Publications by authors named "Shea-ping Yip"

79 Publications

Computer-assisted ultrasound assessment of plaque characteristics in radiation-induced and non-radiation-induced carotid atherosclerosis.

Quant Imaging Med Surg 2021 Jun;11(6):2292-2306

Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, China.

Background: This study investigated the feasibility of using a computer-assisted method to evaluate and differentiate the carotid plaque characteristics in radiation-induced and non-radiation-induced carotid atherosclerosis.

Methods: This study included 107 post-radiotherapy (post-RT) nasopharyngeal carcinoma (NPC) patients and 110 subjects with cardiovascular risk factors (CVRFs). Each participant had a carotid ultrasound examination, and carotid plaques and carotid intima-media thickness (CIMT) were evaluated with grey scale ultrasound. The carotid plaque characteristics were evaluated for grey-scale median (GSM) and detailed plaque texture analysis (DPTA) using specific computer software. In DPTA, five different intra-plaque components were colour-coded according to different grey scale ranges. A multivariate linear regression model was used to evaluate the correlation of risk factors and carotid plaque characteristics.

Results: Post-RT NPC patients have significantly higher CIMT (748±15.1 µm, P=0.001), more patients had a plaque formation (80.4%, P<0.001) and more plaque locations (2.3±0.2, P<0.001) than CVRF subjects (680.4±10.0 µm, 38.2% and 0.5±0.1 respectively). Among the five intra-plaque components, radiation-induced carotid plaques had significantly larger area of calcification (4.8%±7.7%, P=0.012), but lesser area of lipid (42.1%±16.9%, P=0.034) when compared to non-radiation-induced carotid plaques (3.0%±5.7% and 46.3%±17.9% respectively). Age, radiation and number of CVRF were significantly associated with the carotid atherosclerosis burden (P<0.001). Besides, age was significantly associated with the amount of lipid and calcification within carotid plaques (P<0.001).

Conclusions: Radiation caused more severe carotid artery disease than CVRF with larger CIMT and more prevalent of carotid plaque. Radiation-induced carotid plaques tended to have more intra-plaque calcifications, whereas non-radiation-induced carotid plaques had more lipids. Ultrasound aided by computer-assisted image analysis has potential for more accurate assessment of carotid atherosclerosis.
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http://dx.doi.org/10.21037/qims-20-1012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107311PMC
June 2021

Inflammasome Activation-Induced Hypercoagulopathy: Impact on Cardiovascular Dysfunction Triggered in COVID-19 Patients.

Cells 2021 04 16;10(4). Epub 2021 Apr 16.

Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China.

Coronavirus disease 2019 (COVID-19) is the most devastating infectious disease in the 21st century with more than 2 million lives lost in less than a year. The activation of inflammasome in the host infected by SARS-CoV-2 is highly related to cytokine storm and hypercoagulopathy, which significantly contribute to the poor prognosis of COVID-19 patients. Even though many studies have shown the host defense mechanism induced by inflammasome against various viral infections, mechanistic interactions leading to downstream cellular responses and pathogenesis in COVID-19 remain unclear. The SARS-CoV-2 infection has been associated with numerous cardiovascular disorders including acute myocardial injury, myocarditis, arrhythmias, and venous thromboembolism. The inflammatory response triggered by the activation of NLRP3 inflammasome under certain cardiovascular conditions resulted in hyperinflammation or the modulation of angiotensin-converting enzyme 2 signaling pathways. Perturbations of several target cells and tissues have been described in inflammasome activation, including pneumocytes, macrophages, endothelial cells, and dendritic cells. The interplay between inflammasome activation and hypercoagulopathy in COVID-19 patients is an emerging area to be further addressed. Targeted therapeutics to suppress inflammasome activation may have a positive effect on the reduction of hyperinflammation-induced hypercoagulopathy and cardiovascular disorders occurring as COVID-19 complications.
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http://dx.doi.org/10.3390/cells10040916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073302PMC
April 2021

Territorywide Study of Early Coronavirus Disease Outbreak, Hong Kong, China.

Emerg Infect Dis 2021 01;27(1):196-204

Initial cases of coronavirus disease in Hong Kong were imported from mainland China. A dramatic increase in case numbers was seen in February 2020. Most case-patients had no recent travel history, suggesting the presence of transmission chains in the local community. We collected demographic, clinical, and epidemiologic data from 50 patients, who accounted for 53.8% of total reported case-patients as of February 28, 2020. We performed whole-genome sequencing to determine phylogenetic relationship and transmission dynamics of severe acute respiratory syndrome coronavirus 2 infections. By using phylogenetic analysis, we attributed the community outbreak to 2 lineages; 1 harbored a common mutation, Orf3a-G251V, and accounted for 88.0% of the cases in our study. The estimated time to the most recent common ancestor of local coronavirus disease outbreak was December 24, 2019, with an evolutionary rate of 3.04 × 10 substitutions/site/year. The reproduction number was 1.84, indicating ongoing community spread.
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http://dx.doi.org/10.3201/eid2701.201543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774584PMC
January 2021

Vascular Tissue Engineering: Advanced Techniques and Gene Editing in Stem Cells for Graft Generation.

Tissue Eng Part B Rev 2021 02 27;27(1):14-28. Epub 2020 Jul 27.

Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, SAR, China.

