TNF-alpha promoter polymorphisms and primary open-angle glaucoma

PURPOSE: Primary open-angle glaucoma (POAG) is a multifactorial optic neuropathy with a strong hereditary component. Recent studies suggested a role for tumour necrosis factor-alpha(TNF-alpha) in the pathogenesis of POAG. The purpose of the present study was to investigate a hypothesized association between the TNF-alpha-308G>A and -238G>A gene polymorphisms and the presence of POAG in a Caucasian population. METHODS: The present case-control study comprised 114 unrelated patients with POAG and 228 healthy control subjects, matched for age and gender. Genotyping of the TNF-alpha-308G>A and -238G>A polymorphisms was performed using polymerase chain reaction. RESULTS: Allelic frequencies and genotype distributions of both the TNF-alpha-308G>A and -238G>A gene polymorphisms did not significantly differ between patients with POAG and control subjects. Presence of the TNF-alpha-308A-allele was associated with an odds ratio (OR) of 0.96 for POAG, whereas an OR of 0.52 was found among carriers of the TNF-alpha-238A-allele. CONCLUSION: Our data suggest that none of the investigated TNF-alphagene polymorphisms is a major risk factor among Caucasian patients with POAG.     

Gene polymorphisms of the MMP1, MMP9, MMP12, IL‐1β and TIMP1 and the risk of primary open‐angle glaucoma

Background: Primary open‐angle glaucoma (POAG) is the main cause of irreversible blindness worldwide. Matrix metalloproteinases (MMPs) and their regulators (TIMPs and ILs) have been extensively studied as POAG risk factors. Recent reports have showed several single‐nucleotide polymorphisms (SNPs) for MMPs, TIMPs and ILs encoding genes in patients with POAG. The aim of this study was to investigate association of the ‐1607 1G/2G MMP1, ‐the 1562 C/T MMP9, the ‐82 A/G MMP12, the ‐511 C/T IL‐1β and the 372 T/C TIMP1 gene polymorphisms with POAG occurrence and to investigate their impact on main clinical features. Material and methods: In the present case–control study, we examined group of 511 unrelated Caucasian subjects consist of 255 patients with POAG (mean age 70 ± 15) and 256 controls (mean age 67 ± 16). Determination of genes polymorphic variants was made using polymerase chain reaction–restriction fragment length polymorphism technique (PCR‐RFLP). The odds ratios (ORs) and 95% confidence intervals (CIs) for each genotype and allele were calculated. Results: Presented study showed statistically significant increase in the POAG development risk of the ‐1607 2G/2G MMP1 genotype (OR 1.75; 95% CI, 1.11–2.75; p = 0.014) and for the ‐1607 2G MMP1 allele (OR 1.35; 95% CI, 1.05–1.73; p = 0.017), as well as for the ‐1562 C/T MMP9 genotype (OR 1.74; 95% CI, 1.17–2.59; p = 0.006) and the ‐1562 T MMP9 allele (OR 1.55; 95% CI, 1.10–2.17; p = 0.012) in patients with POAG in comparison with healthy control group. We also observed positive association of the ‐511 T/T IL‐1β genotype (OR 2.60; 95% CI, 1.41–4.80; p = 0.002) as well as the ‐511 T IL‐1β allele occurrence with an increased POAG development risk (OR 1.47; 95% CI, 1.13–1.90; p = 0.003). Furthermore, we found an association of the ‐1607 1G/2G MMP1, ‐1562 C/T MMP9 (anova , p < 0.001) and the ‐511 C/T IL‐1β gene polymorphism (anova , p < 0.05) with decreased retinal nerve fibre layer (RNFL) thickness in patients with POAG group. Results displayed also an association of the 372 T/C TIMP1 gene polymorphism with normal range RNFL (anova , p < 0.001). We observed an association of decreased RA value (rim area) with the ‐82 A/G MMP12 (anova , p < 0.001). Normal RA value was observed in patients with POAG group connected with the 372 T/C TIMP1 (anova , p < 0.05) and the ‐511 C/T IL‐1β (anova , p < 0.05) genes polymorphisms occurrence. Finally, results showed an association of the ‐1562 C/T MMP9 (anova , p < 0.001) gene polymorphism with decreased cup/disc index in patients with POAG group. Conclusion: In conclusion, we suggest that the ‐1607 1G/2G MMP1, ‐1562 C/T MMP9, ‐511 C/T IL‐1β gene polymorphisms can be considered as an important risk factors associated with POAG.     

