Association of Genetic Variants with Primary Angle Closure Glaucoma in Two Different Populations

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Abstract

Purpose

A 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.

Method

Patients 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.

Results

After 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.

Conclusion

The 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.

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Most cited references 16

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Splicing mutations of 54-bp exons in the COL11A1 gene cause Marshall syndrome, but other mutations cause overlapping Marshall/Stickler phenotypes.

Elisabeth Friedrich, M Warman, N Shinno … (1999)

Stickler and Marshall syndromes are dominantly inherited chondrodysplasias characterized by midfacial hypoplasia, high myopia, and sensorineural-hearing deficit. Since the characteristics of these syndromes overlap, it has been argued whether they are distinct entities or different manifestations of a single syndrome. Several mutations causing Stickler syndrome have been found in the COL2A1 gene, and one mutation causing Stickler syndrome and one causing Marshall syndrome have been detected in the COL11A1 gene. We characterize here the genomic structure of the COL11A1 gene. Screening of patients with Stickler, Stickler-like, or Marshall syndrome pointed to 23 novel mutations. Genotypic-phenotypic comparison revealed an association between the Marshall syndrome phenotype and splicing mutations of 54-bp exons in the C-terminal region of the COL11A1 gene. Null-allele mutations in the COL2A1 gene led to a typical phenotype of Stickler syndrome. Some patients, however, presented with phenotypes of both Marshall and Stickler syndromes.

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A family with Stickler syndrome type 2 has a mutation in the COL11A1 gene resulting in the substitution of glycine 97 by valine in alpha 1 (XI) collagen.

B. Williams, Cassie Pope, Nicholas Snead … (1996)

Stickler syndrome (hereditary arthro-ophthalmopathy) is the commonest inherited cause of retinal detachment and one of the commonest autosomal dominant connective tissue dysplasias. There is clinical and locus heterogeneity with about two thirds of families linked to the gene encoding type II procollagen (COL2A1). Families with Sticklers syndrome type 1 have a characteristic congenital vitreous anomaly and are linked without recombination to markers at the COL2A1 locus. In contrast families with the type 2 variety have a different vitreo-retinal phenotype and are not linked to the COL2A1 gene. Type XI collagen is a quantitatively minor fibrillar collagen related to type V collagen and associated with the more abundant type II collagen fibrils. A mutation in COL11A2, the gene for alpha 2 (XI) procollagen, has recently been found in a family described as having Stickler syndrome, although there was no ocular involvement. Here we show for the first time that a family with the full Type 2 Stickler syndrome including vitreous and retinal abnormalities is linked to the COL11A1 gene and characterise the mutation as a Glycine to Valine substitution at position 97 of the triple helical domain caused by a single base G-->T mutation. These results are the first to provide confirmation that type XI collagen is an important structural component of human vitreous. They also support previous work suggesting that mutations in the genes encoding collagen XI can give rise to some manifestations of Stickler syndrome, but of these, only mutations in COL11A1 will give the full syndrome including the vitreo-retinal features.

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The prevalence of primary angle closure glaucoma in European derived populations: a systematic review.

Alexander Day, Gianluca Baio, Gus Gazzard … (2012)

To estimate the prevalence of primary angle closure glaucoma (PACG) in European derived populations. Systematic review and modelling of PACG prevalence data from population studies. PACG was defined according to the ISGEO definition requiring structural and/or functional evidence of glaucomatous optic neuropathy. Prevalence estimates were applied to the 2010 United Nations projected population figures to estimate case numbers. The prevalence of PACG in those 40 years or more is 0.4% (95% CI 0.3% to 0.5%). Age-specific prevalence values are 0.02% (CI 0.00 to 0.08) for those 40-49 years, 0.60% (0.27 to 1.00) for those 50-59 years, 0.20% (0.06 to 0.42) for those 60-69 years and 0.94% (0.63 to 1.35) for those 70 years and older. Three-quarters of all cases occur in female subjects (3.25 female to 1 male; CI 1.76 to 5.94). This analysis provides a current evidence-based estimate of PACG prevalence in European derived populations and suggests there are 130,000 people in the UK, 1.60 million people in Europe and 581,000 people in the USA with PACG today. Accounting for ageing population structures, cases are predicted to increase by 19% in the UK, 9% in Europe and 18% in the USA within the next decade. PACG is more common than previously thought, and all primary glaucoma cases should be considered to be PACG until the anterior chamber angle is shown to be open on gonioscopy.

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Author and article information

Contributors

Pedro Gonzalez: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2013

Publication date (Electronic): 28 June 2013

Volume: 8

Issue: 6

Electronic Location Identifier: e67903

Affiliations

[1 ]Department of Ophthalmology, Flinders University, Flinders Medical Centre Adelaide, South Australia, Australia

[2 ]Nepal Glaucoma Eye Clinics, Tilganga Institute of Ophthalmology, Kathmandu, Nepal

[3 ]Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia

Duke University, United States of America

Author notes

* E-mail: awad0002@ 123456flinders.edu.au

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: MSA KPB JEC. Performed the experiments: MSA KPB. Analyzed the data: MSA KPB. Contributed reagents/materials/analysis tools: MSA KPB SST AWH JEC. Wrote the paper: MSA.

Article

Publisher ID: PONE-D-12-39674

DOI: 10.1371/journal.pone.0067903

PMC ID: 3695871

PubMed ID: 23840785

SO-VID: b644dacf-e2ff-47b9-b522-624795fa2ade

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 18 December 2012

Date accepted : 22 May 2013

Page count

Pages: 5

Funding

This work was funded by a grant from the Flinders Medical Centre Foundation. KPB is funded by a National Health and Medical Research Council (NHMRC) of Australia Career Development Award and JEC is an NHMRC Practitioner Fellow. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Association of Genetic Variants with Primary Angle Closure Glaucoma in Two Different Populations

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Abstract

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Most cited references 16

Splicing mutations of 54-bp exons in the COL11A1 gene cause Marshall syndrome, but other mutations cause overlapping Marshall/Stickler phenotypes.

A family with Stickler syndrome type 2 has a mutation in the COL11A1 gene resulting in the substitution of glycine 97 by valine in alpha 1 (XI) collagen.

The prevalence of primary angle closure glaucoma in European derived populations: a systematic review.

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