ANGPTL7 and Glaucoma

The association between ANGPTL7 and glaucoma is underpinned by robust evidence from large-scale case‑control studies. Recent multi‑patient investigations in UK Biobank (82,253 individuals with intraocular pressure data and 4,238 glaucoma patients [PMID:32369491]) and FinnGen (6,537 glaucoma patients [PMID:36192519]) have demonstrated that rare protein‑altering variants in ANGPTL7 are associated with a significant reduction in intraocular pressure and a protective effect against glaucoma. The studies report a consistent reduction in risk of glaucoma by approximately 29–34% among carriers of such variants, underscoring the clinical relevance of these findings.

Genetic evidence is further supported by the identification of a rare missense variant, c.524A>C (p.Gln175His), that exemplifies the type of variant implicated in the protective mechanism. Additional variant classes, including loss‑of‑function and protein‑truncating variants, have been observed and collectively strengthen the genetic association between ANGPTL7 and glaucoma. Although formal segregation analysis in family studies is limited, the large sample sizes and replication across populations contribute to a strong genetic evidence base ([PMID:32369491], [PMID:36192519]).

The mode of inheritance appears to be autosomal dominant with respect to the protective effect conferred by a single copy of the variant. No additional affected relatives with segregating variants were reported in the available studies, which is common in observations that arise from population‑based association analyses. This non‐Mendelian pattern is often seen in risk‑modifying alleles that influence complex traits such as glaucoma.

Functional studies provide moderate support for the pathogenicity mechanism by demonstrating that reduced ANGPTL7 expression leads to lower intraocular pressure. Experiments in human trabecular meshwork cells and Angptl7 knockout mice have validated that decreased levels of secreted ANGPTL7 are associated with a protective phenotype against IOP elevation. These experimental findings are consistent with the genetic data, as lower protein levels by disruptive variants correlate with reduced glaucoma risk ([PMID:37220876], [PMID:19744340]).

Integration of the genetic and functional evidence solidifies the association between ANGPTL7 and glaucoma. Rare coding variants in ANGPTL7, predominantly missense and loss‑of‑function types, have repeatedly been linked with a lowered risk of glaucoma by reducing intraocular pressure. While the allele frequencies are low, the reproducibility across independent cohorts and the experimental validation exceeding typical ClinGen scoring maximums underscore the clinical utility of ANGPTL7 variant screening.

Key take‑home: ANGPTL7 represents a promising target for therapeutic intervention in glaucoma, with protective variants offering clear avenues for future clinical application and personalized medicine.

References

• PLoS Genetics • 2020 • Rare protein‑altering variants in ANGPTL7 lower intraocular pressure and protect against glaucoma PMID:32369491
• Communications Biology • 2022 • ANGPTL7, a therapeutic target for increased intraocular pressure and glaucoma PMID:36192519
• Human Molecular Genetics • 2023 • Rare protective variants and glaucoma‑relevant cell stressors modulate Angiopoietin‑like 7 expression PMID:37220876
• BMC Medical Genomics • 2009 • Glucocorticoids with different chemical structures but similar glucocorticoid receptor potency regulate subsets of common and unique genes in human trabecular meshwork cells PMID:19744340

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