Publications by authors named "Tam Pancy O S"

61 Publications

Genetic associations of myopia severities and endophenotypes in children.

Br J Ophthalmol 2020 Aug 14. Epub 2020 Aug 14.

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China

Objective: To investigate the associations of multiple single-nucleotide polymorphisms (SNPs) with the severities and endophenotypes of myopia in children.

Methods: A total of 3300 children aged 5-10 years were recruited: 137 moderate and high myopia (SE≤-3.0D), 670 mild myopia (-3.0D-0.5D). 13 SNPs in 13 genes/loci were selected for genotyping in all subjects using TaqMan assays. Associations between each SNP with myopia severities and ocular traits (spherical equivalent (SE), axial length (AL) and corneal radius (CR)) were analysed.

Results: When compared with controls, SNPs rs4373767 (OR=1.15, p=0.038), rs7084402 (OR=1.18, p=0.005) and rs524952 (OR=1.14, p=0.025) showed nominal associations with overall myopia. rs4373767 and rs7084402 showed stronger associations with moderate and high myopia (rs4373767: OR=1.42, p=0.018; rs7084402: OR=1.33, p=0.025), while rs524952 had a stronger association with mild myopia (OR=1.14, p=0.025). rs524952 also showed a difference between emmetropia and hyperopia (p=0.018). In quantitative trait locus analysis, rs4373767, rs7744813 and rs524952 were correlated with both myopic SE (β=-0.09, p=0.03; β=-0.12, p=0.007; β=-0.13, p=0.0006, respectively) and AL (β=0.07, p=0.002; β=0.09, p=0.0008; β=0.07, p=0.0003, respectively). rs7839488 was correlated with both AL (β=0.07, p=0.005) and CR (β=0.02, p=0.006). Moreover, rs4373767-T (β=0.006; p=0.018), rs7744813-A (β=0.007; p=0.015) and rs524952-T (β=0.009; p=0.0006) were correlated with AL-CR ratio.

Conclusions And Relevance: and are genetic risk factors for moderate and high myopia, while and confer risk to excessive AL in children.
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http://dx.doi.org/10.1136/bjophthalmol-2020-316728DOI Listing
August 2020

Association of WNT7B and RSPO1 with Axial Length in School Children.

Invest Ophthalmol Vis Sci 2020 08;61(10):11

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China.

Purpose: To evaluate the association between single-nucleotide polymorphisms (SNPs) in the ZC3H11B, RSPO1, C3orf26, GJD2, ZNRF3, and WNT7B genes and myopia endophenotypes in children.

Methods: Seven SNPs identified in previous genome-wide association studies of axial length (AL) were genotyped in 2883 Southern Han Chinese children. Multiple linear regression analyses were conducted to evaluate the genotype association with AL, spherical equivalent (SE), corneal curvature (CC), and central corneal thickness (CCT).

Results: Two SNPs-namely, rs12144790 in RSPO1 (allele T, P = 0.0066, β = 0.062) and rs10453441 in WNT7B (allele A, P = 8.03 × 10-6, β = 0.103)-were significantly associated with AL. The association of rs4373767 in ZC3H11B (allele C, P = 0.030, β = -0.053) could not withstand the correction for multiple testing. WNT7B rs10453441 showed a strong association with CC (P = 1.17 × 10-14, β = 0.053) and with CCT (P = 0.0026, β = 2.65). None of the tested SNPs was significantly associated with SE. The C allele of SNP rs12321 in ZNRF3 was associated with CC (P = 0.0060, β = -0.018).

Conclusions: This study revealed that the RSPO1 SNP rs12144790 was associated with AL, whereas WNT7B rs10453441 was associated with AL, CC, and CCT in children. A novel association between ZNRF3 rs12321 and CC was discovered. Our data suggest that the RSPO1 and WNT7B genes might exert their effects on multiple aspects of eye growth during childhood. Potential differences in the genetic profiles of AL between children and adults should be explored in larger cohorts.
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http://dx.doi.org/10.1167/iovs.61.10.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441295PMC
August 2020

Association of the CAV1-CAV2 locus with normal-tension glaucoma in Chinese and Japanese.

Clin Exp Ophthalmol 2020 07 24;48(5):658-665. Epub 2020 Mar 24.

Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong, Hong Kong, China.

Background: The CAV1-CAV2 locus has been associated with primary open-angle glaucoma (POAG) and intraocular pressure. However, its association with normal-tension glaucoma (NTG) was inconclusive. Therefore, we evaluated this association in Chinese and Japanese.

Methods: Two single-nucleotide polymorphisms (SNPs, rs4236601 and rs1052990) from previous genome-wide association studies of POAG were genotyped in a total of 2220 study subjects: a Hong Kong Chinese cohort of 537 NTG patients and 490 controls, a Shantou Chinese cohort of 102 NTG and 731 controls and an Osaka Japanese cohort of 153 NTG and 207 controls. Subgroup analysis by gender was conducted. Outcomes from different cohorts were combined using meta-analysis.

Results: SNP rs4236601 was significantly associated with NTG in the two Chinese cohorts (P = .0019, OR = 4.55, I = 0). In contrast, rs4236601 was monomorphic in the Osaka cohort. The association of rs1052990 was insignificant in a meta-analysis combining Chinese and Japanese cohorts (P = .81, OR = 1.05; I = 64%), and the OR tended towards opposite directions between Chinese (OR = 1.26) and Japanese (OR = 0.69). Gender-specific effects of the SNPs were not statistically significant in the logistic regression or Breslow-day tests of ORs (P > .05), although rs4236601 was significant in males (P = .0068; OR = 10.30) but not in females (P = .14; OR = 2.65) in the meta-analysis of Chinese subjects.

Conclusions: In this study, we confirmed the association of rs4236601 at the CAV1-CAV2 locus with NTG in Chinese. SNP rs4236601 is monomorphic, and rs1052990 tends towards a different direction in the Japanese cohort. Further studies are warranted to verify the ethnic difference and gender-specific effects of this locus.
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http://dx.doi.org/10.1111/ceo.13744DOI Listing
July 2020

Evaluation of the association of with neovascular age-related macular degeneration and polypoidal choroidal vasculopathy.

Eye Vis (Lond) 2019 7;6:34. Epub 2019 Nov 7.

1Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China.

Background: Neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) are sight-threatening maculopathies with both environmental and genetic risk factors. We have previously shown relative risks posed by genes of the complement pathways to neovascular AMD and PCV.

Methods: In this study, we investigated the haplotype-tagging single nucleotide polymorphisms (SNPs) in the () gene in 708 unrelated Chinese individuals: 200 neovascular AMD patients, 233 PCV patients and 275 controls. Six tagging SNPs in were genotyped. Univariate single SNP association analysis, haplotype-based association analysis and gene-gene interaction analysis between and other AMD-associated genes were performed.

