High-tension Glaucoma Research Articles

Genetic Association at the 9p21 Glaucoma Locus Contributes to Sex Bias in Normal-Tension Glaucoma.

Many genome-wide association studies have identified common single nucleotide polymorphisms (SNPs) at the 9p21 glaucoma locus (CDKN2B/CDKN2B-AS1) to be significantly associated with primary open-angle glaucoma (POAG), with association being stronger in normal tension glaucoma (NTG) and advanced glaucoma. We aimed to determine whether any observed differences in genetic association at the 9p21 locus are influenced by sex. Sex was assessed as a risk factor for POAG for 2241 glaucoma participants from the Australian and New Zealand Registry of Advanced Glaucoma, the Glaucoma Inheritance Study in Tasmania, and the Flinders Medical Centre. A total of 3176 controls were drawn from the Blue Mountains Eye Study and South Australia: 1523 advanced POAG and 718 nonadvanced POAG cases were genotyped along with 3176 controls. We selected 13 SNPs at the 9p21 locus, and association results were subanalyszd by sex for high-tension glaucoma (HTG) and NTG. Odds ratios (ORs) between sexes were compared. A sex bias was present within advanced NTG cases (57.1% female versus 42.9% male, P = 0.0026). In all POAG cases, the strongest associated SNP at 9p21 was rs1063192 (OR, 1.43; P = 4 × 10-18). This association was stronger in females (OR, 1.5; P = 5 × 10-13) than in males (OR, 1.35; P = 7 × 10-7), with a statistically significant difference in female to male OR comparison (P = 1.0 × 10-2). An NTG to HTG subanalysis yielded statistically significant results only in females (OR, 1.63; P = 1.5 × 10-4) but not in males (OR, 1.15; P = 2.8 × 10-1), with a statistically significant difference in female to male OR comparison (P = 1.4 × 10-4). This study demonstrated that female sex is a risk factor for developing advanced NTG. The stronger genetic signals at the 9p21 locus among females may contribute at least in part to the observed sex bias for NTG.

Association of three single nucleotide polymorphisms at the SIX1-SIX6 locus with primary open angle glaucoma in the Chinese population.

This study investigated the genetic association of three single nucleotide polymorphisms (SNPs; rs10483727, rs33912345, and rs146737847) at the SIX1-SIX6 locus with primary open angle glaucoma (POAG) in the Chinese population. A total of 866 subjects with POAG (685 high-tension glaucoma (HTG) and 181 normal-tension glaucoma (NTG)) and 266 control individuals were included. Significant genetic association was identified for rs10483727 in HTG (P=0.02; odds ratio (OR)=1.31), NTG (P=7.41×10(-6); OR=2.71), and POAG (i.e., HTG and NTG combined; P=0.001; OR=1.44). rs33912345 was also significantly associated with HTG (P=0.008; OR=1.36), NTG(P=2.72×10(-6); OR=2.27), and POAG (P=3.84×10(-4); OR=1.49). The rare SIX6 mutation, rs146737847, was not found in the subjects enrolled in this study. Stratification by patient age identified that both rs10483727 and rs33912345 were significantly associated with NTG in patients aged above 40 years (P=2.08×10(-5); OR=2.28), whereas in patients aged between 20-40 years, rs33912345 was significantly associated with NTG (P=0.017; OR=2.06). In HTG, the genetic associations for both rs10483727 and rs33912345 were significant in patients aged between 20-40 years (P=0.006; OR=1.56) but not in those aged above 40 years (P=0.118, OR=1.21 and P=0.042, OR=1.29, respectively). This study replicated the association of POAG with two SNPs at the SIX1-SIX6 locus and demonstrated that SNPs, rs10483727 and rs33912345, are significantly associated with POAG, especially with NTG in patients aged above 40 years.

TBK1 duplication is found in normal tension and not in high tension glaucoma patients of Indian origin.

TBK1 duplication is found in normal tension and not in high tension glaucoma patients of Indian origin.

