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Review

An Updated Review on the Genetics of Primary Open Angle Glaucoma

1
Glaucoma Research Chair, Department of Ophthalmology, College of Medicine, King Saud University, Riyadh 11424, Saudi Arabia
2
Department of Ophthalmology, University of Florida College of Medicine, 580, W, 8th Street, Tower-2, Jacksonville, FL 32209, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2015, 16(12), 28886-28911; https://doi.org/10.3390/ijms161226135
Received: 27 October 2015 / Revised: 19 November 2015 / Accepted: 27 November 2015 / Published: 4 December 2015
(This article belongs to the Special Issue Human Single Nucleotide Polymorphisms and Disease Diagnostics)

Abstract

:
Epidemiological studies suggest that by 2020 the prevalence of primary open angle glaucoma (POAG) is estimated to increase to 76.0 million, and to 111.8 million by 2040 globally due to the population aging. The prevalence of POAG is the highest among those of African descent, followed by Asians, and the lowest in Europeans. POAG is a genetically complex trait with a substantial fraction exhibiting a significant heritability. Less than 10% of POAG cases in the general population are caused by specific gene mutations and the remaining cases are polygenic. Quantitative traits related to POAG pathogenesis such as intra-ocular pressure (IOP), vertical cup/disc ratio (VCDR), optic disc area, and central corneal thickness (CCT) are highly heritable, and likely to be influenced at least in part by genes and show substantial variation in human populations. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) at different loci including CAV1/CAV2, TMCO1, CDKN2B-AS1, CDC7-TGFBR3, SIX1/SIX6, GAS7 and ATOH7 to be associated with POAG and its related quantitative traits (endophenotypes). The chapter provides a brief overview on the different GWAS and SNP association studies and their correlation with various clinical parameters important for POAG in the population worldwide, including the Middle East.

1. Introduction

Glaucoma is a chronic and progressive group of optic neuropathies affecting more than 60 million people globally [1]. It is associated with death of retinal ganglion cells resulting in characteristic cupping or degeneration of the optic nerve head and loss of peripheral vision [2]. Primary open angle glaucoma (POAG) is one of the most common types of glaucoma which is clinically characterized by an open and normal anterior iridocorneal chamber angle [2]. POAG can either occur with increased intraocular pressure (IOP) or normal IOP, the latter being referred to as normal-tension glaucoma (NTG).
Although there are many postulated mechanisms of retinal ganglion cell damage, the exact etiology of POAG still remains obscure. The well-recognized risk factors associated with POAG include elevated IOP, age, family history, gender, ethnicity, central corneal thickness, and myopia. A recent large prospective study indicated that POAG with early paracentral visual field loss displays distinct as well common risk factor profiles as compared to those with peripheral vision loss [3]. Raised IOP is the most important and the only modifiable risk factor in the development and progression of POAG. Several large population-based studies in the past have confirmed that the reduction of IOP reduces the progression of glaucoma in patients with or without elevated IOP [4,5,6,7,8].
Similarly, findings of the meta-analysis from the Eye Diseases Prevalence Research Group have shown that the occurrence of glaucoma increases with increasing age among all ethnicities (Europeans, Blacks, and Hispanics) [7,9]. Age was also reported to be associated with POAG in patients with ocular hypertension in two large population-based studies [5,8]. Family history is another important risk factor in the development of glaucoma [7,10,11,12]. A positive family history of POAG significantly increases the odds (varying from five to 10 times) for the development of POAG [13]. In the Melbourne [14] and Rotterdam studies [11], males showed a trend towards increased risk of POAG which was absent in the Barbados Eye Study [7] and the Beaver Dam Eye Study [10]. Similarly, the Eye Disease Prevalence Research Group [9] reported no gender-related association of glaucoma among the European, African American, and Hispanic subjects. However, a recent systematic review of 3497 POAG cases out of 146,882 participants with gender-specific data showed that the age-adjusted prevalence is higher in men compared to women, and that this finding remains consistent across all ethnic groups provides very strong evidence for the association of POAG with gender [15]. Several studies have shown POAG to be more prevalent with rapid and severe disease progression in people of African-Caribbean as compared to European descent, Hispanics, and Asians [9,16]. Central corneal thickness (CCT) has also been reported to be associated with POAG, particularly in the ocular hypertension patients [17,18]. Although the precise mechanism(s) are still unclear, this may be in part due to the effect of corneal thickness on IOP measurement, and increased susceptibility to optic nerve damage [19,20]. In addition, studies have shown that individuals with thicker corneas are less responsive to topical ocular hypotensive medications [21]. Myopia is also considered to be an important risk factor for POAG as it can increase susceptibility of myopic nerves to glaucomatous damage [22]. Moderate-to-high levels of myopia conferred two- to three-fold increased risk in the Australian [23], US Caucasian [24], and the Chinese populations [25]. Other predisposing factors for POAG include adult-onset diabetes and hypertension. Although there are conflicting reports regarding the risk of POAG in individuals with diabetes [26,27], a recent systematic review and meta-analysis of 13 studies, which included six population-based cohorts and seven case-control studies, showed increased risk of POAG (relative risk of 1.4 and 1.49, respectively) in individuals with diabetes [28]. Multiple epidemiological studies have also reported a role of hypertension as a risk factor for POAG [23,29]. Treatment of hypertensive patients with beta-blockers results in nocturnal hypotension and is a potential risk factor for glaucomatous optic neuropathy [30]. The mechanism(s) by which hypertension induces optic nerve damage are still unclear.
POAG is a genetically complex trait with a substantial fraction exhibiting a significant heritability. Genetic linkage studies of large affected families have so far identified at least 20 chromosomal loci (GLC1A-P) that are linked to POAG. The causative genes that are capable of causing POAG with minimal influence from other gene(s) or the environment and that have been consistently implicated so far include myocilin (MYOC), optineurin (OPTN), WD repeat domain 36 (WDR36), ankyrin repeat and SOCS-box containing 10 (ASB10), Cytochrome P450 family 1, subtype B, polypeptide 1 (CYP1B1), and neurotrophin 4 (NTF4) as reviewed elsewhere [31,32]. Twin studies and family-based studies have discovered a number of genes. However, these disease-causing genes account for <10% of POAG cases in the general population. It is therefore likely that the hereditary aspect of many of the remaining cases of POAG is due to the combined effects of several genes (polygenic) and that gene-environment interactions are important. Quantitative endophenotype traits related to POAG pathogenesis such as IOP, vertical cup-to-disc ratio (VCDR), and CCT [10,33,34] are highly heritable, likely to be influenced at least in part by genes, and are highly polymorphic. Recent advances in genomic technologies and genome-wide association studies (GWAS) have greatly accelerated the discovery and understanding of genes and genomic regions associated with POAG and influencing the quantitative endophenotype traits related to POAG pathogenesis, which will be the main focus of this chapter.