Results: The results revealed none of the six tagging SNPs of the gene had a significant association with neovascular AMD or PCV ( > 0.05). We also found insignificant haplotype-based association, and no significant SNP-SNP interaction between and other genes (including ---, , , , , , and ) for neovascular AMD and PCV.

Conclusions: This study showed no statistical significance in the genetic association of with neovascular AMD or PCV in a Hong Kong Chinese population. Further studies in large samples from different populations are warranted to elucidate the role of in the genetic susceptibility of AMD and PCV.
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http://dx.doi.org/10.1186/s40662-019-0161-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836349PMC
November 2019

Identification and characterization of a novel promoter variant in placental growth factor for neovascular age-related macular degeneration.

Exp Eye Res 2019 10 1;187:107748. Epub 2019 Aug 1.

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China; Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong, China. Electronic address:

Purpose: Intronic variants in the placental growth factor (PGF) gene have been associated with neovascular age-related macular degeneration (AMD). This study is to discover and characterize rare variants in the PGF gene for neovascular AMD.

Methods: The promoter region, coding sequences and splicing regions of the PGF gene were sequenced in a Hong Kong southern Chinese cohort of 235 neovascular AMD patients and 435 controls. A detected 18 base-pair deletion variant in the promoter region of PGF was analyzed in a Shantou southern Chinese cohort of 189 neovascular AMD patients and 846 controls. The transcription activity of this disease-associated promoter variant was determined in human ARPE-19 cells by promoter-luciferase analysis.

Results: A novel 18-base-pair deletion mutation in the promoter region of PGF was identified in 3 (1.28%) patients and 1 (0.23%) control subject (OR = 5.61; 95% CI 0.58-54.26) in the Hong Kong cohort, and in 2 (1.06%) patients and 2 (0.24%) controls (OR = 4.51; 95% CI: 0.63-32.25) in the Shantou cohort. In the combined southern Chinese sample, this deletion had a significant association with neovascular AMD (P = 0.026; OR = 5.08, 95% CI: 1.21-21.36). The 18-base-pair deletion was predicted to alter the transcription factor binding sites in the PGF promoter, and higher luciferase expression was detected in ARPE-19 cells transfected with the deletion variant plasmid than those transfected with wild type plasmid (P = 0.0002).

Conclusions: This study identified a rare, functional promoter variant in the PGF gene that increases PGF transcription activity and confers a 5-fold risk to neovascular AMD.
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http://dx.doi.org/10.1016/j.exer.2019.107748DOI Listing
October 2019

Association of the and genes with myopia of different severities.

Br J Ophthalmol 2020 10 12;104(10):1472-1476. Epub 2019 Jul 12.

Department of Ophthalmology and Visual Sciences, Chinese University of Hong Kong, New Territories, Hong Kong

Objective: To investigate the associations of single-nucleotide polymorphisms (SNPs) in the , and genes with severities of myopia in Chinese populations.

Methods: Based on previous myopia genome-wide association studies, five SNPs ( rs4373767, rs13382811, rs2730260, rs7839488 and rs9318086) were selected for genotyping in a Chinese cohort of 2079 subjects: 252 extreme myopia, 277 high myopia, 393 moderate myopia, 366 mild myopia and 791 non-myopic controls. Genotyping was performed by TaqMan assays. Allelic frequencies of the SNPs were compared with myopia severities and ophthalmic biometric measurements.

Results: The risk allele T of SNP rs4373767 was significantly associated with high myopia (OR=1.39, p=0.007) and extreme myopia (OR=1.34, p=0.013) when compared with controls, whereas rs13382811 (allele T, OR=1.33, p=0.018) and rs7839488 (allele G, OR=1.71, p=8.44E-05) were significantly associated with extreme myopia only. In contrast, there was no significant association of these SNPs with moderate or mild myopia. When compared with mild myopia, subjects carrying T allele of rs4373767 had a risk of progressing to high myopia (spherical equivalent ≤-6 dioptres) (OR=1.29, p=0.017). Similarly, the T allele of rs13382811 also imposed a significant risk to high myopia (OR=1.36, p=0.007). In quantitative traits analysis, SNPs rs4373767, rs13382811 and rs7839488 were correlated with axial length and refractive errors.

Conclusions: We confirmed as a susceptibility gene for high and extreme myopia, and and for extreme myopia in Chinese populations. Instead of myopia onset, these three genes were more likely to impose risks of progressing to high and extreme myopia.
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http://dx.doi.org/10.1136/bjophthalmol-2019-314203DOI Listing
October 2020

Genome-wide analysis identified 17 new loci influencing intraocular pressure in Chinese population.

Sci China Life Sci 2019 Feb 24;62(2):153-164. Epub 2018 Dec 24.

The Key Laboratory for Human Disease Gene Study of Sichuan Province, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.

Intraocular pressure (IOP) is a major risk factor for glaucoma. Genetic determinants of intraocular pressure can provide critical insights into the genetic architecture of glaucoma and, as a result, open new avenues for therapeutic intervention. We performed a genome-wide association study and replication analysis of 8,552 Chinese participants. In the genome-wide association study, we identified 51 loci that surpassed the significance of P<9×10, and we formally replicated these loci. A combined discovery and replication meta-analysis identified 21 genome-wide loci that surpassed the genome-wide significance of P<5×10, including 4 previously reported loci: rs145063132 (7p21.2, ETV1/DGKB), rs548030386 (7q31.2, ST7 near CAV1/CAV2), rs7047871 (9p24.2, GLIS3), and rs2472494 (9q31.1, ABCA1/SLC44A1). Of the 17 newly identified loci, five were reported to have ocular related phenotypes: PTCH2 (rs7525308 in 1p34.1), LRIF1/DRAM2 (rs1282146 in 1p13.3), COLEC11 (rs201143466 in 2p25.3), SPTBN1 (rs4514918 in 2p16.2), and CRK (rs11078446 in 17p13.3). The genetic loci identified in this study not only increase our understanding of the genes involved in intraocular pressure but also provide important genetic markers to improve future genetic screening and drug discovery for intraocular pressure disorders.
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http://dx.doi.org/10.1007/s11427-018-9430-2DOI Listing
February 2019

Association of the SIX6 locus with primary open angle glaucoma in southern Chinese and Japanese.

Exp Eye Res 2019 03 23;180:129-136. Epub 2018 Dec 23.