Vascular and autonomic dysregulation in primary open-angle glaucoma.

The purpose of this review is to discuss whether vascular dysfunction and autonomic dysfunction are related to primary open-angle glaucoma stratified by the intraocular pressure (IOP) level. Patients with primary open angle glaucoma (POAG) across the spectrum of IOP exhibit a variety of ocular and nonocular vascular abnormalities. Interestingly, common genetic variation in nitric oxide synthase 3 (NOS3) and the caveolin 1/caveolin 2 (CAV1/CAV2) genomic regions, which code for proteins involved in setting vascular tone, are associated with POAG. These markers seem to stratify with POAG subtypes stratified by sex or pattern of initial visual field loss and not by IOP level. Overall, it is clear that there is also cardiovascular autonomic dysfunction in high-tension glaucoma and normal-tension glaucoma but it is unclear if this dysfunction is more common in normal-tension glaucoma compared with high-tension glaucoma. Overall, POAG is likely a heterogeneous disease but stratifying cases by IOP level associated with initial optic nerve damage may be less useful than using other endophenotype approaches. Embracing the evidence suggesting systemic endothelial and autonomic dysfunction are operative in POAG will help us move beyond an IOP-centric view of the disease and facilitate 'tearing down the wall' that divides treating physicians and a better understanding of POAG pathogenesis.

Rate of progression of total, upper, and lower visual field defects in patients with open-angle glaucoma and high myopia.

We evaluated the rate of progression of total, upper, and lower visual field defects in patients with treated primary open-angle glaucoma (POAG) with high myopia (HM). Seventy eyes of 70 POAG patients with HM [≤-8 diopters (D)] were examined. The mean deviation (MD) slope and the upper and lower total deviation (upper TD, lower TD) slopes of the Humphrey Field Analyzer were calculated in patients with high-tension glaucoma (HTG) (>21 mmHg) versus normal-tension glaucoma (NTG) (≤21 mmHg). The mean age of all the patients (29 eyes with HTG and 41 eyes with NTG) was 48.5 ± 9.6 years. The MD slope, and upper and lower TD slopes of the HM group were compared to those of the non-HM group (NHM) (>-8 D) selected from 544 eyes in 325 age-matched POAG patients. In all, 70 eyes with HM and NHM were examined. The mean MD slope was -0.33 ± 0.33 dB/year in the HM, and -0.38 ± 0.49 dB/year in the NHM. There were no statistical differences between the HM and NHM (p = 0.9565). In the comparison of HTG versus NTG patients in both groups, the MD slope, and upper and lower TD slopes were similar. The rate of progression of total, upper, and lower visual field defects was similar among patients with HM and NHM. Although HM is a risk factor for the onset of glaucoma, HM may not be a risk factor for progression of visual field defects as assessed by the progression rate under treatment.

Risk Factors for Normal and High-Tension Glaucoma in Poland in Connection with Polymorphisms of the Endothelial Nitric Oxide Synthase Gene.

AimThe purpose of this study was to evaluate the influence of polymorphisms of the eNOS gene on the clinical status of patients with normal and high tension glaucoma.Methods266 Polish Caucasian patients with primary open angle glaucoma were studied. Of the 266, 156 had normal tension glaucoma (NTG) and 110 high tension glaucoma (HTG). DNA material was isolated from peripheral venous blood using commercial kits. Real-time PCR reaction was used to amplify the promoter site of the endothelial nitric oxide synthase (eNOS) gene, including the single nucleotide polymorphism (SNP) site T-786C and part of the 7th exon of eNOS, including G894T SNP. Genotypes were determined with TaqMan SNP Genotyping Assays.ResultsThere were no significant differences in frequencies of the allelic variants of both polymorphisms. In G894T SNP, however, the wild GG form was more common in the HTG group. The SNP of the eNOS gene did not significantly influence the progression rate in either of the groups studied. There were no differences in variants of the eNOS gene regarding the necessity for and success of surgery and the progression of the disease. In the NTG group, no statistical correlation was observed between G894T, T786C polymorphism variants, and risk factors such as optic disc haemorrhages, optic disc notches, and peripapillary atrophy. Mean diastolic and systolic pressure during the day and night were lowest in NTG patients with the CC variant of the T786C polymorphism. No statistical correlation was observed between the G894T and T786C polymorphisms and capillaroscopic examination results.ConclusionsGenotype frequencies are similar for both the eNOS G894T and T-786C polymorphisms in NTG and HTG patients. These polymorphisms do not correlate with risk factors and do not influence the state of the capillary system in NTG patients. Systolic blood pressure is lower in NTG patients with mutated alleles of both polymorphisms.

