👤 Emma Tham

To identify plasma proteins associated with glaucoma and assess the translational potential of key proteins as both biomarkers and therapeutic targets. Genome-wide association study data were obtained from the UK Biobank Pharma Proteomics Project, FinnGen, and the Million Veteran Program. We used a four-stage analytical framework: Stage 1 applied Mendelian randomization and Bayesian colocalization to evaluate associations between 2923 plasma proteins and glaucoma; Stage 2 used summary-based Mendelian randomization to explore transcriptomic and epigenomic associations of the identified proteins with glaucoma risk; Stage 3 involved a prospective association analysis of protein levels and incident glaucoma in the UK Biobank cohort, including 40,170 glaucoma-free participants; and Stage 4 systematically evaluated the druggability of the prioritized protein targets. We identified 26 plasma proteins with putative causal associations with glaucoma, six of which were novel: COL24A1, KAZALD1, EBAG9, CSNK1D, AZI2, and AXIN1. COL24A1 (odds ratio [OR] = 0.85; 95% confidence interval [CI], 0.80-0.90; PFDR < 0.001; PP.H4 = 0.95) and EFEMP1 (OR = 0.88; 95% CI, 0.83-0.92; PFDR < 0.001; PP.H4 = 0.98) emerged as the most compelling candidates. To further elucidate the regulatory mechanisms, multiomics analyses indicated that epigenetic modifications and alternative splicing events affecting these genes were associated with elevated glaucoma risk. Notably, EFEMP1 was significantly associated with glaucoma incidence in the prospective cohort analysis (fully adjusted Cox model: hazard ratio = 1.61; 95% CI, 1.29-2.00; PFDR = 0.002), demonstrating strong predictive performance (C-index = 0.811, area under the curve = 0.806) and representing a promising therapeutic target. Our findings provide new insights into the proteomic basis of glaucoma and highlight promising opportunities for developing targeted therapies. Show less

Low-grade gliomas (LGGs) represent children's most prevalent central nervous system tumor, necessitating molecular profiling to diagnose and determine the most suitable treatment. Developing highly sensitive screening techniques for liquid biopsy samples is particularly beneficial, as it enables the early detection and molecular characterization of tumors with minimally invasive samples. We examined CSF and plasma samples from patients with pilocytic astrocytoma (PA) using custom multiplexed droplet digital polymerase chain reaction (ddPCR) assays based on whole genome sequencing data. These assays included a screening test to analyze Our findings revealed that 5 out of 13 individual cerebrospinal fluid (CSF) samples tested positive for circulating tumor DNA (ctDNA). Among these cases, 3 exhibited the While CNV analysis of CSF samples from LGGs still has some limitations, it has the potential to serve as a valuable complementary tool. Furthermore, it can also be multiplexed with other aberrations, for example, to the Show less

To identify genetic alleles associated with differences in choroidal thickness (CT) in a population-based multiethnic Asian cohort. A population-based multiethnic Asian cohort without retinal pathology was subjected to spectral-domain OCT (SD-OCT) and genotyping of risk alleles in CFH, VIPR2, ARMS2, and CETP. Subfoveal choroidal thickness (SFCT) values were assessed from SD-OCT, and associations with the risk alleles were determined for each cohort. A total of 1045 healthy Asian individuals (550 Chinese, 147 Indians, 348 Malays) were prospectively enrolled in the study. Several CFH alleles (rs800292, rs1061170, and rs1329428) were associated with increased SFCT in Indians (+18.7 to +31.7 µm; P = 0.001-0.038) and marginally associated with decreased SFCT in Malays (-12.7 to -20.6 µm; P = 0.014-0.022). Haplotype analysis of CFH revealed variable associations with SFCT among races, with the H6 haplotype being associated with a 29.08-µm reduction in SFCT in the Chinese cohort (P = 0.02) but a 35.2-µm increase in SFCT in the Indian cohort (P < 0.001). Finally, subfield analysis of the Chinese cohort identified associations between the CFH risk allele rs1061170 and reduced CT in the nasal and superior sectors (-20.2 to -25.8 µm; P = 0.003-0.027). CFH variants are variably associated with CT among Asian ethnic groups. This has broad implications for the pathogenesis of common diseases such as age-related macular degeneration and central serous choroidopathy, the pathogenesis of which is associated with CT. Show less