The common occurrence of cardiovascular diseases and the lack of proper autologous tissues prompt and promote the pressing development of tissue-engineered vascular grafts (TEVGs). Current progress on scaffold production, genetically modified cells, and use of nanotechnology-based monitoring has considerably improved the long-term patency of engineered tissue grafts. However, challenges abound in the autologous materials and manipulation of genes and cells for tissue engineering. This review overviews current development in TEVGs and discusses recent improvements in scaffolding techniques and the efficiency of gene-editing tools and their ability to fill the existing gaps in stem cell and regenerative therapies. Current advances in three-dimensional printing approaches for fabrication of engineered tissues are also reviewed together with specific biomaterials for vascular tissues. In addition, the natural and synthetic polymers that hold increasing significance for vascular tissue engineering are highlighted. Both animal models and nanotechnology-based monitoring are proposed for preclinical evaluation of engineered grafts in view of their historical significance in tissue engineering. The ultimate success of tissue regeneration, which is yet to be fully realized, depends on the optimal performance of culture systems, biomaterial constructs, and stem cells in a suitable artificial physiological environment.
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http://dx.doi.org/10.1089/ten.TEB.2019.0264DOI Listing
February 2021

Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error.

Commun Biol 2020 03 19;3(1):133. Epub 2020 Mar 19.

Department of Ophthalmology, Erasmus Medical Center, 3000 CA, Rotterdam, The Netherlands.

Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia.
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http://dx.doi.org/10.1038/s42003-020-0802-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081241PMC
March 2020

The myopia susceptibility locus vasoactive intestinal peptide receptor 2 (VIPR2) contains variants with opposite effects.

Sci Rep 2019 12 3;9(1):18165. Epub 2019 Dec 3.

Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China.

Myopia is the commonest eye disorder in the world. High myopes are predisposed to ocular pathologies. The vasoactive intestinal peptide receptor 2 (VIPR2) gene was identified as a myopia susceptibility locus by our group and another group. We continued to fine-map this locus. A case-control study was performed in 4 sequential stages with a total of 941 highly myopic subjects and 846 control subjects, all unrelated Chinese. Stage 1 experimentally genotyped 64.4% of the entire cohort for 152 single-nucleotide polymorphisms (SNPs) and Stage 2 the remaining subjects for 21 SNPs. Stage 3 combined the genotypes for 21 SNPs for the entire cohort, and identified one group of high-risk haplotypes and one group of protective haplotypes significantly associated with high myopia. Stage 4 imputed genotypes for variants in the VIPR2 region and identified two independent groups of variants: one group with high-risk minor alleles and another with protective minor alleles. Variants within each group were generally in strong linkage disequilibrium among themselves while high-risk variants were in linkage equilibrium with protective variants. Therefore, the VIPR2 locus seems to contain variants with opposite effects. This is the first study that has examined the genetic architecture of a myopia susceptibility locus in detail.
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http://dx.doi.org/10.1038/s41598-019-54619-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890636PMC
December 2019

A Genome-Wide Association Study for Susceptibility to Visual Experience-Induced Myopia.

Invest Ophthalmol Vis Sci 2019 02;60(2):559-569

School of Optometry & Vision Sciences, Cardiff University, Cardiff, United Kingdom.

Purpose: The rapid rise in prevalence over recent decades and high heritability of myopia suggest a role for gene-environment (G × E) interactions in myopia susceptibility. Few such G × E interactions have been discovered to date. We aimed to test the hypothesis that genetic analysis of susceptibility to visual experience-induced myopia in an animal model would identify novel G × E interaction loci.

Methods: Chicks aged 7 days (n = 987) were monocularly deprived of form vision for 4 days. A genome-wide association study (GWAS) was carried out in the 20% of chicks most susceptible and least susceptible to form deprivation (n = 380). There were 304,963 genetic markers tested for association with the degree of induced axial elongation in treated versus control eyes (A-scan ultrasonography). A GWAS candidate region was examined in the following three human cohorts: CREAM consortium (n = 44,192), UK Biobank (n = 95,505), and Avon Longitudinal Study of Parents and Children (ALSPAC; n = 4989).

Results: A locus encompassing the genes PIK3CG and PRKAR2B was genome-wide significantly associated with myopia susceptibility in chicks (lead variant rs317386235, P = 9.54e-08). In CREAM and UK Biobank GWAS datasets, PIK3CG and PRKAR2B were enriched for strongly-associated markers (meta-analysis lead variant rs117909394, P = 1.7e-07). In ALSPAC participants, rs117909394 had an age-dependent association with refractive error (-0.22 diopters [D] change over 8 years, P = 5.2e-04) and nearby variant rs17153745 showed evidence of a G × E interaction with time spent reading (effect size -0.23 D, P = 0.022).

Conclusions: This work identified the PIK3CG-PRKAR2B locus as a mediator of susceptibility to visually induced myopia in chicks and suggests a role for this locus in conferring susceptibility to myopia in human cohorts.
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http://dx.doi.org/10.1167/iovs.18-25597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363377PMC
February 2019

Long non-coding RNAs in hematological malignancies: translating basic techniques into diagnostic and therapeutic strategies.

J Hematol Oncol 2018 11 22;11(1):131. Epub 2018 Nov 22.

Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Y9/F, Lee Shau Kee Building, Hung Hom, Hong Kong SAR, China.

