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

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Severe intraocular pressure response to periocular or intravitreal steroid treatment in Australia and New Zealand: data from the Australian and New Zealand Ophthalmic Surveillance Unit.

BACKGROUND: Increase in intraocular pressure is a recognized complication of corticosteroid treatment via intravitreal or periocular injections for treatment of a range of conditions including macular oedema and retinal neovascularization. DESIGN: This surveillance study was designed to determine the incidence and nature of severe intraocular pressure elevation as a complication of intravitreal or periocular corticosteroid injections in Australia and New Zealand. PARTICIPANTS: Seventeen cases meeting the defined criteria of severe intraocular pressure elevation, above 35 mmHg, following an intravitreal or periocular corticosteroid injection were included in the study. METHODS: Over an 18-month period, ophthalmologists were invited to report cases to the Australian and New Zealand Ophthalmic Surveillance Unit. After reporting, further demographic and clinical information was sought via a follow-up questionnaire. MAIN OUTCOME MEASURES: Intraocular pressure elevation above 35 mmHg. RESULTS: Follow-up questionnaires were received for 20 cases of 34 initially reported to the unit. Seventeen met the defined criteria. Triamcinolone acetonide was used in all 17 cases, with 16 delivered as a 4-mg intravitreal injection. There was an absence of identified underlying risk factors in the majority of cases with personal history of glaucoma in 2 of 17 cases. No cases reported a positive family history of glaucoma. Trabeculectomy was performed in 8 of 17 patients (47%) for intraocular pressure management. CONCLUSIONS: Severe intraocular pressure elevation following intravitreal or periocular corticosteroid injection can occur in the absence of risk factors such as personal and family history of glaucoma. The severe intraocular pressure elevation may ultimately require trabeculectomy.

Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma.

Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness worldwide. We performed a genome-wide association study in an Australian discovery cohort comprising 1,155 cases with advanced POAG and 1,992 controls. We investigated the association of the top SNPs from the discovery stage in two Australian replication cohorts (932 cases and 6,862 controls total) and two US replication cohorts (2,616 cases and 2,634 controls total). Meta-analysis of all cohorts identified three loci newly associated with development of POAG. These loci are located upstream of ABCA1 (rs2472493[G], odds ratio (OR) = 1.31, P = 2.1 × 10(-19)), within AFAP1 (rs4619890[G], OR = 1.20, P = 7.0 × 10(-10)) and within GMDS (rs11969985[G], OR = 1.31, P = 7.7 × 10(-10)). Using RT-PCR and immunolabeling, we show that these genes are expressed within human retina, optic nerve and trabecular meshwork and that ABCA1 and AFAP1 are also expressed in retinal ganglion cells.

Higher prevalence of myocilin mutations in advanced glaucoma in comparison with less advanced disease in an Australasian disease registry.

OBJECTIVES: To determine the proportion of all Myocilin coding mutations responsible for advanced primary open-angle glaucoma (POAG) in early-age-at-onset individuals and to investigate the prevalence of exon 3 Myocilin mutations in advanced POAG at any age at onset in a large Australasian cohort. DESIGN: Cross-sectional study using a national disease registry. PARTICIPANTS: One thousand sixty individuals with advanced POAG (103 with age at onset of 40 years or younger) and 320 with nonadvanced POAG all recruited by the Australian and New Zealand Registry of Advanced Glaucoma. METHODS: Participants were examined and referred by their eye practitioner, and Myocilin genetic testing was performed by direct sequencing. Cascade genetic testing was made available for relatives of participants found to carry a Myocilin mutation. MAIN OUTCOME MEASURES: Advanced glaucoma diagnosis based on strict visual field entry criteria. Prevalence and spectrum of Myocilin mutations in individuals with advanced and nonadvanced POAG. RESULTS: This is the first study to report Myocilin mutations in an advanced POAG cohort. No pathogenic Myocilin mutations were identified in exons 1 and 2 in early-age-at-onset advanced POAG cases. Exon 3 Myocilin mutations were identified in 45 advanced POAG patients (4.2%), which is significantly higher (P = 0.02) compared with nonadvanced POAG patients (1.6%). A novel mutation (Trp373X) and a new variant of uncertain pathogenicity (Ala447Thr) also were reported. The prevalence of Myocilin mutations rose from 16% to 40% in selected advanced POAG subgroups based on different thresholds of maximum recorded intraocular pressure, age at diagnosis, and the presence and strength of positive family history. Twenty-six individuals with Myocilin mutations were identified through cascade genetic testing of first-degree relatives of affected mutation carriers. CONCLUSIONS: The prevalence of Myocilin mutations in glaucoma cases with severe visual field loss is significantly greater than in nonadvanced glaucoma patients. Myocilin screening in phenotypically selected cases can have a much higher yield than in previous unselected series. Identifying individuals who have Myocilin mutations provides an opportunity to screen at-risk clinically unaffected relatives and to reduce glaucoma blindness through early management and intervention. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.