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REVIEW

CURRENT
OPINION Primary angle closure glaucoma genomic
associations and disease mechanism
Chang Liu a, Monisha E. Nongpiur a,b, Chiea-Chuen Khor a,c,
Eranga N. Vithana a,b, and Tin Aung a,b,d

Purpose of review
The genetic basis of primary angle closure (PAC) glaucoma is slowly being elucidated. In recent years,
genome-wide association studies have identified eight new susceptibility loci for PAC. Our purpose in this
review is to summarize our current knowledge of genetics in angle closure, to take a closer look at the
eight novel loci and what we have learned about their function, and consider what they might teach us
about angle closure disease.
Recent findings
Multiple novel loci associated with PAC glaucoma have been identified in large genome-wide association
studies. Moreover, primary open angle glaucoma and PAC glaucoma are found to have partly overlapping
genetic features.
Summary
The genetic basis of PAC glaucoma is being deciphered. Even though there is still much more to be
uncovered, this process has already provided new insights in the pathogenesis of this blinding disease.
A better understanding of the pathogenic mechanisms through genomics may be valuable for the
development of novel therapies.
Keywords
angle closure glaucoma, genetics, genomics

INTRODUCTION neuropathy (GON). Of the people with PACS, a

An important goal of genetics research is to identify
risk factors for common complex diseases, and for
rare Mendelian diseases. Understanding the biolog-
ical basis of these genetic characteristics will help us
gain a deeper understanding of disease mechanisms
and might aid in the development of novel thera-
pies. A new and exciting field, termed personalized
medicine, explores possibilities to tailor healthcare
to individual patients based on their genetic and
other biological features. As defining an individual’s
genetic background is becoming more affordable
and available, genetic studies will bring personalized
medicine closer to clinical practice.
One of the common, complex diseases for which
the genetic contribution to disease is being eluci-
dated, is primary angle closure glaucoma (PACG).
Worldwide, but even more so in Asian populations,
PACG is a great burden causing irreversible blind-
ness and estimated to affect over 20 million people
[1]. In the spectrum of angle closure disease, primary
angle closure suspect (PACS) is the earliest stage
defined as narrow angles without elevated intraoc-
ular pressure (IOP) or signs of glaucomatous optic
minority will progress to primary angle closure
(PAC), in which the IOP is elevated but GON is
absent. Of those with PAC, 30% will progress into
PACG in 5 years [2].
An important role of genetics for PACG was
postulated as early as 1955, when an unusually high
incidence of PACG among siblings of patients was
described [3]. Since then, the higher angle closure
risk in family members of patients with PAC or
PACG has been corroborated in Chinese, South
Indians, whites and Inuits [4–6]. In Singaporean
Chinese individuals with PAC or PACG, there is a
a
Singapore Eye Research Institute and Singapore National Eye Centre,
b
Duke-NUS Medical School, cHuman Genetics, Genome Institute of
Singapore and dDepartment of Ophthalmology, Yong Loo Lin School
of Medicine, National University Health System & National University of
Singapore, Singapore, Singapore
Correspondence to Tin Aung, Singapore Eye Research Institute and
Singapore National Eye Centre, Singapore, Singapore.
Tel: +65 62277255; e-mail: aung.tin@singhealth.com.sg
Curr Opin Ophthalmol 2020, 31:000–000
DOI:10.1097/ICU.0000000000000645

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Glaucoma
KEY POINTS
 The current eight genome-wide association studies
identified primary angle closure glaucoma (PACG) loci
yet only explain 1.8% of the genetic basis of PACG,
confirming the need for larger or more targeted studies
in the future.
 All genome-wide association studies loci encode for
genes that are expressed in the iridocorneal angle and,
among others, play a role in extracellular matrix
remodeling, cellular adhesion, anterior chamber depth
and intraocular pressure regulation.
 The genetic basis of PACG is partly overlapping with
primary open angle glaucoma, implying common
disease pathways.
 The discovery of novel genes is important for our
understanding of PACG disease mechanisms to
develop targeted and effective therapies.
sibling recurrence risk for having narrow angles of
49% and a relative risk of 7.6. Similar results were
found in south Indian families [4,7], but there are
evident differences in heritability across ethnicities
[5,6].
With new technological advances, the genetic
mapping of PACG is unveiling possible biological
mechanisms involved in PACG, conveying new
therapeutic targets and the prospect of individual-
ized patient care. In this review, we will discuss
the current knowledge regarding the genetic basis
of angle closure.
THE IDENTIFICATION OF PRIMARY ANGLE
CLOSURE GLAUCOMA GENES
The following is a description of the methods used
and the genes identified thus far for PACG.