Recent studies have revealed that non-coding regions comprise the vast majority of the human genome and long non-coding RNAs (lncRNAs) are a diverse class of non-coding RNAs that has been implicated in a variety of biological processes. Abnormal expression of lncRNAs has also been linked to different human diseases including cancers, yet the regulatory mechanisms and functional effects of lncRNAs are still ambiguous, and the molecular details also need to be confirmed. Unlike protein-coding gene, it is much more challenging to unravel the roles of lncRNAs owing to their unique and complex features such as functional diversity and low conservation among species, which greatly hamper their experimental characterization. In this review, we summarize and discuss both conventional and advanced approaches for the identification and functional characterization of lncRNAs related to hematological malignancies. In particular, the utility and advancement of clustered regularly interspaced short palindromic repeats (CRISPR)-Cas system as gene-editing tools are envisioned to facilitate the molecular dissection of lncRNAs via different knock-in/out strategies. Besides experimental considerations specific to lncRNAs, the roles of lncRNAs in the pathogenesis and progression of leukemia are also highlighted in the review. We expect that these insights may ultimately lead to clinical applications including development of biomarkers and novel therapeutic approaches targeting lncRNAs.
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http://dx.doi.org/10.1186/s13045-018-0673-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251105PMC
November 2018

Characterization and Regulation of Gap Junctions in Porcine Ciliary Epithelium.

Invest Ophthalmol Vis Sci 2018 07;59(8):3461-3468

School of Optometry, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China.

Purpose: Gap junctions provide a conduit between the intracellular fluids of the pigmented (PE) and non-pigmented (NPE) ciliary epithelial cells, and are therefore critical in the secretion of the aqueous humor (AH). However, opinions differ concerning the connexin (Cx) composition of the gap junctions. Therefore, we aimed to characterize the expression of Cx in the porcine ciliary epithelium (CE), a favorable model for humans; and determine the contribution of the highest expressed Cx to AH secretion.

Methods: Freshly-harvested porcine CE cells were used. The mRNA and protein expressions of gap junctions were assessed by reverse transcription polymerase chain reaction (RT-PCR) and Western blotting (WB), respectively. The relative gene expressions of various Cx were determined by quantitative PCR. The gap junction permeability of isolated PE-NPE cell couplets was evaluated by Lucifer Yellow dye transfer.

Results: Using RT-PCR and WB, Cx43, Cx45, Cx47, Cx50, and Cx60 were present in porcine CE, with Cx43 being the most abundant isoform, having over 200-fold higher expression than other Cx. Cx43 was primarily localized in the PE-NPE interface and the basolateral membranes of PE cells. Knockdown of Cx43 by siRNA significantly reduced gene and protein expressions, resulting in reduction of transcellular fluid flow by 90%.

Conclusions: Cx43 was found to be the major component of gap junctions in porcine CE. Consistent with results from a bovine model, our results support the important role of Cx43 in mediating AH secretion. This finding may shed light on the development of a novel ocular hypotensive agent.
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http://dx.doi.org/10.1167/iovs.18-24682DOI Listing
July 2018

Computer-aided assessment of regional vascularity of thyroid nodules for prediction of malignancy.

Sci Rep 2017 10 30;7(1):14350. Epub 2017 Oct 30.

Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, SAR, China.

Color Doppler vascular index (VI) was assessed alone and in combination with grey-scale ultrasound (GSU) in regionally subdivided thyroid nodules in diagnosing thyroid cancer. Color Doppler sonograms of 111 thyroid nodules were evaluated by a home-developed algorithm that performed "offsetting" (algorithm for changing the area of a region of interest, ROI, without distorting the ROI's contour) and assessed peripheral, central and overall VI of thyroid nodules. Results showed that the optimum offset for dividing peripheral and central regions of nodule was 22%. At the optimum offset, the mean VI of peripheral, central, and overall regions of malignant nodules were significantly higher than those of benign nodules (26.5 ± 16.2%, 21.7 ± 19.6%, 23.8 ± 4.6% v/s 18.2 ± 16.7%, 11.9 ± 15.1% and 16.6 ± 1.8% respectively, P < 0.05). The optimum cut-off of peripheral, central, and overall VI was 19.7%, 9.1% and 20.2% respectively. When compared to GSU alone, combination of VI assessment with GSU evaluation of thyroid nodules increased the diagnostic accuracy from 58.6% to 79.3% (P < 0.05). In conclusion, a novel algorithm for regional subdivision and quantification of thyroid nodular VI in ultrasound images was established, and the optimum offset and cut-off were derived. Assessment of intranodular VI in conjunction with GSU can increase the accuracy in ultrasound diagnosis of thyroid cancer.
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http://dx.doi.org/10.1038/s41598-017-14432-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662577PMC
October 2017

Region-specific differential corneal and scleral mRNA expressions of MMP2, TIMP2, and TGFB2 in highly myopic-astigmatic chicks.

Sci Rep 2017 09 12;7(1):11423. Epub 2017 Sep 12.

School of Optometry, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR.

Myopia and astigmatism, two common refractive errors frequently co-exist, are affecting vision at all working distances in the affected populations worldwide. Eyeballs having these refractive errors are known to exhibit abnormal eye shape at the anterior and posterior eye segments, but whether the outer coats of these abnormal eyeballs, cornea anteriorly and sclera posteriorly, are regulated by region-specific molecular mechanism remains unclear. Here we presented the changes in mRNA expression levels of three genes (MMP2, TIMP2, and TGFB2), all known to participate in extracellular matrix organization, at five regions of the cornea and sclera in chickens developing high myopia and astigmatism induced by form deprivation. We found that, compared to normal chicks, the highly myopic-astigmatic chicks had significantly higher expression of all three genes in the superior sclera (Mann-Whitney tests, all p ≤ 0.05), as well as higher TIMP2 expression in the central cornea and nasal sclera (Mann-Whitney tests, both p ≤ 0.05). Strikingly, the superior scleral region stood out as showing the strongest and most widespread correlations between mRNA expression and biometry parameters including axial and astigmatic components (r = + 0.52~ + 0.85, all p < 0.05). These results imply that local molecular mechanism may manipulate the eye shape remodeling across the globe during refractive-error development.
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http://dx.doi.org/10.1038/s41598-017-08765-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595952PMC
September 2017

Genetic Association Study of Polymorphisms with High Myopia.

