new study led by Manuel A. Rivas of Stanford University, California, USA, utilized the UK biobank and FinnGen population cohorts to discover rare protein-altering variants that reduce IOP and test whether those variants confer protection against glaucoma. The results of the study were published in the journal PLoS Genetics.
Corneal-compensated and Goldmann-correlated tonometry were used as measures of IOP in 82,253 unrelated participants in the UK Biobank. A missense substitution (p.Gln175His) in the gene ANGPTL7 was significantly associated, below the Bonferroni-corrected P value < 1.0×10-6, with lower IOP measurements. Three other rare variants in ANGPTL7 were also identified but they were less significant.
In UK biobank participants with IOP measurements it was estimated that the ANGPTL7 variant lowered glaucoma risk by 34%. The association of reduced glaucoma risk with ANGPTL7 was reproduced by a different variant (p.Arg220Cys) in the FinnGen subset of 6,537 glaucoma patients and 170,362 controls, providing strong support that protein-altering variants in ANGPTL7 can protect against glaucoma.
ANGPTL7 encodes angiopoietin-related protein 7, a member of a family that are structurally similar to angiopoietin, and recent studies reveal that they function in angiogenesis, lipid & energy metabolism as well as regulation of inflammation. No severe medical consequences were identified that would negate the possibility of developing a therapeutic targeting ANGPTL7 to mimic the effect of the glaucoma risk reducing alleles discovered in this biobank study.
The study did not establish whether the protective variants were complete loss-of-function, partial loss-of-function, dominant negative, or gain of function. It is unclear in which cells the ANGPTL7 variants exert their function.
“This study establishes strong genetic evidence for the involvement of ANGPTL7 in glaucoma risk in which a powerful allelic series, including multiple low-frequency missense substitutions and a single premature stop-gain substitution, is conclusively associated with reduced disease risk and endophenotype-lowering effects,” concluded the authors.