Association of tumour necrosis factor alpha -308 gene polymorphism with primary open-angle glaucoma in Chinese

PURPOSE: Genetic factors are known to play a role in the aetiology of glaucoma, and in particular the role of the immune system is highly suspected. In this study, we evaluated the association between tumour necrosis factor alpha -308 (TNF alpha -308) and primary open-angle glaucoma (POAG). METHODS: A total of sixty POAG patients and 103 healthy volunteers as control group were enrolled in this case-controlled study. Furthermore, we used polymerase chain reaction based analysis to resolve the TNF alpha -308 polymorphism. Statistical analysis for the relative risk of TNF alpha -308 polymorphism was compared by the chi(2) test. RESULTS: There were significant differences in the distribution of the polymorphism between the POAG patients and the control subjects (P = 0.00016; P < 0.05) and it was found that the A(-308) allele occurred more frequently in POAG patients (odds ratio: 2.72; 95% confidence interval: 1.66-4.45). CONCLUSION: The results of our study concluded that the distribution of TNF alpha -308 was significantly higher in the POAG patients than in the control group. Therefore, the A(-308) allele appears to be associated with POAG and, therefore, could be used as a genetic marker for disease mapping. POAG is a complex disease, and a single gene could not be responsible. Understanding the role of genetic polymorphisms, like TNF alpha, could be a prediction of the disease and useful for developing new treatments for POAG.     

Clinical relevance of optineurin sequence alterations in Japanese glaucoma patients

Purpose:To study the clinical relevance of sequence alterations in the optineurin gene (OPTN) among Japanese patients with open-angle glaucoma, including both primary open-angle glaucoma (POAG) and normal tension glaucoma (NTG). Methods:Genomic DNA was isolated from 83 patients with open-angle glaucoma (55 with POAG and 28 with NTG) and 58 control subjects. The 13 exons of OPTN corresponding to the coding region were amplified by polymerase chain reaction and directly sequenced. Clinical factors were compared between glaucoma patients with and without a certain nucleotide change. Results:The reported heterozygous mutations, c.458G > A(Glu50Lys) in exon 4 and c.691_692insAG in exon 6, were not found in any glaucoma patients or control subjects. The reported c.603T > A(Met98Lys) in exon 5 was significantly more prevalent in the POAG (8/55, 14.5%, p = 0.0147) and NTG (4/28, 14.2%, p = 0.0369) patients, and even in both the POAG and NTG patients combined (12/83, 14.4%, p = 0.0149, Fisher exact probability test), than in the control subjects (1/58, 1.7%). The rates of the reported c.1944G > A(Arg545Gln) in exon 16 were not significantly different between open-angle glaucoma patients (3/83, 3.6%) and control subjects (4/58, 6.8%). In addition, a heterozygous change, c.412G > A(Thr34Thr) in exon 4 was found in 18 (21.6%) open-angle glaucoma patients and seven (12.0%) control subjects. Another heterozygous change, c.457C > T(Thr49Thr), in exon 4 was found only in three POAG patients. The 18 open-angle glaucoma patients with c.412G > A showed significantly larger cup-to-disc ratios (p = 0.0178, Mann-Whitney U test), significantly more deteriorated mean deviations of the visual field in the left eye at the final visit (p = 0.0076), and a significantly higher rate of surgery and/or laser history (p = 0.0321, Fisher exact probability test) than the 65 open-angle glaucoma patients without the nucleotide change. Conclusions:Met98Lys is a risk-associated alteration for open-angle glaucoma, including POAG and NTG, in the Japanese population as initially reported. The amino acid-preserving polymorphism, c.412G > A, may be a genetic risk factor for the progression of open-angle glaucoma in this Japanese population.     

Myocilin mt.1 gene promoter single nucleotide polymorphism (-1000C>G) in Brazilian patients with primary open angle glaucoma

Background: The myocilin (MYOC) gene promoter polymorphism -1000C>G (MYOC mt.1) can be associated with faster progression of primary open angle glaucoma (POAG). The purpose of this study was to investigate the MYOC mt.1 in Brazilian patients with POAG and to evaluate its possible role on the phenotype and the severity of the disease.