Candidate genes
One of the early approaches to conduct genetic
association studies focused on allelic variation
within specific genes of interest that are suspected
to play a role in a certain trait or phenotype of
disease. Although more than 50 candidate genes
have been assessed for association with angle closure
disease, the association of individual genes varies
across different study populations in their character-
istics such as allele frequency, statistical significance
and odds ratio (OR). A systematic review and meta-
analysis identified five candidate genes for PACG
risk: HGF (rs17427817-C and rs5745718-A), heat
shock protein 70 (HSP70) (rs1043618), membrane-
type Frizzled-related protein (MFRP) (rs2510143-C
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and rs3814762-G), MMP9 (rs3918249-C) and nitric
oxide synthase 3 (NOS3) (rs7830-A) [8]. HGF encodes
hepatocyte growth factor and was associated with
PACG and hyperopia in different populations [8]. It
is increased in the aqueous humor of glaucomatous
eyes [9], and its receptors are found in trabecular
meshwork cells [10]. The MFRP has a role in axial
length regulation and is associated with the autoso-
mal recessive form of nanophthalmos [11]. Matrix
metalloproteinase-9 (MMP9) is a gene involved in
extracellular matrix (ECM) remodeling and found
to be associated with PACG in different populations,
although with a moderate heterogeneity (I2 ¼ 41.6%)
between white and Chinese populations [8,12–14].
Significantly, NOS3 acts as an activator for MMP9 [15]
and HSP70 plays a role in MMP9 transcription [16].
Thus, these three genes may be involved in ECM
remodeling pathways, which can play a role in PACG
in several ways, including short axial length,
increased trabecular outflow resistance, and fibrosis
at the optic nerve head and lamina cribrosa [17,18].
However, none of these candidate genes have been
confirmed in large genome-wide association studies
(GWAS) studies of PACG, leaving their significance in
PACG pathogenesis uncertain.
Genome-wide association studies
GWAS are an unbiased method for mapping suscep-
tibility loci in large cohorts from a specific popula-
tion with a specific disease that does not follow
simple Mendelian inheritance patterns. Generally,
these studies compare genomic DNA markers
between patients and healthy controls to identify
differences in genetic variants. Two large GWAS
have led to the discovery of eight susceptibility loci
for PACG. The first GWAS included 1854 PACG
cases and 9608 controls from five Asian countries
with replication in 1917 cases and 8943 indepen-
dent controls from Singapore, China, India, Saudi
&&
Arabia and the United Kingdom [19 ]. In this
GWAS, three novel loci were identified: pleckstrin
homology domain containing, family A member 7
(PLEKHA7) rs11024102 (per-allele OR ¼ 1.22,
P ¼ 5.33  10 –12), COL11A1 rs3753841 (per-allele
OR ¼ 1.20, P ¼ 9.22  10 –10) and PCMTD1-ST18
rs1015213 (per-allele OR ¼ 1.50, P ¼ 3.29  10 –9).
The second GWAS including a combined total of
10 404 PACG cases and 29 343 controls from 23
countries across Asia, Australia, Europe, North and
South America, found five new genetic loci upon
&&
meta-analysis [20 ]. These loci are at EPDR1
rs3816415 (OR ¼ 1.24, P ¼ 3.49  1015), CHAT
rs1258267 (OR ¼ 1.22, P ¼ 3.73  1016), GLIS3
rs736893 (OR ¼ 1.18, P ¼ 1.15  1014), FERMT2
rs7494379 (OR ¼ 1.13, P ¼ 6.32  1011), and DPM2-
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Angle closure glaucoma genomic associations and disease mechanism Liu et al
FAM102A rs3739821 (OR ¼ 1.15, P ¼ 6.77  1012).
All genetic loci were expressed in tissues of the irido-
corneal angle and retained a significant association
with PACG across all stratifications. The following
section provides a brief report on the current knowl-
edge of these eight loci.