2. Epidemiology of POAG

Recent epidemiological studies suggest that, in 2013, almost 64.3 million people (aged between 40 and 80 years) were affected by glaucoma globally, and this number is expected to increase to 76.0 million by 2020 and to 111.8 million by 2040 due to the population aging [35]. POAG accounts for a major three-quarters (74%) of all glaucoma cases [1]. Another recent meta-analysis estimated the global number of POAG cases in 2015 at 57.5 million, rising to 65.5 million by 2020 [15]. Almost half (47%) of these will those of Asian descent, while a quarter (24%) will be European [1]. The risk and subtypes of glaucoma are known to vary among races and countries [36]. A meta-analysis conducted by the Eye Disease Prevalence Research Group showed that, in the United States, African Americans have a higher POAG prevalence than Caucasians. The prevalence of POAG in individuals ≥40 years old was observed to be 1.86%, including 1.57 million Caucasian and 398,000 African American subjects. In 2020, this number is estimated to rise up to 3.36 million due to the population aging [9]. In all the age groups, there was an increased prevalence of glaucoma in individuals of African descent compared with European-derived individuals [37]. Similarly, a recent meta-analysis of 81 studies including 37 countries, 216,214 participants, and 5266 POAG cases reported that the Black populations had the highest POAG prevalence of 5.2% (95% credible interval (CrI) 3.7%, 7.2%) at 60 years, rising to 12.2% (95% CrI 8.9% to 16.6%) at 80 years. The increase in POAG prevalence per decade of age was found to be highest among the Hispanics (2.31, 95% CrI 2.12, 2.52) and Caucasian populations (1.99, 95% CrI 1.86, 2.12), and lowest in East and South Asians (1.48, 95% CrI 1.39, 1.57; 1.56, 95% CrI 1.31, 1.88, respectively). In addition, men were more likely to have POAG than women (1.30, 95% CrI 1.22, 1.41). It is clearly evident that individuals of African descent are associated with increased risk (estimated incidence is two to five times higher) of developing glaucoma compared with individuals of European descent. The reasons for this increased risk of glaucoma among individuals of African descent are still not clear. The Barbados Eye Study reported a prevalence of 7% in Africans, suggesting an influence of ancestral factors [7]. Several other factors that may also be influential could be physiological or anatomical differences in the optic disc or corneas, environmental factors, social differences or genetics [26].