Material and methods: One hundred sixty-seven POAG patients and 130 normal controls were enrolled. DNA samples were prepared and the MYOC mt.1 polymorphism was screened by real-time polymerase chain reaction (RT – PCR) in an Single-nucleotide polymorphism (SNP) assay. Frequencies of the MYOC mt.1 promoter polymorphism were determined for both groups and compared by Fisher’s exact test and Chi-square test with Yate’s correction. Intraocular pressure (IOP), cup-to-disc ratio (C/D), number of glaucoma medications, and number of glaucoma surgeries were compared between MYOC mt.1 carriers and non-carriers.

Results: MYOC mt.1 genotype frequencies did not differ between POAG and controls (P = 0.420); 14.6% of controls and 16.4% of POAG patients were MYOC mt.1 carriers (CG or GG). Frequencies of the G allele were similar between glaucomatous patients and controls (7.3% and 9.2%, respectively; P = 0.477). Among POAG patients, there were no differences in mean C/D ratio, IOP, number of glaucoma medications, and surgical procedures for IOP control between carries and non-carriers of the MYOC mt.1 promoter polymorphism (p>0.05).

Conclusion: The G allele of the MYOC mt.1 promoter polymorphism was equally distributed among POAG patients and healthy subjects and it is possibly unrelated to the risk and severity of disease in the Brazilian population.     

Analysis of risk factors that may be associated with progression from ocular hypertension to primary open angle glaucoma

Background: As a multifactorial disease, glaucoma may be associated with pressure‐dependent and pressure‐independent factors. Ocular hypertension (OHT) may develop into primary open angle glaucoma (POAG) for many patients. Groups with OHT and POAG were compared for pressure‐dependent and independent risk factors. A high prevalence of any factor(s) could indicate a contribution to progression from OHT to POAG. Methods: A sample of patients with POAG (n = 438) and with OHT (n = 301) were selected from those attending a tertiary referral private glaucoma practice, and data were collected regarding age and intraocular pressure at the time of diagnosis, sex, family history of glaucoma, systemic hypertension, diabetes, Raynaud's phenomenon, migraine and myopia. Results: After multivariate analysis, older age at time of diagnosis (χ²₅ = 73.89, P < 0.001), myopia (odds ratio [OR] = 1.5, 95% confidence interval [CI] 1.0?2.2; P < 0.05), a family history of glaucoma (OR = 1.6, 95% CI 1.1?2.3; P < 0.01) and a high intraocular pressure (χ²₄ = 16.96; P = 0.002) were found to be more prevalent among those with POAG. No other significant differences could be found between the two groups. Conclusion: Patients who have OHT may be at higher risk of developing POAG if they also have myopia, a family history of glaucoma or are of older age.     

Neurodegenerative Genes Polymorphisms of the -491A/T APOE,the -877T/C APP and the Risk of Primary Open-angle Glaucoma in the Polish Population

Background: Glaucoma is characterized by optic neuropathy of the retinal ganglion cell. It may be possible that β-amyloid (Aβ) and apolipoprotein E (APOE), the main proteins of the pathogenesis of AD, play a role in glaucoma development. The aim of this study was to evaluate a relationship between the APP and APOE gene polymorphisms and the risk of primary open-angle glaucoma (POAG) occurrence.

Materials and methods: The study consisted of 183 patients with POAG and 209 healthy subjects. Genomic DNA was extracted from peripheral blood. Analysis of the gene polymorphisms was performed using PCR-RFLP.

Results: We found a statistically significant increase of the -491?T allele frequency (p?=?0.02; OR?=?1.48; 95% CI?=?1.06–2.08) of APOE in POAG compared to healthy controls. There were no differences in the genotype and allele distributions and odds ratios of the APP polymorphism between patients and controls group. We also found an association between APOE polymorphic variant and retinal nerve fiber layer (RNFL). There was a statistically significant difference in the APOE gene A/T genotype frequency in the early POAG stage and middle-advanced POAG stage in comparison to the advanced POAG stage (p?=?0.04; OR?=?3.38; 95% CI?=?1.04–10.97).

