ABCC5, a Gene That Influences the Anterior Chamber Depth, Is Associated with Primary Angle Closure Glaucoma

Monisha E Nongpiur,Balekudaru Shantha,Yang Li,Takanori Mizoguchi,Mineo Ozaki,Zheng Li,Guangxian Tang,Seng-Chee Loon,Masako Kuroda,Do Nhu Hon,Tin Aung,Raghavan Lavanya,Belinda K Cornes,Sujie Fan,Ching-Lin Ho,Naushin Waseem,Jost B Jonas,Lingam Vijaya,Shamira A Perera,Serena M L Ting,Ileana Soto,Nagaswamy Soumittra,Alicia C How,Victor H K Yong,Saleh A Al-Obeidan,K Saidas Nair,R Rand Allingham,Azhany Yaakub,Michael A Hauser,Govindasamy Kumaramanickavel,Hongyan Jia,Cameron P Simmons,Tran Nguyen Bich Chau,Sancy Low,Hon-Tym Wong,Paul J Foster,Ronnie George,Eranga N Vithana,Yasuo Kurimoto,Yik-Ying Teo,Chunyan Qiao,Yi-Xin Zeng,Simon W M John,Mingzhi Zhang,Hua Wang,Bo Feng,Liang Xu,Chiea‐Chuen Khor ,Chi‐Pui Pang ,Vedam Lakshmi Ramprasad ,Khaled K Abu-Amero ,Seang‐Mei Saw ,Yaxing Wang ,Ke Wang ,Lijia Chen ,Kee‐Seng Chia ,Donald Tan ,Essam Osman ,Jin‐Xin Bei ,Clement C Tham ,Tien‐Yin Wong ,Renyi Wu ,Siladitya Bhattacharya ,Tina Wong ,E Shyong Tai ,Hua Meng ,Yingfeng Zheng ,Ching‐Yu Cheng ,Tan D ,Paul Chew ,Daniel Su ,Ahmad Tajudin Liza-Sharmini

doi:10.1371/journal.pgen.1004089

Abstract

Anterior chamber depth (ACD) is a key anatomical risk factor for primary angle closure glaucoma (PACG). We conducted a genome-wide association study (GWAS) on ACD to discover novel genes for PACG on a total of 5,308 population-based individuals of Asian descent. Genome-wide significant association was observed at a sequence variant within ABCC5 (rs1401999; per-allele effect size = −0.045 mm, P = 8.17×10−9). This locus was associated with an increase in risk of PACG in a separate case-control study of 4,276 PACG cases and 18,801 controls (per-allele OR = 1.13 [95% CI: 1.06–1.22], P = 0.00046). The association was strengthened when a sub-group of controls with open angles were included in the analysis (per-allele OR = 1.30, P = 7.45×10−9; 3,458 cases vs. 3,831 controls). Our findings suggest that the increase in PACG risk could in part be mediated by genetic sequence variants influencing anterior chamber dimensions.

Highlights

Primary angle closure glaucoma (PACG) remains a major cause of irreversible blindness, in Asian countries such as China [1], Mongolia [2], Singapore [3], and India [4] with up to 80% of the estimated 15 million people afflicted with primary angle closure glaucoma (PACG) resident in Asia [5]
Association between ABCC5 rs1401999 and PACG For the second analysis, we examined if this variant was associated with PACG, and proceeded to conduct analysis of 1,854 PACG cases and 9,608 controls from 5 cohorts (Table S2), all genotyped with Illumina SNP-arrays, and a further 2,422 cases and up to 9,193 controls from 7 independent collections genotyped using the Sequenom MassArray or Taqman platforms
The anterior chamber is the space within the eye which is bound by the cornea, and the anterior surfaces of the iris and lens

Summary

Introduction

Primary angle closure glaucoma (PACG) remains a major cause of irreversible blindness, in Asian countries such as China [1], Mongolia [2], Singapore [3], and India [4] with up to 80% of the estimated 15 million people afflicted with PACG resident in Asia [5]. We recently conducted a genome-wide association study (GWAS) on PACG with 3,771 PACG cases and 18,551 controls, and identified 3 strongly associated genetic variants: rs11024102 in PLEKHA7, rs3753841 in COL11A1 and rs1015213 located between PCMTD1 and ST18 on Chromosome 8q [6]. Quantitative phenotypes allow individuals to be viewed along the continuum of risk, and may provide additional information which could complement dichotomous measures of affection status [7], [8] Such an approach has been used in the study of genetic variants controlling lipid traits and susceptibility to coronary artery disease [7], [8]

Methods

Results

Discussion

Conclusion