Glaucoma Structural and Functional Progression in American and Korean Cohorts

To compare the rate of glaucoma structural and functional progression in American and Korean cohorts. Retrospective longitudinal study. Three hundred thirteen eyes from 189 glaucoma and glaucoma suspects, followed up for an average of 38 months. All subjects were examined semiannually with visual field (VF) testing and spectral-domain optical coherence tomography. All subjects had 5 or more reliable visits. The rates of change of retinal nerve fiber layer (RNFL) thickness, cup-to-disc (C/D) ratios, and VF mean deviation (MD) were compared between the cohorts. Variables affecting the rate of change for each parameter were determined, including ethnicity, refraction, baseline age and disease severity, disease subtype (high- vs. normal-tension glaucoma), clinical diagnosis (glaucoma vs. glaucoma suspect), and the interactions between variables. The Korean cohort predominantly demonstrated normal-tension glaucoma, whereas the American cohort predominantly demonstrated high-tension glaucoma. Cohorts had similar VF parameters at baseline, but the Korean eyes had significantly thicker mean RNFL and larger cups. Korean glaucoma eyes showed a faster thinning of mean RNFL (mean, -0.71 μm/year vs. -0.24 μm/year; P < 0.01). There were no detectable differences in the rate of change between the glaucoma cohorts for C/D ratios and VF MD and for all parameters in glaucoma suspect eyes. Different combinations of the tested variables significantly impacted the rate of change. Ethnicity, baseline disease severity, disease subtype, and clinical diagnosis should be considered when comparing glaucoma progression studies.

Lamina depth and thickness correlate with glaucoma severity.

Purpose:To evaluate the correlation between lamina cribrosa (LC) morphology and glaucoma severity in patients with primary forms of open-angle glaucoma (OAG) using enhanced depth imaging spectral-domain optical coherence tomography (SD-OCT) and Humphrey visual field test (HVF).Subjects and Methods:Patients with OAG (n = 166), divided into normal-tension glaucoma (NTG) and high-tension glaucoma (HTG) groups (n = 66 and n = 100), were imaged using SD-OCT to obtain horizontal B-scan images of the optic nerve head (ONH). Laminar depth (LD) and laminar thickness (LT) were measured at the center of ONH.Results:The mean (±standard deviation) values of LD, LT, and visual field mean deviation (MD) were 555.4 ± 142.3 μm, 179.9 ± 49.7 μm, and − 5.7 ± 6.4 dB, respectively. In the multivariate linear regression analysis, LD, LT, and intraocular pressure (IOP) were significantly correlated with MD (P = 0.007, P = 0.037, and P = 0.004, respectively). In the subgroup analyses, only LD was associated with MD in the NTG group (n = 66), whereas LT and IOP were correlated with MD in the HTG group (n = 100). Neither axial length nor central corneal thickness was associated with LD or LT.Conclusions:Glaucoma severity, as measured by HVF MD, shows significant correlations with LD and LT, with greater severity associated with increasing LD and decreasing LT. Normal- and high-tension OAG patients have different associations with LD and LT, which implies that the pathogenesis of these two entities might be different.

Challenging Glaucomas: Update on Diagnosis and Management.

