A cross-ethnicity investigation of genes previously implicated in primary angle closure glaucoma

Purpose: To investigate the underlying genetic variation between candidate genes and primary angle closure glaucoma (PACG) in both Nepalese and Australian populations. Methods: A total of 213 patients with PACG (106 Nepalese and 107 Australian) and 492 age and sex matched controls (204 Nepalese and 288 Australian) were included in the current study. Three candidate genes were selected; methyltetrahydrofolate reductase (MTHFR), calcitonin receptor-like receptor gene (CALCRL), and membrane frizzled-related protein (MFRP). Tag single nucleotide polymorphisms (SNPs) were selected and genotyped to capture the majority of common variation across each locus. Allele and haplotype analyses were conducted using PLINK. Results: SNPs in the nanophthalmos gene MFRP were found to be nominally associated with PACG under the allelic model. Two SNPs were associated in the Australian cohort (rs948414; p=0.02 and rs36015759; p=0.02), and a single SNP in the Nepalese cohort (rs10790289; p=0.03), however these SNPs failed to remain significant after adjustment for sex and age. A haplotype at the CALCRL gene (AATACAGAT) was associated in the Australian cohort (corrected p-value= 0.024). No association was observed in either cohort for MTHFR. Conclusions: This study implicates genetic variation at the CALCRL gene in the pathogenesis of PACG in an Australian Caucasian cohort. Additionally, the MFRP gene shows tendency to be associated with PACG in both the Australian and Nepalese cohorts. Further investigation in a larger cohort is warranted to confirm these findings. No statistically significant associations were identified between MTHFR and PACG in either population

Association of eNOS polymorphisms with primary angle-closure glaucoma

Author version made available in accordance with the publisher's policy.Purpose: Recently, several studies have investigated genetic associations between Cytochrome P450 (CYP1B1), Endothelial nitric oxide synthase (eNOS) and Neurotrophin-4 (NTF4) with primary angle-closure glaucoma (PACG) in various ethnic groups. Here we investigate the association of these candidate genes with PACG in samples from Australia and Nepal. Method: A total of 235 patients with PACG (106 Nepalese and 129 Australian) and 492 controls (204 Nepalese and 288 Australian) were included. Tag single nucleotide polymorphisms (SNPs) were selected to cover the majority of common variation within the candidate genes and genotyped in DNA extracted from peripheral whole blood. Allele and haplotype analyses were conducted in PLINK. Bonferroni correction was applied for the total number of SNPs in this study (p=0.05/15=0.003) Results: In the Australian cohort, one eNOS SNP rs3793342 shows significance association with PACG in the Australian cohort after Bonferroni correction (p-value 0.003, OR 0.5 95% CI 0.3-0.8). After adjusting the results for sex and age both SNPs rs3793342 and rs7830 showed significance after Bonferroni correction (p-value of 0.001 and 0.003, respectively). The eNOS haplotype of all 7 typed SNPs showed significant association with a global p-value of 0.019, with the CGCAATC haplotype giving a specific p-value of 0.008 and odds ratio of 1.5 (95% CI 0.9-2.4). In the Nepalese cohort, SNPs in CYP1B1 and NTF4 genes showed borderline association with PACG but did not survive Bonferroni correction. Conclusions: The present data support the involvement of common variations in eNOS with PACG pathogenesis. Differences were observed in the two populations studied, and additional replication studies in other populations are necessary to confirm these association

Association of genetic variants with primary angle closure glaucoma in two different populations

