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A novel single nucleotide polymorphism, IVS2 -97A>T, in the prostaglandin F2alpha receptor gene was identified among the Malaysian patients with glaucoma

Peng HB, Zahary MN, Tajudin LS, Lin CL, Teck CM, Sidek MR, et al.

Kobe J Med Sci, 2007;53(1-2):49-52.
PMID: 17582204

The Prostaglandin F2alpha (PGF2alpha) receptor gene has been found to play an important role in reducing the intraocular pressure of the glaucomatous patients. Variations of the PGF2alpha receptor gene may be responsible for the differences in the response to an antiglaucoma drug, Latanoprost. A combined method of denaturing High Performance Liquid Chromatography (dHPLC) and sequencing was applied to detection of the PGF2alpha receptor gene variant among the 76 Malaysian patients with glaucoma, and a novel single nucleotide polymorphism (SNP), IVS -97A>T, was identified. According to the genotyping analysis, 36.8% of the subjects were heterozygous for the variant allele T, while 9.2% homozygous. The frequency of variant allele T was 0.28. Although with a limited number of samples, our data suggested that this polymorphism is common in the Malaysian patients with glaucoma.

Matched MeSH terms: Glaucoma/genetics*
Fulltext Collagen-related genes influence the glaucoma risk factor, central corneal thickness

Vithana EN, Aung T, Khor CC, Cornes BK, Tay WT, Sim X, et al.

Hum Mol Genet, 2011 Feb 15;20(4):649-58.
PMID: 21098505 DOI: 10.1093/hmg/ddq511

Central corneal thickness (CCT) is a risk factor of glaucoma, the most common cause of irreversible blindness worldwide. The identification of genetic determinants affecting CCT in the normal population will provide insights into the mechanisms underlying the association between CCT and glaucoma, as well as the pathogenesis of glaucoma itself. We conducted two genome-wide association studies for CCT in 5080 individuals drawn from two ethnic populations in Singapore (2538 Indian and 2542 Malays) and identified novel genetic loci significantly associated with CCT (COL8A2 rs96067, p(meta) = 5.40 × 10⁻¹³, interval of RXRA-COL5A1 rs1536478, p(meta) = 3.05 × 10⁻⁹). We confirmed the involvement of a previously reported gene for CCT and brittle cornea syndrome (ZNF469) [rs9938149 (p(meta) = 1.63 × 10⁻¹⁶) and rs12447690 (p(meta) = 1.92 × 10⁻¹⁴)]. Evidence of association exceeding the formal threshold for genome-wide significance was observed at rs7044529, an SNP located within COL5A1 when data from this study (n = 5080, P = 0.0012) were considered together with all published data (reflecting an additional 7349 individuals, p(Fisher) = 1.5 × 10⁻⁹). These findings implicate the involvement of collagen genes influencing CCT and thus, possibly the pathogenesis of glaucoma.

Matched MeSH terms: Glaucoma/genetics*
Fulltext Association of Glaucoma Risk Genes with Retinal Nerve Fiber Layer in a Multi-ethnic Asian Population: The Singapore Epidemiology of Eye Diseases Study

Chai X, Low KY, Tham YC, Chee ML, Thakur S, Zhang L, et al.

Invest Ophthalmol Vis Sci, 2020 08 03;61(10):37.
PMID: 32821913 DOI: 10.1167/iovs.61.10.37