This special issue is focused on the current approaches used to identify and manage particular groups of glaucoma that we define as challenging glaucomas, because of difficulties in either diagnosis or therapy. Malignant glaucoma is a good example of difficulties in both diagnosis and management, and J. Foreman-Larkin et al. provide a complete overview on the clinical management of malignant glaucoma. Pseudoexfoliation is also typified by very high pressures at times and rapid damage to the optic nerve and P. Plateroti et al. focus their paper on pseudoexfoliation syndrome and pseudoexfoliative glaucoma with a review of the literature and updates on surgical management. Raised pressure and inflammation can be very challenging and D. Lewkowicz et al. cover the clinical outcome of hypertensive uveitis. Infection after glaucoma surgery is one of the most challenging situations and K. Ohtomo et al. report their outcomes of late-onset bleb related endophthalmitis treated with pars plana vitrectomy. The aetiology of different variants of the glaucoma with higher and lower ranges of pressure still poses a challenge to us. D. Wrobel-Dudzinska et al. describe the risk factors in normal-tension glaucoma and high-tension glaucoma in relation to polymorphisms of the endothelin-1 gene and the endothelin-1 receptor type A gene. Vascular changes may play a part in the pathogenesis of glaucoma, and E. C. Koch et al. discuss blood pressure and heart rate variability in the detection of vascular dysregulation in glaucoma. Assessment of the cellular layers that get damaged may provide further clues in the assessment and diagnosis, and A. Perdicchi et al. present a research article on the evaluation of agreement between HRT 3 and I-Vue OCT in glaucoma and ocular hypertension patients comparing different tomographic approaches to evaluate retinal ganglion cells. As the variety of topics presented in this special issue suggests, there are still many difficulties related to the diagnosis and therapies for glaucoma. This pathology, especially in its most advanced stages, can have a real impact on the quality of life and outlook of patients. L. Zuo et al. write about vision health-related quality of life in Chinese glaucoma patients, describing how glaucoma can influence the quality of life in patients. There are some particular forms of glaucoma, which more than others, represent a challenge for the ophthalmologist. For example, pigmentary glaucoma has many grey areas that still need to be clarified, including its pathogenesis and the involvement of retinal structures. As mentioned, pseudoexfoliative glaucoma also presents many difficulties for both clinical and therapeutic approaches. However, paediatric forms of glaucoma represent one of the greatest clinical challenges, due to the variation in diagnostic criteria as well as in potential treatments and the response of individual patients. This is especially the case with those forms of glaucoma secondary to other congenital diseases of the anterior segment of the eye, particularly if associated with facial anomalies and other malformations of intraocular structures. This group of disorders is particularly complex for the ophthalmologist, with obstacles in the management of these patients from diagnosis to treatment. However, daunting these challenges, the future looks encouraging as recent advances in translational research are reshaping modern ophthalmology including whole genome analysis and understanding of epigenetic influences and bioinformatics. This should allow the gradual identification of the link between different clinical phenotypes and specific mutation in genes regulating the normal formation and maturation of the eye, which should ultimately give rise to new therapeutic hypotheses and approaches. Thanks to nanotechnologies, new methods of drug administration and the controlled release of molecules used to decrease intraocular pressure are being developed. Surgical treatments are also moving forward with new minimally invasive procedures and with other devices which show promising results with fewer side effects. Furthermore, recent diagnostic criteria define glaucoma as a true neurodegenerative pathology, which affects not only the eye but also the whole optic tract and possibly involves the supportive cells of the central nervous system. This is the reason why, not only will future research focus on lowering IOP but also it will increasingly include therapies with neuroenhancing and neuroprotective effects and, in the most optimistic hypotheses, will lead to neuroregeneration. Gianluca Scuderi Peng T. Khaw Felipe A. Medeiros Gianluca Manni

Phenotypic differences in normal vs high tension glaucoma.

Normal tension glaucoma (NTG) and high tension open angle glaucoma (HTG) are associated with characteristic patterns of optic nerve findings and corresponding patterns of visual field loss. In the past, clinicians viewed NTG and HTG as distinct entities, with separate underlying pathophysiologies and often different clinical presentations and courses. Literature review. Optic nerve and visual field findings in NTG have been reported to be dissimilar to those in HTG. In more recent years, however, there has been increasing recognition of the shared features NTG and HTG. There is now a trend to consider these two entities as part of a spectrum of glaucoma with overlapping pathophysiology and clinical characteristics.