PLEKHA7: PLEKHA7 encodes for a protein that
has a role in the formation of adherens junctions
and its expression has been found in various ocular
tissues [21]. The PLEKHA7 protein stabilizes apical
junctional adhesion complexes [22], controlling the
paracellular permeability, blood aqueous barrier
(BAB) and thus fluid regulation. Recently, it is con-
firmed that PLEKHA7 is down-regulated in ocular
tissues of PACG patients, suggesting a causative effect
of a ‘leaky’ BAB impeding aqueous humor outflow
[23]. This is consistent with earlier studies that impli-
cated a BAB breakdown with leakage of inflammatory
factors as a mechanism for the IOP rise in PACG
[24,25]. This inflammatory response could also
induce peripheral anterior synechiae formation. Fur-
thermore, the higher iris volume seen in angle closure
eyes upon dilation compared with eyes with open
angles [26–28] could be related to the reduced levels
of PLEKHA7 and a subsequently heightened perme-
ability at the vascular endothelium or pigment epi-
thelium of the iris. On the other hand, no association
was found with axial length or anterior chamber
depth (ACD) in two population-based studies: the
European Prospective Investigation of Cancer-Nor-
folk Eye Study [29] and three Singapore population
cohorts (Singapore Epidemiology of Eye Diseases
Study) [30]. Significantly, PLEKHA7 has recently been
found to be associated with IOP and primary open
& &
angle glaucoma (POAG) [31 ,32 ], suggesting it also
modifies disease risk through an increase in IOP.
COL11A1: COL11A1 encodes the alpha-1 chain
of type XI collagen, which is a major component of
the interstitial ECM. Rare mutations in this gene
cause Marshall syndrome, type 2 Stickler syndrome
or Stickler-like syndrome [33]. In these syndromes,
abnormal collagen in the sclera is the probable cause
for axial myopia, which is one of the typical signs.
Conversely, the common variants of this gene are
&&
associated with PACG on GWAS [19 ], with angle
closure eyes usually being hyperopic with a shorter
axial length. This suggests that the common var-
iants at COL11A1 may result in a different pheno-
typic effect, of which the details are yet to be
elucidated. Moreover, studies did not find an asso-
ciation of COL11A1 with axial length and ACD
[29,30,34]. Recently, two polymorphisms of
COL11A1 were found to be associated with more
severe PACG [34]. As COL11A1 is also expressed in
the trabecular meshwork, it might directly influence
IOP through aqueous outflow.
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PCMTD1-ST18: PCMTD1 encodes for a protein
of which the function in unknown, named protein-
L-isoaspartate O-methyltransferase domain-contain-
ing protein 1. Significantly, a meta-analysis suggests
that PCMTD1 is associated with PACG only in Asian
populations, but this association remains inconclu-
sive in whites [35]. ST18 encodes for Suppression of
Tumorigenicity 18, a tumor suppressor gene known
to regulate apoptosis and inflammation in fibro-
blasts and it’s expression is decreased in breast can-
cer cells [36,37]. It is expressed in the human fetal
eye as well as in the human and mouse retina but
how these genes work to increase the risk of PACG is
still unknown. PCMTD1-ST18 has been found to be
associated with PACS status, the earliest stage in the
angle closure spectrum of disease, suggesting that it
is linked with the phenotypical narrow angle con-
&
figuration [38 ].
EPDR1: EPDR1 encodes the protein Ependymin
Related 1. This protein acts as a type II transmem-
brane protein and it is generally thought to repre-
sent an antiadhesive molecule, active within the
collagen fibrils of the ECM. Although its function
in the eye remains unknown, it could be hypothe-
sized that changes in the trabecular meshwork ECM
is the basis of EPDR1’s role in PACG [39].
GLIS3: GLIS3 encodes one of the GLI-similar
proteins, a subfamily of Kruppel-like zinc finger pro-
teins. It is expressed dynamically in the developing
eye and has a role in apoptosis and autophagy
through regulation of cell transcription [40,41],
and it is highly expressed in the brain with a dynamic
role during embryonic neurulation [40]. Mutations
in GLIS3 are identified to cause an array of disorders
including congenital hypothyroidism, osteoarthritis,
Alzheimer’s disease type 1,2 and neonatal diabetes
[42–45]. It has repeatedly been found to be associated
& & &
with IOP [31 ,32 ,46 ,47], but the exact mechanism
by which it causes PACG is not understood.
DPM2-FAM102A: DPM2 encodes Dolichol phos-
phate-mannose biosynthesis regulatory protein,
mutations in which will cause severe neurological
phenotypes through congenital defects in glycoly-
sation [48]. FAM102A symbolizes family with
sequence similarity 102 member A and is expressed
ubiquitously in human tissues [49]. Its function is
largely unknown, but there are clues for a role in
actin-polymerization, cell migration, oncogenesis
and bone remodeling [50,51]. DPM2-FAM102A is,
&
like PCMTD1-ST18, associated with PACS status [38 ].
CHAT: CHAT encodes for the enzyme choline
acetyltransferase, which is important in the synthe-
sis of the neurotransmitter acetylcholine. This neu-
rotransmitter is an essential link in the autonomic
nervous system and is involved in parasympathetic
pupillary reflexes amongst many other ocular
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Glaucoma
functions [52,53]. Remarkably, a role has been deter-
mined in retinal ganglion cell loss via oxidative
stress in the presence of a subtype acetylcholine
receptor deficiency. Thus, targeting this receptor
may lead to the discovery of novel therapies for the
promotion of retinal ganglion cell survival [54,55].