Biomed Res Int 2017 13;2017:3024156. Epub 2017 Aug 13.

Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hung Hom, Hong Kong.

Identification of genetic variations related to high myopia may advance our knowledge of the etiopathogenesis of refractive error. This study investigated the role of potassium channel gene polymorphisms in high myopia. We performed a case-control study of 1563 unrelated Han Chinese subjects (809 cases of high myopia and 754 emmetropic controls). Five tag single-nucleotide polymorphisms (SNPs) of were genotyped, and association testing with high myopia was conducted using logistic regression analysis adjusted for sex and age to give values, and multiple comparisons were corrected by permutation test to give values. All five noncoding SNPs were associated with high myopia. The SNP rs7744813, previously shown to be associated with refractive error and myopia in two GWAS, showed an odds ratio of 0.75 (95% CI 0.63-0.90; = 0.0058) for the minor allele. The top SNP rs9342979 showed an odds ratio of 0.75 (95% CI 0.64-0.89; = 0.0045) for the minor allele. Both SNPs are located within enhancer histone marks and DNase-hypersensitive sites. Our data support the involvement of gene polymorphisms in the genetic susceptibility to high myopia and further exploration of as a risk factor for high myopia.
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http://dx.doi.org/10.1155/2017/3024156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572591PMC
May 2018

Precipitation of PEG/Carboxyl-Modified Gold Nanoparticles with Magnesium Pyrophosphate: A New Platform for Real-Time Monitoring of Loop-Mediated Isothermal Amplification.

ACS Appl Mater Interfaces 2017 Mar 20;9(12):10472-10480. Epub 2017 Mar 20.

Interdisciplinary Division of Biomedical Engineering, ‡Department of Health Technology and Informatics, The Hong Kong Polytechnic University , Hung Hom, Kowloon, Hong Kong, China.

Gold nanoparticles have proven to be promising for decentralized nucleic acid testing by virtue of their simple visual readout and absorbance-based quantification. A major challenge toward their practical application is to achieve ultrasensitive detection without compromising simplicity. The conventional strategy of thermocycling amplification is unfavorable (because of both instrumentation and preparation of thermostable oligonucleotide-modified gold nanoparticle probes). Herein, on the basis of a previously unreported co-precipitation phenomenon between thiolated poly(ethylene glycol)/11-mercaptoundecanoic acid co-modified gold nanoparticles and magnesium pyrophosphate crystals (an isothermal DNA amplification reaction byproduct), a new ultrasensitive and simple DNA assay platform is developed. The binding mechanism underlying the co-precipitation phenomenon is found to be caused by the complexation of carboxyl and pyrophosphate with free magnesium ions. Remarkably, poly(ethylene glycol) does not hinder the binding and effectively stabilizes gold nanoparticles against magnesium ion-induced aggregation (without pyrophosphate). In fact, a similar phenomenon is observed in other poly(ethylene glycol)- and carboxyl-containing nanomaterials. When the gold nanoparticle probe is incorporated into a loop-mediated isothermal amplification reaction, it remains as a red dispersion for a negative sample (in the absence of a target DNA sequence) but appears as a red precipitate for a positive sample (in the presence of a target). This results in a first-of-its-kind gold nanoparticle-based DNA assay platform with isothermal amplification and real-time monitoring capabilities.
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http://dx.doi.org/10.1021/acsami.7b00046DOI Listing
March 2017

Pathway analysis of complex diseases for GWAS, extending to consider rare variants, multi-omics and interactions.

Biochim Biophys Acta Gen Subj 2017 Feb 23;1861(2):335-353. Epub 2016 Nov 23.

Centre for Myopia Research, School of Optometry, The Hong Kong Polytechnic University, Hong Kong SAR, China.

Background: Genome-wide association studies (GWAS) is a major method for studying the genetics of complex diseases. Finding all sequence variants to explain fully the aetiology of a disease is difficult because of their small effect sizes. To better explain disease mechanisms, pathway analysis is used to consolidate the effects of multiple variants, and hence increase the power of the study. While pathway analysis has previously been performed within GWAS only, it can now be extended to examining rare variants, other "-omics" and interaction data.

Scope Of Review: 1. Factors to consider in the choice of software for GWAS pathway analysis. 2. Examples of how pathway analysis is used to analyse rare variants, other "-omics" and interaction data.

Major Conclusions: To choose appropriate software tools, factors for consideration include covariate compatibility, null hypothesis, one- or two-step analysis required, curation method of gene sets, size of pathways, and size of flanking regions to define gene boundaries. For rare variants, analysis performance depends on consistency between assumed and actual effect distribution of variants. Integration of other "-omics" data and interaction can better explain gene functions.

General Significance: Pathway analysis methods will be more readily used for integration of multiple sources of data, and enable more accurate prediction of phenotypes.
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http://dx.doi.org/10.1016/j.bbagen.2016.11.030DOI Listing
February 2017

Platinum nanoparticles on reduced graphene oxide as peroxidase mimetics for the colorimetric detection of specific DNA sequence.

J Mater Chem B 2016 Jun 24;4(23):4076-4083. Epub 2016 May 24.

Interdisciplinary Division of Biomedical Engineering, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China.