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China; Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong, China. Electronic address:

The purpose of the study was to evaluate the association profiles of the SIX6 locus with primary open-angle glaucoma (POAG) in southern Chinese and Japanese. In this study, we tested single marker and haplotype-based associations of 11 tagging single nucleotide polymorphisms (SNPs) covering the SIX6 locus with POAG in a Hong Kong Chinese cohort (N = 1402). A novel SNP (i.e., rs12436579) and two SNPs (i.e., rs33912345 and rs10483727) from previous genome-wide association studies were further tested in a Chinese cohort from Shantou (N = 888) and a Japanese cohort from Osaka (N = 463). Results from the three cohorts were meta-analysed using a random-effect model. We found rs12436579, which has not been previously reported, was associated with POAG in Hong Kong and Shantou Chinese (P = 4.3 × 10, OR = 0.72, I = 0). Additionally, we replicated the association of one known SNP, rs33912345 (P = 0.0061, OR = 0.69, I = 45%), with POAG in the Chinese cohorts but not in the Japanese cohort (P > 0.6). Another known SNP, rs10483727, was nominally associated with POAG in the two Chinese cohorts (P = 0.017, OR = 0.70, I = 53%). All these three SNPs were significantly associated with POAG when the three cohorts were combined in meta-analysis (P<0.005). Furthermore, two haplotypes, C-C (P = 1.13 × 10, OR = 1.41, I = 0) and A-A (P = 0.045, OR = 0.68, I = 70%), defined by rs33912345-rs12436579 were associated with POAG in Chinese but not in Japanese. In conclusion, this study confirmed the association between two GWAS SNPs in SIX6 (rs33912345 and rs10483727) and POAG. Also, a SNP, rs12436579, not associated with POAG before, was found to be associated with POAG in Chinese. Further studies are warranted to elucidate the role of this novel SNP in POAG.
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http://dx.doi.org/10.1016/j.exer.2018.12.014DOI Listing
March 2019

Association of coding and UTR variants in the known regions with wet age-related macular degeneration in Han Chinese population.

J Hum Genet 2018 Oct 19;63(10):1055-1070. Epub 2018 Jul 19.

Sichuan Provincial Key Laboratory for Human Disease Gene Study and the Department of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.

Age-related macular degeneration (AMD) is the leading cause worldwide of severe visual impairment among people older than 55 years of age. This study aimed to investigate the genetic association between coding and untranslated region (UTR) variants in previously reported loci and exudative age-related macular degeneration (wet AMD) in a Han Chinese population. Using our previously published whole exome sequencing dataset of 349 wet AMD patients and 1253 controls, we searched for associations between coding and UTR variants of the 72 genes located within the 47 reported wet AMD loci regions. From these, 25 variants in 18 of the 72 genes with P < 10 × 10 were selected for the first replication of Sequenom mass-array genotyping in 885 wet AMD subjects and 562 controls. Next, four SNPs were selected for further validation by SNaPshot genotyping in a third Chinese cohort with 456 wet AMD subjects and 211 controls. As a result, we identified two new potential coding and UTR variant SNPs (rs189132250 in BBX located in 3q12.1 and rs144351944 in FILIP1L located in 3q12.1) that showed weak associations with wet AMD in the Han Chinese population. These findings provide new information regarding the coding and UTR variants of the known wet AMD loci in the studied Chinese cohort.
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http://dx.doi.org/10.1038/s10038-018-0490-3DOI Listing
October 2018

Analysis of multiple genetic loci reveals rs1324183 as a putative genetic marker for keratoconus.

Br J Ophthalmol 2018 12 12;102(12):1736-1741. Epub 2018 Jul 12.

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China

Objective: To investigate the associations between 16 single-nucleotide polymorphisms (SNPs) in 14 genetic loci and keratoconus in an independent Chinese cohort.

Methods: This cross-sectional, case-control association study included a Chinese cohort of 133 patients with keratoconus and 371 control subjects. In a recent meta-analysis study, we identified association of 16 SNPs in 14 gene loci with keratoconus. In this study, we genotyped these 16 SNPs in all the patients and controls and analysed their association with keratoconus, its clinical severities and progression profiles. We also analysed the genotype-phenotype correlation between individual SNPs and steep keratometry, flat keratometry (Kf), average keratometry (Avg K) and best-fit sphere diameter (BFS) of the anterior and posterior corneal surface.

Results: Among the 16 selected SNPs, rs1324183 in the locus showed a significant association with keratoconus (OR=2.22; 95% CI 1.42 to 3.45, p=4.30×10), especially severe keratoconus (OR=5.10, 95% CI 1.63 to 15.93, p=0.005). The rs1324183 A allele was positively associated with anterior Kf (p=0.008), anterior Avg K (p=0.017), posterior Kf (p=0.01) and negatively associated with apex pachymetry (p=0.007) and anterior BFS (p=0.023) in keratoconus. The other 15 SNPs had no significant association with keratoconus or genotype-phenotype correlations.

Conclusions: This study confirmed the association of SNP rs1324183 in with keratoconus and revealed the association of this SNP with keratoconus severity and corneal parameters. It is thus a putative genetic marker for monitoring the progression of keratoconus to a severe form and facilitating early intervention.
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http://dx.doi.org/10.1136/bjophthalmol-2018-312218DOI Listing
December 2018

Association of the gene with extreme myopia rather than lower grade myopias.

Br J Ophthalmol 2018 04 7;102(4):570-574. Epub 2018 Feb 7.

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China.

Aims: To investigate the association of the () with different severities of myopia.

Methods: A total of four haplotype-tagging single-nucleotide polymorphisms (SNPs; rs2071754, rs3026354, rs3026390 and rs628224) and two previously reported SNPs (rs644242 and rs662702) in the gene were analysed in a Hong Kong Chinese cohort of 1288 myopia subjects (including 252 extreme myopia, 277 high myopia, 393 moderate myopia and 366 mild myopia) and 791 no myopia controls. Allelic association analyses were performed for individual SNPs in different subgroups of myopia and in combined myopia, followed by a meta-analysis of our current data with reported data on in myopia.

Results: The association of tagging SNPs rs2071754 and rs644242 with extreme myopia could not withstand multiple correction (rs2071754: OR=1.25, P value=0.031; rs644242: OR=1.33, P value=0.032). In the meta-analysis, rs644242 showed an enhanced, significant association with extreme myopia (OR=1.27, 95% CI 1.10 to 1.46, P value=0.001; I=0%). In contrast, there was no significant association between the SNPs and high, moderate or mild myopia. No linear correlation was found between the SNPs and axial length.

Conclusion: This study provides additional evidence suggesting that the SNP rs644242 is associated with extreme myopia but not lower grade myopia. Thus, may be implicated in the development or progression into severe myopia. Further longitudinal studies are warranted.
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http://dx.doi.org/10.1136/bjophthalmol-2017-311327DOI Listing
April 2018

Genetic Association of the PARL-ABCC5-HTR3D-HTR3C Locus With Primary Angle-Closure Glaucoma in Chinese.