Conclusions: The -491?T allele of APOE polymorphism may be associated with a risk of POAG occurrence in the Polish population.     

Association of apolipoprotein E-219T>G promoter polymorphism with primary open angle glaucoma in Turkish population

AIM: To investigate the association between apolipoprotein E (APOE) -219 T>G promoter polymorphism and primary open angle glaucoma (POAG).METHODS: Patients and healthy subjects were genotyped with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Genotype/allele frequencies were compared between 122 healthy subjects and in 75 POAG patients using Chi-square test.RESULTS:Although the frequency of APOE -219 GG genotype was higher in POAG group (13.3%) than in control group (6.6%), this finding was not statistically significant (P=0.09). In glaucoma patients carrying GG genotype, mean linear C/D ratio was higher and progression was more compared to glaucoma patients with GT genotype.CONCLUSION: APOE -219 T>G polymorphism does not seem to be a risk factor for the presence of glaucoma, but might play a role in deterioration of the disease, which needs further evaluation.     

Quantifying the effect of intraocular pressure reduction on the occurrence of glaucoma

Purpose: To estimate the effect of reducing intraocular pressure (IOP) on: (i) the incidence of primary open‐angle glaucoma (POAG) in patients with ocular hypertension (OH), and (ii) the progression of glaucoma. Methods: A meta‐analysis of relevant randomized controlled trials was conducted. A literature search was performed to identify trials with: a randomized comparison of IOP‐lowering intervention versus placebo or no treatment; visual field loss or optic disc changes as outcome; and follow‐up >6 months. A pooled relative risk (RR) was calculated by a random effects model. Risk reduction of glaucoma conversion per mmHg of IOP reduction was quantified in a meta‐regression model. Results: We identified nine OH and one POAG trials. A meta‐analysis of OH trials gives a pooled RR of 0.61 [95% confidence interval (CI) 0.45–0.83]. A meta‐regression shows a decrease of the RR of glaucoma conversion by 14% with each mmHg extra IOP reduction (P = 0.045). No meta‐analysis of POAG trials was performed because only one study has been identified. Conclusion: There is sufficient evidence that OH therapy reduces the risk of conversion to glaucoma. This risk reduction increases with greater IOP reduction.     

Prothrombin polymorphism A19911G,factor V HR2 haplotype A4070G,and plasminogen activator-inhibitor-1 polymorphism 4G/5G and the risk of retinal vein occlusion

Background: Thus far, no data has become available to evaluate systematically the prevalences of prothrombin polymorphism A19911G (PT A19911G), factor V HR2 haplotype A4070G (FV A4070G), or plasminogen activator-inhibitor-1 polymorphism 4G/5G (PAI-1 4G/5G) in patients who develop retinal vein occlusion (RVO) without cardiovascular risk factors.

Materials and methods: We retrospectively evaluated comprehensive thrombophilia data from 42 preselected RVO patients without cardiovascular risk factors. The prevalences of different gene mutations and polymorphisms including factor V Leiden mutation G1691A (FVL), FV A4070G, prothrombin mutation G20210A, PT A19911G, and PAI-1 4G/5G were compared with 241 healthy controls matched for age and sex.

Results: A total of 20 patients (47.7%) were found to carry thrombophilic gene polymorphisms including FVL, FV A4070G, and homozygous PT A19911G compared with 72 of 241 controls (29.9%; p = 0.03). Subgroup analysis of patients with a significant personal or family history of thromboembolism revealed a high prevalence of FVL, FV A4070G, and homozygous PT A19911G (p = 0.005). FV A4070G was found to be significantly associated with at least two other heterozygous or one homozygous gene polymorphisms (p = 0.02). Multivariate analysis revealed the presence of FVL (p = 0.0017) and homozygous PT A19911G (p = 0.03) polymorphism as independent risk factors for the development of RVO.

Conclusions: Our results indicate that in selected RVO patients screening for thrombophilic gene polymorphisms including FVL, FV A4070G and homozygous PT G19911A may be helpful in a high percentage of cases. Our findings suggest that hereditary thrombophilia associated with RVO is more likely to be multigenic than caused by any single risk factor.     