3. Genotype-Phenotype Association in POAG

Association studies using the candidate-gene approach and GWASs have been particularly useful tools in identifying genetic factors, each of which may have a relatively small effect but contributes to a large number of cases. Unlike the candidate-gene approach, GWAS is an unbiased (without bias to known protein functionality gene) genome-wide approach that compares the genotypic profile of single nucleotide polymorphisms (SNPs) throughout the genome in cases (affected) and controls (unaffected), thus identifying genomic region(s) associated with a disease or trait of interest. The large population sample required in GWASs to achieve a genome-wide statistical significance (p-value of less than 5 × 10−8) has been greatly facilitated by the formation of the International Consortia. However, since GWAS can rarely identify functional or causal variant(s), further in-depth genotyping and functional testing in addition to replication studies in independent cohorts of different population groups are considered a standard requirement to conclusively validate genes or genomic regions identified from GWAS. Using this powerful approach (GWAS), recent genetic studies have identified genes or genetic variants with modest effect to be associated with POAG and related quantitative traits (Table 1). These studies have provided better insights into the genetic basis of POAG and improved our understanding of the underlying pathophysiology of the disease.
Table 1. Genes and polymorphisms identified in POAG using genome-wide and candidate-gene approaches in the Middle East and other populations.
Table 1. Genes and polymorphisms identified in POAG using genome-wide and candidate-gene approaches in the Middle East and other populations.
StudiesGene/ChromosomeSNP IDPopulation *Study TypeStudy Size (POAG/Controls) *OR/Beta, p ValueAny Clinical Association *
GWAS Studies
Nakano et al., 2009 [38]PLXDC2 (10p12.31)rs7081455D: Japan
R: Japan
GWASD: 1519
R: 857
OR = 1.49, p = 1 × 10−5
TMTC2 (12q21.31)rs7961953OR = 1.37, p = 7 × 10−5
ZP4 (1q43)rs547984OR = 1.34, p = 6 × 10−5
rs540782OR =1.34, p = 6 × 10−5
rs693421OR = 1.35, p = 4 × 10−5
rs2499601OR = 1.33, p = 9 × 10−5
Meguro et al., 2010 [39]SRBD1 (2p21)rs3213787JapaneseGWASD: 305
R: 355
OR = 2.80, p = 2.5 × 10−9Associated with NPG
ELOVL5 (6p12.1)rs735860OR = 1.69, p = 4.1 × 10−6Associated with NPG
Thorleifsson et al., 2010 [40]CAV1/CAV2 (7q31.1)rs4236601D: Iceland
R1: SW, UK, AU
R2: China
GWASD: 36,140
R1: 4239
R2: 879
OR = 1.36, p = 5 × 10−10Nominal association was observed for increased IOP (p = 0.034)
rs1052990OR = 1.32, p = 1.1 × 10−9
Burdon et al., 2011 [41]CDKN2B-AS (9p21.3)rs4977756AU, NZGWASD: 590/3956
R: 4148
OR = 1.50, p = 4.7 × 10−9
TMCO1 (1q24)rs4656461OR = 1.68, p = 6.1 × 10−10
Wiggs et al., 2012 [42]CDKN2B-AS (9p21)rs2157719US CaucasianGWASD: 3146/3487OR = 0.69, p = 1.86 × 10−18Also associated with NPG. OR =  0.58, p  =  1.17 × 10−12
SIX1/SIX6 (14q23)rs10483727OR = 1.32, p = 3.87 × 10−11
8q22rs284489OR = 0.62, p = 8.88 × 10−10Associated with NPG
Osman et al., 2012 [43]CDKN2B-AS (9p21)rs1063192JapaneseGWASD: 7993
R: 9014
OR = 0.75, p = 5.2 × 10−11
SIX1/SIX6 (14q23)rs10483727OR = 0.79, p = 9.49 × 10−8
NCKAP5 (2q21.2)rs7588567OR = 0.85, p = 3.89 × 10−7
Nakano et al., 2012 [44]CDKN2B-AS (9p21.3)rs7865618JapaneseGWASD: 833/686
R: 411/289
OR = 1.78, p = 9.0 × 10−11Strongly associated with POAG and POAG/NPG, but not with HPG
rs523096OR = 1.76, p =1.6 × 10−10
Takamoto et al., 2012 [45]CDKN2B (9p21)rs523096JapaneseGWASD: 286/557
R: 183/514
OR = 2.13, p =4.96 × 10−11Associated with NTG
Chen et al., 2014 [46]ABCA1 (9q31.1)rs2487032Asian Southern ChineseGWASD: 1007/1009
R: 1899/4965
OR = 0.69, p = 1.66 × 10−8; ORR = 0.73, pR = 2.79 × 10−9
PMM2 (16p13.2)rs3785176OR = 1.42, p = 3.18 × 10−6; ORR = 1.30, pR = 5.77 × 10−10
Gharahkhani et al., 2014 [47]ABCA1 (9q31.1)rs2472493D: Australian
R1: Australian
R2: US
GWASD: 1155/1992
R1: 932/6862
R2: 2616/2634
OR = 1.31, p = 2.1 × 10−19
AFAP1 (4p16.1)rs4619890OR = 1.20, p = 7.0 × 10−10
GMDS (6p25.3)rs11969985OR = 1.31, p = 7.7 × 10−10
Li et al., 2015 [48]CDKN2B-AS1 (9p21)rs2157719Asian, African and EuropeanGWASD: 3504/9746
R: 9173/26,780
OR = 0.71, p = 2.81 × 10−33
CDC7-TGFBR3 (1p22)rs1192415OR = 1.13, p = 1.60 × 10−8Associated with optical disk, vertical CD ratio
FNDC3B (3q25.31)rs4894796OR = 0.89, p = 7.93 × 10−8 in Asians only
van Koolwijk et al., 2012 [49]GAS7 (17p13.1)rs11656696D: NL
R: UK, AU, Canada, NZ
SNP: NL, GE
GWASD: 11,972
R: 7482
SNP: 1432
p = 1.4 × 10−8
SNP: P = 2.4 × 10−2
Associated with IOP reduction
TMCO1 (1q24.1)rs7555523p = 1.6 × 10−8
SNP: P = 9.1 × 10−4
Associated with IOP increase
Hysi et al., 2014 [50]FNDC3B (3q25.31)rs6445055Asian, EuropeanGWASD: 35,296
R: 4284/95,560
p = 4.19 × 10−8All 4 loci associated with IOP
ABCA1 (9q31.1)rs2472493p = 2.8 × 10−11
ABO (9q34.2)rs8176693p = 6.39 × 10−11
11p11.2rs747782p = 1.04 × 10−11
Chen et al., 2015 [51]FAR2 (12p11.22)rs4931170US CaucasianGWASD: 1660p = 1.2 × 10−5Associated with IOP
GGA3 (17q25.1)rs52809447p = 6.7 × 10−5
PKDREJ (22q13.31)rs7291444p = 7.4 × 10−5
Springelkamp et al., 2015 [52]ARHGEF12 (11q23.3)rs58073046D: NL
R: NL, UK
GWASD: 8105
R: 1125/4117
β = 0.44, p = 1.87 × 10−8
OR = 1.66, p = 2.81 × 10−9 (HPG)
OR = 1.29, p = 4.23 × 10−2 (NPG)
Associated with increasing IOP
Ramdas et al., 2010 and 2011 [53,54]ATOH7 (10q21.3-22.1)rs1900004D: NL
R: NL, UK
GWASD: 7360
R: 4455
β = −0.068, p = 2.05 × 10−32Optic disc area (−)/VCDR (−)
CDC7/TGFBR3 (1p22)rs1192415β = 0.064, p = 1.82 × 10−27Optic disc area (+)
CDKN2B (9p21)rs1063192β = −0.014, p = 1.96 × 10−14VCDR (−)
SIX1 (14q22.3-q23)rs10483727β =0.012, p = 9.30 × 10−11VCDR (+)
SALL1 (16q12.1)rs1362756β = 0.028, p = 6.48 × 10−8Optic disc area (+)
Macgregor et al., 2010 [55]ATOH7 (10q21.3-22.1)rs3858145D: AU
R: UK
GWASD: 1368
R: 848
p = 3.4 × 10−10Associated with mean disc area
RFTN1 (3p24)rs690037p = 1.6 × 10−6Explained 2.1% cup area variation in AU cohort
Khor et al., 2011 [56]CARD10 (22q13.1)rs9607469D: Asian