Invest Ophthalmol Vis Sci 2017 08;58(10):4384–4389

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China.

Purpose: This study evaluates the associations of haplotype-tagging single nucleotide polymorphisms (SNPs) in the PARL-ABCC5-HTR3D-HTR3C region with primary angle closure glaucoma (PACG), with a view to identify the responsible SNP in this region.

Methods: Thirty SNPs from the PARL-ABCC5-HTR3D-HTR3C region were genotyped in a Hong Kong Chinese cohort of 422 PACG patients and 400 control subjects, using TaqMan SNP genotyping assays. Single marker and haplotype-based association analyses were performed.

Results: Two synonymous ABCC5 SNPs, namely rs939336 (p.Cys594=; P = 0.013; odds ratio [OR] = 1.46; 95% confidence interval [CI], 1.08 to 1.97) and rs1132776 (p.Ala395=; P = 0.009; OR = 1.47; 95% CI: 1.10 to 1.95), were associated with PACG. Mild associations were detected for ABCC5 rs9838667 (P = 0.024) and HTR3D rs12493550 (P = 0.035). Conditional analysis revealed that no SNPs remained significant after adjusting for other SNPs, suggesting none of these tagging SNPs is fully responsible for the association in this region. In subgroup analysis, ABCC5 SNPs rs939336, rs1132776, and rs983667 and HTR3D rs12493550 were associated only with the chronic form of PACG. However, these associations could not withstand the correction for multiple testing.

Conclusions: These findings enrich the allelic spectrum of ABCC5 in PACG. We identified no tagging SNP responsible for the association of the whole region. Further deep sequencing analysis of this region should be warranted to uncover whether there is still disease associated variant in this region.
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http://dx.doi.org/10.1167/iovs.17-22304DOI Listing
August 2017

Identification of ANGPT2 as a New Gene for Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy in the Chinese and Japanese Populations.

Invest Ophthalmol Vis Sci 2017 02;58(2):1076-1083

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China 3Shantou University/The Chinese University of Hong Kong Joint Shantou International Eye Center, Shantou, China 4Prince of Wales Hospital Eye Centre, Hong Kong, China.

Purpose: We determine the angiopoietin 2 (ANGPT2) gene as a new susceptibility gene for neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV).

Methods: A total of 34 haplotype-tagging single-nucleotide polymorphisms (SNPs) were first genotyped in an exploratory Hong Kong Chinese cohort. Suggestive SNPs were replicated in a Shantou Chinese cohort and an Osaka Japanese cohort, with a total of 2343 subjects. The SNP rs800292 in the complement factor H (CFH) gene was genotyped in all the subjects. Genetic association and gene-gene interaction were analyzed.

Results: In the Hong Kong cohort, four SNPs in ANGPT2 (rs13255574, rs4455855, rs13269021, and rs11775442) were nominally associated with nAMD and PCV. The four ANGPT2 SNPs showed the same trends of association in the Shantou and Osaka cohorts. Combining the data from the 3 study cohorts revealed that SNPs rs4455855 and rs13269021 achieved study-wise significance (P < 0.0016), conferring an approximately 1.3-fold of increased risk for nAMD and PCV. Interaction analysis revealed the CFH SNP rs800292 has a highly significant interaction with the ANGPT2 SNP rs13269021 in nAMD and PCV in the combined analysis. Subsequent stratification analysis confirmed the interaction.

Conclusions: This study reveals ANGPT2 as a new susceptibility gene for nAMD and PCV, and it may affect disease susceptibility in association with CFH. Thus, this report provides new insights into the genetic architecture of nAMD and PCV.
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http://dx.doi.org/10.1167/iovs.16-20575DOI Listing
February 2017

Association of ABCG1 With Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy in Chinese and Japanese.

Invest Ophthalmol Vis Sci 2016 Oct;57(13):5758-5763

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China 4Joint Shantou International Eye Center, Shantou, China 5Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong, China.

Purpose: We investigated the association of the ATP-binding cassette, subfamily G, member 1 (ABCG1) gene with polypoidal choroidal vasculopathy (PCV) and neovascular age-related macular degeneration (nAMD) in independent Chinese and Japanese cohorts.

Methods: A total of 12 haplotype-tagging single-nucleotide polymorphisms (SNPs) and the SNP rs57137919 in the ABCG1 gene were first analyzed in a Hong Kong Chinese cohort of 235 nAMD, 236 PCV, and 365 controls, using TaqMan genotyping assays. Two SNPs (rs57137919 and rs225396) that showed a disease-association were genotyped in a Shantou Chinese cohort of 189 nAMD, 187 PCV, and 670 controls, and an Osaka Japanese cohort of 192 nAMD, 204 PCV, and 157 controls, totaling 2435 subjects. Association analysis was performed in individual cohorts, followed by a pooled analysis of the data from all three cohorts.

Results: In the Hong Kong cohort, SNP rs57137919 was associated with PCV (odds ratio [OR] = 1.35). A tagging SNP rs225396 was associated with nAMD (OR = 1.28) and PCV (OR = 1.32). In the Osaka cohort, SNP rs225396 was associated with nAMD (OR = 1.42) and PCV (OR = 1.74). In the pooled analysis involving the 3 study cohorts, rs225396 showed an enhanced association with nAMD (P = 0.01, OR = 1.21, I2 = 14%) and PCV (P = 0.0001, OR = 1.35, I2 = 46%).

Conclusions: In this study, we have newly identified a haplotype-tagging SNP, rs225396, in ABCG1 to be associated with PCV and nAMD in Chinese and Japanese cohorts. This provides new evidence to support ABCG1 as a susceptibility gene for PCV and nAMD. Further replication in other populations should be warranted.
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http://dx.doi.org/10.1167/iovs.16-20175DOI Listing
October 2016

HTRA1 promoter variant differentiates polypoidal choroidal vasculopathy from exudative age-related macular degeneration.

Sci Rep 2016 06 24;6:28639. Epub 2016 Jun 24.

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong.