Purpose: Genome-wide association studies have identified several genes associated with glaucoma. However, their roles in the pathogenesis of glaucoma remain unclear, particularly their effects on retinal nerve fiber layer (RNFL) thickness. The aim of this study was to investigate the associations between the identified glaucoma risk genes and RNFL thickness.
Methods: A total of 3843 participants (7,020 healthy eyes) were enrolled from the Singapore Epidemiology of Eye Diseases (SEED) study, a population-based study composing of three major ethnic groups-Malay, Indian, and Chinese-in Singapore. Ocular examinations were performed, and spectral-domain optical coherence tomography (SD-OCT) was used to measure circumpapillary RNFL thickness. We selected 35 independent glaucoma-associated genetic loci for analysis. An linear regression model was conducted to determine the association of these variants with circumpapillary RNFL, assuming an additive genetic model. We conducted association analysis in each of the three ethnic groups, followed by a meta-analysis of them.
Results: The mean age of the included participants was 59.4 ± 8.9 years, and the mean RFNL thickesss is 92.3 ± 11.2 µm. In the meta-analyses, of the 35 glacuoma loci, we found that only SIX6 was significantly associated with reduction in global RNFL thickness (rs33912345; β = -1.116 um per risk allele, P = 1.64E-05), and the effect size was larger in the inferior RNFL quadrant (β = -2.015 µm, P = 2.9E-6), and superior RNFL quadrant (β = -1.646 µm, P = 6.54E-5). The SIX6 association were consistently observed across all three ethnic groups. Other than RNFL, we also found several genetic varaints associated with vertical cuo-to-disc ratio (ATOH7, CDKN2B-AS1, and TGFBR3-CDC7), rim area (SIX6 and CDKN2B-AS1), and disc area (SIX6, ATOH7, and TGFBR3-CDC7). The association of SIX6 rs33912345 with NRFL thickness remained similar after further adjusting for disc area and 3 other disc parameter associated SNPs (ATOH7, CDKN2B-AS1, and TGFBR3-CDC7).
Conclusions: Of the 35 glaucoma identified risk loci, only SIX6 is significantly and independently associated with thinner RNFL. Our study further supports the involvement of SIX6 with RNFL thickness and pathogensis of glaucoma.

Matched MeSH terms: Glaucoma/genetics*
Fulltext Long Non-Coding RNA-MALAT1 Mediates Retinal Ganglion Cell Apoptosis Through the PI3K/Akt Signaling Pathway in Rats with Glaucoma

Li HB, You QS, Xu LX, Sun LX, Abdul Majid AS, Xia XB, et al.

Cell Physiol Biochem, 2017;43(5):2117-2132.
PMID: 29065394 DOI: 10.1159/000484231

BACKGROUND/AIMS: The aim of the present study is to investigate the effect of long non-coding RNA-MALAT1 (LncRNA-MALAT1) on retinal ganglion cell (RGC) apoptosis mediated by the PI3K/Akt signaling pathway in rats with glaucoma.
METHODS: RGCs were isolated and cultured, and monoclonal antibodies (anti-rat Thy-1, Brn3a and RBPMS) were examined by immunocytochemistry. An overexpression vector MALAT1-RNA activation (RNAa), gene knockout vector MALAT1-RNA interference (RNAi), and control vector MALAT1-negative control (NC) were constructed. A chronic high intraocular pressure (IOP) rat model of glaucoma was established by episcleral vein cauterization. The RGCs were divided into the RGC control, RGC pressure, RGC pressure + MALAT1-NC, RGC pressure + MALAT1-RNAi and RGC pressure + MALAT1-RNAa groups. Sixty Sprague-Dawley (SD) rats were randomly divided into the normal, high IOP, high IOP + MALAT1-NC, high IOP + MALAT1-RNAa and high IOP + MALAT1-RNAi groups. qRT-PCR and western blotting were used to detect the expression levels of LncRNA-MALAT1 and PI3K/Akt. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) and flow cytometry were used to detect RGC apoptosis.
RESULTS: Immunocytochemistry revealed that the cultured RGCs reached 90% purity. Compared with the RGC pressure + MALAT1-NC group, the RGC pressure + MALAT1-RNAa group exhibited elevated expression levels of MALAT1, lower total protein levels of PI3K and Akt and decreased RGC apoptosis, while these expression levels were reversed in the RGC pressure + MALAT1-RNAi group. RGC numbers and PI3K/Akt expression levels in the high IOP model groups were lower than those in the normal group. In the high IOP + MALAT1-RNAa group, the mRNA and protein expression levels of PI3K/Akt were reduced but higher than those in the other three high IOP model groups. Additionally, RGC numbers in the high IOP + MALAT1-RNAa group were lower than those in the normal group but higher than those in the other three high IOP model groups.
CONCLUSION: Our study provides evidence that LncRNA-MALAT1 could inhibit RGC apoptosis in glaucoma through activation of the PI3K/Akt signaling pathway.

Matched MeSH terms: Glaucoma/genetics