Publications by authors named "Shi Yao Lu"

9 Publications

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Association of polymorphisms in , and with myopia progression and polygenic risk prediction in children.

Br J Ophthalmol 2021 Apr 2. Epub 2021 Apr 2.

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

Aims: To assess the association of single-nucleotide polymorphisms (SNPs) with myopia progression for polygenic risk prediction in children.

Methods: Six SNPs ( rs4373767, rs13382811, rs7744813, rs2073560, rs7839488 and rs524952) were analysed in 1043 school children, who completed 3-year follow-up, using TaqMan genotyping assays. SNP associations with progression in spherical equivalent (SE) were analysed by logistic regression. Polygenic risk scores (PRS) were applied for computing the sum of the risk alleles of multiple SNPs corresponding to myopia progression, weighted by the effect sizes of corresponding SNPs.

Results: rs524952 showed significant association with fast progression (OR=1.32, 95% CI 1.10 to 1.59; p=0.003) and rs7744813 had nominal association (OR=1.32, 95% CI 1.04 to 1.67; p=0.02). In quantitative traits locus analysis, rs524952 and rs7744813 were associated with progression in SE (β=-0.038 D/year, p=0.008 and β=-0.042 D/year, p=0.02) and axial elongation (β=0.016 mm/year, p=0.01 and β=0.017 mm/year, p=0.027). rs13382811 also showed nominal association with faster progression in SE (β=-0.041 D/year, p=0.02). PRS analysis showed that children with the highest PRS defined by rs13382811, rs7744813 and rs524952 had a 2.26-fold of increased risk of fast myopia progression (p=4.61×10). PRS was also significantly associated with SE progression (R=1.6%, p=3.15×10) and axial elongation (R=1.2%, p=2.6×10).

Conclusions: In this study, multi-tiered evidence suggested SNPs in , and as risk factors for myopia progression in children. Additional attention and appropriate interventions should be given for myopic children with high-risk PRS as defined by rs524952, rs7744813 and rs13382811.
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http://dx.doi.org/10.1136/bjophthalmol-2020-318708DOI Listing
April 2021

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

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

Association of Polymorphisms at the SIX1-SIX6 Locus With Primary Open-Angle Glaucoma.

Invest Ophthalmol Vis Sci 2019 07;60(8):2914-2924

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

Purpose: To evaluate the association of single-nucleotide polymorphisms (SNPs) in the SIX1-SIX6 locus with primary open-angle glaucoma (POAG) through a systematic review and meta-analysis from 22 studies.

Methods: To our knowledge, all case-control association studies on SNPs in the SIX1-SIX6 locus and POAG reported up to August 30, 2018, in PubMed, Embase, and Web of Science were retrieved. Unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for each SNP were calculated using a fixed- or random-effect model according to interstudy heterogeneity.

Results: This meta-analysis involved 12 SNPs in SIX1-SIX6 reported in 22 studies. The association of rs10483727 with POAG has been presented in 16 studies involving 14,402 patients and 27,425 controls, whereas rs33912345 has been investigated in 12 studies involving 10,563 patients and 16,740 controls. Meta-analyses revealed significant associations of these two SNPs with POAG in the pooled populations under all genetic models. Stratified analyses by population detected significant association of both SNPs in the East Asian and Caucasian subgroups, but not in South Asian or African subgroups. Among the other SNPs that were reported by up to four cohorts of East Asian and African ancestries, only rs12436579 showed a significant association in the meta-analysis (OR = 0.79, P = 1.08 × 10-4).

Conclusions: This meta-analysis confirmed the association of rs10483727 and rs33912345 in SIX1-SIX6 with POAG. The associations of both SNPs were specifically detected in East Asian and Caucasian cohorts, rather than in South Asian and African cohorts, suggesting an ethnic difference. SNP rs12436579 is a candidate variant for the disease that awaits validation in other populations.
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http://dx.doi.org/10.1167/iovs.18-26489DOI Listing
July 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

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