Identification of Novel Genetic Loci for Primary Angle-Closure Glaucoma

Monisha E. Nongpiur and Tin Aung

Primary angle-closure glaucoma (PACG) is a major cause of blindness and visual morbidity worldwide, particularly in Asia. The involvement of multiple anatomical and physiological factors in the pathogenesis of PACG suggests that this is a complex disease.

A genetic etiology for PACG is supported by several epidemiological and clinical studies which showed familial aggregation and higher risk of the disease in family members of affected individuals,^1,2 as well as high heritability of risk factors for PACG, such as anterior chamber depth.³

Genome-wide association studies (GWAS) are a useful and efficient study design for the identification of genes associated with complex diseases. This approach has been successful in identifying genetic variants associated with several eye diseases, including pseudoexfoliation, age related macula degeneration and primary open-angle glaucoma.

To identify the genetic determinants that confer susceptibility to PACG, a two-staged GWAS was recently conducted involving 3,771 cases and 18,551 controls.⁴ Stage 1 (GWAS discovery) comprised 1,854 cases and 9,608 controls enrolled from Singapore, Hong Kong, India, Malaysia, and Vietnam. Stage 2 (replication) comprised a further 1,917 cases and 8,943 controls recruited independently from Singapore, China (one collection from Beijing and a second from Shantou), India, Saudi Arabia, and the UK. Significant association for PACG were identified at three new genetic loci; rs11024102 at PLEKHA7 (per-allele odds ratio (OR) = 1.22; P = 5.33 10^-12), rs3753841 at COL11A1 (per-allele OR = 1.20; P = 9.22 x 10^-10) and rs1015213 located between PCMTD1 and ST18 on Chromosome 8q (per-allele OR = 1.50; P = 3.29 x 10^-9).⁴

Interestingly, significant expression of PLEKHA7, COL11A1, and PCMTD1 were found in the iris and trabecular meshwork of the eye, the ocular tissues intimately involved in the pathogenesis of PACG. PLEKHA7 encodes for Pleckstrin-homology-domain-containing protein 7, which is critical for the maintenance and stability of adherens junctions.^5,6 Since adherens junctions aid in controlling para-cellular permeability,⁷ it is possible that PLEKHA7 may be involved in the pathophysiology of angle closure related to aberrant fluid dynamics. COL11A1 encodes for one of the two alpha chains of type XI collagen and being a structural protein, it may contribute towards anatomical risk via the sclera or iris. Interestingly, mutations in COL11A1 have been described in patients with Stickler syndrome.⁸ PCMTD1 encodes for protein-L-isoaspartate O-methyltransferase domain-containing protein 1, whose function remains unknown.

The study findings provide exciting new perspectives into the genetic basis of PACG. It will be fascinating to know how the genes identified are involved in PACG disease pathways in the eye. By further unravelling the genetic architecture of PACG, it may be possible in future to develop a clinically useful genetic profile for early identification or risk stratification of at-risk individuals, as well as to perhaps develop novel therapies for this blinding disorder.