R: NL
GWASD: 4445
R: 9326
p = 2.73 × 10−12Associated with optic disc area
ATOH7 (10q21.3-22.1)rs7916697p = 2.00 × 10−15Associated with optic disc area in Asians
CDC7/TGFBR3 (1p22)rs1192415p = 7.57 × 10−17
Iglesias et al., 2014 [57 ]SIX6 (14q23)rs33912345 (His141Asn)D: NL, UK
R: NL, UK
GWASD: 292/1208
R: 11,473
p = 7.74 × 10−7Associated with VCDR and POAG
rs146737847 (Glu29Lys)p = 5.0 × 10−3Associated with VCDR
Vitart et al., 2010 [58]COL5A1 9q34.2rs1536482Croatia, ScotlandGWASD: 7711
R: 2681
β = 0.22, p = 7.1 × 10−8Associated with CCT
ZNF469 16q24.2rs12447690β = 0.23, p = 4.4 × 10−9
AKAP13 15q24-25rs6496932β = 0.13, p = 1.4 × 10−8
AVGR8 13q12.11rs1034200β = 0.14, p = 3.5 × 10−9
Vithana et al., 2011 [59]ZNF469 (16q24)rs12447690D1: SG-Malay D2: SG-ChineseGWASD1: 3280
D2: 3400
β = −5.068, p = 1.92 × 10−14Associated with CCT
rs9938149β = −6.248, p = 1.63 × 10−16
COL5A1/RXRA (9q34.2-q34.3)rs1536478β = −4.63, p = 3.05 × 10−9
rs7044529β = 2.7, p = 1.2 × 10−4
COL8A2 (1p34.2)rs96067β = −4.799, p = 5.40 × 10−13
Ulmer et al., 2012 [60]ZNF469 (16q24)rs12447690D: US-Cau
SNP: US-Cau
GWASD: 1117
SNP: 6469
β = −5.08, p = 0.001Associated with CCT
NTM (11q25)rs7481514β = −6.89, p = 1.03 × 10−5Associated with reduced CCT
OR = 1.28, p = 9.9 × 10−4and POAG risk in low-tension subset
Candidate Gene Studies
Chen et al., 2012 [61]2p16.3rs1533428ChinaSNP462/577OR = 2.16, p = 0.00025Associated with late-onset POAG
Kim et al., 2014 [62]10p12.31rs7098387KoreaSNP211/904OR = 2.0, p = 0.00038Associated with POAG
Fan et al., 2005 [63]APOE 19q13.2rs429358
rs7412
JapanSNP400/281OR = 0.4, p = 0.007APOE4 confers a protective effect against NTG
Lam et al., 2006 [64]rs429358
rs7412
ChinaSNP400/300OR = 0.36, p = 0.008APOE4 confers a protective effect against NTG
Lake et al., 2004 [65]rs429358
rs7412
UKSNP155/349p = nsNone
Cao et al., 2012 [66]ATOH7 10q21.3-22.1rs7916697African-CaribbeanSNP272/165OR = 0.67, p = 0.0096Interacts with rs1063192 near CDKN2B to reduce POAG risk
rs1900004OR = 1.02, p = 0.9076None
rs3858145OR = 0.98, p = 0.9138None
Mabuchi et al., 2012 [67]rs1900004JapanSNP425/191p = 0.028Associated with NTG
Chen et al., 2012 [68]rs3858145China SNP 142/289 OR = 2.69, p < 0.05Showed interaction with RFTN1 rs690037
rs61854782β = −0.088, p = 0.004Associated with VCDR in controls but not POAG
Fan et al., 2011 [69]rs1900004US-CaucasianSNP539/336OR = 1.89, p = 0.025Associated with increased optic nerve area
Dimasi et al., 2012 [70]rs1900004AU, NZSNP873/886OR = 1.12′, p = 0.18No association
rs3858145OR = 1.13, p = 0.12
Wiggs et al., 2011 [71]CAV1/CAV2 7q31.1rs4236601US-CaucasianSNP1000/1183OR = 1.31, p = 0.0007Significantly associated in women more than men
rs1052990OR = 1.25, p = 0.0084Significantly associated in women; and nominally associated with NPG (p = 0.039)
Cao et al., 2012 [66]rs4236601African-CaribbeanSNP272/165OR = 1.15, p = 0.3332No association
Loomis et al., 2014 [72] rs4236601US-Caucasian SNP R1: 976/2132
R2: 1140/2290
pmeta = 2.61 × 10(−7), pwomen = 1.59 × 10(−5)Associated with early paracentral VF defect
rs17588172pmeta = 1.07 × 10(−4)Associated with early paracentral VF defect
Kuehn et al., 2011 [73]rs4236601USSNP545/297p = 0.5No association
Cao et al., 2012 [66]CARD10 22q13.1rs9607469African-CaribbeanSNP272/165OR = 1.13, p = 0.5096No association
Cao et al., 2012 [66] CDC7/TGFBR3 1p22rs1192415African-CaribbeanSNP272/165OR = 1.14, p = 0.4802No association
Dimasi et al., 2012 [70]rs1192415AU, NZSNP873/886OR = 1.22, p = 0.03Showed nominal significance with optic disc area
Cao et al., 2012 [66] CDKN2B (-AS1) 9p21rs1063192African-Caribbean SNP 272/165 OR = 0.39, p = 0.0008Minor allele was protective against POAG
rs4977756OR = 0.89, p = 0.4507No association
Fan et al., 2011 [69]rs1063192US-CaucasianSNP539/336OR = 0.73, p = 0.0006Associated with decreased VCDR and POAG risk
Mabuchi et al., 2012 [67]rs1063192JapanSNP425/191β = 0.11, p = 0.0043Associated with VCDR; and NTG (p = 0.023)
Dimasi et al., 2012 [70]rs1063192AU, NZSNP873/886OR = 0.74, p = 2.2 × 10−5More strongly associated with advanced open-angle glaucoma
Burdon et al., 2012 [74]rs10120688 rs7049105AU, NZSNP1432/595VCDR – β = 0.016, p = 0.03; IOP – β = −2.135, p = 0.001Associated with larger VCDR and lower IOP
Mabuchi et al., 2012 [67]CHEK2 22q12.1rs1547014JapanSNP425/191β = 0.11, p = 0.0079Associated with VCDR; and HTG (p = 0.013)
Dimasi et al., 2012 [70]rs1547014AU, NZSNP873/886OR = 0.98, p = 0.77No association
Dimasi et al., 2012 [70] COL5A1/RXRA 9q34.2-q34.3rs1536482AU, NZ SNP 873/886OR = 0.94, p = 0.46No association
rs7044529OR = 1.00, p = 0.98
Desronvil et al., 2010 [75]COL8A2 1p34.2rs274754US-CaucasianSNP100p = 0.018Associated with corneal thickness
Dimasi et al., 2010 [76]FBN1 15q21.1rs17352842AU-CaucasianSNP956p = 0.02Associated with CCT
Rocha et al., 2011 [77]GSTT1/GSTM1 1p13.3null > positiveBrazilSNP87/85OR = 2.4, p = 0.016T1M0 genotype associated with higher IOP and severe defect of right eye optic nerve and visual field
Juronen et al., 2000 [78]positive > nullEstoniaSNP250/202OR = 1.83, p = 0.002GSTM1 were at significant risk for glaucoma and even higher in smokers (OR = 3.86, p = 0.012)
Jansson et al., 2003 [79]positive = nullSwedenSNP200/200p = nsNo association
Fan et al., 2010 [80]positive = nullChinaSNP405/201p = nsNo association
Liu et al., 2010 [81]NTF4 19q13.33Whole geneUS-CaucasianSNP443/533Not associated with POAG
Rao et al., 2010 [82]Whole geneIndiaSNP141/285p = 0.2No association
Vithana et al., 2010 [83]c.338T>CChinaSNP174/91Rare cause of POAG in Chinese
Chen et al., 2012 [84]c.470G>C c.545C>TChinaSNP720/230May be a rare cause of POAG
Aung et al., 2002 [85] OPA1 3q28-q29rs166850UK SNP 163/86 OR = 3.1, p = 0.002rs166850 combined with rs10451941 was more strongly associated with NTG (p = 0.00001)
rs10451941p = 0.03
Mabuchi et al., 2007 [86]rs10451941JapanSNP285/185OR = 2.27, p = 0.004Increased risk of NTG; and age at diagnosis in HTG (p = 0.048)
Yao et al., 2006 [87]rs166850 rs10451941African-CaribbeanSNP109/48p = nsNo association
