Srujana Sahebjada

Evaluating the Association Between Keratoconus and the Corneal Thickness Genes in an Independent Australian Population

PURPOSE A recent genome-wide association study (GWAS) identified six loci associated with central corneal thickness that also conferred associated risk of keratoconus (KC). We aimed to assess whether genetic associations existed for these loci with KC or corneal curvature in an independent cohort of European ancestry. METHODS In total, 157 patients with KC were recruited from public and private clinics in Melbourne, Australia, and 673 individuals without KC were identified through the Genes in Myopia study from Australia. The following six single-nucleotide polymorphisms (SNPs) that showed a statistically significant association with KC in a recent GWAS study were selected for genotyping in our cohort: rs4894535 (FNDC3B), rs1324183 (MPDZ-NF1B), rs1536482 (RXRA-COL5A1), rs7044529 (COL5A), rs2721051 (FOXO1), and rs9938149 (BANP-ZNF469). The SNPs were assessed for their association with KC or corneal curvature using logistic or linear regression methods, with age and sex included as covariates. Bonferroni corrections were applied to account for multiple testing. RESULTS Genotyping data were available for five of the SNPs. Statistically significant associations with KC were found for the SNPs rs1324183 (P = 0.001; odds ratio [OR], 1.68) and rs9938149 (P = 0.010; OR, 1.47). Meta-analysis of previous studies yielded genome-wide significant evidence of an association for rs1324183, firmly establishing it as a KC risk variant. None of the SNPs were significantly associated with corneal curvature. CONCLUSIONS The SNPs rs1324183 in the MPDZ-NF1B gene and rs9938149 (between BANP and ZNF4659) were associated with KC in this independent cohort, but their association was via a non-corneal curvature route.

The M4 muscarinic antagonist MT-3 inhibits myopia in chick: evidence for site of action

Citation information: McBrien NA, Arumugam B, Gentle A, Chow A & Sahebjada S. The M4 muscarinic antagonist MT‐3 inhibits myopia in chick: evidence for site of action. Ophthalmic Physiol Opt 2011, 31, 529–539. doi:10.1111/j.1475‐1313.2011.00841.x

Association of the Hepatocyte Growth Factor Gene with Keratoconus in an Australian Population

Purpose A previous study has indicated suggestive association of the hepatocyte growth factor (HGF) gene with Keratoconus. We wished to assess this association in an independent Caucasian cohort as well as assess its association with corneal curvature. Participants Keratoconus patients were recruited from private and public clinics in Melbourne, Australia. Non-keratoconic individuals were identified from the Genes in Myopia (GEM) study from Australia. A total of 830 individuals were used for the analysis including 157 keratoconic and 673 non keratoconic subjects. Methods Tag single nucleotide polymorphisms (tSNPs) were chosen to encompass the hepatocyte growth factor gene as well as 2 kb upstream of the start codon through to 2 kb downstream of the stop codon. Logistic and linear regression including age and gender as covariates were applied in statistical analysis with subsequent Bonferroni correction. Results Ten tSNPs were genotyped. Following statistical analysis and multiple testing correction, a statistically significant association was found for the tSNP rs2286194 {p = 1.1×10-3 Odds Ratio 0.52, 95% CI - 0.35, 0.77} for keratoconus. No association was found between the 10 tSNPs and corneal curvature. Conclusions These findings provide additional evidence of significant association of the HGF gene with Keratoconus. This association does not appear to act through the corneal curvature route.

Assessment of anterior segment parameters of keratoconus eyes in an Australian population.