Ganglion Cell Complex Map for Detecting Early Damage in High Tension and Normal Tension Glaucoma

Glaucoma is one of the leading causes of irreversible blindness worldwide. We aimed to compare the findings of a ganglion cell complex (GCC) test with a test of the retinal nerve fibre layer (RNFL) in high and normal tension glaucoma patients. Sixty-two patients were enrolled in the study: 12 glaucoma suspects, 30 with diagnosed glaucoma and 20 with normal tension glaucoma. All subjects had visual acuity testing, tonometry, computer perimetry (Humphrey) and optical coherence tomography (OCT) with an OCT RTvue (RNFL 3.45, NHM4 and GCC). In 58 % of the glaucoma suspects, there were no changes in the perimetry results, as well as with OCT. In 42 % of the subjects, pathological changes in the GCC map preceded those of the RNFL. In patients with HTG, an almost linear correlation was found between the RNFL changes and GCC alterations. Statistical analysis showed that, in glaucoma suspects, the diagnostic value of the average GCC thickness was more significant than the average NFL thickness (0.90 [0.02] to 0.78 [0.02] µm). In 56 % of normal tension glaucoma patients, changes in the RNFL prevailed over those in the GCC. OCT diagnosis is an important tool for detecting early glaucoma changes. In glaucoma suspects, however, GCC changes can be more sensitive. In NTG, the results are still considered controversial. Nevertheless, in the majority of subjects, the RNFL changes prevailed over the GCC changes. The findings in NTG are similar to those in neurological diseases such as multiple sclerosis and Alzheimer's disease.

Progression to Legal Blindness in Patients With Normal Tension Glaucoma: Hospital-Based Study.

To determine the probability of an eye with normal tension glaucoma (NTG) progressing to legal blindness under standard ophthalmic care. Patients diagnosed with NTG (n = 382) between 1985 and 2007 at Gifu University Hospital were followed for at least 5 years under standard ophthalmic care. The collected data included the best-corrected visual acuity (BCVA), intraocular pressure (IOP), and visual field status. Blindness was defined as a BCVA of <20/400 or a constriction of the central visual field to <10° according to the World Health Organization criteria. Kaplan-Meier life table analysis was used to estimate the probability of progressing to blindness in one or both eyes. The mean follow-up period after diagnosis was 13.3 ± 5.4 years with a range of 5.0 to 29.1 years. At diagnosis, 18 patients (4.7%) had unilateral blindness due to glaucoma. At final examination, 34 patients had progressed to unilateral blindness and 5 to bilateral blindness. The Kaplan-Meier life table analysis estimate for unilateral blindness was 5.8 ± 1.3% at 10 years and 9.9 ± 1.9% at 20 years. Similarly, that for bilateral blindness was 0.3 ± 0.3% at 10 years and 1.4 ± 0.8% at 20 years. A Cox proportional hazard model analysis showed that a lower initial BCVA (P < 0.001), a worse initial AGIS (Advanced Glaucoma Intervention Study) score (P = 0.002), and the frequency of changing glaucoma medications during the follow-up periods (P < 0.001) were significantly correlated with the development of blindness in at least one eye. The probability of blindness in eyes with NTG is much lower than previously reported in patients with high-tension glaucoma. Nevertheless, special care should be taken to follow NTG patients, and especially those with worse BCVA and more advanced visual field loss at diagnosis.

Genetic Variants Associated With Different Risks for High Tension Glaucoma and Normal Tension Glaucoma in a Chinese Population.