In this work, we developed a simple and sensitive colorimetric detection platform for specific DNA sequences by using peroxidase mimetics of platinum nanoparticles supported on reduced graphene oxide. This nanocomposite possessed the combined advantages of platinum nanoparticles (superior peroxidase-like activity) and reduced graphene oxide (π-stacking interaction with single-stranded but not double-stranded DNA). The catalytic activity was strongly dependent on the chloroplatinic acid-to-graphene oxide mass ratio during the synthesis step, with an optimum ratio of 7 : 1. Unlike natural peroxidase, the nanocomposite had excellent stability over wide ranges of temperature (4-90 °C) and pH (1-13). For DNA detection, the nanocomposite had higher affinity for the single-stranded probe (in the absence of target) than the probe-target duplex. The probe-bound nanocomposite was stabilized against salt-induced aggregation and thus upon the addition of 3,3',5,5'-tetramethylbenzidine and hydrogen peroxide to the supernatant, an intense blue color was generated. The linear range and limit of detection of this assay platform were 0.5-10 nM and 0.4 nM, respectively. Moreover, this platform featured high specificity that 3-base-mismatched sequence could be distinguished with the naked eye and 1-base-mismatched sequence with absorbance measurement. Furthermore, the applicability for real sample detection was demonstrated by polymerase chain reaction product analysis. Taken together, this new platform is well suited for point-of-care and on-site nucleic acid testing.
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http://dx.doi.org/10.1039/c6tb00741dDOI Listing
June 2016

Meta-analysis of gene-environment-wide association scans accounting for education level identifies additional loci for refractive error.

Nat Commun 2016 Mar 29;7:11008. Epub 2016 Mar 29.

Department of Ophthalmology, Sisters of Mercy University Hospital, Zagreb 10000, Croatia.

Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10(-5)), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.
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http://dx.doi.org/10.1038/ncomms11008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820539PMC
March 2016

Association between genetic polymorphisms and carotid atherosclerosis in patients treated with radiotherapy for nasopharyngeal carcinoma.

Radiat Oncol 2015 Feb 13;10:39. Epub 2015 Feb 13.

Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, SAR, China.

Background: Radiotherapy (RT) of the neck is commonly given to nasopharyngeal carcinoma (NPC) patients for preventing cervical lymph node metastasis. However, neck RT may induce the development of carotid atherosclerosis. The mechanisms of radiation-induced carotid atherosclerosis are still unclear and no previous study has investigated the genetic involvement of radiation-induced carotid atherosclerosis. The present study aims to determine the association between genetic polymorphisms and carotid atherosclerosis in patients treated with RT for nasopharyngeal carcinoma.

Methods: The present study recruited 128 post-RT NPC patients. Carotid plaque score was assessed using ultrasonography. Thirteen single nucleotide polymorphisms (SNPs) that affect the function of anti-atherosclerotic genes, including SOD2, SOD3, CAT, PON1, PPARG, ADIPOQ, IL10, TGFB1 and NOS3, were genotyped. Association between the 13 SNPs and carotid atherosclerosis was evaluated using multiple regression after adjustment for covariates (PLINK). Multiple testing was corrected using Benjamini-Hochberg step-up false discovery rate controlling procedure.

Results: rs662 and rs705379 of PON1 were close to be significantly associated with carotid plaque score (Corrected P value, P cor  =0.0528 and P cor  =0.0842). When the two SNPs were combined together, TC haplotype in rs662-rs705379 of PON1 was significantly associated with higher carotid plaque score (P cor  < 0.05). None of the other SNPs showed significant association with carotid plaque score.

Conclusions: TC haplotype in rs662-rs705379 of PON1 is likely to be a genetic risk factor of carotid plaque score. Post-RT NPC patients with the TC haplotype may need earlier and more frequent carotid ultrasound examinations for early detection of carotid atherosclerosis.
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http://dx.doi.org/10.1186/s13014-015-0341-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4332433PMC
February 2015

Ultrasound Evaluation of Carotid Atherosclerosis in Post-Radiotherapy Nasopharyngeal Carcinoma Patients, Type 2 Diabetics, and Healthy Controls.

Ultraschall Med 2017 Apr 1;38(2):190-197. Epub 2015 Apr 1.

Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong.

 To comprehensively evaluate and compare the degree of carotid atherosclerosis in patients treated with radiotherapy (RT) for nasopharyngeal carcinoma (NPC) and in patients with type 2 diabetes mellitus (DM), and using healthy subjects as controls.  The present study recruited 69 post-RT NPC patients without conventional cardiovascular risk factors, 70 type 2 diabetic patients without previous RT, and 76 healthy controls without conventional cardiovascular risk factors and previous RT. For each participant, 5 carotid atherosclerotic parameters, namely carotid intima-media thickness (CIMT), carotid arterial stiffness (CAS), presence of carotid plaque, carotid plaque score, and presence of ≥ 50 % carotid stenosis, were assessed using ultrasonography. The differences in these carotid atherosclerotic parameters between study groups were compared using ANCOVA or logistic regression after the adjustment for age and gender. Multiple comparisons were corrected using the Benjamini-Hochberg false discovery rate.  Post-RT NPC patients and type 2 diabetics had a significantly higher CIMT, CAS and carotid plaque burden compared to the healthy subjects (corrected P-value, Pcor < 0.05). In addition, carotid atherosclerosis in post-RT NPC patients tended to be more severe with significantly higher CAS and carotid plaque burden than that in type 2 diabetics (Pcor < 0.05).  Neck RT for NPC is an independent risk factor of carotid atherosclerosis, and radiation induces more severe carotid atherosclerosis in post-RT NPC patients. Thus, assessment of carotid atherosclerosis using ultrasonography may be necessary for these patients and should be indicated in the routine follow-up of NPC.
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http://dx.doi.org/10.1055/s-0034-1399293DOI Listing
April 2017

Identification of myopia-associated WNT7B polymorphisms provides insights into the mechanism underlying the development of myopia.