Purpose To assess anterior segment parameters of eyes with keratoconus (KC) at different clinical stages of disease. Methods KC and non-KC patients were recruited from public and private clinics in Melbourne, Australia. Axial length (AL), mean front corneal curvature (Front Km), mean back corneal curvature (Back Km), central corneal thickness (CCT), corneal thickness at the apex (CTA), corneal thickness at the thinnest point (CTT), anterior chamber depth (ACD), and corneal volume were noted for all the eyes. Results A total of 181 individuals comprising 44 (24.3%) subclinical KC, 118 (65.2%) clinical KC, and 19 (10.5%) control subjects were analyzed. Significant differences were noticed between the subclinical KC and control group for ACD and CTT, whereas between clinical and control groups, significant differences were obtained for AL, CCT, CTA, CTT, and ACD (p < 0.05). In the case of mild, moderate, and severe KC groups, Back Km, CCT, CTA, and CTT were significantly associated (p < 0.001) with increasing disease severity. We further did receiver operating characteristic analysis to confirm the importance of pachymetric parameters in differentiating between control and KC eyes. The area under the receiver operating characteristic curve value of CTT for subclinical and clinical KC was 0.68 and 0.82, which showed that it may be a potential marker for the early detection and prevention of KC. Conclusions This study identified the anterior chamber parameters that differ between subclinical and clinical KC as well as the severity of KC. There is a significant reduction in CTT between control and subclinical eyes, although there are no significant alterations in Front and Back Km or AL between the two groups. Also, a progressive reduction in the pachymetric readings at the pupil center, apex, and thinnest corneal point was identified when comparing mild to severe KC groups. Thus, corneal thickness represents an important parameter that needs to be considered in monitoring KC disease severity.

Assessment of macular parameter changes in patients with keratoconus using optical coherence tomography

Keratoconus is typically diagnosed through changes at the anterior ocular surface. However, we wished to assess if macular parameter changes might also occur in these patients. We assessed posterior changes through the use of optical coherence tomography and compared to a nonkeratoconus patient group. All subjects underwent clinical examination including macular thickness measurements. The generalized estimation equation model was used to estimate the means and compare the differences in various measurements between keratoconus and nonkeratoconus patients. A total of 129 keratoconus eyes of 67 cases and 174 nonkeratoconus eyes of 87 controls were analysed. Keratoconus individuals presented with a significantly greater mean retinal thickness in the central fovea, inner, and outer macula compared to the nonkeratoconus group (p < 0.05). In addition, individuals presenting with the early signs of keratoconus had significantly greater inner and outer macular volume compared to the nonkeratoconus group (p < 0.05). This study indicates the retina appears to thicken at the fovea and macula and had increased macular volume in keratoconus individuals compared to nonkeratoconus individuals. Thus we posit that structural retinal changes exist in keratoconus eyes that are additional to those typically seen in the anterior segment.

Gene Patents Related to Common Diseases of the Eye

Visual impairment and blindness impose substantial morbidity and premature mortality on the population. The direct costs for vision disorders have been shown to be more than the cost of coronary heart disease, stroke, arthritis or depression and were estimated to be

Pooled genome wide association detects association upstream of FCRL3 with Graves’ disease

9.85 billion in 2004 in Australia. Hence it is important to identify the causes of common eye diseases and understand their aetiology which in turn would allow determination of better management strategies and treatment options. Age related Macular Degeneration, Cataract, Diabetic Retinopathy, Glaucoma and uncorrected refractive errors represent the majority of the visual impairment and blindness in Australia and various parts of the world. This article reviews the gene patents available for these eye conditions and highlights the important discoveries that have so far contributed to our understanding of these diseases and provides valuable information as to where research will be heading in the future.

Impact of Keratoconus in the Better Eye and the Worse Eye on Vision-Related Quality of Life

BackgroundGraves’ disease is an autoimmune thyroid disease of complex inheritance. Multiple genetic susceptibility loci are thought to be involved in Graves’ disease and it is therefore likely that these can be identified by genome wide association studies. This study aimed to determine if a genome wide association study, using a pooling methodology, could detect genomic loci associated with Graves’ disease.ResultsNineteen of the top ranking single nucleotide polymorphisms including HLA-DQA1 and C6orf10, were clustered within the Major Histo-compatibility Complex region on chromosome 6p21, with rs1613056 reaching genome wide significance (p = 5 × 10−8). Technical validation of top ranking non-Major Histo-compatablity complex single nucleotide polymorphisms with individual genotyping in the discovery cohort revealed four single nucleotide polymorphisms with p ≤ 10−4. Rs17676303 on chromosome 1q23.1, located upstream of FCRL3, showed evidence of association with Graves’ disease across the discovery, replication and combined cohorts. A second single nucleotide polymorphism rs9644119 downstream of DPYSL2 showed some evidence of association supported by finding in the replication cohort that warrants further study.ConclusionsPooled genome wide association study identified a genetic variant upstream of FCRL3 as a susceptibility locus for Graves’ disease in addition to those identified in the Major Histo-compatibility Complex. A second locus downstream of DPYSL2 is potentially a novel genetic variant in Graves’ disease that requires further confirmation.