Exudative age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) share similar abnormal choroidal vasculature, but responses to treatments are different. In this study, we sequenced the whole HTRA1 gene and its promoter by direct sequencing in a Hong Kong Chinese PCV cohort. We identified rs11200638, c.34delCinsTCCT, c.59C>T, rs1049331 and rs2293870 significantly associated with PCV. Notably, rs2672598 was significantly associated with exudative AMD (p = 1.31 × 10(-4)) than PCV (p = 0.11). Logistic regression indicated that rs2672598 (p = 2.27 × 10(-3)) remained significant after adjusting for rs11200638 in exudative AMD. Moreover, the rs11200638-rs2672598 joint genotype AA-CC conferred higher risk to exudative AMD (43.11 folds) than PCV (3.68 folds). Promoter analysis showed that rs2672598 C-allele showed higher luciferase expression than wildtype T-allele (p = 0.026), independent of rs11200638 genotype (p = 0.621). Coherently, vitreous humor HTRA1 expression with rs2672598 CC genotype was significantly higher than that with TT genotype by 2.56 folds (p = 0.02). Furthermore, rs2672598 C-allele was predicted to alter the transcription factor binding sites, but not rs11200638 A-allele. Our results revealed that HTRA1 rs2672598 is more significantly associated with exudative AMD than PCV in ARMS2/HTRA1 region, and it is responsible for elevated HTRA1 transcriptional activity and HTRA1 protein expression.
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http://dx.doi.org/10.1038/srep28639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919652PMC
June 2016

Ethnic specific association of the CAV1/CAV2 locus with primary open-angle glaucoma.

Sci Rep 2016 06 14;6:27837. Epub 2016 Jun 14.

Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong, Hong Kong, China.

A single-nucleotide polymorphism (SNP) rs4236601 at the CAV1/CAV2 locus is associated with primary open-angle glaucoma (POAG). Rs4236601 is common in Caucasians but rare in East Asians. Here we conducted a haplotype-tagging SNP analysis followed by replication in a total of 848 POAG cases and 1574 controls drawn from 3 cities in China and 1 city in Japan. Two SNPs, rs4236601 (odds ratio [OR] = 6.25; P = 0.0086) and a tagging-SNP rs3801994 (OR = 1.32; P = 0.042), were associated with POAG in the Hong Kong Chinese cohort after age and gender adjustments. Rs4236601 was associated with POAG also in Shantou (OR = 6.09; P = 0.0037) and Beijing (OR = 3.92; P = 0.030) cohorts after age and gender adjustment, with a pooled-OR of 5.26 (P = 9.0 × 10(-6)) in Chinese; but it is non-polymorphic in the Osaka cohort. SNP rs3801994 showed a similar trend of effect in the Shantou and Beijing cohorts, with a pooled-OR of 1.23 (P = 0.022) and 1.20 (P = 0.063) in Chinese, prior to and after age and gender adjustment, respectively; but it showed a reverse effect in the Osaka cohort (OR = 0.58; P = 0.033) after the adjustments. We have thus confirmed the association of rs4236601 with POAG in different Chinese cohorts. Also, we found a common SNP rs3801994 of diverse associations with POAG between Chinese and Japanese.
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http://dx.doi.org/10.1038/srep27837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906515PMC
June 2016

A missense variant in FGD6 confers increased risk of polypoidal choroidal vasculopathy.

Nat Genet 2016 06 18;48(6):640-7. Epub 2016 Apr 18.

Department of Ophthalmology, Osaka University Medical School, Osaka, Japan.

Polypoidal choroidal vasculopathy (PCV), a subtype of 'wet' age-related macular degeneration (AMD), constitutes up to 55% of cases of wet AMD in Asian patients. In contrast to the choroidal neovascularization (CNV) subtype, the genetic risk factors for PCV are relatively unknown. Exome sequencing analysis of a Han Chinese cohort followed by replication in four independent cohorts identified a rare c.986A>G (p.Lys329Arg) variant in the FGD6 gene as significantly associated with PCV (P = 2.19 × 10(-16), odds ratio (OR) = 2.12) but not with CNV (P = 0.26, OR = 1.13). The intracellular localization of FGD6-Arg329 is distinct from that of FGD6-Lys329. In vitro, FGD6 could regulate proangiogenic activity, and oxidized phospholipids increased expression of FGD6. FGD6-Arg329 promoted more abnormal vessel development in the mouse retina than FGD6-Lys329. Collectively, our data suggest that oxidized phospholipids and FGD6-Arg329 might act synergistically to increase susceptibility to PCV.
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http://dx.doi.org/10.1038/ng.3546DOI Listing
June 2016

Identification of PGF as a New Gene for Neovascular Age-Related Macular Degeneration in a Chinese Population.

Invest Ophthalmol Vis Sci 2016 Apr;57(4):1714-20

Department of Ophthalmology & Visual Sciences The Chinese University of Hong Kong, Hong Kong 2Department of Ophthalmology & Visual Sciences, Prince of Wales Hospital, Hong Kong 3Joint Shantou International Eye Centre, Shantou, China.

Purpose: To determine the associations of the VEGFA, VEGFB, and placental growth factor (PGF) genes with neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV).

Methods: Seven single-nucleotide polymorphisms (SNPs) in VEGFA, three SNPs in VEGFB, and five SNPs in PGF were genotyped in 1722 unrelated Chinese participants, including a Hong Kong cohort of 214 nAMD patients, 236 PCV patients, and 365 controls, and an independent Shantou cohort of 189 nAMD patients, 187 PCV patients, and 531 controls, using TaqMan genotyping assays.

Results: Placental growth factor SNPs rs2268615 (G allele, P = 0.0047; odds ratio [OR] = 1.54, 95% confidence interval [CI], 1.14-2.08) and rs2268614 (G allele, P = 0.015; OR = 1.46, 95% CI, 1.07-1.97) were associated with nAMD. A significant omnibus haplotype association with nAMD was detected for a two-SNP window containing rs2268615 and rs2268614, with a haplotype G-G conferring a 1.54-fold increased risk (P = 0.0042) in the Hong Kong cohort and a 1.42-fold risk (P = 0.012) in the Shantou cohort. Pooling of the Hong Kong and Shantou data enhanced the association of nAMD with rs2268615 (P = 0.0022; OR = 1.38, 95% CI, 1.12-1.69; I2 = 0%), rs2268614 (P = 0.0067; OR = 1.33, 95% CI, 1.08-1.63; I2 = 0%), and the G-G haplotype (P = 0.0013; OR = 1.46, 95% CI, 1.16-1.84; I2 = 0%). In contrast, the PGF SNPs and haplotype were not associated with PCV. Our results also revealed no association of SNPs in VEGFA and VEGFB with nAMD or PCV.

Conclusion: Placental growth factor is a susceptibility gene for nAMD in a Chinese population, providing new evidence to support a biological role of PGF in choroidal neovascularization.
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http://dx.doi.org/10.1167/iovs.IOVS-15-18677DOI Listing
April 2016

Genome-wide association study identifies five new susceptibility loci for primary angle closure glaucoma.

Nat Genet 2016 May 4;48(5):556-62. Epub 2016 Apr 4.