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. In this study, we investigated the haplotype-tagging single nucleotide polymorphisms (SNPs) in the The results revealed none of the six tagging SNPs of the This study showed no statistical significance in the genetic association of Show less

To identify genes and genetic markers associated with corneal astigmatism. A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for corneal and refractive astigmatism and the spherical equivalent were calculated for Europeans using LD score regression. The meta-analysis of all cohorts identified a genome-wide significant locus near the platelet-derived growth factor receptor alpha ( In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the Show less

We evaluated automated OCT-derived drusen volume measures in a population-based study (n = 4,512) aged ≥40 years, and its correlation with conventional color fundus photographs (CFP)-derived early AMD features. Participants had protocol-based assessment to capture medical and ocular history, genotyping for SNPs in CFH, ARMS2, and CETP, CFP-based AMD grading and automated drusen volume based on SD-OCT using built-in software (Cirrus OCT advanced RPE analysis software). Significantly fewer eyes with early AMD features (drusen, hyperpigmentation, soft or reticular drusen) had drusen volume = 0 mm Show less

Recent genome-wide association studies (GWAS) have identified multiple loci associated with coronary artery disease (CAD) among predominantly Europeans. However, their relevance to multi-ethnic populations from Southeast Asia is largely unknown. We performed a meta-analysis of four GWAS comprising three Chinese studies and one Malay study (Total N = 2,169 CAD cases and 7,376 controls). Top hits (P < 5 × 10 Show less

Hand-foot syndrome (HFS) is a common adverse effect of capecitabine treatment. To compare the incidence and time to onset of grade 2 or greater HFS in patients receiving pyridoxine vs placebo and to identify biomarkers predictive of HFS. This single-center, randomized double-blind, placebo-controlled phase 3 trial conducted at National Cancer Centre Singapore assessed whether oral pyridoxine could prevent the onset of grade 2 or higher HFS in 210 patients scheduled to receive single-agent capecitabine chemotherapy for breast, colorectal, and other cancers. Patients were randomized to receive concurrent pyridoxine (200 mg) or placebo daily for a maximum of 8 cycles of capecitabine, with stratification by sex and use in adjuvant or neoadjuvant vs palliative setting. Patients were withdrawn from the study on development of grade 2 or higher HFS or cessation of capecitabine. Primary end point was the incidence of grade 2 or higher HFS in patients receiving pyridoxine. Secondary end points included the time to onset (days) of grade 2 or higher HFS and identification of biomarkers predictive of HFS, including baseline folate and vitamin B12 levels, as well as genetic polymorphisms with genome-wide arrays. In this cohort of 210 patients (median [range] age, 58 [26-82] years; 162 women) grade 2 or higher HFS occurred in 33 patients (31.4%) in the pyridoxine arm vs 39 patients (37.1%) in the placebo arm (P = .38). The median time to onset of grade 2 or higher HFS was not reached in both arms. In univariate analysis, the starting dose of capecitabine (odds ratio [OR], 1.99; 95% CI, 1.32-3.00; P = .001), serum folate levels (OR, 1.27; 95% CI, 1.10-1.47; P = .001), and red blood cell folate levels (OR, 1.25; 95% CI, 1.08-1.44; P = .003) were associated with increased risk of grade 2 or higher HFS. In multivariate analyses, serum folate (OR, 1.30; 95% CI, 1.12-1.52; P < .001) and red blood cell folate (OR, 1.28; 95% CI, 1.10-1.49; P = .001) were the only significant predictors of grade 2 or higher HFS. Grade 2 or higher HFS was associated with 300 DNA variants at genome-wide significance (P < 5 × 10-8), including a novel DPYD variant (rs75267292; P = 1.57 × 10-10), and variants in the MACF1 (rs183324967, P = 4.80 × 10-11; rs148221738, P = 5.73 × 10-10) and SPRY2 (rs117876855, P < 1.01 × 10-8; rs139544515, P = 1.30 × 10-8) genes involved in wound healing. Pyridoxine did not significantly prevent or delay the onset of grade 2 or higher HFS. Serum and red blood cell folate levels are independent predictors of HFS. clinicaltrials.gov Identifier: NCT00486213. Show less

We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r(2) = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer. Show less