FERMT2: FERMT2 encodes for the protein pleck-
strin homology domain-containing family C mem-
ber 1 (PLEKHC1), a close relative of the PLEKHA7
protein. This focal adhesion protein also forms a
part of the ECM and plays a role in its collagen
metabolism.
Its dysfunction is associated with Alzheimer’s
disease [56] and a modulation of carcinoma behav-
ior and prognosis [57–60]. Recently, it has been
established that PLEKHC1 (analogs to PLEKHA7)
has a vital role in maintaining the vascular barrier
via stabilization of adherens junctions [61], and a
knockdown mouse model exhibited impaired
wound healing with increased neovascular perme-
ability [62]. Another similarity with PLEKHA7
emerged when FERMT2 was also shown to be asso-
& &
ciated with IOP and POAG [31 ,32 ], marking both
as disease risk mediators through IOP regulation.
Quantitative trait locus
Another technique to identify genetic factors in a
complex disease is to focus on heritable quantitative
traits, or endophenotypes, which are associated with
the disease. Via GWAS, a quantitative trait locus for
ACD was found within ATP-binding Cassette Sub-
family C Member 5 (ABCC5) rs1401999, which con-
veys an increased risk for PACG in a separate case-
& &
control study [63 ]. ABCC5, also known as multidrug
resistance protein 5 is expressed in most human
tissues, including several ocular structures relevant
&
to PACG such as the iris, ciliary body and lens [63 ]. It
plays a role in tissue defense and cellular signal
transduction, but the exact mechanism in the con-
text of angle closure disease is unknown [64–67]. The
association with ACD was strengthened when a sub-
group of open angle glaucoma controls were included
in the analysis, suggesting that the increase in PACG
risk is in part mediated by genetic variants that influ-
&
ence ACD [63 ]. However, ABCC5 did not emerge
with genome-wide significance from the latest PACG
&&
GWAS [20 ], suggesting that our current understand-
ing linking ACD and PACG remains incomplete.
CLINICAL IMPLICATIONS OF GENETIC
CHARACTERISTICS IN ANGLE CLOSURE
DISEASE
Since the discovery of the susceptibility genes for
PACG, the relation to different clinical phenotypes
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and disease states has been investigated. When the
first GWAS for PACG identified susceptibility genes
COL11A1, PLEKHA7 and PCMTD-ST18, subsequent
studies failed to show a consistent association
between these single nucleotide polymorphisms
(SNPs) and differences in ocular biometric factors
[30], nor in markers of disease severity and progression
[68]. This could be due to insufficient power of the
study or simply because these genes confer their effect
in unknown mechanisms that were not evaluated.
A recent study investigating all GWAS identified
PACG genes in patients with PACS status confirmed
PCMTD-ST18 and DPM2-FAM102A were associated
&
with PACS status [38 ]. Therefore, it could be
deduced that these two genes are so-called nar-
row-angle genes. The other PACG genes were not
found to be associated with this earliest stage in the
angle closure spectrum, suggesting they in turn may
&
be involved in later stages of disease [38 ]. At pres-
ent, genetic risk scoring will have limited clinical
value since the eight GWAS genes combined can
only explain 1.8% of the genetic component of
PACG. A recent study investigated the added diag-
nostic value of the eight susceptibility genes in the
detection of PACG compared with ACD only. Dis-
appointingly, PACG detection was only marginally
improved with 0.5% after incorporating the eight
&
susceptibility loci [69 ].
Until recently, it was thought that PACG and
POAG have completely different genetic profiles,
since no overlapping genetic markers were found
in large GWAS. Significantly however, in a multi-
ethnic GWAS for IOP in untreated Participants,
GLIS3 was identified to be associated with IOP
[46 ]. GLIS3 has a role in ocular development and
was already known to be associated with PACG
&
[46 ]. This finding was subsequently replicated in
a GWAS for IOP in a Chinese population [47] and
& &
again in two large GWAS [31 ,32 ] which addition-
ally identified HGF, PLEKHA7, FERMT2 and MFRP as
IOP-associated genes that were also known PACG-
genes. Furthermore, of these so-called IOP-genes,
PLEKHA7 and FERMT2 were also associated with
&
POAG [32 ]. Possible common pathways that could
lead to elevated IOP in both POAG and PACG is
implied by these results and further research might
uncover more shared genetic characteristics.