We investigated the association of genetic factors with primary open angle glaucoma (POAG), including high tension glaucoma (HTG) and normal tension glaucoma (NTG), in a Han Chinese population. We recruited 1157 POAG cases, including 860 HTG and 297 NTG, and 934 normal controls. A total of 13 previously reported single nucleotide polymorphisms (SNPs) located at four gene regions (TMCO1, CDKN2B-AS1, ATOH7, and SIX1/SIX6) was genotyped. Distributions of allele frequencies were compared between cases and controls as well as in the HTG and NTG subgroups. The IOP, vertical cup-to-disc ratio (VCDR), central corneal thickness (CCT), axial length (AL), and age at diagnosis also were investigated as quantitative phenotypes with genotypes of these SNPs. The SNPs rs4656461 and rs7555523 at TMCO1, rs523096 and rs2157719 at CDKN2B-AS1, as well as rs33912345 and rs10483727 at SIX1/SIX6 showed statistically significant association with POAG. The SNPs at ATOH7 did not show statistically significant association with POAG in our dataset. In the subgroup analysis of HTG and NTG, multiple variants at CDKN2B-AS1 and SIX1/SIX6 showed stronger association with NTG than HTG. The SNPs rs523096 and rs2157719 at CDKN2B-AS1 as well as rs33912345 and rs10483727 at SIX1/SIX6 were found to be associated with IOP where the minor alleles were associated with an increase in IOP. In contrast, SNPs at TMCO1 showed significant association with HTG only. Genetic variants in CDKN2B-AS1, SIX1/SIX6, and TMCO1 were associated with POAG in a Han Chinese population. Genes CDKN2B-AS1 and SIX1/SIX6 seem to harbor a tendency toward POAG with lower IOP, while carriers of risk alleles at TMCO1 seem to be predisposed to developing POAG with higher IOP.

Coexistence and Development of an Open-Angle Glaucoma in Eyes With Superior Segmental Optic Hypoplasia

Superior segmental optic hypoplasia (SSOH) is a congenital disorder that is expected not to progress. This study aimed to determine the prevalence and clinical characteristics of coexistent open-angle glaucoma (OAG) in patients with SSOH. We retrospectively reviewed the records of 61 patients diagnosed with SSOH. The estimated prevalence and clinical characteristics of concomitant OAG among patients with SSOH were investigated. Of the 61 patients with SSOH, 12 patients presented with concomitant OAG (mean age, 44.8±19.2 y). Mean follow-up period was 84.9±50.9 months. Five patients (8.2%) were diagnosed with both high-tension glaucoma (HTG) and SSOH; 4 had HTG and SSOH in both the eyes; and the other had HTG only in the eye with SSOH. Seven patients (11.5%) were diagnosed with both normal-tension glaucoma (NTG) and SSOH. Two patients had NTG and SSOH in both eyes and 5 patients had unilateral NTG. The estimated prevalence of OAG in patients with SSOH was 19.7% (95% confidence interval, 9.7%-29.7%). Primary OAG, including HTG and NTG, could develop in eyes with SSOH, regarded as having a nonprogressive visual field defect. The estimated prevalence of OAG, including both NTG and HTG, might be relatively higher in the SSOH patients. Thus, continuous follow-up examinations of patients with SSOH are required.

ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure.

Primary open-angle glaucoma (POAG) is a blinding disease. Two important risk factors for this disease are a positive family history and elevated intraocular pressure (IOP), which is also highly heritable. Genes found to date associated with IOP and POAG are ABCA1, CAV1/CAV2, GAS7 and TMCO1. However, these genes explain only a small part of the heritability of IOP and POAG. We performed a genome-wide association study of IOP in the population-based Rotterdam Study I and Rotterdam Study II using single nucleotide polymorphisms (SNPs) imputed to 1000 Genomes. In this discovery cohort (n = 8105), we identified a new locus associated with IOP. The most significantly associated SNP was rs58073046 (β = 0.44, P-value = 1.87 × 10(-8), minor allele frequency = 0.12), within the gene ARHGEF12. Independent replication in five population-based studies (n = 7471) resulted in an effect size in the same direction that was significantly associated (β = 0.16, P-value = 0.04). The SNP was also significantly associated with POAG in two independent case-control studies [n = 1225 cases and n = 4117 controls; odds ratio (OR) = 1.53, P-value = 1.99 × 10(-8)], especially with high-tension glaucoma (OR = 1.66, P-value = 2.81 × 10(-9); for normal-tension glaucoma OR = 1.29, P-value = 4.23 × 10(-2)). ARHGEF12 plays an important role in the RhoA/RhoA kinase pathway, which has been implicated in IOP regulation. Furthermore, it binds to ABCA1 and links the ABCA1, CAV1/CAV2 and GAS7 pathway to Mendelian POAG genes (MYOC, OPTN, WDR36). In conclusion, this study identified a novel association between IOP and ARHGEF12.

