Introduction PACG has long been thought to have a significant genetic basis. 1,2

1. Program Number: 6221 Genetic Susceptibility Variations and Visual Field Progression in Singaporean Chinese Patients with Primary Angle Closure Glaucoma Xin Wei B.Sc,1,2Chiea-Chuen Khor MD PhD,3,4 John Mark S. de Leon MD,2 Eranga N Vithana PhD,2,4 Monisha Nongpiur MD,2,4 Shamira A. Perera FRCOphth,2 Tin Aung FRCSE FRCOphth PhD,2,4 1Duke-National University of Singapore Graduate Medical School, Singapore, 2Singapore Eye Research Institute & Singapore National Eye Center, Singapore, 3Human Genetics, Genome Institute of Singapore, Singapore 4Department of Ophthalmology, National University Health System & National University of Singapore, Singapore • Introduction • PACG has long been thought to have a significant genetic basis.1,2 • Recently three novel genetic susceptibility loci for PACG (rs3753841 in COL11A1, rs1015213 located between PCMTD1 and ST18, and rs11024102 in PLEKHA7) were identified through a genome-wide association study (GWAS).3 • It is not known whether these genetic variations are associated with specific clinical features in PACG, a disorder with variable clinical presentation and disease course. • Aim • To investigate the association between clinical features, such as age at diagnosis, need for filtration surgery and incidence of visual field progression, with the three PACG susceptibility loci. • Methods • In this retrospective case series, 246 well-characterized Singaporean Chinese PACG patients who had been previous genotyped, and who had ≥5 years of follow-up and ≥5 visual field (VF) tests (static automated perimetry, central 24-2 threshold test) were included. • VF analysis was performed using point-wise linear regression (PROGRESSOR, Medisoft, Ltd, Leeds, England). VF progression was defined as 2 or more adjacent progressing points (slope p<0.01) in the same hemifield. • Individual SNP genotypes were coded according to the number of copies of the variant allele present: 0 for the wild-type, 1 for heterozygous carriers and 2 for individuals homozygous for the minor allele. Association testing was done using a 1-degree-of-freedom test using logistic regression for categorical variables or linear regression for continuous variables. A P value of <0.017 (0.05/3) was considered statistically significant after Bonferroni correction. • Results • The minor allele frequency in the three loci, rs3753841 (COL11A1), rs1015213 (PCMTD1-ST18) and rs11024102 (PLEKHA7) was 33.5%, 2% and 37%, respectively (Table 1). • Results (cont) • There were no significant differences in the age at diagnosis, duration of follow-up, gender, laterality of glaucoma or need for filtration surgery amongst patients with different genotypes at the three loci (Table 1, all P>0.017). • Results (cont) • We noted no significant association between visual field progression with any of the three PACG susceptibility loci (Table 2, all P>0.017). There was also no difference in the mean number of progressing points, the mean slope of sensitivity loss in the whole VF or among the progressing points and mean number of progressing points (Table 2, all P>0.017) • Discussion • We did not find any correlation between PACG susceptibility loci and a range of clinical features such as age at diagnosis, need for filtration surgery and incidence of visual field progression. • The mechanisms by which the three PACG susceptibility loci cause disease is not fully understood. Possible mechanisms include effects on ocular anatomical as well as dynamic physiological parameters. • For rs3753841 (COL11A1) and rs11024102 (PLEKHA7), our sample size had more than 80% power to detect an association with visual field progression if the true per-allele OR is 2. Due to a low minor allele frequency at SNP rs1015213 (PCMTD1-ST18), we may have been underpowered to detect an association. • The strength of this study were the well-characterized patient population and the strict inclusion criteria. The limitations included the limited sample size, non-standardization of treatment and inclusion of only a single ethnic group. • Conclusions • The lack of association with visual field progression suggests that the three SNPs although strongly associated with PACG, do not impart a different disease phenotype in terms of progression. FundingThe study was supported by grants from the National Medical Research Council, Singapore and the National Research Foundation, Singapore.References • Amerasinghe, N., et al., The Heritability and Sibling Risk of Angle Closure in Asians. Ophthalmology, 2011. 118(3): p. 480-485. • Lowe, R.F., Primary angle-closure glaucoma. Inheritance and environment. Br J Ophthalmol, 1972. 56(1): p. 13-20. • Vithana, E.N., et al., Genome-wide association analyses identify three new susceptibility loci for primary angle closure glaucoma. Nat Genet, 2012. 44(10): p. 1142-6. Contact: wx@nus.edu.sg