THE ROLE OF FAMILIAL GENETICS AND FAMILY HISTORY AS RISK FACTORS FOR PRIMARY GLAUCOMA: A SYSTEMATIC REVIEW OF RANDOMISED CONTROLLED TRIALS AND PRIMARY STUDIES

Abstract

Introduction. Primary glaucoma—comprising primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG)—is the leading global cause of irreversible blindness. Although raised intraocular pressure (IOP) remains the only modifiable determinant, the disease demonstrates conspicuous familial aggregation, and both a self-reported family history and the aggregate burden of common risk alleles are now recognised as major non-modifiable determinants of susceptibility.

Methods. The study strictly adhered to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020 guidelines. Eligible: RCTs, cohort, case-control, cross-sectional, and observational studies; systematic reviews excluded from characteristics tables. Risk of bias assessed with Newcastle-Ottawa Scale mapped to ROBINS-E domains and RoB 2 for randomised evidence; GRADE for certainty.

Results. Thirty-one primary studies comprising 587,832 participants. A positive family history in first-degree relatives was significantly associated with POAG (pooled OR 3.31; 95%CI 2.54–4.31; I²=71.4%; p<0.001). The risk gradient was steepest for siblings (OR 3.69–11.29), intermediate for parents (2.17–8.76), and weakest for offspring. Direct examination of relatives disclosed glaucoma in 10.4–64.7% of siblings versus 0.7–1.5% of controls. Lifetime risk among first-degree relatives was 22.0% versus 2.3% (RR 9.2; 95%CI 1.2–73.9), with a population attributable fraction of 16.4%. Family history also predicted PACG (OR 4.82; 95%CI 2.08–11.19) and disease severity (OR 1.61–1.81). Pathogenic MYOC variants explained 27–36% of familial juvenile-onset disease but only 1.6–4.2% of unselected adult-onset disease, with p.Gln368Ter penetrance reaching 25.4%. Polygenic risk scores produced a 5.7-fold prevalence gradient between lowest and highest deciles and RR 3.99–7.40. Adding PRS to a clinical model increased concordance from 0.75 to 0.82.

Discussion. The evidence is biologically coherent and reproducible across populations, satisfying Bradford Hill criteria. Residual heterogeneity is largely attributable to differences in exposure ascertainment: self-reported family history is misclassified because 60–69% of community glaucoma is undiagnosed. Genomic markers circumvent this misclassification and now provide reproducible risk stratification.

Conclusion. A positive family history of glaucoma confers an approximately three-fold to nine-fold increase in risk of primary glaucoma and identifies a population sufficiently enriched to justify targeted case-finding. Cascade clinical screening of first-degree relatives—particularly siblings—from the fourth decade of life, supplemented by MYOC cascade testing and polygenic risk stratification in appropriate settings, is supported by moderate-certainty evidence and should be incorporated into national glaucoma-blindness prevention strategies.