Nat Commun 2015 Mar 31;6:6689. Epub 2015 Mar 31.

Centre for Myopia Research, School of Optometry, The Hong Kong Polytechnic University, Hong Kong SAR 99907, China.

Myopia can cause severe visual impairment. Here, we report a two-stage genome-wide association study for three myopia-related traits in 9,804 Japanese individuals, which was extended with trans-ethnic replication in 2,674 Chinese and 2,690 Caucasian individuals. We identify WNT7B as a novel susceptibility gene for axial length (rs10453441, Pmeta=3.9 × 10(-13)) and corneal curvature (Pmeta=2.9 × 10(-40)) and confirm the previously reported association between GJD2 and myopia. WNT7B significantly associates with extreme myopia in a case-control study with 1,478 Asian patients and 4,689 controls (odds ratio (OR)meta=1.13, Pmeta=0.011). We also find in a mouse model of myopia downregulation of WNT7B expression in the cornea and upregulation in the retina, suggesting its possible role in the development of myopia.
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http://dx.doi.org/10.1038/ncomms7689DOI Listing
March 2015

Predictors of the extent of carotid atherosclerosis in patients treated with radiotherapy for nasopharyngeal carcinoma.

PLoS One 2014 31;9(12):e116284. Epub 2014 Dec 31.

Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, China.

Objective: To determine the predictors of the extent of carotid atherosclerosis in patients treated with radiotherapy (RT) for nasopharyngeal carcinoma (NPC).

Methods: The present study investigated 129 post-RT NPC patients. Carotid atherosclerotic parameters, such as carotid intima-media thickness, carotid arterial stiffness and carotid plaque burden (plaque score, the presence of plaque and ≥50% stenosis) were assessed using ultrasonography. The association between carotid atherosclerotic parameters and nine potential predictors, including age, gender, post-RT duration, radiation dose, chemotherapy, diabetes mellitus, hypertension, hypercholesterolemia, and smoking, were determined using multiple regression. The cutoff values of age, post-RT duration and number of cardiovascular risk factors for the presence of carotid plaque or ≥50% carotid stenosis were analyzed using receiver operating characteristic (ROC) curve analysis. Multiple testing was corrected using Benjamini-Hochberg false discovery rate.

Results: Age, post-RT duration and number of cardiovascular risk factors were significantly associated with carotid plaque burden (corrected P value, Pcor<0.05). Age of 44.5 years (sensitivity = 99.2% and specificity = 50%, Pcor<0.01) and post-RT duration of 8.5 years (sensitivity = 75.7% and specificity = 64.3%, Pcor<0.001) were the cutoff values for detecting carotid plaque, while post-RT duration of 13.5 years (sensitivity = 66.7% and specificity = 71.6%, Pcor<0.001) and 1.5 cardiovascular risk factors (sensitivity = 40.7% and specificity = 84.3%, Pcor<0.05) were the cutoff values for screening ≥50% carotid stenosis.

Conclusions: Age, post-RT duration and number of cardiovascular risk factors are significant predictors of carotid atherosclerosis in post-RT NPC patients. Post-RT NPC patients, who are at least 45 years old, with post-RT duration of 9 years or above, and/or have ≥2 cardiovascular risk factors, are more susceptible to carotid atherosclerosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0116284PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281159PMC
January 2016

Genetic association between germline JAK2 polymorphisms and myeloproliferative neoplasms in Hong Kong Chinese population: a case-control study.

BMC Genet 2014 Dec 20;15:147. Epub 2014 Dec 20.

Background: Myeloproliferative neoplasms (MPNs) are a group of haematological malignancies that can be characterised by a somatic mutation (JAK2V617F). This mutation causes the bone marrow to produce excessive blood cells and is found in polycythaemia vera (~95%), essential thrombocythaemia and primary myelofibrosis (both ~50%). It is considered as a major genetic factor contributing to the development of these MPNs. No genetic association study of MPN in the Hong Kong population has so far been reported. Here, we investigated the relationship between germline JAK2 polymorphisms and MPNs in Hong Kong Chinese to find causal variants that contribute to MPN development. We analysed 19 tag single nucleotide polymorphisms (SNPs) within the JAK2 locus in 172 MPN patients and 470 healthy controls. Three of these 19 SNPs defined the reported JAK2 46/1 haplotype: rs10974944, rs12343867 and rs12340895. Allele and haplotype frequencies were compared between patients and controls by logistic regression adjusted for sex and age. Permutation test was used to correct for multiple comparisons. With significant findings from the 19 SNPs, we then examined 76 additional SNPs across the 148.7-kb region of JAK2 via imputation with the SNP data from the 1000 Genomes Project.

Results: In single-marker analysis, 15 SNPs showed association with JAK2V617F-positive MPNs (n = 128), and 8 of these were novel MPN-associated SNPs not previously reported. Exhaustive variable-sized sliding-window haplotype analysis identified 184 haplotypes showing significant differences (P < 0.05) in frequencies between patients and controls even after multiple-testing correction. However, single-marker alleles exhibited the strongest association with V617F-positive MPNs. In local Hong Kong Chinese, rs12342421 showed the strongest association signal: asymptotic P = 3.76 × 10-15, empirical P = 2.00 × 10-5 for 50,000 permutations, OR = 3.55 for the minor allele C, and 95% CI, 2.59-4.87. Conditional logistic regression also signified an independent effect of rs12342421 in significant haplotype windows, and this independent effect remained unchanged even with the imputation of additional 76 SNPs. No significant association was found between V617F-negative MPNs and JAK2 SNPs.

