Editorial

Genetic Basis of Primary Angle Closure Glaucoma: The
Role of Collagens and Extracellular Matrix

Elahe Elahi, PhD

Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran

ORCID:
Elahe Elahi: https://orcid.org/0000-0002-6897-2223

J Ophthalmic Vis Res 2020; 15 (1): 1–3

Glaucoma is a heterogeneous group of optic neu-
ropathies characterized by a specific pattern of
optic nerve degeneration and visual field loss that
is usually accompanied by increased intraocular
pressure (IOP).[1] It is a major cause of irreversible
blindness worldwide.[2] Primary glaucoma is classi-
fied into three major forms based on the anatomy
of the anterior chamber drainage angle of the eye
and the age of onset: primary congenital glaucoma
(PCG), primary open angle glaucoma (POAG), and
primary angle closure glaucoma (PACG).[1] In glau-
coma patients with increased IOP, the increase is
thought to be mainly due to impaired drainage of
aqueous humor from the anterior chamber.[3]

The etiology of all forms of glaucoma includes
a genetic component as evidenced by variable
prevalence in different ethnic groups, observations
on familial clustering, and results of pedigree
and sib-pair studies. For PCG, which is usually a
monogenetic Mendelian disease, three causative
genes have been identified.[4–7] POAG and PACG
are generally considered complex multifactorial
disorders.[8] Several POAG-causing genes have
been identified, but mutations in these account for
disease in less than 10% of patients.[9–13]

Compared to the other forms of glaucoma, there
is much less definitive genetic data pertaining to
PACG. This likely reflects the contribution of multi-
ple genetic and perhaps environmental factors that
affect various anatomical and functional features
associated with PACG. PACG is an important public
health entity. It is estimated that 15.7 million indi-
viduals in the world are affected with PACG. It is
projected that 21 million will be affected by 2020,
and that PACG by that time will cause bilateral
blindness in 5.3 million people.[14–16] Most PACG
patients are from Asia, particularly China, Mongolia,
Singapore, and India.

Ultimately, the defining feature of PACG in indi-
viduals with glaucomatous optic nerve damage
is iridocorneal angle closure. Recently, COL18A1
which encodes collagen type XVIII was identified
as a gene that affects angle closure in patients of
three unrelated families.[17] The inheritance pattern
of angle closure causing mutations in COL18A1
was autosomal dominant. It appears that mutations
in this gene may cause angle closure in the
fourth decade of life or later. Furthermore, COL18A1
mutations are not expected to be a common
cause of angle closure-related phenotypes. The
significance of having identified COL18A1 as a
potential PACG-causing gene lies in emphasis on
the importance of collagens and the extracellular
matrix in glaucoma pathology.

In pursuit of identifying genes that contribute
to PACG disease, association studies and candi-
date gene studies have been performed and the
results of these have implicated possible roles for
several genes.[18–25] However, these findings are
not generally considered definitive, and putative
roles of genes suggested by some studies were not
confirmed in independent studies. Factors known
to be associated with PACG include hyperoptic
refractive error, shallow anterior chamber, thick
crystalline lens, short axial length, small corneal
diameter, and narrow iridocorneal angle.[26–28]
Clearly, some of these also associate with each
other. In an article published in this issue of the
Journal of Ophthalmic and Vision Research, the
authors relied on transcriptome data pertaining
to eye anterior segment tissues to select five
single nucleotide polymorphisms (SNPs) whose
genotypes may be associated with PACG among
patients of Northeast Iran.[29–31] Interestingly, one
of the SNPs for which an association with PACG
was reported is positioned in a gene (FERMT2) that

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Editorial; Elahi

encodes a component of the ECM. Results of an
association study that included tens of thousands
of patients and controls had also implicated the
same gene with respect to PACG.[20]

There exists accumulating evidence that impli-
cates various collagens specifically and the extra-
cellular matrix more generally in the pathogenesis
of glaucoma.[7, 32–36] Eight loci were identified in
one or both of two recent large genome-wide
association (GWA) studies on PACG patients, and
COL11A1 that encodes one of the alpha chains of
type XI collagen was one of the genes identified
in both of the studies.[18, 20] An SNP in COL1A1
was associated with increased risk of myopia in
Japanese and Chinese individuals.[37, 38] A GWA
study of PACG in a dog breed identified COL1A2
as a susceptibility locus.[39] And of course, COL18A1
was identified as a gene that affects iridocorneal
angle closure in humans.[17] In addition to collagens,
genes with roles in the extracellular matrix and also
associated with glaucoma include MMP-9, MTHFR,
LTBP2, CYP1B1, and SPARC. It has been suggested
that inter-individual differences in tolerance to IOP
as reflected in glaucoma diagnosis with normal
tension in some and ocular hypertension without
glaucoma in others reflect variations in biomechan-
ical properties of the extracellular matrix of relevant
ocular tissues.[32]

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DOI:
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How to cite this article: Elahi E. Genetic Basis of Primary Angle Closure
Glaucoma: The Role of Collagens and Extracellular Matrix. J Ophthalmic Vis
Res 2020;15:1–3.

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