Association of single-nucleotide polymorphisms in non-coding regions of the TLR4 gene with primary open angle glaucoma in a Mexican population

Background: Toll-like receptor 4 (TLR4) non-coding polymorphisms are associated to primary open angle glaucoma (POAG), normal tension glaucoma, and pseudoexfoliation glaucoma. This study was performed to determine whether non-coding single nucleotide polymorphisms (SNPs) in the TLR4 gene contribute to POAG in a Mexican population.

Material and methods: A total of 187 unrelated Mexican patients with POAG and 109 control subjects were included. Allelic, genotypic, and haplotypic diversity was assessed for the non-coding polymorphisms rs11536889, rs1927911, rs12377632, and rs2149356 of the TLR4 gene. Genotyping of target SNPs was performed by 5′ exonuclease allelic discrimination assays.

Results: Strong linkage disequilibrium was observed among the SNPs (D’ > 0.818), which were located in one haplotype block. The rs11536889 polymorphism was not associated to POAG in any case. The frequency of the minor allele of rs2149356 was significantly higher in the glaucoma group, conferring an increased risk of POAG (p = 0.0018, OR = 1.803, 95% CI 1.2556–2.5890) whereas minor allele of rs12377632 was significantly lower, attributing a protective effect (p = 0.0001, OR = 0.6662, 95% CI 0.4753–0.9339). Subjects with genotypes carrying the minor allele of rs1927911 and rs2149356 shown an increased risk for POAG (p = 0.03, OR = 1.78, 95% CI 1.10–2.87, and p < 0.0004, OR =2.62, 95%CI 1.61–4.27 respectively). Finally, we found significant risk haplotypes. The GTT haplotype (constituted by rs1927911, rs12377632, and rs2149356) reached the higher OR (p = 0.0026, OR = 4.70, 95% CI 1.73–12.77).

Conclusions: We have identified intronic TLR4 SNPs as genetic susceptibility alleles for POAG in a Mexican population. Our findings support the association of the TLR4 gene with POAG.     

Lack of Association Between LOXL1 Gene Polymorphisms and Primary Open Angle Glaucoma in the Saudi Arabian Population

Purpose: To investigate whether major single nucleotide polymorphisms (SNPs) in the LOXL1 gene associated with pseudoexfoliation glaucoma are associated with primary open angle glaucoma (POAG) in the Saudi Arabian population.

Methods: The regions of the LOXL1 gene associated with pseudoexfoliation glaucoma, encompassing the three common SNPs, (rs1048661, rs3825942 and rs2165241), were sequenced in a Saudi Arabian dataset consisting of 96 POAG cases and 101 healthy controls.

Results: The allele frequency of the G exfoliation risk allele for SNP rs1048661 in POAG cases and controls was 0.75 and 0.76 (p?=?0.886), respectively and the allele frequency difference was not statistically significant (p?=?0.866). There was no statistically significant difference in the genotypes between patients and controls (p?=?0.261 and 0.156 for genotypes G/G and G/T respectively). As for SNP rs3825942, the frequency of the “G” allele in the POAG patients was comparable to that in the controls (p?=?0.477) and there was no statistically significant difference in genotype G/G and A/G frequency in the study groups. As for SNP rs2165241, the “T” allele frequency in the POAG patients (0.46) was slightly higher than the frequency in controls (0.39), but this difference was not statistically significant (p?=?0.176).

Conclusion: The Saudi Arabian POAG population, similar to all other populations studied to date, demonstrates no association with SNPs associated with pseudoexfoliation glaucoma.     

Chronic ocular GVHD: limbal and conjunctival stem cell allografts from the same hematopoietic stem cell donor