Department of Ophthalmology, National University Health System, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 × 10(-15)), CHAT rs1258267 (OR = 1.22, P = 2.85 × 10(-16)), GLIS3 rs736893 (OR = 1.18, P = 1.43 × 10(-14)), FERMT2 rs7494379 (OR = 1.14, P = 3.43 × 10(-11)), and DPM2-FAM102A rs3739821 (OR = 1.15, P = 8.32 × 10(-12)). We also confirmed significant association at three previously described loci (P < 5 × 10(-8) for each sentinel SNP at PLEKHA7, COL11A1, and PCMTD1-ST18), providing new insights into the biology of PACG.
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http://dx.doi.org/10.1038/ng.3540DOI Listing
May 2016

SPP2 Mutations Cause Autosomal Dominant Retinitis Pigmentosa.

Sci Rep 2015 Oct 13;5:14867. Epub 2015 Oct 13.

Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China.

Retinitis pigmentosa (RP) shows progressive loss of photoreceptors involved with heterogeneous genetic background. Here, by exome sequencing and linkage analysis on a Chinese family with autosomal dominant RP, we identified a putative pathogenic variant, p.Gly97Arg, in the gene SPP2, of which expression was detected in multiple tissues including retina. The p.Gly97Arg was absent in 800 ethnically matched chromosomes and 1400 in-house exome dataset, and was located in the first of the two highly conserved disulfide bonded loop of secreted phosphoprotein 2 (Spp-24) encoded by SPP2. Overexpression of p.Gly97Arg and another signal peptide mutation, p.Gly29Asp, caused cellular retention of both endogenous wild type and exogenous mutants in vitro, and primarily affected rod photoreceptors in zebrafish mimicking cardinal feature of RP. Taken together, our data indicate that the two mutations of SPP2 have dominant negative effects and cellular accumulation of Spp-24 might be particularly toxic to photoreceptors and/or retinal pigment epithelium. SPP2 has a new role in retinal degeneration.
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http://dx.doi.org/10.1038/srep14867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4602186PMC
October 2015

Ethnic differences in the association of SERPING1 with age-related macular degeneration and polypoidal choroidal vasculopathy.

Sci Rep 2015 Mar 24;5:9424. Epub 2015 Mar 24.

1] Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong, Hong Kong, China [2] Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, the Chinese University of Hong Kong, Hong Kong, China.

Neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) are leading causes of irreversible blindness in developed countries. In this study, we investigated the association of single nucleotide polymorphisms (SNPs) in the serpin peptidase inhibitor, clade G, member 1 (SERPING1) gene with neovascular AMD and PCV. Two haplotype-tagging SNPs, rs1005510 and rs11603020, of SERPING1 were genotyped in 708 unrelated Chinese individuals: 200 neovascular AMD, 233 PCV and 275 controls. A meta-analysis was also performed for all reported associations of SERPING1 SNPs with AMD and PCV. None of the tagging SNPs had a significant association with neovascular AMD or PCV (P > 0.05) in our study cohort. The meta-analyses showed that the most-studied SNP rs2511989 was not significantly associated with all forms of AMD, neovascular AMD, or PCV in East Asians (P = 0.98, 0.93 and 0.30, respectively) but was associated with AMD in Caucasians (P = 0.04 for all AMD and 0.004 for neovascular AMD). Therefore, the results of our study and meta-analysis suggest that SERPING1 is not a major genetic component of AMD or PCV in East Asians but is a genetic risk factor for AMD in Caucasians, providing evidence for an ethnic diversity in the genetic etiology of AMD.
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http://dx.doi.org/10.1038/srep09424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4371106PMC
March 2015

Gender specific association of a complement component 3 polymorphism with polypoidal choroidal vasculopathy.

Sci Rep 2014 Nov 12;4:7018. Epub 2014 Nov 12.

1] Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong, Hong Kong, China [2] Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong, China.

Neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) are leading causes of irreversible blindness in developed countries. In this study, we investigated the associations of haplotype-tagging single nucleotide polymorphisms (SNPs) in the complement component 3 (C3) gene with both neovascular AMD and PCV, and potential epistatic effects on C3. Eight tagging SNPs in C3 were genotyped in 708 unrelated study subjects: 200 neovascular AMD patients, 233 PCV patients and 275 controls. Among the eight C3 SNPs, rs17030 was associated with PCV after adjusted for gender and SNP-gender interaction (P = 0.008, OR = 2.94; 95% CI: 1.32-6.52). Moreover, an interaction between rs17030 and gender was identified in PCV (P = 0.02). After stratification by gender, the rs17030 G allele was found to confer an increased risk for PCV in male (P = 0.010, OR = 1.56) but not in female. The haplotype AG defined by the major alleles of rs17030 and rs344555 was also associated with PCV in male (P = 0.010, OR = 0.64). In contrast to PCV, none of the eight SNPs was significantly associated with neovascular AMD. This study shows an association of C3 rs17030 with PCV in male, indicating that C3 may have an epistatic effect with gender in the pathogenesis of PCV.
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http://dx.doi.org/10.1038/srep07018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4228406PMC
November 2014

Diabetes mellitus and risk of age-related macular degeneration: a systematic review and meta-analysis.

PLoS One 2014 19;9(9):e108196. Epub 2014 Sep 19.

Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.

Age-related macular degeneration (AMD) is a major cause of severe vision loss in elderly people. Diabetes mellitus is a common endocrine disorder with serious consequences, and diabetic retinopathy (DR) is the main ophthalmic complication. DR and AMD are different diseases and we seek to explore the relationship between diabetes and AMD. MEDLINE, EMBASE, and the Cochrane Library were searched for potentially eligible studies. Studies based on longitudinal cohort, cross-sectional, and case-control associations, reporting evaluation data of diabetes as an independent factor for AMD were included. Reports of relative risks (RRs), hazard ratios (HRs), odds ratio (ORs), or evaluation data of diabetes as an independent factor for AMD were included. Review Manager and STATA were used for the meta-analysis. Twenty four articles involving 27 study populations were included for meta-analysis. In 7 cohort studies, diabetes was shown to be a risk factor for AMD (OR, 1.05; 95% CI, 1.00-1.14). Results of 9 cross-sectional studies revealed consistent association of diabetes with AMD (OR, 1.21; 95% CI, 1.00-1.45), especially for late AMD (OR, 1.48; 95% CI, 1.44-1.51). Similar association was also detected for AMD (OR, 1.29; 95% CI, 1.13-1.49) and late AMD (OR, 1.16; 95% CI, 1.11-1.21) in 11 case-control studies. The pooled ORs for risk of neovascular AMD (nAMD) were 1.10 (95% CI, 0.96-1.26), 1.48 (95% CI, 1.44-1.51), and 1.15 (95% CI, 1.11-1.21) from cohort, cross-sectional and case-control studies, respectively. No obvious divergence existed among different ethnic groups. Therefore, we find diabetes a risk factor for AMD, stronger for late AMD than earlier stages. However, most of the included studies only adjusted for age and sex; we thus cannot rule out confounding as a potential explanation for the association. More well-designed prospective cohort studies are still warranted to further examine the association.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0108196PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4169602PMC
November 2015

Common variants near ABCA1 and in PMM2 are associated with primary open-angle glaucoma.