FUTURE RESEARCH
Even though an explosion of genetic knowledge has
occurred over the past decade, the current eight
GWAS identified susceptibility loci for PACG can
only explain up to 1.8% of the overall genetic vari-
ance observed in PACG, similar to many other com-
&&
plex diseases [20 ]. Recent reports of the success of
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Angle closure glaucoma genomic associations and disease mechanism Liu et al
polygenic risk scores for POAG have illustrated the
need of at least 50–100 genetic loci to achieve a
& Papers of particular interest, published within the annual period of review, have
useful screening tool [32 ]; exemplifying the path to
follow for PACG. As whole genome sequencing
becomes more affordable and available, the discov-
ery of additional novel loci becomes more feasible.
However, a major limitation in GWAS is the need for
correction of significance level to account for mul-
tiple testing, leading to an extremely high threshold
for a signal to be considered significant. Conse-
quently, studies are underpowered to detect all
the relevant SNPs and extremely large sample sizes
are needed. To partly overcome this limitation,
future studies can apply GWAS with deep phenotyp-
ing or studies comparing the two extremes in disease
progression or disease severity. These methods are
challenging but will be nonetheless necessary to
find more clinically relevant markers. Another limi-
tation of GWAS lies in the fact that it does not
necessarily pinpoint causal variants at the identified
locus, as multiple genetic variants due to linkage
disequilibrium are present in the region of the iden-
tified gene. Therefore, further investigations such as
deep sequencing are often required to isolate the
true association signal. Moreover, multiethnic rep-
lications are necessary to explain the racial differ-
ences in PACG prevalence. Nonetheless, GWAS is
providing us with many clues and insights into
PACG disease mechanisms for in depth exploration.
CONCLUSION
In the past decade, important steps have been taken in
mapping of the genetic profile of PACG. The GWAS
findings suggest the role of mechanisms in the path-
ogenesis of PACG such as ECM remodeling and cellu-
lar adhesion processes. For most of the identified loci,
their specific role in the pathogenesis and pathophys-
iology of PACG are yet to be elucidated. Significantly,
overlap between POAG and PACG have been con-
firmed in IOP-related genes, implying shared path-
ways and changing the way we see these two types of
glaucoma. The development of useful clinical appli-
cations from this growing genetic knowledge could
lead to not only improved personalized management,
but more importantly, present novel pathways for
therapeutic interventions.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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REFERENCES AND RECOMMENDED
READING
been highlighted as:
& of special interest
&& of outstanding interest
1. Tham Y-C, Li X, Wong TY, et al. Global prevalence of glaucoma and
projections of glaucoma burden through 2040: a systematic review and
meta-analysis. Ophthalmology 2014; 121:2081–2090.
2. Foster PJ, Buhrmann R, Quigley HA, Johnson GJ. The definition and classi-
fication of glaucoma in prevalence surveys. Br J Ophthalmol 2002;
86:238–242.
3. Weekers R, Gougnard-Rion C, Gougnard L. No title. Bull Soc Belge Ophthal
1955; 110:2.
4. Kavitha S, Zebardast N, Palaniswamy K, et al. Family history is a strong risk
factor for prevalent angle closure in a South Indian population. Ophthalmology
2014; 121:2091–2097.
5. Lowe RF. Primary angle closure glaucoma: geographic and racial variations.
Trans Ophthalmol Soc N Z 1973; 25:81–84.
6. Yip JLY, Foster PJ. Ethnic differences in primary angle-closure glaucoma. Curr
Opin Ophthalmol 2006; 17:175–180.
7. Amerasinghe N, Zhang J, Thalamuthu A, et al. The heritability and sibling risk of
angle closure in Asians. Ophthalmology 2011; 118:480–485.
8. Rong SS, Tang FY, Chu WK, et al. Genetic associations of primary angle-
closure disease: a systematic review and meta-analysis. Ophthalmology
2016; 123:1211–1221.
9. Hu DN, Ritch R. Hepatocyte growth factor is increased in the aqueous humor
of glaucomatous eyes. J Glaucoma 2001; 10:152–157.
10. Wordinger RJ, Clark AF, Agarwal R, et al. Cultured human trabecular mesh-
work cells express functional growth factor receptors. Invest Ophthalmol Vis
Sci 1998; 39:1575–1589.
11. Sundin OH, Leppert GS, Silva ED, et al. Extreme hyperopia is the result of null
mutations in MFRP, which encodes a Frizzled-related protein. Proc Natl Acad
Sci U S A 2005; 102:9553–9558.
12. Cong Y, Guo X, Liu X, et al. Association of the single nucleotide polymorph-
isms in the extracellular matrix metalloprotease-9 gene with PACG in southern
China. Mol Vis 2009; 15:1412–1417.