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.PURPOSE: A recent large genome-wide association study (GWAS) identified multiple variants associated with primary angle-closure glaucoma (PACG). The present study investigated the role of these variants in two cohorts with PACG recruited from Australia and Nepal. METHOD: Patients with PACG and appropriate controls were recruited from eye clinics in Australia (n = 232 cases and n = 288 controls) and Nepal (n = 106 cases and 204 controls). Single nucleotide polymorphisms (SNPs) rs3753841 (COL11A1), rs1015213 (located between PCMTD1 and ST18), rs11024102 (PLEKHA7), and rs3788317 (TXNRD2) were selected and genotyped on the Sequenom. Analyses were conducted using PLINK and METAL. RESULTS: After adjustment for age and sex, SNP rs3753841 was found to be significantly associated with PACG in the Australian cohort (p = 0.017; OR = 1.34). SNPs rs1015213 (p = 0.014; OR 2.35) and rs11024102 (p = 0.039; OR 1.43) were significantly associated with the disease development in the Nepalese cohort. None of these SNPs survived Bonferroni correction (p = 0.05/4 = 0.013). However, in the combined analysis, of both cohorts, rs3753841 and rs1015213 showed significant association with p-values of 0.009 and 0.004, respectively both surviving Bonferroni correction. SNP rs11024102 showed suggestive association with PACG (p-value 0.035) and no association was found with rs3788317. CONCLUSION: The present results support the initial GWAS findings, and confirm the SNP's contribution to PACG. This is the first study to investigate these loci in both Australian Caucasian and Nepalese populations

Genetic analysis localizes a novel locus on chromosome 4q for the glaucoma endophenotype, cup-to-disc ratio: The Jiri Eye Study

Purpose: Glaucoma is a heterogeneous disease influenced by genetic risk factors. However, not all genetic risk factors have been identified. The aim of this project is to localize genetic factors influencing known glaucoma endophenotypes: intraocular pressure (IOP), central corneal thickness (CCT), and vertical cup-to-disc ratio (VCDR). Methods: This family-based study design utilizes phenotypic and genomic data from a single well-characterized pedigree residing in the Jiri region of Nepal. Measures of IOP, CCT and VCDR were obtained by Goldmann applanation tonometry, OCT, and slit lamp biomicroscopy, respectively. Using a genome-wide genotype data set (~550,000 SNPs), we performed a genome-wide linkage scan for IOP, CCT, and VCDR adopting a quantitative approach in SOLAR. For localized quantitative trait locus (QTL) signals, we screened all SNPs within the 1-LOD (95% confidence) interval using the classical measured genotype approach to association analysis and allowing for non-independence amongst the pedigree members. Results: For this study, phenotypic and genotype data from 1,163 (55% female) members of the Jirel population were available. The mean age of the sample is 43.8 (SD=15.7) years. IOP (h2=19%, p=6.1×10-5), CCT (h2=57%, p=1.6×10-26), and VCDR (h2=48%, p=9.7×10-22) were significantly heritable. We localized a significant QTL for VCDR on chromosome 4 (LOD=3.05 at 86.83 Mb). The top association signal within this QTL was for an intronic SNP (rs4148155; p=2.01×10-6, b=0.24) in the ABCG2 (ATP binding cassette subfamily G member 2) gene, which satisfied our QTL-specific Bonferroni-corrected significance criterion (p\u3c6.59×10-5). ABCG2 is a known stem cell marker, which is positively expressed in clonal human trabecular meshwork stem cells. Another positional candidate gene of note is SCD5 (Stearoyl-CoA desaturase 5), which is shown to suppress neurite outgrowth, a marker of neuronal differentiation. SCD5 is of significant interest given that expression of myocilin (MYOC) also inhibits neurite outgrowth. Conclusions: To our knowledge, the VCDR QTL on chromosome 4 is a novel locus and does not overlap with other glaucoma endophenotypes or glaucoma disease status. These results highlight the importance of continued evaluation of genetic factors influencing glaucoma endophenotypes in under-studied populations, such as the Jirels, as new information may be elucidated