AIM: To investigate common polymorphisms in VEGF, ACE, TNF and GST genes with retinopathy of prematurity (ROP) risk among Chinese infants. METHODS: Nine polymorphisms in the above genes were genotyped on 724 advanced cases of ROP and 878 prematurely-born infants of low birth weight who were without any ophthalmologic disease. The frequencies of the polymorphisms were compared between cases and controls to identify the association present, if any. RESULTS: Of the nine polymorphisms, only two showed significant associations: ACE ID polymorphism (P=0.031) and TNF -308G/A polymorphism (P<0.001). The former was associated with a reduced ROP risk (ID genotype, adjusted OR (aOR): 0.603, 95%CI: 0.427-0.893, P=0.034; DD genotype, aOR: 0.468, 95%CI: 0.229-0.626, P=0.002), while the latter showed an increased risk (GA genotype, aOR: 1.956, 95%CI: 1.396-2.465, P<0.001; AA genotype, aOR: 2.809, 95%CI: 1.802-4.484, P<0.001). The association was also noted at the allele level (ACE D allele aOR: 0.698, 95%CI: 0.294-0.883, P<0.001; TNF -308A allele aOR: 1.776, 95%CI: 1.446-2.561, P<0.001). CONCLUSION: The ACE ID polymorphism can protect against ROP development while the TNF -308G/A can increase the risk of the disease among Chinese infants.     

Influence of polymorphisms in VEGF, ACE, TNF and GST genes on the susceptibility to retinopathy of prematurity among Chinese infants

AIM: To investigate common polymorphisms in VEGF, ACE, TNF and GST genes with retinopathy of prematurity (ROP) risk among Chinese infants. METHODS: Nine polymorphisms in the above genes were genotyped on 724 advanced cases of ROP and 878 prematurely-born infants of low birth weight who were without any ophthalmologic disease. The frequencies of the polymorphisms were compared between cases and controls to identify the association present, if any. RESULTS: Of the nine polymorphisms, only two showed significant associations: ACE insertion deletion (ID) polymorphism (P=0.031) and TNF -308G/A polymorphism (P<0.001). The former was associated with a reduced ROP risk [ID genotype, adjusted OR (aOR): 0.603, 95%CI: 0.427-0.893, P=0.034; DD genotype, aOR: 0.468, 95%CI: 0.229-0.626, P=0.002], while the latter showed an increased risk (GA genotype, aOR: 1.956, 95%CI: 1.396-2.465, P<0.001; AA genotype, aOR: 2.809, 95%CI: 1.802-4.484, P<0.001). The association was also noted at the allele level (ACE D allele aOR: 0.698, 95%CI: 0.294-0.883, P<0.001; TNF -308A allele aOR: 1.776, 95%CI: 1.446-2.561, P<0.001). CONCLUSION: The ACE ID polymorphism can protect against ROP development while the TNF -308G/A can increase the risk of the disease among Chinese infants.     

Predictive value of the vitamin K epoxide reductase complex subunit 1 G-1639A and C1173T single nucleotide polymorphisms in retinal vein occlusion

Background: To determine if vitamin K epoxide reductase complex subunit 1 gene polymorphisms have an effect on the risk of having a retinal vein occlusion. Design: Case‐control study. Participants: The study population consisted of 68 patients who were newly diagnosed with retinal vein occlusion and 66 sex‐matched controls. Methods: Genomic DNA was extracted from peripheral leukocytes from ethylenediamine tetra‐acetic acid‐anticoagulated blood. Genotyping of the vitamin K epoxide reductase complex subunit 1 G‐1639A (rs 9923231) and C1173T (rs 9934438) single nucleotide polymorphisms was performed using real‐time polymerase chain reaction and commercially available kits. Main Outcome Measures: A full ophthalmological evaluation was performed in each subject, and all subjects were screened for hypertension, hypercholesterolaemia and diabetes. The genotypes of the vitamin K epoxide reductase complex subunit 1 single nucleotide polymorphisms were determined. Results: The vitamin K epoxide reductase complex subunit 1 GG and CC genotypes were more frequent (41% vs. 21%; P = 0.021), and the combined GA/AA and CT/CC genotypes were less frequent in patients with retinal vein occlusion than in control subjects. After adjusting for hypertension, age, plasma fibrinogen levels and prevalence of diabetes and hypercholesterolaemia, the GG and CC genotypes were found to be an independent predictor of retinal vein occlusion (B = 2.28; odds ratio = 9.79; P = 0.003; 95% confidence interval: 2.22–43.24). Conclusion: It was found that subjects with the vitamin K epoxide reductase complex subunit 1 GG and CC genotypes had a higher risk of retinal vein occlusion.     