13. Awadalla MS, Burdon KP, Kuot A, et al. Matrix metalloproteinase-9 genetic
variation and primary angle closure glaucoma in a Caucasian population. Mol
Vis 2011; 17:1420–1424.
14. Wang I-J, Chiang T-H, Shih Y-F, et al. The association of single nucleotide
polymorphisms in the MMP-9 genes with susceptibility to acute primary
angle closure glaucoma in Taiwanese patients. Mol Vis 2006; 12:
1223–1232.
15. Iwakura A, Shastry S, Luedemann C, et al. Estradiol enhances recovery after
myocardial infarction by augmenting incorporation of bone marrow–derived
endothelial progenitor cells into sites of ischemia-induced neovascularization
via endothelial nitric oxide synthase–mediated activation of matrix metallo-
proteinase-9. Circulation 2006; 113:1605–1614.
16. Lee K-J, Kim YM, Kim DY, et al. Release of heat shock protein 70 (Hsp70) and
the effects of extracellular Hsp70 on matric metalloproteinase-9 expression in
human monocytic U937 cells. Exp Mol Med 2006; 38:364–374.
17. Vranka JA, Kelley MJ, Acott TS, Keller KE. Extracellular matrix in the trabecular
meshwork: intraocular pressure regulation and dysregulation in glaucoma.
Exp Eye Res 2015; 133:112–125.
18. Wallace DM, O’Brien CJ. The role of lamina cribrosa cells in optic nerve head
fibrosis in glaucoma. Exp Eye Res 2016; 142:102–109.
19. Vithana EN, Khor C-C, Qiao C, et al. Genome-wide association analyses
&& identify three new susceptibility loci for primary angle closure glaucoma. Nat
Genet 2012; 44:1142–1146.
This article reports the discovery of three novel susceptibility loci for PACG
through GWAS and reviews the current knowledge on the functions of these loci.
20. Khor CC, Do T, Jia H, et al. Genome-wide association study identifies five new
&& susceptibility loci for primary angle closure glaucoma. Nat Genet 2016;
48:556–562.
This article reports the discovery of five novel susceptibility loci for PACG through
a large GWAS and provides new insights into the pathofysiology of PACG.
21. Lee MC, Chan ASY, Goh SR, et al. Expression of the primary angle closure
glaucoma (PACG) susceptibility gene PLEKHA7 in endothelial and epithelial
cell junctions in the eye. Investig Opthalmol Vis Sci 2014; 55:3833.
22. Pulimeno P, Paschoud S, Citi S. A role for ZO-1 and PLEKHA7 in recruiting
paracingulin to tight and adherens junctions of epithelial cells. J Biol Chem
2011; 286:16743–16750.
23. Lee M-C, Shei W, Chan AS, et al. Primary angle closure glaucoma (PACG)
susceptibility gene PLEKHA7 encodes a novel Rac1/Cdc42 GAP that
modulates cell migration and blood-aqueous barrier function. Hum Mol Genet
2017; 26:40114027.
24. Kong X, Liu X, Huang X, et al. Damage to the blood–aqueous barrier in eyes
with primary angle closure glaucoma. Mol Vis 2010; 16:2026–2032.
25. Chua J, Vania M, Cheung CMG, et al. Expression profile of inflammatory
cytokines in aqueous from glaucomatous eyes. Mol Vis 2012; 18:431–438.
www.co-ophthalmology.com 5
CE: Swati; ICU/310209; Total nos of Pages: 6;
ICU 310209
Glaucoma
26. Quigley HA, Silver DM, Friedman DS, et al. Iris cross-sectional area decreases
with pupil dilation and its dynamic behavior is a risk factor in angle closure. J
Glaucoma 2009; 18:173–179.
27. Aptel F, Denis P. Optical coherence tomography quantitative analysis of iris volume
changes after pharmacologic mydriasis. Ophthalmology 2010; 117:3–10.
28. Narayanaswamy A, Zheng C, Perera SA, et al. Variations in Iris volume with
physiologic mydriasis in subtypes of primary angle closure glaucoma. Investig
Opthalmol Vis Sci 2013; 54:708.
29. Day AC, Luben R, Khawaja AP, et al. Genotype–phenotype analysis of SNPs
associated with primary angle closure glaucoma (rs1015213, rs3753841
and rs11024102) and ocular biometry in the EPIC-Norfolk Eye Study. Br J
Ophthalmol 2013; 97:704–707.
30. Nongpiur ME, Wei X, Xu L, et al. Lack of association between primary angle-
closure glaucoma susceptibility loci and the ocular biometric parameters
anterior chamber depth and axial length. Investig Opthalmol Vis Sci 2013;
54:5824.