Chemical Tuning of Fibers Drawn from Extensible Hyaluronic Acid Networks

© 2020 American Chemical Society. Polymer fibers with specific chemical and mechanical properties are key components of many biomaterials used for regenerative medicine and drug delivery. Here, we develop a bioinspired, low-energy process to produce mechanically tunable biopolymer fibers drawn from aqueous solutions. Hyaluronic acid (HA) forms dynamic cross-links with branched polyethylene glycol polymers end-functionalized with boronic acids of varied structure to produce extensible polymer networks. This dynamic fiber precursor (DFP) is directly drawn by pultrusion into HA fibers that display high aspect ratios, ranging from 4 to 20 μm in diameter and up to ∼10 m in length. Dynamic rheology measurements of the DFP and tensile testing of the resulting fibers reveal design considerations to tune the propensity for fiber formation and fiber mechanical properties, including the effect of polymer structure and concentration on elastic modulus, tensile strength, and ultimate strain. The materials' humidity-responsive contractile behavior, a unique property of spider silks rarely observed in synthetic materials, highlights possibilities for further biomimetic and stimulus-responsive fiber applications. This work demonstrates that chemical modification of dynamic interactions can be used to tune the mechanical properties of pultrusion-based fibers and their precursors.Leona M. and Harry B. Helmsley Charitable Trust (Grant 2017PG-T1D027)NIH (Grants F32DK118785, K99EB025254 and PDF-2015-90-A-N)National Cancer Institute (Grant P30-CA14051

Prevalence of visual impairment, cataract surgery and awareness of cataract and glaucoma in Bhaktapur district of Nepal: The Bhaktapur Glaucoma Study

<p>Abstract</p> <p>Background</p> <p>Cataract and glaucoma are the major causes of blindness in Nepal. Bhaktapur is one of the three districts of Kathmandu valley which represents a metropolitan city with a predominantly agrarian rural periphery. This study was undertaken to determine the prevalence of visual impairment, cataract surgery and awareness of cataract and glaucoma among subjects residing in this district of Nepal.</p> <p>Methods</p> <p>Subjects aged 40 years and above was selected using a cluster sampling methodology and a door to door enumeration was conducted for a population based cross sectional study. During the community field work, 11499 subjects underwent a structured interview regarding awareness (heard of) and knowledge (understanding of the disease) of cataract and glaucoma. At the base hospital 4003 out of 4800 (83.39%) subjects underwent a detailed ocular examination including log MAR visual acuity, refraction, applanation tonometry, cataract grading (LOCSΙΙ), retinal examination and SITA standard perimetry when indicated.</p> <p>Results</p> <p>The age-sex adjusted prevalence of blindness (best corrected <3/60) and low vision (best corrected <6/18 ≥3/60) was 0.43% (95%C.I. 0.25 - 0.68) and 3.97% (95% C.I. 3.40 - 4.60) respectively. Cataract (53.3%) was the principal cause of blindness. The leading causes of low vision were cataract (60.8%) followed by refractive error (12%). The cataract surgical coverage was 90.36% and was higher in the younger age group, females and illiterate subjects. Pseudophakia was seen in 94%. Awareness of cataract (6.7%) and glaucoma (2.4%) was very low. Among subjects who were aware, 70.4% had knowledge of cataract and 45.5% of glaucoma. Cataract was commonly known to be a 'pearl like dot' white opacity in the eye while glaucoma was known to cause blindness. Awareness remained unchanged in different age groups for cataract while for glaucoma there was an increase in awareness with age. Women were significantly less aware (odds ratio (OR): 0.63; 95%, confidence interval (CI): 0.54 - 0.74) for cataract and (OR: 0.64; 95% CI: 0.50 - 0.81) for glaucoma. Literacy was also correlated with awareness.</p> <p>Conclusion</p> <p>The low prevalence of visual impairment and the high cataract surgical coverage suggests that cataract intervention programs have been successful in Bhaktapur. Awareness and knowledge of cataract and glaucoma was very poor among this population. Eye care programs needs to be directed towards preventing visual impairment from refractive errors, screening for incurable chronic eye diseases and promoting health education in order to raise awareness on cataract and glaucoma among this population.</p