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Genetic Risk Factors for Glaucoma and Exfoliation Syndrome Identified by Genome-wide Association Studies.

ABSTRACT: BACKGROUND:Glaucoma is a neurodegenerative disease characterized by the progressive loss of retinal ganglion cells and optic nerve axons. According to its anatomical features, glaucoma is mainly subdivided into primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG). Exfoliation syndrome (XFS) and glaucoma (XFG) are characterized by the accumulation of extracellular materials in ocular tissues, particularly the lens surface and pupillary border. In addition to the two major forms of glaucoma, XFG is the most common cause of secondary open-angle glaucoma. Recent genome-wide association studies(GWASs) revealed genetic loci associated with each glaucoma subtype. METHODS:Review of literatures regarding GWASs for POAG, PACG and XFS. RESULTS:Several genetic loci were found to be independently associated with POAG, PACG, and XFS by large-scale GWASs. CONCLUSIONS:Genetic studies may not only provide a better understanding of the pathophysiological mechanisms underlying the diseases, but also facilitate the development of new drugs or treatments.

SUBMITTER: Sakurada Y

PROVIDER: S-EPMC6120117 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Genetic Risk Factors for Glaucoma and Exfoliation Syndrome Identified by Genome-wide Association Studies.

Sakurada Yoichi Y Mabuchi Fumihiko F

Current neuropharmacology 20180101 7

<h4>Background</h4>Glaucoma is a neurodegenerative disease characterized by the progressive loss of retinal ganglion cells and optic nerve axons. According to its anatomical features, glaucoma is mainly subdivided into primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG). Exfoliation syndrome (XFS) and glaucoma (XFG) are characterized by the accumulation of extracellular materials in ocular tissues, particularly the lens surface and pupillary border. In addition to the tw ...[more]

PMID: 28721823

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Project description:An increasing proportion of the worldwide population is affected by allergic diseases such as allergic rhinitis (AR), atopic dermatitis (AD) and allergic asthma and improved treatment options are needed particularly for severe, refractory disease. Allergic diseases are complex and development involves both environmental and genetic factors. Although the existence of a genetic component for allergy was first described almost 100 years ago, progress in gene identification has been hindered by lack of high throughput technologies to investigate genetic variation in large numbers of subjects. The development of Genome-Wide Association Studies (GWAS), a hypothesis-free method of interrogating large numbers of common variants spanning the entire genome in disease and non-disease subjects has revolutionised our understanding of the genetics of allergic disease. Susceptibility genes for asthma, AR and AD have now been identified with confidence, suggesting there are common and distinct genetic loci associated with these diseases, providing novel insights into potential disease pathways and mechanisms. Genes involved in both adaptive and innate immune mechanisms have been identified, notably including multiple genes involved in epithelial function/secretion, suggesting that the airway epithelium may be particularly important in asthma. Interestingly, concordance/discordance between the genetic factors driving allergic traits such as IgE levels and disease states such as asthma have further supported the accumulating evidence for heterogeneity in these diseases. While GWAS have been useful and continue to identify novel genes for allergic diseases through increased sample sizes and phenotype refinement, future approaches will integrate analyses of rare variants, epigenetic mechanisms and eQTL approaches, leading to greater insight into the genetic basis of these diseases. Gene identification will improve our understanding of disease mechanisms and generate potential therapeutic opportunities.

Project description:PURPOSE: Single nucleotide polymorphisms (SNPs) in the LOXL1 gene have been implicated in exfoliation syndrome (XFS) and exfoliation glaucoma (XFG). We have shown that these SNPs are not associated with the primary glaucomas such as primary open-angle (POAG) glaucoma and primary angle-closure glaucoma (PACG). To further establish the specificity of LOXL1 SNPs for XFS and XFG, we determined whether these SNPs were involved in pigment dispersion syndrome (PDS) and pigmentary glaucoma (PG). METHODS: Three SNPs of LOXL1 (rs1048661, rs3825942, and rs2165241) were screened in a cohort of 78 unrelated and clinically well characterized glaucoma cases comprising of PG (n=44) and PDS (n=34) patients as well as 108 ethnically matched normal controls of Caucasian origin. The criteria for diagnosis of PDS/PG were Krukenberg spindle, hyperpigmentation of the trabecular meshwork, and wide open angle. Transillumination defects were detected by infrared pupillography, and the presence of a Zentmayer ring was considered as a confirmatory sign. All three SNPs were genotyped in cases and controls by resequencing the genomic region of LOXL1 harboring these variants and were further confirmed by polymerase chain reaction (PCR)-based restriction digestions. Haplotypes were generated from the genotype data, and the linkage disequilibrium (LD) and haplotype analysis were done with Haploview software that uses the expectation maximization (EM) algorithm. RESULTS: The LOXL1 SNPs showed no significant association with PDS or PG. There was no significant difference in the frequencies of the risk alleles of rs1048661 ('G' allele; p=0.309), rs3825942 ('G' allele' p=0.461), and rs2165241 ('T' allele; p=0.432) between PG/PDS cases and controls. Similarly, there was no involvement of the XFS/XFG-associated haplotypes, 'G-G' (p=0.643; [OR=1.08, 95%CI, 0.59-1.97]) and 'T-G' (p=0.266; [OR=1.35, 95%CI, 0.70-2.60]), with the PDS/PG phenotypes. The risk haplotype 'G-G' was observed in ~55% of the normal controls. CONCLUSIONS: There was no involvement of the LOXL1 SNPs in patients with PDS and PG. The results further indicate that the associations of these SNPs are specific to XFS/XFG.

Dataset Information

Genetic Risk Factors for Glaucoma and Exfoliation Syndrome Identified by Genome-wide Association Studies.

Publications

Genetic Risk Factors for Glaucoma and Exfoliation Syndrome Identified by Genome-wide Association Studies.

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