31. Khawaja AP, Cooke Bailey JN, Wareham NJ, et al. Genome-wide analyses
& identify 68 new loci associated with intraocular pressure and improve risk
prediction for primary open-angle glaucoma. Nat Genet 2018; 50:778–782.
The study identifies four known primary angle closure glaucoma (PACG) genes to
be associated with intraocular pressure (IOP) in POAG.
32. MacGregor S, Ong J-S, An J, et al. Genome-wide association study of
& intraocular pressure uncovers new pathways to glaucoma. Nat Genet
2018; 50:1067–1071.
The study reports the discovery of IOP-genes, of which two are known to be
associated with PACG as well as POAG, further corroborating the shared genetic
and biological basis of the two glaucomas.
33. Richards AJ, McNinch A, Martin H, et al. Stickler syndrome and the vitreous
phenotype: mutations in COL2A1 and COL11A1. Hum Mutat 2010;
31:E1461–E1471.
34. Wan Y, Li S, Gao Y, et al. COL11A1 polymorphisms are associated with
primary angle-closure glaucoma severity. J Ophthalmol 2019; 2019:1–7.
35. Liao L, Gong X, Lu M, et al. Associations of polymorphisms of rs1015213 with
primary angle closure glaucoma-recent evidence and a meta-analysis. Int J
Clin Exp Med 2015; 8:10804–10814.
36. Jandrig B, Seitz S, Hinzmann B, et al. ST18 is a breast cancer tumor suppressor
gene at human chromosome 8q11.2. Oncogene 2004; 23:9295–9302.
37. Yang J, Siqueira MF, Behl Y, et al. The transcription factor ST18 regulates
proapoptotic and proinflammatory gene expression in fibroblasts. FASEB J
2008; 22:3956–3967.
38. Nongpiur ME, Cheng C-Y, Duvesh R, et al. Evaluation of primary angle-closure
& glaucoma susceptibility loci in patients with early stages of angle-closure
disease. Ophthalmology 2018; 125:664–670.
The article identifies two genes that are associated with primary angle closure
suspect, suggesting they are related to narrow angle trait.
39. Gregorio-King CC, McLeod JL, Collier FM, et al. MERP1: a mammalian
ependymin-related protein gene differentially expressed in hematopoietic
cells. Gene 2002; 286:249–257.
40. Kim Y-S, Nakanishi G, Lewandoski M, Jetten AM. GLIS3, a novel member of
the GLIS subfamily of Kruppel-like zinc finger proteins with repressor and
activation functions. Nucleic Acids Res 2003; 31:5513–5525.
41. Calderari S, Ria M, Gérard C, et al. Molecular genetics of the transcription
factor GLIS3 identifies its dual function in beta cells and neurons. Genomics
2018; 110:98–111.
42. Casalone E, Tachmazidou I, Zengini E, et al. A novel variant in GLIS3 is
associated with osteoarthritis. Ann Rheum Dis 2018; 77:620–623.
43. Duarte GCK, Assmann TS, Dieter C, et al. GLIS3 rs7020673 and
rs10758593 polymorphisms interact in the susceptibility for type 1 diabetes
mellitus. Acta Diabetol 2017; 54:813–821.
44. Kang HS, Kumar D, Liao G, et al. GLIS3 is indispensable for TSH/TSHR-
dependent thyroid hormone biosynthesis and follicular cell proliferation. J Clin
Invest 2017; 127:4326–4337.
45. Cruchaga C, Kauwe JSK, Harari O, et al. GWAS of cerebrospinal fluid tau levels
identifies risk variants for Alzheimer’s disease. Neuron 2013; 78:256–268.
46. Choquet H, Thai KK, Yin J, et al. A large multiethnic genome-wide association
& study identifies novel genetic loci for intraocular pressure. Nat Commun
2017; 8:2108.
The report described the discovery of novel genes for IOP in untreated eyes, and
was the first to suggest shared genetic components for PACG and POAG.
47. Huang L, Chen Y, Lin Y, et al. Genome-wide analysis identified 17 new loci
influencing intraocular pressure in Chinese population. Sci China Life Sci
2019; 62:153–164.
6 www.co-ophthalmology.com
Copyright © 2019 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
48. Fiumara A, Barone R, Del Campo G, et al. Electroclinical features of early-
onset epileptic encephalopathies in congenital disorders of glycosylation
(CDGs). JIMD Rep 2015; 27:93–99.
49. HUGO Gene Nomenclature Committee. www.genenames.org/data/gene-
symbol-report/#!/hgnc_id/HGNC:31419.
