Association of genetic variants with primary angle closure glaucoma in two different populations.

Mona S Awadalla,Kathryn P Burdon,Alex W Hewitt,Jamie E Craig,Suman S Thapa,Pedro Gonzalez

doi:10.1371/journal.pone.0067903

Abstract

PurposeA recent large genome-wide association study (GWAS) identified multiple variants associated with primary angle-closure glaucoma (PACG). The present study investigated the role of these variants in two cohorts with PACG recruited from Australia and Nepal.MethodPatients with PACG and appropriate controls were recruited from eye clinics in Australia (n = 232 cases and n = 288 controls) and Nepal (n = 106 cases and 204 controls). Single nucleotide polymorphisms (SNPs) rs3753841 (COL11A1), rs1015213 (located between PCMTD1 and ST18), rs11024102 (PLEKHA7), and rs3788317 (TXNRD2) were selected and genotyped on the Sequenom. Analyses were conducted using PLINK and METAL.ResultsAfter adjustment for age and sex, SNP rs3753841 was found to be significantly associated with PACG in the Australian cohort (p = 0.017; OR = 1.34). SNPs rs1015213 (p = 0.014; OR 2.35) and rs11024102 (p = 0.039; OR 1.43) were significantly associated with the disease development in the Nepalese cohort. None of these SNPs survived Bonferroni correction (p = 0.05/4 = 0.013). However, in the combined analysis, of both cohorts, rs3753841 and rs1015213 showed significant association with p-values of 0.009 and 0.004, respectively both surviving Bonferroni correction. SNP rs11024102 showed suggestive association with PACG (p-value 0.035) and no association was found with rs3788317.ConclusionThe present results support the initial GWAS findings, and confirm the SNP’s contribution to PACG. This is the first study to investigate these loci in both Australian Caucasian and Nepalese populations.

Highlights

After adjustment for age and sex, SNP rs3753841 was found to be significantly associated with Primary angle-closure glaucoma (PACG) in the Australian cohort (p = 0.017; OR = 1.34)
SNP rs11024102 showed suggestive association with PACG (p-value 0.035) and no association was found with rs3788317
Primary angle-closure glaucoma (PACG) is a subtype of glaucoma characterised by obstruction of the irido-corneal angle, increase in the intraocular pressure, and slow progressive destruction of the optic nerve with corresponding loss of the peripheral visual field

Summary

Introduction

Primary angle-closure glaucoma (PACG) is a subtype of glaucoma characterised by obstruction of the irido-corneal angle, increase in the intraocular pressure, and slow progressive destruction of the optic nerve with corresponding loss of the peripheral visual field. [1] Glaucoma is the leading cause of irreversible blindness worldwide, with primary angle-closure glaucoma accounting for almost half of all blind glaucoma patients. [2] The number of patients with PACG is expected to rise by approximately 5 million people from 16 million over the decade. [1].Interestingly, affected individuals tend to exhibit a consistent spectrum of anatomical biometric features such as reduced anterior chamber depth along with narrowing in the irido-corneal drainage, increased lens thickness and change in its position, hyperopic refractive error, and short axial length. [3] The disease is more prevalent in older age groups, in females, and in certain populations including Eskimos and Asians. [4].Primary angle-closure glaucoma is a complex heterogeneous disease, with the genetic susceptibility under investigation.Recently, a two staged genome wide association study (GWAS) was conducted on a large cohort with PACG (3,771 cases and 18,551 controls) from multiple ethnicities. Primary angle-closure glaucoma (PACG) is a subtype of glaucoma characterised by obstruction of the irido-corneal angle, increase in the intraocular pressure, and slow progressive destruction of the optic nerve with corresponding loss of the peripheral visual field. [1] Glaucoma is the leading cause of irreversible blindness worldwide, with primary angle-closure glaucoma accounting for almost half of all blind glaucoma patients. Primary angle-closure glaucoma is a complex heterogeneous disease, with the genetic susceptibility under investigation. Three susceptibility loci were detected at genome-wide significance on meta-analysis of all data from both stages; PLEKHA7 rs11024102, COL11A1 rs3753841, and rs1015213 located between PCMTD1 and ST18. [9] It was proposed that mutation in PLEKHA7 could affect the fluid dynamics in the pathophysiology of angle-closure glaucoma. Adherens junction (AJ) are required for organization of the epithelial architecture [7], and contribute to tissue homoeostasis. [8] It is likely to be involved in affecting the fluid flow across the inner wall of Schlemm’s canal. [9] It was proposed that mutation in PLEKHA7 could affect the fluid dynamics in the pathophysiology of angle-closure glaucoma. [10]

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