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Editors Selection IGR 9-2
Basic Science: Gene studies
Comment by Tin Aung & Chiea-Chuen Khor on:
52751 Association of eNOS polymorphisms with primary angle-closure glaucoma, Awadalla MS; Thapa SS; Hewitt AW et al., Investigative Ophthalmology and Visual Science, 2013; 54: 2108-2114
In this paper, Awadalla and co-authors selected several genes previously implicated in primary open angle glaucoma (POAG) for assessment of potential involvement in primary angle closure glaucoma (PACG). They selected single nucleotide polymorphism (SNP) markers representative of common genetic variation within the genes encoding for Cytochrome P450 (CYP1B1), Endothelial nitric oxide synthase (eNOS), and Neurotrophin-4 (NTF4). These SNPs were assayed in freshly collected cases of primary angle closure glaucoma (PACG) of Australian and Nepalese descent.
Within the Australian PACG sample collection (N = 129 cases and N = 288 controls), significant evidence of association (P < 0.05) was observed between multiple genetic markers encoding for eNOS and PACG, whereas CYP1B1 and NTF4 were not associated. This finding however could not be replicated in the Nepalese collection (N = 106 cases and N = 204 controls).
In the field of complex disease genetics (such as PACG and POAG), where effect sizes conferred by genetic loci are usually very modest (per-allele odds ratio of < 2), very large, well-characterized sample sizes complemented by an unbiased genome-wide perspective are usually necessary in order to establish convincing evidence of association with disease.1 However, there have been successful examples of loci selected based on the candidate gene approach (e.g., in systemic lupus erythematosus, and in the field of lipid genetics, to name but a few) proving to be true positive associations when genome-wide association analysis became available.2,3
The status of eNOS as a true susceptibility locus for PACG will thus have to await further verification.
References
- Todd JA. Statistical false positive or true disease pathway? Nat Genet 2006; 38: 731-733
- Graham RR, et al. A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus. Nat Genet 2006; 38: 550-555
- Romeo S, et al. Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL. Nat Genet 2007; 39: 513-516
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