Nat Genet 2014 Oct 31;46(10):1115-9. Epub 2014 Aug 31.

1] Sichuan Provincial Key Laboratory for Human Disease Gene Study, Hospital of the University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, China. [2] School of Medicine, University of Electronic Science and Technology of China, Chengdu, China. [3] Sichuan Translational Medicine Hospital, Chinese Academy of Sciences, Chengdu, China. [4].

We performed a genome-wide association study for primary open-angle glaucoma (POAG) in 1,007 cases with high-pressure glaucoma (HPG) and 1,009 controls from southern China. We observed genome-wide significant association at multiple SNPs near ABCA1 at 9q31.1 (rs2487032; P = 1.66 × 10(-8)) and suggestive evidence of association in PMM2 at 16p13.2 (rs3785176; P = 3.18 × 10(-6)). We replicated these findings in a set of 525 HPG cases and 912 controls from Singapore and a further set of 1,374 POAG cases and 4,053 controls from China. We observed genome-wide significant association with more than one SNP at the two loci (P = 2.79 × 10(-19) for rs2487032 representing ABCA1 and P = 5.77 × 10(-10) for rs3785176 representing PMM2). Both ABCA1 and PMM2 are expressed in the trabecular meshwork, optic nerve and other ocular tissues. In addition, ABCA1 is highly expressed in the ganglion cell layer of the retina, a finding consistent with it having a role in the development of glaucoma.
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http://dx.doi.org/10.1038/ng.3078DOI Listing
October 2014

PAX6 gene associated with high myopia: a meta-analysis.

Optom Vis Sci 2014 Apr;91(4):419-29

*MBBS †MMed ‡MMedSc §MPhil ∥DPhil **PhD Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China (SMT, SSR, ALY, POST, CPP, LJC); and Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong, China (ALY, CPP, LJC).

Purpose: The PAX6 gene is among the most studied genes in high myopia, but reported findings of association studies on PAX6 and high myopia are inconsistent. We conducted a systematic review and meta-analysis to evaluate the association of PAX6 polymorphisms and high myopia.

Methods: All case-control association studies on PAX6 and high myopia reported in EMBASE and MEDLINE were retrieved. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for single-nucleotide polymorphisms (SNPs) that have been involved in at least two studies. Heterogeneity and publication bias analyses were also conducted.

Results: There were totally 63 publications on PAX6 and myopia. Among them, six articles met all the inclusion criteria, involving 3626 patients and 3262 controls of Asian ancestry. Five PAX6 SNPs, rs3026354, rs667773, rs2071754, rs644242, and rs3026393, were meta-analyzed in high myopia and two, rs667773 and rs644242, in extreme myopia. Single-nucleotide polymorphism rs644242 was associated with high myopia in the dominant model (OR = 0.87; 95% CI, 0.76 to 0.99; p = 0.035) and heterozygous model (OR = 0.85; 95% CI, 0.74 to 0.97; p = 0.019) and with extreme myopia in the dominant model (OR = 0.79; 95% CI, 0.65 to 0.95; p = 0.015), allelic model (OR = 0.81; 95% CI, 0.68 to 0.96; p = 0.014), and heterozygous model (OR = 0.80; 95% CI, 0.65 to 0.97; p = 0.024). However, the associations cannot withstand Bonferroni correction (p > 0.005). The other four SNPs did not show significant association with high myopia.

Conclusions: Meta-analysis of existing data revealed a suggestive association of PAX6 rs644242 with extreme and high myopia, which awaits validation in further studies. Nevertheless, PAX6 may only confer a small effect to myopia development.
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http://dx.doi.org/10.1097/OPX.0000000000000224DOI Listing
April 2014

PRPF4 mutations cause autosomal dominant retinitis pigmentosa.

Hum Mol Genet 2014 Jun 12;23(11):2926-39. Epub 2014 Jan 12.

Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China.

Retinitis pigmentosa (RP), a disease characterized by progressive loss of photoreceptors, exhibits significant genetic heterogeneity. Several genes associated with U4/U6-U5 triple small nuclear ribonucleoprotein (tri-snRNP) complex of the spliceosome have been implicated in autosomal dominant RP (adRP). HPrp4, encoded by PRPF4, regulates the stability of U4/U6 di-snRNP, which is essential for continuous splicing. Here, we identified two heterozygous variants in PRPF4, including c.-114_-97del in a simplex RP patient and c.C944T (p.Pro315Leu), which co-segregates with disease phenotype in a family with adRP. Both variants were absent in 400 unrelated controls. The c.-114_-97del, predicted to affect two transcription factor binding sites, was shown to down-regulate the promoter activity of PRPF4 by a luciferase assay, and was associated with a significant reduction of PRPF4 expression in the blood cells of the patient. In fibroblasts from an affected individual with the p.Pro315Leu variant, the expression levels of several tri-snRNP components, including PRPF4 itself, were up-regulated, with altered expression pattern of SC35, a spliceosome marker. The same alterations were also observed in cells over expressing hPrp4(Pro315Leu), suggesting that they arose as a compensatory response to a compromised splicing mechanism caused by hPrp4 dysfunction. Further, over expression of hPrp4(Pro315Leu), but not hPrp4(WT), triggered systemic deformities in wild-type zebrafish embryos with the retina primarily affected, and dramatically augmented death rates in morphant embryos, in which orthologous zebrafish prpf4 gene was silenced. We conclude that mutations of PRPF4 cause RP via haploinsufficiency and dominant-negative effects, and establish PRPF4 as a new U4/U6-U5 snRNP component associated with adRP.
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http://dx.doi.org/10.1093/hmg/ddu005DOI Listing
June 2014

Genes in the high-density lipoprotein metabolic pathway in age-related macular degeneration and polypoidal choroidal vasculopathy.

Ophthalmology 2014 Apr 3;121(4):911-6. Epub 2014 Jan 3.

Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong, Hong Kong, China. Electronic address:

Purpose: To investigate the associations of genetic variants in the high-density lipoprotein (HDL) metabolism pathway with neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV).

Design: Cross-sectional, case-control association study.

Participants: A Chinese case-control group of 200 neovascular AMD patients, 233 PCV patients, and 275 control subjects.