The sick body is not associated with the sicker eye

Introduction: Systemic diseases such as hypertension and diabetes mellitus (DM) have been identified as the risk factor for glaucoma. However, there is minimal knowledge on the impact of systemic diseases on severity of glaucoma. This study aimed to determine the association between systemic disease and systemic treatment and severity of glaucoma. Materials and Methods: A cross-sectional study was conducted involving 298 primary open-angle glaucoma (POAG; 169 high tension glaucoma (HTG) and 129 normal tension glaucoma (NTG)) patients presented at the eye clinic of two tertiary hospitals in Malaysia between March and August 2012. The severity of POAG was based on Hodapp-Parrish-Anderson'(HODAPP) classification on Humphrey visual field 24-2 analysis. Only the right eye was selected when both eyes were eligible. Systemic diseases and treatment were retrieved from medical record or traced from the private practitioner or health clinic. Results: Systemic hypertension was the commonest systemic disease (56.4%) among POAG. There was no significant association between systemic diseases and severity of POAG. More than two systemic diseases were found in43.8% of patients with mild glaucoma. There was also no significant association of systemic treatment such as systemic antihypertensive drugs with severity of glaucoma. Conclusion: Systemic diseases such as systemic hypertension are not associated with severity of POAG. In fact, the presence of systemic disease (sick body) may lead to early detection of glaucoma (sick eye).'Sick body' may prevent 'sicker eye'.

Risk Factors in Normal-Tension Glaucoma and High-Tension Glaucoma in relation to Polymorphisms of Endothelin-1 Gene and Endothelin-1 Receptor Type A Gene.

The aim of the research is to analyse the influence of polymorphisms of endothelin-1 gene and endothelin-1 receptor type A gene on the clinical condition of patients with primary open angle glaucoma. Methods. 285 Polish patients took part in the research (160 normal-tension glaucoma and 125 high-tension glaucoma). DNA was isolated by standard methods and genotype distributions of four polymorphisms in genes encoding endothelin-1 (K198N) and endothelin-1 receptor type A polymorphisms (C1222T, C70G, and G231A) were determined. Genotype distributions were compared between NTG and HTG groups. The clinical condition of participants was examined for association with polymorphisms. Results. A similar frequency of occurrence of the polymorphic varieties of the studied genes was observed in patients with NTG and HTG. There is no relation between NTG risk factors and examined polymorphisms. NTG patients with TT genotype of K198N polymorphism presented with the lowest intraocular pressure in comparison to GG + GT genotype (p = 0.03). In NTG patients with CC genotype of C1222T polymorphism (p = 0.028) and GG of C70G polymorphism (p = 0.03) the lowest values of mean blood pressure were observed. Conclusions. The studied polymorphic varieties (K198N, C1222T) do have an influence on intraocular pressure as well as arterial blood pressure in NTG patients.