Graves' ophthalmopathy and gene polymorphisms in interleukin-1α, interleukin-1β, interleukin-1 receptor and interleukin-1 receptor antagonist

Purpose: Interleukin‐1 (IL‐1) is known to have an important role in pathogenesis of Graves' ophthalmopathy (GO). Polymorphisms in IL‐1 gene have been associated with autoimmune reactions. This study aimed to investigate the association of GO with single‐nucleotide polymorphisms (SNPs) in the IL‐1 family (IL‐1α, IL‐1β, IL‐1 receptor [IL‐1R] and IL‐1 receptor antagonist [IL‐1RA]). Methods: A total of 57 patients of Graves' disease without GO, 50 patients with GO and 140 healthy controls were enrolled. Patients were recruited consecutively from the outpatient endocrine clinic of a large university general hospital. Cytokine typing was performed by the polymerase chain reaction with sequence‐specific primers assay. The allele and genotype frequencies of the following polymorphisms were determined: IL‐1α (?889C/T), IL‐1β (?511C/T), IL‐1β (+3962C/T), IL‐1R (Pst‐1 1970C/T) and IL‐1RA (Mspa‐1 11100C/T). Genotype distributions among patients were in Hardy–Weinberg equilibrium for all polymorphisms. Results: Among the five SNPs studied, the frequencies of the T allele and the TT genotype of IL‐1α (?889C/T) were significantly higher among patients with GO than those without GO (odds ratio [OR] = 2.16, 95% confidence interval [CI] = 1.25–3.74; P = 0.006 and 5.67, 95% CI = 1.66–49.34; P = 0.005, respectively). For IL‐1RA (Mspa‐1 11100C/T), the frequencies of the C allele and the CC genotype were significantly higher among patients with GO (OR = 2.31, 95% CI = 1.34–4.00; P = 0.004 and 6.73 95% CI = 1.94–23.36; P = 0.004, respectively; P < 0.01). No significant association was found for other SNPs. Conclusion: This is the first study to show a positive correlation between polymorphisms in the IL‐1α and IL‐1RA genes and susceptibility to GO. These findings promote further research into genetic correlates of GO.     

Analysis of the polymorphic variants of RAN and GEMIN3 genes and risk of Primary Open-Angle Glaucoma in the Polish population

Background: Glaucoma is considered as a neurodegenerative disorder in which the optic nerve damage leads to irreversible blindness. Many scientific findings indicate miRNA implication in the neurodegeneration process. In this study, we aimed to evaluate the polymorphic variants of miRNA processing genes, RAN (rs14035) and GEMIN3 (rs197388), and their association with a risk of primary open-angle glaucoma (POAG) in relation to selected clinical parameters.

Materials and methods: The study included 246 POAG patients and 188 controls. The selected gene polymorphisms were analyzed by TaqMan SNP Genotyping Assay using DNA extracted from blood samples.

Results: The obtained results indicated that the AA genotype of rs197388 as well as the A allele in the same gene may be associated with an elevated risk of POAG development (P = 0.021, P = 0.017 respectively). The correlation between the data and clinical parameters has shown that the A allele of rs197388 in relation to retinal nerve fiber layer(RNFL) could be responsible for an increased risk of glaucoma occurrence (P = 0.028), while the AT genotype could be associated with a decreased risk of POAG according to the mean deviation parameter (P = 0.023).

Conclusion: Our data has shown that GEMIN3 gene (rs197388) polymorphisms might be associated with a risk of POAG development in the Polish population. This is the first report evaluating the polymorphic variants of miRNA processing genes, RAN and GEMIN3, with a changed risk of glaucoma.     

How significant is a family history of glaucoma? Experience from the Glaucoma Inheritance Study in Tasmania