Fan et al., 2010 [80]rs166850 rs10451941ChinaSNP405/201p = nsNo association
Dimasi et al., 2010 [76]PAX6 11p13rs3026398AU-CaucasianSNP956p = 0.02Associated with CCT; more strongly with rs662702 haplotype (p = 0.009)
Chen et al., 2012 [61]PLXDC2 10p12.31rs7081455ChinaSNP462/577OR = 1.25, p = 0.31No association
Cao et al., 2012 [66]rs7081455African-CaribbeanSNP272/165OR = 1.04, p = 0.8052No association
Chen et al., 2012 [68]RFTN1 3p24.3rs3858145ChinaSNP142/289β = 25.66, p = 0.029Associated with CCT
Fan et al., 2011 [69]SIX1/SIX6 14p22-23rs10483727US-CaucasianSNP539/336OR = 1.33, p = 0.0043Associated with increased VCDR and POAG risk
Dimasi et al., 2012 [70]rs10483727AU, NZSNP873/886OR = 1.38, p = 6.2 × 10−6Strongly associated with open-angle glaucoma
Cao et al., 2012 [66]rs10483727African-CaribbeanSNP272/165OR = 0.77, p = 0.4151No association
Mabuchi et al., 2012 [67]rs10483727JapanSNP425/191p = 0.017Associated with age at diagnosis in NTG
Carnes et al., 2014 [88] rs10483727US—Caucasians SNP262/256 OR = 1.32, p = 3.87 × 10−11Significantly associated with POAG
rs33912345SNPOR = 1.27, p = 4.2 × 10−10Associated with POAG; and thickness of retinal nerve fiber layer
Mabuchi et al., 2011 [89]SRBD1 2p21rs3213787JapanSNP370/191p = 0.0003 in NTG and p = 0.0013 in HTGAssociated with HTG and NTG including late-onset
Cao et al., 2012 [66]rs3213787African-CaribbeanSNP272/165OR = 0.45, p = 0.2882None
Takano et al., 2012 [90]TLR4 9q33.1rs2149356JapanSNP449/107p = 0.000058Associated with NTG
Chen et al., 2012 [61]rs7037117ChinaSNP462/577OR = 0.99, p = 0.99No association
Shibuya et al., 2008 [91]rs7037117JapanSNP215/318p = 0.00951.47- to 1.65-fold increased risk of NTG; strongest association with rs10759930 haplotype
Cao et al., 2012 [66]rs7037117African-CaribbeanSNP272/165OR = 0.73, p = 0.0571No association
Sharma et al., 2012 [92]TMCO1 1q24rs4656461AU, NZSNP1420β = −2.56, p = 0.004Correlation with age at diagnosis
Ozel et al., 2014 [93]rs7518099US-CaucasianSNP6.236p = 8 × 10−8Strongly associated with IOP
Chen et al., 2012 [61]TMTC2 12q21.31rs7961953ChinaSNP462/577OR = 1.15, p = 0.35No association
Cao et al., 2012 [66]rs7961953African-CaribbeanSNP272/165OR = 0.89, p = 0.5559No association
Fan et al., 2010 [80]TNFα 6p21.3rs1800629ChinaSNP405/201p = 0.012Associated with HTG
Wang et al., 2012 [94]rs4645836ChinaSNP234/230OR = 0.63, p = 0.017Protective for POAG
Mossböck et al., 2006 [95]rs1800629AU SNP 114/228 OR = 0.96, p > 0.05Not associated among Caucasian
rs361525OR = 0.52, p > 0.05
Rao et al., 2010 [82] VAV2 9q34.1rs2156323India SNP 141/285 p = 0.533No association
VAV3 1p13.3rs2801219p = 0.133
Dimasi et al., 2012 [70] ZNF469 16q24rs12447690AU, NZ SNP 873/886 OR = 1.01, p = 0.91No association
rs9938149OR = 0.94, p = 0.46
Chen et al., 2012 [61]ZP4 1q43rs693421ChinaSNP462/577OR = 0.98, p = 0.31No association
Cao et al., 2012 [66]rs547984African-CaribbeanSNP272/165OR = 1.05, p = 0.7374No association
Kim et al., 2014 [62]rs693421KoreaSNP211/904OR = 1.4, p = 0.0082Associated with POAG
Li et al., 2015 [48]CDKN2B-AS1 9p21rs2157719Saudi ArabiaSNPR **: 236/655OR = 1.24, p = 0.146
CDC7-TGFBR3 1p22rs1192415OR = 1.24, p = 0.146
FNDC3B 3q25.31rs4894796OR = 1.03, p = 0.779
Neamatzadeh et al., 2015 [96]TP53 17p13.1rs1042522IranianSNP65/65OR = 2.1, p < 0.05Pro72 allele is associated with POAG risk
Emam et al., 2014 [97]NOS3 7q36rs2070744EgyptSNP160/110OR = 1.86, p < 0.0001rs2070744 is associated with high tension glaucoma; and with plasma nitrite/nitrate levels (p < 0.001)
rs1799983OR = 1.28, p = 0.21
27 bp-VNTR-a/bOR = 0.81, p = 0.33
Abu-Amero et al., 2013 [98]CAT 11p13rs1001179Saudi ArabiaSNP225/403OR = 0.81, p = 0.218Associated with age of onset, and trend towards IOP, and duration of glaucoma
Abu-Amero et al., 2014 [99]SOD2 6q25.3rs4880Saudi ArabiaSNP226/403OR = 1.0, p = 0.988Trend towards age of onset and IOP
Abu-Amero et al., 2012 [100]CAV1/CAV2 7q31rs4236601Saudi ArabiaSNP220/405OR = 1.06, p = 0.699
Abu-Amero et al., 2012 [101]LOXL1 15q24.1rs1048661Saudi ArabiaSNP 96/101p = 0.866
rs3825942p = 0.477
rs2165241p = 0.176
Abu-Amero et al., 2006 [102]MYOC 1q24.322259 G/T (G324V)Saudi ArabiaSNP27/96p = 0.74
OPTN 10p13412 G/A (T34T)p = 0.61
469 G/C (Q53H)p = 0.28
Zanon-Moreno et al., 2013 [103]SLC23A2 20p13rs1279683MediterraneanSNP250/250OR = 2.47, p < 0.001Associated with POAG risk; and plasma vitamin C levels (p < 0.001)
TTPA 8q12.3rs6994076OR = 1.38, p = 0.122Associated with plasma vitamin E levels (p < 0.001)
SEC14L2/TAP 22q12.2rs737723OR = 2.24, p < 0.001Associated with POAG risk; and nominal (p = 0.047) gene-gene interaction with SNP rs1279683
GPX4 19p13.3rs757228OR = 0.80, p = 0.337
Zanon-Moreno et al., 2011 [104]RBP1 3q23rs176990MediterraneanSNP150/150OR = 0.97, p = 0.826
rs190910OR = 0.83, p = 0.315
SLC23A1 5q31.2rs10063949OR = 1.19, p = 0.552
SLC23A2 20p13rs1279683OR = 1.67, p = 0.010Associated with POAG risk; and plasma vitamin C levels (p < 0.001)
Abu-Amero et al., 2008 [105]GSTT1/GSTM1 1p13.3T0M0Saudi ArabiaSNP49/120OR = 5.67, p = 0.06GSTT1 and GSTM1 positive genotypes are at risk for POAG
T1M0OR = 10.2, p = 0.00001
T0M1OR = 11.3, p = 0.00001
Unal et al., 2007 [106]GSTT1/GSTM1 1p13.3T0M1TurkeySNP144/121OR = 3.46, p < 0.005GSTM1 positive and GSTT1 null genotypes are associated with increased risk of POAG
Al-Dabbagh et al. [107]APOE 19q13.2rs429358
rs7412
Saudi ArabiaSNP60/130OR = 2.75, p = 0.034APOE4 allele is a risk factor for POAG
Saglar et al., 2009 [108] APOE 19q13.2rs429358
rs7412
TurkeySNP75/119p = 0.38
TP53 17prs1042522p = 0.12
Nilforoushan et al. [109]MTHFR 1p36.3rs1801133Iran73/90p = 0.337
* AU—Australia; CCT—central corneal thickness; D—discovery cohort; GE—Germany; HPG—high-pressure glaucoma; HTG—high-tension glaucoma; IOP—intraocular pressure; POAG—primary open angle glaucoma; NPG—normal-pressure glaucoma; NTG—normal-tension glaucoma; NL—Netherland; NZ—New Zealand; R—replication cohort; SG—Singapore; SW—Sweden; UK—United Kingdom; US—United States; VCDR—vertical cup-to-disc ratio. ** Part of an International Glaucoma Genetics Consortium Replication Study.