Conclusion: With a large sample size, we reported the association between JAK2V617F-positive MPNs and 15 tag JAK2 SNPs and the association of rs12342421 being independent of the JAK2 46/1 haplotype in Hong Kong Chinese population.
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http://dx.doi.org/10.1186/s12863-014-0147-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293821PMC
December 2014

Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium.

Hum Genet 2015 Feb 4;134(2):131-46. Epub 2014 Nov 4.

National Human Genome Research Institute, National Institutes of Health, 333 Cassell Drive Suite 1200, Baltimore, MD, 21224, USA.

To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged <25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged <25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E-8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E-07), TOX (rs7823467, P = 3.47E-07) and LINC00340 (rs12212674, P = 1.49E-06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = -0.59, P = 2.10E-04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.
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http://dx.doi.org/10.1007/s00439-014-1500-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4291519PMC
February 2015

Gradually increased training intensity benefits rehabilitation outcome after stroke by BDNF upregulation and stress suppression.

Biomed Res Int 2014 19;2014:925762. Epub 2014 Jun 19.

Interdisciplinary Division of Biomedical Engineering, The Hong Kong Polytechnic University, Hong Kong.

Physical training is necessary for effective rehabilitation in the early poststroke period. Animal studies commonly use fixed training intensity throughout rehabilitation and without adapting it to the animals' recovered motor ability. This study investigated the correlation between training intensity and rehabilitation efficacy by using a focal ischemic stroke rat model. Eighty male Sprague-Dawley rats were induced with middle cerebral artery occlusion/reperfusion surgery. Sixty rats with successful stroke were then randomly assigned into four groups: control (CG, n = 15), low intensity (LG, n = 15), gradually increased intensity (GIG, n = 15), and high intensity (HG, n = 15). Behavioral tests were conducted daily to evaluate motor function recovery. Stress level and neural recovery were evaluated via plasma corticosterone and brain-derived neurotrophic factor (BDNF) concentration, respectively. GIG rats significantly (P < 0.05) recovered motor function and produced higher hippocampal BDNF (112.87 ± 25.18 ng/g). GIG and LG rats exhibited similar stress levels (540.63 ± 117.40 nM/L and 508.07 ± 161.30 nM/L, resp.), which were significantly lower (P < 0.05) than that (716.90 ± 156.48 nM/L) of HG rats. Training with gradually increased intensity achieved better recovery with lower stress. Our observations indicate that a training protocol that includes gradually increasing training intensity should be considered in both animal and clinical studies for better stroke recovery.
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http://dx.doi.org/10.1155/2014/925762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4090448PMC
March 2015

Association of and gene haplotypes with the development of radiation-induced fibrosis in patients with nasopharyngeal carcinoma.

Mol Clin Oncol 2014 Jul 14;2(4):553-558. Epub 2014 Apr 14.

Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, SAR, P.R. China.

Radiation-induced fibrosis is one of the late complications of radiotherapy (RT) for nasopharyngeal carcinoma (NPC). The aim of this study was to investigate the association between X-ray repair cross-complementing protein 1 and 3 ( and , respectively) gene haplotypes and radiation-induced fibrosis in NPC patients. Genomic DNA was extracted from blood samples of 120 NPC patients previously treated with RT. In total, 12 tag single-nucleotide polymorphisms (SNPs) were selected from the and genes and were genotyped using restriction fragment length polymorphism analysis or unlabeled probe melting analysis. Single-marker and haplotype analyses were performed using multivariate logistic regression analysis. The functional variant rs861539 of may be associated with radiation-induced fibrosis [asymptotic P-value (P)<0.05]. No significant association was observed between radiation-induced fibrosis and any of the tag SNPs of and in either single-marker or haplotype analysis after 10,000 permutations [empirical P-value (P)>0.05]. Our preliminary results indicated that the rs861539 variant of may be associated with an increased risk of radiation-induced fibrosis; however, a large-scale study is required to confirm this result.
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http://dx.doi.org/10.3892/mco.2014.276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4051552PMC
July 2014

Modulating effect of SIRT1 activation induced by resveratrol on Foxo1-associated apoptotic signalling in senescent heart.

J Physiol 2014 Jun 17;592(12):2535-48. Epub 2014 Mar 17.

Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China

Elevations of cardiomyocyte apoptosis and fibrotic deposition are major characteristics of the ageing heart. Resveratrol, a polyphenol in grapes and red wine, is known to improve insulin resistance and increase mitochondrial biogenesis through the SIRT1-PGC-1α signalling axis. Recent studies attempted to relate SIRT1 activation by resveratrol to the regulation of apoptosis in various disease models of cardiac muscle. In the present study, we tested the hypothesis that long-term (8-month) treatment of resveratrol would activate SIRT1 and improve the cardiac function of senescent mice through suppression of Foxo1-associated pro-apoptotic signalling. Our echocardiographic measurements indicated that the cardiac systolic function measured as fractional shortening and ejection fraction was significantly reduced in aged mice when compared with the young mice. These reductions, however, were not observed in resveratrol-treated hearts. Ageing significantly reduced the deacetylase activity, but not the protein abundance of SIRT1 in the heart. This reduction was accompanied by increased acetylation of the Foxo1 transcription factor and transactivation of its target, pro-apoptotic Bim. Subsequent analyses indicated that pro-apoptotic signalling measured as p53, Bax and apoptotic DNA fragmentation was up-regulated in the heart of aged mice. In contrast, resveratrol restored SIRT1 activity and suppressed elevations of Foxo1 acetylation, Bim and pro-apoptotic signalling in the aged heart. In parallel, resveratrol also attenuated the ageing-induced elevations of fibrotic collagen deposition and markers of oxidative damage including 4HNE and nitrotyrosine. In conclusion, these novel data demonstrate that resveratrol mitigates pro-apoptotic signalling in senescent heart through a deacetylation mechanism of SIRT1 that represses the Foxo1-Bim-associated pro-apoptotic signalling axis.
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http://dx.doi.org/10.1113/jphysiol.2014.271387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4080936PMC
June 2014

