Genome-wide association analyses identify three new susceptibility loci for primary angle closure glaucoma

1] Singapore Eye Research Institute, Singapore National Eye Centre, Singapore. [2] Department of Ophthalmology, National University Health System & National University of Singapore, Singapore. [3] [4].
Nature Genetics (Impact Factor: 29.35). 08/2012; 44(10):1142-6. DOI: 10.1038/ng.2390
Source: PubMed


Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study including 1,854 PACG cases and 9,608 controls across 5 sample collections in Asia. Replication experiments were conducted in 1,917 PACG cases and 8,943 controls collected from a further 6 sample collections. We report significant associations at three new loci: rs11024102 in PLEKHA7 (per-allele odds ratio (OR) = 1.22; P = 5.33 × 10(-12)), rs3753841 in COL11A1 (per-allele OR = 1.20; P = 9.22 × 10(-10)) and rs1015213 located between PCMTD1 and ST18 on chromosome 8q (per-allele OR = 1.50; P = 3.29 × 10(-9)). Our findings, accumulated across these independent worldwide collections, suggest possible mechanisms explaining the pathogenesis of PACG.

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Available from: Ahmad Tajudin Liza-Sharmini
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    • "This percentage is closer to those calculated for Asian than for European populations [4]. Although a hereditary component for PACG exists, causative genes have not yet been identified until recently where a significant association at three new loci: rs11024102 in PLEKHA7 (per-allele odds ratio (OR) = 1.22; P = 5.33 × 10(-12)), rs3753841 in COL11A1 (per-allele OR = 1.20; P = 9.22 × 10(-10)) and rs1015213 located between PCMTD1 and ST18 on chromosome 8q (per-allele OR = 1.50; P = 3.29 × 10(-9) were reported [5]. The three SNPs may explain in part some aspects of the PACG pathogenesis, but not all. "
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    ABSTRACT: To evaluate total antioxidant status (TAS) in the plasma of primary angle closure glaucoma (PACG) patients and to compare it to that of the control group. Additionally, we aim to investigate the association of various PACG clinical indices with TAS level. Plasma samples were obtained from 139 PACG patients and 149 glaucoma-free controls of matching age, sex, and ethnicity. TAS in all samples was determined by spectrophotometric and enzyme-linked immunosorbent assay methods. We studied the possible association of the TAS level with various clinical indices relevant to PACG. The mean (+/-SD) total antioxidant (TAS) value was almost similar in patients 1 (+/-0.22) compared to controls 0.97 (+/-0.43); p = 0.345. Among cases, mean TAS concentration showed a statistically significant lower pattern among subjects with glaucoma onset at the age of <= 50 years (p = 0.037) and female subjects (p = 0.014) as well as having a family history of glaucoma (p = 0.010). Interestingly, a statistically significant inverse correlation was detected between TAS concentration and intra ocular pressure (IOP), (R = -0.14, p = 0.037). The inverse correlation of TAS level with IOP, highlights TAS potential role as a predictive-marker for PACG-severity.
    Full-text · Article · Mar 2014 · BMC Research Notes
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    • "Several studies have shown that genetic factors play an important role in the development of PACG [4-6]. Although several susceptible loci and genes have been investigated for PACG, the precise genes underlying PACG have not been identified [7-12]. PACG has been shown to be associated with a shallow anterior chamber depth (ACD), a thick lens, and a short axial length (AL) of the eye [13-16]. "
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    ABSTRACT: Mouse serine protease 56 (Prss56) mutants show a phenotype of angle-closure glaucoma with a shortened ocular axial length. Mutations in the human PRSS56 gene are associated with posterior microphthalmia and nanopthalmos. In this study, variations in PRSS56 were evaluated in patients with either primary angle-closure glaucoma (PACG) or high hyperopia. A total of 561 participants were enrolled in this study, including 189 individuals with PACG, 110 individuals with simple high hyperopia (sphere refraction ≥+5.00 D), and 262 normal control subjects (-0.5 D<sphere refraction<+0.5 D). Polymerase chain reaction (PCR) and Sanger sequencing were performed to detect sequence variations in PRSS56. Novel variations were evaluated using online tools, such as PolyPhen-2 and SIFT. The frequencies of the variations were compared between patients and controls using Fisher's exact test (α=0.05). Eleven variants including ten novel variants and one known variant, involving 15 alleles, were detected in 14 patients (five patients with PACG and nine patients with high hyperopia). Of the 11 variants, two novel variants were detected in four out of 262 normal controls, involving four alleles. The frequency of the variants in the patients with high hyperopia significantly differed from that in the controls (p=0.003). The results indicate that variants in PRSS56 may be implicated in PACG and high hyperopia.
    Full-text · Article · Nov 2013 · Molecular vision
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    • "ST18 encodes the suppression of tumorigenicity 18 protein, expressed in the cornea and lens, but not in the TM [14]. In our study, the minor allele frequency of rs1015213 was low, which is consistent with previous reports [14, 22]. Little is known about the function of PCMTD1 or ST-18. "
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    ABSTRACT: Genome-wide association study (GWAS) analysis identified three new susceptibility loci for PACG. In this study, we aimed to investigate whether these three loci in PLEKHA7, COL11A1, and PCMTD1-ST18 are associated with PAC and ocular biometric characteristics, such as axial length (AL), anterior chamber depth (ACD), and diopter of spherical power (DS). The study was a part of the Jiangsu Eye Study. The samples were collected from 232 PAC subjects and 306 controls from a population-based prevalence survey conducted in Funing County of Jiangsu, China. The single nucleotide polymorphisms (SNPs) of rs11024102 in PLEKHA7, rs3753841 in COL11A1, and rs1015213 in PCMTD1-ST18 were genotyped by TaqMan-MGB probe using the RT-PCR system. None of the three polymorphisms showed differences in the distribution of genotypes and allele frequencies between the PAC group and the control group. No significant association was determined between the 3 SNPs and AL, ACD, or DS of PAC subjects. We concluded that even though PLEKHA7 rs11024102, COL11A1 rs3753841, and PCMTD1-ST18 rs1015213 are associated with PACG, those sequence variations are not associated with PAC in a Han Chinese population. Our results also did not support a significant role for these three SNPs in ocular biometry such as AL, ACD, and DS.
    Full-text · Article · Oct 2013 · Journal of Ophthalmology
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