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Glaucoma Protective Variants Uncovered in Genetic Data From UK, Finland

NEW YORK – A team from the University of Helsinki, Stanford University and elsewhere has narrowed in on a rare missense variant in the angiopoietin-like 7 factor-coding gene ANGPTL7 that is particularly common in Finland and appears to protect against glaucoma risk. The results appeared in PLOS Genetics on Tuesday.

"The variant we identified is more than 50 times more common in the Finnish population than elsewhere in the world," co-senior author Mark Daly, director of the University of Helsinki's Institute for Molecular Medicine Finland (FIMM), said in a statement. "In fact, more than 8 percent of Finns carry it and have a substantially reduced risk of glaucoma."

Using genetic sequence and clinical data for more than 337,000 UK Biobank participants and nearly 177,000 individuals from the FinnGen cohort, the researchers searched for rare and lower-frequency variants outside the major histocompatibility complex immune region of the genome that were more or less common in individuals with glaucoma or related traits, focusing on those with predicted functional effects.

From the UK Biobank data — which included measurements on intraocular pressure, a glaucoma risk factor, for almost 82,300 genotyped participants — they saw an over-representation of rare missense changes in ANGPTL7 that coincided with reduced risk of the optic nerve-damaging disease or lower-than-usual intraocular pressure.

The team also tracked down a rare ANGPTL7 variant called rs147660927 that appeared to be particularly common in Finnish individuals. It estimated that the rs147660927 variant corresponded to a 29 percent dip in glaucoma risk based on findings from a follow-up analysis that included 6,537 individuals with glaucoma and 170,362 unaffected controls.

"Our results position angiopoietin-like 7 as an appealing and safe target for glaucoma therapies," Daly said. "If a drug can be developed that mimics the protective effect of these mutations, intraocular pressure in at-risk individuals could be lowered."

On the other hand, the team's broader analyses of genetic and clinical data from the UK Biobank and FinnGenn projects did not unearth lifespan or other worrisome changes in those with rare mutations in the gene that are expected to produce lower-than-usual angiopoietin-like 7 levels or activity, hinting that it may one day be possible to curb intraocular pressure and glaucoma risk by therapeutically targeting ANGPTL7 without raising the risk of other conditions.

"Our results highlight the benefits of multi-cohort analysis for the discovery of rare protein-altering variants in common diseases, and ANGPTL7 provides the best therapeutic hypothesis out there for glaucoma," co-senior author Manuel Rivas, a biomedical data science researcher at Stanford, said in a statement.