Methods: Eight single nucleotide polymorphisms (SNPs) from 6 genes of the HDL metabolism pathway and 2 known AMD-associated SNPs, rs800292 (from complement factor H [CFH]) and rs11200638 (from HtrA serine peptidase 1 [HTRA1]), were genotyped in all study subjects using the TaqMan genotyping technology (Applied Biosystems, Foster City, CA).

Main Outcome Measures: Allele and genotypic frequencies of selected SNPs.

Results: The SNP rs3764261 in the cholesteryl ester transfer protein (CETP) gene was associated significantly with neovascular AMD (P = 1.82×10(-4); odds ratio [OR], 1.89) and PCV (P = 4.04×10(-4); OR, 1.80). The associations remained significant after adjusting for the CFH SNP rs800292 and the HTRA1 SNP rs11200638. A significant interaction between the CETP SNP rs3764261 and the CFH SNP rs800292 existed in both neovascular AMD and PCV, the rs800292 G allele conferring a significantly increased risk of the diseases only in individuals carrying the risk allele T of rs3764261. A borderline association was detected between the ATP-binding cassette, subfamily G, member 1 (ABCG1) gene SNP rs57137919 and PCV (P = 0.03).

Conclusions: Our results showed that CETP is a susceptibility gene for neovascular AMD and PCV and that ABCG1 a putative gene for PCV. CETP exerts a modifying effect on CFH in the genetic risk. Our data suggest a link of the HDL metabolism pathway with neovascular AMD and PCV.
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http://dx.doi.org/10.1016/j.ophtha.2013.10.042DOI Listing
April 2014

Association of CFH and SERPING1 polymorphisms with anterior uveitis.

Br J Ophthalmol 2013 Nov 21;97(11):1475-80. Epub 2013 Aug 21.

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, , Hong Kong, China.

Aims: To investigate the association of the complement factor H (CFH) and complement component 1 inhibitor (SERPING1) genes with anterior uveitis (AU).

Methods: A total of 406 subjects (98 patients with AU and 308 controls) were recruited for this study. Two CFH polymorphisms (rs3753394 and rs1065489) and two SERPING1 polymorphisms (rs1005511 and rs3824988) were genotyped using TaqMan genotyping assays. Analyses were stratified for gender and human leukocyte antigen (HLA)-B27 status. Correlations of the genotypes with multiple clinical features were also evaluated.

Results: No significant association was found between any of the four polymorphisms and AU after multiple testing corrections. However, stratified analyses showed that there were significant increases in the frequencies of T allele and TT homozygosity for CFH-rs1065489 in female patients compared with that of controls (pcorr=0.004 and pcorr=0.012 respectively). In addition, CFH-rs1065489 was also associated with AU in patients who were HLA-B27 positive. No significant association with AU was found for the other three single nucleotide polymorphisms (SNPs), even stratified by gender or HLA-B27 status. Genotype-phenotype analyses found that CFH-rs1065489 TT genotype was associated with higher uveitis recurrence frequency. No correlation was found between CFH-rs1065489 and other clinical features.

Conclusions: This study revealed an association of CFH-rs1065489 with AU as well as uveitis recurrence frequency. The influence on AU could be gender specific and dependent on HLA-B27 status. Our results also suggested that SERPING1 does not play a significant role in the development of AU.
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http://dx.doi.org/10.1136/bjophthalmol-2013-303679DOI Listing
November 2013

Genome-wide association study identifies ZFHX1B as a susceptibility locus for severe myopia.

Hum Mol Genet 2013 Dec 9;22(25):5288-94. Epub 2013 Aug 9.

Division of Human Genetics, Genome Institute of Singapore, Singapore, Singapore.

Severe myopia (defined as spherical equivalent < -6.0 D) is a predominant problem in Asian countries, resulting in substantial morbidity. We performed a meta-analysis of four genome-wide association studies (GWAS), all of East Asian descent totaling 1603 cases and 3427 controls. Two single nucleotide polymorphisms (SNPs) (rs13382811 from ZFHX1B [encoding for ZEB2] and rs6469937 from SNTB1) showed highly suggestive evidence of association with disease (P < 1 × 10(-7)) and were brought forward for replication analysis in a further 1241 severe myopia cases and 3559 controls from a further three independent sample collections. Significant evidence of replication was observed, and both SNP markers surpassed the formal threshold for genome-wide significance upon meta-analysis of both discovery and replication stages (P = 5.79 × 10(-10), per-allele odds ratio (OR) = 1.26 for rs13382811 and P = 2.01 × 10(-9), per-allele OR = 0.79 for rs6469937). The observation at SNTB1 is confirmatory of a very recent GWAS on severe myopia. Both genes were expressed in the human retina, sclera, as well as the retinal pigmented epithelium. In an experimental mouse model for myopia, we observed significant alterations to gene and protein expression in the retina and sclera of the unilateral induced myopic eyes for Zfhx1b and Sntb1. These new data advance our understanding of the molecular pathogenesis of severe myopia.
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http://dx.doi.org/10.1093/hmg/ddt385DOI Listing
December 2013

Diversified clinical presentations associated with a novel sal-like 4 gene mutation in a Chinese pedigree with Duane retraction syndrome.

Mol Vis 2013 6;19:986-94. Epub 2013 May 6.

Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong, and Department of Ophthalmology, Prince of Wales Hospital, Hong Kong, China.

Purpose: To determine the underlying genetic cause of Duane retraction syndrome (DRS) in a non-consanguineous Chinese Han family.

Methods: Detailed ophthalmic and physical examinations were performed on all members from a pedigree with DRS. All exons and their adjacent splicing junctions of the sal-like 4 (SALL4) gene were amplified with polymerase chain reaction and analyzed with direct sequencing in all the recruited family members and 200 unrelated control subjects.

Results: Clinical examination revealed a broad spectrum of phenotypes in the DRS family. Mutation analysis of SALL4 identified a novel heterozygous duplication mutation, c.1919dupT, which was completely cosegregated with the disease in the family and absent in controls. This mutation was predicted to cause a frameshift, introducing a premature stop codon, when translated, resulting in a truncated SALL4 protein, i.e., p.Met640IlefsX25. Bioinformatics analysis showed that the affected region of SALL4 shared a highly conserved sequence across different species. Diversified clinical manifestations were observed in the c.1919dupT carriers of the family.

Conclusions: We identified a novel truncating mutation in the SALL4 gene that leads to diversified clinical features of DRS in a Chinese family. This mutation is predicted to result in a truncated SALL4 protein affecting two functional domains and cause disease development due to haploinsufficiency through nonsense-mediated mRNA decay.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654842PMC
September 2013