4. GWAS and POAG

Nakano et al. described the first GWAS in the Japanese POAG population with patients predominantly having NTG [38]. This was a two-stage GWAS involving a discovery cohort and a replication cohort. The study reported significant loci on chromosomes 1, 10 and 12 that included genes such as ZP4, PLXDC2 and TMCT2 (DKFZp762A217), respectively. However, none of the SNPs achieved a genome-wide significance (p < 5 × 10−8) even in the combined analysis and, therefore, they await further evaluation in additional cohorts. Meguro et al. reported the first genome-wide significant (p = 2.5 × 10−9, odds ratio (OR) = 2.80) association for SNP rs3213787 in SRBD1 in the Japanese NTG population [39]. Two other studies have replicated this finding in a Japanese NTG and high-tension glaucoma (HTG) cohort [89] and a US Caucasian POAG cohort [110], but not in the African-Caribbean cohort [66].
GWASs have been able to identify certain common variants that are of significance to the understanding of POAG pathogenesis. These include SNPs near CAV1 and CAV2 in an Icelandic cohort [40], in TMCO1 and CDKN2B-AS1 in an Australian cohort [41], in CDKN2B-AS1, SIX1/SIX6, and the 8q22 locus in Europeans [42], in GAS7 and TMCO1 in US Caucasians [49], and in CDKN2B-AS1, CDC7/TGFBR3 and FNDC3B in Asian, African and European cohorts [48].
The caveolin genes have been postulated to influence transforming growth factor-beta (TGF-β) or nitric oxide signaling pathways involved in POAG pathogenesis. The locus on chromosome 7q31 has been studies in US Caucasians, Africans, and the Saudi Arabian population with inconsistent results [40,66,71,72,73,100]. A recent meta-analysis of five studies, including 5774 POAG cases and 40,598 healthy controls, suggested that SNP rs4236601 is associated with POAG risk in Caucasian and Asian populations but not in African and Saudi populations [111]. Australian GWAS identified two loci, TMCO1 (1q24) and CDKN2B-AS1 (9p21), to be associated with advanced glaucoma. The association of the TMCO1 locus with POAG has been replicated in another GWAS for a Caucasian cohort [49], and associated with increase in IOP as well [49,93]; the carriers of risk alleles for SNP rs4656461 have been reported to be associated with a younger age at diagnosis [92]. The ciliary body, trabecular meshwork and retina show abundant TMCO1 expression. However, its precise role in POAG pathogenesis is unclear. So far, there are no published reports of association studies at the TMCO1 locus in the Middle East population.
Since the identification of the association between the CDKN2B/CDKN2B-AS1 locus and POAG in the Australian cohort, several GWASs have replicated this association in the US Caucasian [42], Japanese [43,44,45], Asian, African, and European populations [48], providing strong evidence for the association of this locus with POAG. In addition, many studies have reported a positive association of SNPs in CDKN2B in several other populations using a candidate-gene approach [66,67,69,70,74]. These SNPs are located in an anti-sense non-protein coding gene, CDKN2BAS, within the CDKN2A/B gene cluster. CDKN2B is a tumor suppressor gene and, with its suggested role in the TGF-β pathway, may play a critical role in glaucoma pathogenesis [112,113]. Interestingly, carriers of the CDKN2B-AS1 risk alleles are associated with larger VCDR [53,54] and low IOP as compared to the wild-type carriers [74]. On the basis of these findings, it has been suggested that the CDKN2B/CDKN2B-AS1 locus of 9p21 may possibly predispose a person to glaucomatous optic neuropathy in a mechanism that may not be dependent on IOP and highlights the importance of the chromosome 9p21 susceptibility locus as a risk factor in the development of POAG [114].
Recently, Li et al. performed a GWAS on 3504 POAG cases and 9746 controls. The positive significant findings of this phase were then replicated in 9173 POAG cases and 26,780 controls across 18 different collections of Asian, African, and European populations including a replication cohort from our center in Saudi Arabia [48]. The study confirmed and provided strong evidence of an association at the CDKN2B-AS1 locus (rs2157719, OR = 0.71, p = 2.81 × 10−33), and also identified SNP rs1192415 in the CDC7-TGFBR3 gene (1p22) showing significant association with POAG (OR = 1.13, p = 1.60 × 10−8) in the Asian, African and European populations, as well as SNP rs4894796 in FNDC3B (3q25.31) showing a significant association in Asians only (OR = 0.89, p = 7.93 × 10−8). Interestingly, these results were found to be non-significant in the Saudi replication cohort, indicating that the genetic cause for POAG in the Saudi population may be different than those from Asian, African and European descent.
GWAS studies by Wiggs et al. and Osman et al. in the Caucasian POAG and Japanese POAG cases, respectively, have demonstrated a strong association of SNP rs10483727 located in the in the intergenic region between the SIX1 and SIX6 locus (14q23) [42,43]. SIX6 has been shown to express in the developing and adult human retina [115]. Moreover, the association of SNP rs10483727 in the SIX1/SIX6 region has also been replicated in other Caucasian POAG cohorts [67,69,70,88] but not in the African-Caribbean subjects [66]. After the association of the CDKN2B-AS1 region on chromosome 9p21, the second most consistent association with POAG has been observed in the SIX1/SIX6 locus and so it would be interesting to know if this locus is associated with POAG in the Saudi or other Middle Eastern populations. However, currently there are no published reports of association of SIX1/SIX6 locus with POAG in the middle-east population.
Recently, 11p11.2 (containing multiple genes), ABCA1, ABO, AFAP1, ARHGEF12, FAR2, GGA3, GMDS, PKDREJ, and PMM2 were added to the newly discovered genes associated with POAG [46,47,50,51,52]. These variants were significantly associated with glaucoma and the related functional visual field loss that could make them future study targets for glaucoma patients in the Middle East.

5. GWAS and Quantitative Endophenotype Traits

The genetic evaluation of quantitative endophenotype traits is often very useful in complex multifactorial diseases to understand the contribution of specific traits to the overall disease phenotype. A similar strategy has been successfully used in POAG to understand the contribution of proposed endophenotypes including IOP, VCDR, optic disc area and CCT to the overall disease process. GWASs have been performed to examine the genetic components of these endophenotypes in POAG and the normal population. van Koolwijk and colleagues performed a GWAS for IOP in POAG patients of European descent and identified SNPs rs11656696 and rs7555523, located in GAS7 and TMCO1, respectively, suggesting a role for these two genes in IOP regulation [49]. Other loci found to be associated with IOP so far include FNDC3B, ABCA1, ABO, 11p11.2, ARHGEF12 [50,52]. Another three loci, FAR2, GGA3, and PKDREJ, did not reach a genome-wide significance level (p < 10−5) [51]. Three independent GWASs have evaluated the association of optic disc parameters (VCDR and optic disc area) in the normal general population. The loci associated included ATOH7, CDC7/TGFBR3 and SALL1, CARD10 for the optic disc area, and CDKN2B, SIX1, SCYL1/LTBP3, CHEK2, and DCLK1, in addition to ATOH7, for the VCDR [53,54,55,56]. An exome sequencing also reported the SIX6 locus to influence VCDR (p = 7.74 × 10−7) [57]. A subsequent meta-analysis of the Rotterdam study with the Twin UK study [54] demonstrated a strong association of ATOH7, CDKN2B, and SIX1 in POAG with borderline association for CDC7/TGFBR3 and SALL4 (both p = 0.04). CARD10 was not found to be associated with African-Caribbean POAG cases [66], whereas CHEK2 was reported to be associated with VCDR and HTG among the Japanese [67] but not in Europeans [70]. Moreover, multiple studies have provided strong evidence of association of ATOH7 [66,67,68,69] CDKN2B(-AS1) [66,67,69,70,74] and SIX1/SIX6 [69,70] with POAG. CCT is an important risk factor for POAG in individuals with increased IOP, and over 26 loci have been reported [116]. GWASs have identified several loci associated with CCT in the normal general population (Asian and European descent) and POAG cases (US Caucasians). These loci include ZNF469, COL5A1, AKAP13, AVGR8, and COL8A2 [58,59,60]. The ZNF469 and COL5A1 loci have been found to be associated with CCT in both the Caucasian and Asian cohorts [58,59].
The possible role of these newly discovered loci associated with POAG and its endophenotypes in understanding the pathophysiology of POAG has been elegantly reviewed by Iglesias et al. elsewhere [117]. The review integrates current knowledge in POAG from human and experimental data and dissects the contribution of the newly discovered genetic loci with the known molecular and biological processes, including extracellular matrix remodeling; TGF-β and tumor necrosis factor α (TNF-α) signaling; and the vascular tone pathway, that have been implicated in the pathogenesis of POAG.