TNF-α Gene Polymorphisms and Primary Open Angle Glaucoma in Romanian Population / Polimorfisme ale genei TNF-α în populația română cu glaucom primar cu unghi deschis

AbstractPrimary open-angle glaucoma (POAG) represents the most common form of a heterogeneous group of glaucomatous optic neuropathies which are a worldwide cause of irreversible blindness. Immune dysregulation and the genetic background are considered important risk factors. The influence on susceptibility to POAG of single nucleotide polymorphisms (SNPs) of tumor necrosis factor-α (TNF-α) was intensively studied, mostly on Asian population. We investigated the possible association of two TNF-α SNPs (-308G/A and -857C/T) with susceptibility to POAG and its clinical characteristics. A case-control association study of aforementioned TNF-α SNPs was performed on 197 POAG patients (divided into two subgroups: high-tension and normal-tension glaucoma - HTG/ NTG) versus 208 ethnically matched controls. This is the first study performed on Romanian population. No significant differences were found in terms of allelic frequencies, genotype distribution of the studied SNPs, or their haplotypes between POAG and healthy control groups. In the subgroup analysis, TT genotype of TNF-α -857T-allele was found to be associated with higher values of central corneal thickness (CCT) in NTG subgroup (p-value 0.032). In order to confirm the association between -857C/T SNP of TNF-α and CCT in NTG subgroup of POAG patients, additional studies on different populations should be performed.

Involvement of Genetic Variants Associated With Primary Open-Angle Glaucoma in Pathogenic Mechanisms and Family History of Glaucoma

To investigate the associations between the non-intraocular pressure (IOP)-related genetic variants (genetic variants associated with vulnerability of the optic nerve independent of IOP) and primary open-angle glaucoma (POAG), including normal-tension glaucoma (NTG) and high-tension glaucoma (HTG), and between the non-IOP-related genetic variants and a family history of glaucoma. Case-control study. Japanese patients with NTG (n = 213) and HTG (n = 212) and 191 control subjects were genotyped for 5 non-IOP-related genetic variants predisposing to POAG near the SRBD1, ELOVL5, CDKN2B/CDKN2B-AS1, SIX1/SIX6, and ATOH7 genes. The load of these genetic variants was compared between the control subjects and patients with NTG or HTG and between the POAG patients with and without a family history of glaucoma. The total number of POAG risk alleles and the product of the odds ratios (POAG risk) of these genetic variants were significantly larger (P < .0025) in patients with both NTG and HTG than in the control subjects, and were significantly larger (P = .0042 and P = .023, respectively) in POAG patients with a family history of glaucoma than in those without. As the number of relatives with glaucoma increased, the total number of risk alleles and the product of the odds ratios increased (P = .012 and P = .047, respectively). Non-IOP-related genetic variants contribute to the pathogenesis of HTG as well as NTG. A positive family history of glaucoma in cases of POAG is thought to reflect the influence of genetic variants predisposing to POAG.

Copy Number Variations of TBK1 in Australian Patients With Primary Open-Angle Glaucoma

To investigate the presence of TBK1 copy number variations in a large, well-characterized Australian cohort of patients with glaucoma comprising both normal-tension glaucoma and high-tension glaucoma cases. A retrospective cohort study. DNA samples from patients with normal-tension glaucoma and high-tension glaucoma and unaffected controls were screened for TBK1 copy number variations using real-time quantitative polymerase chain reaction. Samples with additional copies of the TBK1 gene were further tested using custom comparative genomic hybridization arrays. Four out of 334 normal-tension glaucoma cases (1.2%) were found to carry TBK1 copy number variations using quantitative polymerase chain reaction. One extra dose of the TBK1 gene (duplication) was detected in 3 normal-tension glaucoma patients, while 2 extra doses of the gene (triplication) were detected in a fourth normal-tension glaucoma patient. The results were further confirmed by custom comparative genomic hybridization arrays. Further, the TBK1 copy number variation segregated with normal-tension glaucoma in the family members of the probands, showing an autosomal dominant pattern of inheritance. No TBK1 copy number variations were detected in 1045 Australian patients with high-tension glaucoma or in 254 unaffected controls. We report the presence of TBK1 copy number variations in our Australian normal-tension glaucoma cohort, including the first example of more than 1 extra copy of this gene in glaucoma patients (gene triplication). These results confirm TBK1 to be an important cause of normal-tension glaucoma, but do not suggest common involvement in high-tension glaucoma.