Purpose: To determine what proportion of primary open angle glaucoma (POAG) in Tasmania, Australia is familial. Methods: Between 1994 and 1996 an audit of Tasmanian patients diagnosed with glaucoma was performed. Identified probands along with their family members were invited to participate. Family history of POAG was noted and pedigrees constructed. Each participant underwent a detailed examination, including visual acuity, intraocular pressure measurement, gonioscopy, optic disc assessment and visual field testing. Participants were classified as normal, suspect or POAG. Data from 467 participants in the Twins Eye Study in Tasmania (TEST) were used as a reference for the general population. Results: Of 2062 participants examined, 1700 were classified as POAG. A total of 1014 participants (59.6%) belonged to families in which other members were affected (familial glaucoma). Six hundred and fifty‐six of these 1014 familial cases (64.8%) had a first‐degree relative affected. The number of affected members in the family groups varied from two to 29. Six hundred and eighty‐eight participants had no known family history of POAG (sporadic glaucoma). There were significantly more POAG patients with a family history of POAG compared to the TEST population (χ² = 161.81, P < 0.0001), and for a person with POAG the odds ratio of having a positive family history was 4.1 (95% confidence interval: 3.2–5.2). Conclusion: Approximately 60% of POAG in Tasmania is familial. This percentage is higher than most previous reports of familial glaucoma and emphasizes the importance of genetics in POAG, with major implications for screening and future research.     

Investigation of CAV1/CAV2 rs4236601 and CDKN2B-AS1 rs2157719 in primary open-angle glaucoma patients from Brazil

Large-scale genome-wide association studies have identified several susceptibility variants associated with the risk of primary open-angle glaucoma (POAG), among which rs4236601 (CAV1/CAV2) at chromosome 7q31 and rs2157719 at chromosome 9p21 (CDKN2B-AS1). The purpose of this study was to investigate whether these variants contribute to the incidence of POAG in a sample of the Brazilian Southeastern population and to determine the best-fitted genetic model for these single nucleotide polymorphisms (SNPs). A case-control study with 557 individuals, 310 with POAG, and 247 controls was conducted through PCR and direct sequencing. We observed a significant effect of the heterozygous genotype (G/A) of rs2157719 that occurred more frequently in the control group (p = 0.0004; OR: 0.517, CI 95%: 0.357–0.745). Allele frequencies also differed between cases and controls (p = 0.006; OR: 0.694, CI 95%: 0.522–0.922) with the best-fitted genetic model for rs2157719 being the codominant model. No differences were observed for genotype and allele distributions in relation to rs4236601 in the CAV1/CAV2 region. The association of rs2157719 (CDKN2B-AS1) with the POAG phenotype corroborates previously published results, reinforcing the importance of this variant in POAG etiology.     

Variants in optineurin gene and their association with tumor necrosis factor-alpha polymorphisms in Japanese patients with glaucoma

PURPOSE: To investigate sequence variations in the optineurin (OPTN) gene and their association with TNF-alpha polymorphisms in Japanese patients with glaucoma. METHODS: The OPTN gene was analyzed in blood samples from 629 Japanese subjects. There were 194 patients with primary open-angle glaucoma (POAG), 217 with normal-tension glaucoma (NTG), and 218 with no eye disease (control subjects). The gene was screened for mutations by denaturing high-performance liquid chromatography. Genotyping of three polymorphisms of -308G-->A, -857C-->T, and -863C-->A in the TNF-alpha promoter region was performed. The associations between the genotypes and age, intraocular pressure (IOP), and visual field defects at the time of diagnosis were examined. RESULTS: A possible glaucoma-causing mutation, His26Asp, was identified in 1 of the 411 Japanese patients with glaucoma. A c.412G-->A (Thr34Thr) polymorphism in the OPTN gene was significantly associated with POAG (genotype frequency, P = 0.011; allele frequency, P = 0.003). The frequency of TNF-alpha/-857T and optineurin/412A carriers was significantly higher (P = 0.006) in patients with POAG than in control subjects. Among the patients with POAG who were carriers of TNF-alpha/-857T, the optineurin/412A carriers had significantly worse (P = 0.020) visual field scores than the non-optineurin/412A ones. The frequency of TNF-alpha/-863A and optineurin/603A (or Lys98) carriers was significantly higher in patients with POAG (P = 0.008) or NTG (P = 0.027) than in control subjects. Among the patients with POAG who were carriers of TNF-alpha/-863A, the ones with optineurin/603A (or Lys98) had significantly worse (P = 0.026) visual field scores than did those with non-optineurin/603A (or Lys98). CONCLUSIONS: These findings demonstrated that the OPTN gene is associated with POAG rather than NTG in the Japanese. Statistical analysis showed a possible interaction between polymorphisms in the OPTN and the TNF-alpha genes that would increase the risk for glaucoma.