6. Candidate Genes and POAG

Recent reviews by Takamota and Araie [32] and Janssen et al. [31] presented a list of genes identified from numerous GWAS and association studies thus far. Taken together, the list of almost 50 genes may represent highly likely candidate genes that may be involved in POAG pathogenesis. Many studies have been performed to replicate the GWAS findings in the Asian, African-Caribbean and Caucasian/European populations using the candidate-gene approach [61,66,67,69,70,71,72,73,74,75,76,84,89,92,93]. Also, many studies were performed to test the association of specific known genes/SNPs with POAG using the same approach in different populations including Middle Eastern [61,62,63,64,65,66,76,77,78,79,80,81,82,83,84,85,86,87,90,91,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109]. These SNP replication and genetic association studies in the Middle Eastern and other populations are also listed in Table 1. Among these, consistent findings have been reported for ATOH7 [66,67,68,69], CDKN2B(-AS1) [66,67,69,70,74], GSTT1/GSTM1 [77,78,105,106], SIX1/SIX6 [69,70] and TMCO1 [92,93] loci, indicating a potential role of these genes/loci in the pathogenesis of POAG. However, except for the glutathione-S transferase (GST) polymorphism, none of these loci have been either found to be associated with POAG (e.g., CAV1/CAV2, CDC7/TGFBR3, FNDC3) or the association has not been reported yet (e.g., ATOH7, CDKN2B(-AS1), SIX1/SIX6, TMCO1) in the Middle Eastern population. However, the positive findings of GSTT1 and GSTM1 genotypes in the Middle Eastern population may be very interesting, highlighting the role of anti-oxidants and/or oxidative stress-related pathways/mechanisms in the pathogenesis of POAG in this population. This view is strongly supported by recent meta-analysis studies that examined the association of GST polymorphisms and the risk of POAG [118,119,120]. We have previously studied SNPs in two of the anti-oxidant genes, CAT (rs1001179) and SOD2 (rs4880) [98,99], in the Saudi POAG patients. However, the studies did not provide any direct association with POAG but indicated a trend towards an association with IOP and age of onset of POAG. In addition, some studies have demonstrated moderate evidence for association of SNPs in TP53, NOS3, SEC14L2/TAP, and APOE [96,97,103,107]. However, these studies have been limited by sample size and would need further investigations in a large population-based cohort. The examination of causative genes such as MYOC, OPTN and LOXL1 in Saudi POAG cases has also provided negative results [102,105]. Table 2 list all genes associated with POAG and their possible role in POAG pathogenesis.