50. Bureau J-F, Cassonnet P, Grange L, et al. The SRC-family tyrosine kinase
HCK shapes the landscape of SKAP2 interactome. Oncotarget 2018;
9:13102–13115.
51. Choi HK, Kang HR, Jung E, et al. Early estrogen-induced gene 1, a novel
RANK signaling component, is essential for osteoclastogenesis. Cell Res
2013; 23:524536.
52. Dobransky T, Rylett RJ. A model for dynamic regulation of choline acetyl-
transferase by phosphorylation. J Neurochem 2005; 95:305–313.
53. McDougal DH, Gamlin PD. Autonomic control of the eye. In: Hoboken NJ,
editor. Comprehensive physiology. USA: John Wiley & Sons, Inc.; 2014. pp.
439–473. ; 5.
54. Strang CE, Long Y, Gavrikov K E, et al. Nicotinic and muscarinic acetylcholine
receptors shape ganglion cell response properties. J Neurophysiol 2015;
113:203217.
55. Laspas P, Zhutdieva MB, Brochhausen C, et al. The M1 muscarinic acetylcho-
line receptor subtype is important for retinal neuron survival in aging mice. Sci
Rep 2019; 9:5222.
56. Chapuis J, Flaig A, Grenier-Boley B, et al. Genome-wide, high-content
siRNA screening identifies the Alzheimer’s genetic risk factor FERMT2 as
a major modulator of APP metabolism. Acta Neuropathol 2017; 133:
955–966.
57. Lin J, Lin W, Ye Y, et al. Kindlin-2 promotes hepatocellular carcinoma invasion
and metastasis by increasing Wnt/b-catenin signaling. J Exp Clin Cancer Res
2017; 36:134.
58. Lu X, Zhou C, Li RF, et al. Kindlin-2 promotes gallbladder cancer metastasis
and invasion by inducing epithelial-mesenchymal transition. Zhonghua Wai Ke
Za Zhi 2018; 56:617–622.
59. Wang P, Chu W, Zhang X, et al. Kindlin-2 interacts with and stabilizes DNMT1
to promote breast cancer development. Int J Biochem Cell Biol 2018;
105:41–51.
60. Wang P, Zhan J, Song J, et al. Differential expression of Kindlin-1 and Kindlin-2
correlates with esophageal cancer progression and epidemiology. Sci China
Life Sci 2017; 60:1214–1222.
61. Pluskota E, Bledzka KM, Bialkowska K, et al. Kindlin-2 interacts with en-
dothelial adherens junctions to support vascular barrier integrity. J Physiol
2017; 595:6443–6462.
62. Ying J, Luan W, Lu L, et al. Knockdown of the KINDLIN-2 gene and
reduced expression of kindlin-2 affects vascular permeability in
angiogenesis in a mouse model of wound healing. Med Sci Monit 2018;
24:5376–5383.
63. Nongpiur ME, Khor CC, Jia H, et al. ABCC5, a gene that influences the
& anterior chamber depth, is associated with primary angle closure glaucoma.
PLoS Genet 2014; 10:e1004089.
This article reports a novel locus identified by GWAS associated with anterior
chamber depth.
64. Jansen RS, Mahakena S, de Haas M, et al. ATP-binding cassette sub-
family C member 5 (ABCC5) functions as an efflux transporter of
glutamate conjugates and analogs. J Biol Chem 2015; 290:
30429 – 30440.
65. Wielinga P, Hooijberg JH, Gunnarsdottir S, et al. The human multidrug
resistance protein MRP5 transports folates and can mediate cellular resis-
tance against antifolates. Cancer Res 2005; 65:4425–4430.
66. Jedlitschky G, Burchell B, Keppler D. The multidrug resistance protein 5
functions as an ATP-dependent export pump for cyclic nucleotides. J Biol
Chem 2000; 275:30069–30074.
67. Pratt S, Shepard RL, Kandasamy RA, et al. The multidrug resistance
protein 5 (ABCC5) confers resistance to 5-fluorouracil and transports
its monophosphorylated metabolites. Mol Cancer Ther 2005; 4:
855 – 863.
68. Wei X, Nongpiur ME, de Leon MS, et al. Genotype–phenotype correlation
analysis for three primary angle closure glaucoma-associated genetic poly-
morphisms. Investig Opthalmol Vis Sci 2014; 55:1143.
69. Nongpiur ME, Khor C-C, Cheng C-Y, et al. Integration of genetic and
& biometric risk factors for detection of primary angle closure glaucoma. Am
J Ophthalmol 2019; 208:160–165.
The article discusses the added value of PACG genes in the clinical diagnosis of
PACG.
Volume 31  Number 00  Month 2020