Ultrasensitive and closed-tube colorimetric loop-mediated isothermal amplification assay using carboxyl-modified gold nanoparticles.

Small 2014 Apr 13;10(8):1495-9. Epub 2014 Mar 13.

Interdisciplinary Division of Biomedical Engineering, The Hong Kong Polytechnic University Hung Hom, Kowloon, Hong Kong, China.

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http://dx.doi.org/10.1002/smll.201302348DOI Listing
April 2014

Desacyl ghrelin prevents doxorubicin-induced myocardial fibrosis and apoptosis via the GHSR-independent pathway.

Am J Physiol Endocrinol Metab 2014 Feb 10;306(3):E311-23. Epub 2013 Dec 10.

Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China.

Doxorubicin is an effective chemotherapeutic agent used to treat malignancies, but it causes cardiomyopathy. Preliminary evidence suggests that desacyl ghrelin might have protective effects on doxorubicin cardiotoxicity. This study examined the cellular effects of desacyl ghrelin on myocardial fibrosis and apoptosis in a doxorubicin cardiomyopathy experimental model. Adult C57BL/6 mice received an intraperitoneal injection of doxorubicin to induce cardiomyopathy, followed by 4-day treatment of saline (control) or desacyl ghrelin with or without [d-Lys3]-GHRP-6 (a growth hormone secretagogue receptor or GHSR1a antagonist). Ventricular structural and functional parameters were evaluated by transthoracic echocardiography. Molecular and cellular measurements were performed in ventricular muscle to examine myocardial fibrosis and apoptosis. Cardiac dysfunction was induced by doxorubicin, as indicated by significant decreases in ventricular fractional shortening and ejection fraction. This doxorubicin-induced cardiac dysfunction was prevented by the treatment of desacyl ghrelin no matter with or without the presence of [d-Lys3]-GHRP-6. Doxorubicin induced fibrosis (accumulated collagen deposition and increased CTGF), activated apoptosis (increased TUNEL index, apoptotic DNA fragmentation, and caspase-3 activity and decreased Bcl-2/Bax ratio), and suppressed phosphorylation status of prosurvival signals (ERK1/2 and Akt) in ventricular muscles. All these molecular and cellular alterations induced by doxorubicin were not found in the animals treated with desacyl ghrelin. Notably, the changes in the major markers of apoptosis, fibrosis, and Akt phosphorylation were found to be similar in the animals following the treatment of desacyl ghrelin with and without GHSR antagonist [d-Lys3]-GHRP-6. These findings demonstrate clearly that desacyl ghrelin protects the cardiomyocytes against the doxorubicin-induced cardiomyopathy by preventing the activation of cardiac fibrosis and apoptosis, and the effects are probably mediated through GHSR-independent mechanism.
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http://dx.doi.org/10.1152/ajpendo.00123.2013DOI Listing
February 2014

Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant.

J Clin Invest 2013 Nov;123(11):4909-17

Lumbar disc degeneration (LDD) is associated with both genetic and environmental factors and affects many people worldwide. A hallmark of LDD is loss of proteoglycan and water content in the nucleus pulposus of intervertebral discs. While some genetic determinants have been reported, the etiology of LDD is largely unknown. Here we report the findings from linkage and association studies on a total of 32,642 subjects consisting of 4,043 LDD cases and 28,599 control subjects. We identified carbohydrate sulfotransferase 3 (CHST3), an enzyme that catalyzes proteoglycan sulfation, as a susceptibility gene for LDD. The strongest genome-wide linkage peak encompassed CHST3 from a Southern Chinese family–based data set, while a genome-wide association was observed at rs4148941 in the gene in a meta-analysis using multiethnic population cohorts. rs4148941 lies within a potential microRNA-513a-5p (miR-513a-5p) binding site. Interaction between miR-513a-5p and mRNA transcribed from the susceptibility allele (A allele) of rs4148941 was enhanced in vitro compared with transcripts from other alleles. Additionally, expression of CHST3 mRNA was significantly reduced in the intervertebral disc cells of human subjects carrying the A allele of rs4148941. Together, our data provide new insights into the etiology of LDD, implicating an interplay between genetic risk factors and miRNA.
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http://dx.doi.org/10.1172/JCI69277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3809787PMC
November 2013

Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error.

Am J Hum Genet 2013 Aug;93(2):264-77

Department of Ophthalmology, National University of Singapore and National University Health System, Singapore 119228, Singapore; Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore 117597, Singapore; Singapore Eye Research Institute, Singapore National Eye Centre, Singapore 168751, Singapore; Centre for Quantitative Medicine, Office of Clinical Sciences, Duke-National University of Singapore Graduate Medical School, Singapore 169857, Singapore.

Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways.
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http://dx.doi.org/10.1016/j.ajhg.2013.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772747PMC
August 2013