7. Final Remarks

There is significant progress in understanding the genetic basis of POAG, largely due to the application of GWAS methodology in different populations. In recent years, GWASs have identified several loci associated with POAG including CAV1/CAV2, TMCO1, CDKN2B-AS1, CDC7-TGFBR3, SIX1/SIX6, GAS7 and ATOH7.
The association between the CDKN2B(-AS1) locus on chromosome 9p21 and POAG has been extensively established across different populations and represents a major genetic risk factor for POAG. Studies involving the SIX1/SIX6 and the ATOH7 loci affecting the optic disc parameters and POAG itself have also been reproducible. Other loci seem to be more ethnicity-specific. CAV1/CAV2 and CDC7-TGFBR3 loci do not seem to contribute to POAG in the Middle East and the role of other newly discovered loci is yet to be established. Moreover, the GSTT1/GSTM1 genotypes were found to be strongly associated with POAG in the Middle Eastern population and more studies may be needed to examine the role of oxidative stress and anti-oxidant pathways in this population.
Based on the current and new genes identified in glaucoma, it may be possible to develop an algorithm of SNP risk scores to assess the future risk of POAG in patients, which could be clinically useful. However, despite the tremendous progress, the genetic basis of POAG is still not completely understood and further investigations are needed to identify novel genes and pathways contributing to glaucoma that may help define disease-specific targets and facilitate the development of diagnostic and therapeutic strategies.
Table 2. Possible pathogenesis role of various genes associated with POAG.
Table 2. Possible pathogenesis role of various genes associated with POAG.
GeneGene NameFunctionRole in Ophthalmic Diseases
PLXDC2Plexin Domain Containing 2May play a role in tumor angiogenesisPossible role through inhibition of angiogenesis and possible involvement in protecting against inflammation
TMTC2Transmembrane and Tetratricopeptide Repeat Containing 2Protein binding calcium ion homeostasisUnknown
ZP4Zona Pellucida Glycoprotein 4Signal transducer activityUnknown
SRBD1S1 RNA Binding Domain 1Nucleic acid binding, RNA binding, hydrolase activity, acting on ester bondsAppears to contribute to glaucomatous optic neuropathy as a non–IOP-related genetic factor; exact mechanism is not known
ELOVL5ELOVL Fatty Acid Elongase 5Catalytic activityAppears to contribute to glaucomatous optic neuropathy as a non–IOP-related genetic factor; exact mechanism is not known
CAV1/CAV2Caveolin 1/Caveolin 2Receptor binding, structural molecule activityDysfunction of cellular signaling and transport leading to the damage in tissues
CDKN2B-ASCyclin-Dependent Kinase Inhibitor 2B Protein coding gene, inhibits CDK4Associated with systemic diseases inside and outside the eyes causing disruption in cell cycle
TMCO1Transmembrane And Coiled-Coil Domains 1Encoding transmembrane proteinAssociation with cellular malfunction and oxidative stress
SIX1SIX Homeobox 1Regulation of cell proliferation, apoptosis and embryonic development.Associated with developmental malformation of anterior angle, TM and CB
NCKAP5NCK-Associated Protein 5Protein coding geneUnknown
ABCA1ATP-Binding Cassette, Sub-Family A (ABC1), Member 1Cholesterol carrying out of the cellExpressed highly in TM network, thought to be involved in raising IOP
AFAP1Actin Filament Associated Protein 1signaling pathwaysPossible involvement in aqueous outflow and IOP
GMDSGDP-Mannose 4,6-DehydrataseCatalytic activityGMDS encodes a protein that is required for the first step in de novo synthesis of fucose. Fucose is required for diverse biological functions such as growth factor receptor signalling. Several studies have suggested the effects of growth factors on development of glaucoma
CDC7Cell Division Cycle 7PhosphorylationImpairment of cellular function in CB, TM and RGC
FNDC3BFibronectin Type III Domain Containing 3BPoly(A) RNA bindingAssociated with IOP through as yet unknown mechanism
GAS7Growth Arrest-Specific 7Protein coding gene sequence-specific DNA binding transcription factor activityInvolved in developmental and functional impairment of RGC
ABOABO Blood Group (Transferase A, Alpha 1-3-N-Acetylgalactosaminyltransferase; Transferase B, Alpha 1-3-Galactosyltransferase)Basis of the ABO blood group systemThought to play a role in IOP elevation; Exact mechanism is not known
FAR2Fatty Acyl CoA Reductase 2Catalytic activityUnknown
GGA3Golgi-Associated, Gamma Adaptin Ear Containing, ARF Binding Protein 3Protein sorting and trafficking between the trans-Golgi network (TGN) and endosomesUnknown
PKDREJPolycystin (PKD) Family Receptor For Egg JellyMay have a central role in fertilizationElevated IOP through undetermined mechanism
ARHGEF12Rho Guanine Nucleotide Exchange Factor (GEF) 12May play a role in the regulation of RhoA GTPaseElevated IOP through undetermined mechanism
ATOH7Atonal Homolog 7Involved in the differentiation of retinal ganglion cellsInvolved in developmental problems of retinal vasculature
SALL1Spalt-Like Transcription Factor 1OrganogenesisSALL1 is involved in development of calcium homeostasis in the endoplasmic reticulum
RFTN1Raftlin, Lipid Raft Linker 1Formation and/or maintenance of lipid rafts.Related to vertical cup-to-disc ratio
CARD10Caspase Recruitment Domain Family, Member 10Protein binding, receptor signalingDevelopmental problems of neuronal tissues
COL5A1Collagen, Type V, Alpha 1Fibril formationAssociated with malformation of connective tissues leading to problems in cornea and TM
ZNF469Zinc Finger Protein 469Transcriptional regulationThought to be involved in central corneal thickness
AKAP13A Kinase (PRKA) Anchor Protein 13Protein binding, cAMP-dependent protein kinase activityInvolvement in corneal thickness and disruptions in signaling pathways in CB, TM and RGCs
COL8A2Collagen, Type VIII, Alpha 2Protein binding, extracellular matrix structural constituentAssociated with malformation of connective tissues leading to problems in cornea and TM
NTMNeurotriminProtein bindingUnknown
APOEApolipoprotein EProtein binding, receptor bindingRole in oxidative stress and disrupted cellular homeostasis in CB, TM, LC and RGC
CHEK2Checkpoint Kinase 2Protein kinase activityHigh expression is associated with problems in optic nerve and cup disk ratio
FBN1Fibrillin 1Extracellular matrix structural constituentMutations in FBN1 could cause backward bowing by compromising the mechanical properties of the iris
GSTT1Glutathione S-Transferase Theta 1Glutathione transferase activityOxidative stress in all the POAG-involved tissues
NTF4Neurotrophin 4Protein binding, receptor bindingRetinal ganglion cells survival and apoptosis
OPA1Optic Atrophy 1Protein bindingInvolved in Oxidative stress in cornea, CB and TM
PAX6Paired Box 6Sequence-specific DNA binding RNA polymerase II transcription factor activityDevelopmental impairment of neuro ophthalmic system
PLXDC2Plexin Domain Containing 2Receptor bindingDevelopmental problems leading to fewer retinal ganglion cells
SIX6SIX Homeobox 6DNA binding, protein bindingAssociated with developmental malformation of anterior angle, TM and CB
TLR4Toll-Like Receptor 4Receptor bindingInvolved in Oxidative stress and decreased cellular viability
TMTC2Transmembrane And Tetratricopeptide Repeat Containing 2Identical protein bindingTMTC2 is implicated in calcium homeostasis in the endoplasmic reticulum
TNFαTumor Necrosis FactorProtease binding, cytokine activityMay be activated in reaction to POAG-related indices (increased IOP, oxidative stress and increase in disregulation of cellular homeostasis
VAV2Vav 2 Guanine Nucleotide Exchange FactorEpidermal growth factor receptor bindingUnknown
LOXL1Lysyl Oxidase-Like 1Copper ion bindingThrough the loss of elastin formation and resulting friction between the iris and the anterior lens capsule
ZNF469Zinc Finger Protein 469DNA bindingAssociated with developmental malformation of connective tissues leading to problems in cornea and TM
Zp4Zona Pellucida Glycoprotein 4Signal transducer activityUnknown
TP53Tumor Protein P53Core promoter sequence-specific DNA bindingUnknown
NOS3Nitric Oxide Synthase 3 (Endothelial Cell)Receptor bindingDysregulation of the vascular tone particularly through interaction with endothelial nitric oxide synthase and production of nitric oxide (NO) in the vascular endothelia. This may lead to decreased AH outflow and increased IOP
CATCatalaseCatalytic activityDetoxification of reactive oxygen species—linked to POAG through oxidative stress
SOD2Superoxide Dismutase 2, MitochondrialOxygen binding, DNA bindingPossible role through oxidative stress mechanism
OPTNOptineurinProtein bindingThrough oxidative stress/the mitochondrial caspase-dependent cell death
TTPATocopherol (Alpha) Transfer ProteinTransporter activityLinked to vitamin C loss and that in turn is linked to POAG development through yet undiscovered mechanism
RBP1Retinol Binding Protein 1, CellularTransporter activity, retinoid bindingThrough retinol and oxidative stress mechanism
MTHFRMethylenetetrahydrofolate Reductase (NAD(P)H)Methylenetetrahydrofolate reductase (NAD(P)H) activityLinked through homocysteine level, link to POAG is not established
GPX4Glutathione Peroxidase 4Glutathione peroxidase activityEffect on decreased level of vitamins E and C. Lower level of vitamin C is linked to glaucoma through unknown mechanism.
SEC14L2SEC14-Like 2 (S. Cerevisiae)Phospholipid bindingEffect on decreased level of vitamin C. Lower level of vitamin C is linked to glaucoma through unknown mechanism
SLC23A1Solute Carrier Family 23 (Ascorbic Acid Transporter), Member 1Nucleobase transmembrane transporter activityEffect on decreased level of vitamin C. Lower level of vitamin C is linked to glaucoma through unknown mechanism
PMM2Phosphomannomutase 2Catalytic activityExpressed highly in TM network, thought to be involved in raising IOP
SLC23A2Solute Carrier Family 23 (Ascorbic Acid Transporter), Member 2Nucleobase transmembrane transporter activityMay be through lowering the plasma level of vitamin C. Low level of vitamin C was found in POAG patients carrying mutation in this gene. Exact link between low vitamin C level and POAG is not determined
Since the advent of GWAS studies, more and more genes and SNPs have been discovered in association of POAG. However, the usefulness (in term of clinical application and developing therapeutic modalities) of those discoveries is still limited. It will take multiple genotype-phenotype studies in various centers and multiethnic groups before establishing the applicability of those SNPs and/or genes to POAG or POAG clinical indices. As for the development of new therapeutic agents, the process will be lengthy and may take several years before effective therapeutic modalities for POAG are available. The whole process from discovering new genetic markers (SNPs) or genes to developing new therapeutic agents may take several steps and many years. Those steps are: (i) Discover those genes and/or SNPs associated with POAG, which is underway thanks to new emerging technologies in molecular genetics such as exome sequencing and GWAS technologies. This may take up to 10 years to complete; (ii) Establish the association of various SNPs and genes with POAG in various ethnicities, larger cohorts, and in multiple centers. This is important as initial discovery studies are conducted on specific ethnicities and in smaller cohorts; (iii) Conduct functional studies in order to understand how those genes and/or SNPs contribute to POAG pathogenesis; (iv) Develop therapeutic agents based on our understanding of the function of the genes associated with POAG. This step is the longest and expected to take at least 10–15 years. This should not hold us back or make us think less of genetic studies as those may prove to be the only way to improve our current understanding of the etiology of glaucoma and facilitate the development of diagnostic and therapeutic strategies.

Author Contributions

Khaled Abu-Amero and Altaf A. Kondkar reviewed the literature and participated equally in writing the manuscript. Kakarla V. Chalam, supervised the whole process, revised the clinical information reported All three authors approved the final version of the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

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Abu-Amero, K.; Kondkar, A.A.; Chalam, K.V. An Updated Review on the Genetics of Primary Open Angle Glaucoma. Int. J. Mol. Sci. 2015, 16, 28886-28911. https://doi.org/10.3390/ijms161226135

AMA Style

Abu-Amero K, Kondkar AA, Chalam KV. An Updated Review on the Genetics of Primary Open Angle Glaucoma. International Journal of Molecular Sciences. 2015; 16(12):28886-28911. https://doi.org/10.3390/ijms161226135

Chicago/Turabian Style

Abu-Amero, Khaled, Altaf A. Kondkar, and Kakarla V. Chalam. 2015. "An Updated Review on the Genetics of Primary Open Angle Glaucoma" International Journal of Molecular Sciences 16, no. 12: 28886-28911. https://doi.org/10.3390/ijms161226135

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