👤 Geik Yong Ang

Apolipoprotein E (APOE) and proprotein convertase subtilisin/kexin type 9 (PCSK9) are both lipid proteins and related to immunity/inflammation. We hypothesized that PCSK9 impacts on Alzheimer's disease (AD) risk in an We used the Framingham Heart Study (FHS) Offspring cohort (Gen 2), with data on plasma PCSK9 protein concentration, as the baseline exposure for 1,704 study subjects. Using Cox regression models, the outcomes were incidents of AD or all-cause dementia. Using another FHS dataset with 3,048 individuals with genetic data, we examined the association between PCSK9 genotypes and the incidence of AD/dementia, stratifying the analysis based on Higher plasma PCSK9 protein levels were associated with a lower risk of AD (HR [95%CI]: 0.74 [0.58, 0.94]; Our study suggests that high blood PCSK9 levels are protective against AD risk in Show less

C-reactive protein (CRP) is a key marker of systemic inflammation that affects blood vessel endothelial function, including in the brain. Since endothelial dysfunction is linked to Alzheimer's disease (AD), we investigated whether elevated CRP level interacts with genetic pathways in brain endothelial cells to influence AD risk. Using AD genome-wide association study (GWAS) data, we developed multiple polygenic risk scores (PRSs) including single nucleotide polymorphisms (SNPs) in genes expressed in brain endothelial cells, excluding the APOE region, that are involved in inflammation, synaptic transmission, and other pathways. Analysis across three independent cohorts revealed that individuals with low inflammatory PRSs (<50%) and elevated blood CRP level were associated with an increased risk of AD; in contrast, those with high inflammatory PRSs (≥50%) did not exhibit this CRP-related AD risk increase. Further examination of individuals with a low inflammatory PRS showed that elevated CRP was associated with lower cerebrospinal fluid (CSF) Aβ42 level and temporal lobe atrophy. Among individuals with a high inflammatory PRS, elevated CRP level was negatively correlated with CSF pTau181 and brain tauopathy, suggesting a potential protective mechanism against tau pathology. Key inflammatory PRS genes, which were impacted by circulating CRP for AD, included APP, IL6ST, and FN1, are involved in amyloid pathology, wound healing, and coagulation. Our findings highlight two distinct genetic-dose dependent backgrounds: "vulnerable" (<50% inflammatory PRS) and "resilient" (≥50% inflammatory PRS), and support a Genome-Internal Environment (G×IE) interaction model, linking peripheral inflammation to AD risk. Show less

Brain metastasis occurs in up to 40% of patients with non-small cell lung cancer (NSCLC). Considerable genomic heterogeneity exists between the primary lung tumor and respective brain metastasis; however, the identity of the genes capable of driving brain metastasis is incompletely understood. Here, we carried out an in vivo genome-wide CRISPR activation screen to identify molecular drivers of brain metastasis from an orthotopic xenograft model derived from a patient with NSCLC. We found that activating expression of the Alzheimer's disease-associated beta-secretase 1 (BACE1) led to a substantial increase in brain metastases. Furthermore, genetic and pharmacological inhibition of BACE1 blocked NSCLC brain metastasis. Mechanistically, we identified that BACE1 acts through epidermal growth factor receptor to drive this metastatic phenotype. Together, our data highlight the power of in vivo CRISPR activation screening to unveil molecular drivers and potential therapeutic targets of NSCLC brain metastasis. Show less

This study aims to explore the association between plasma metabolites and chronic kidney disease progression in individuals with type 2 diabetes. We performed a comprehensive metabolomic analysis in a prospective cohort study of 5144 multi-ancestral individuals with type 2 diabetes in Singapore, using eGFR slope as the primary outcome of kidney function decline. In addition, we performed genome-wide association studies on metabolites to assess how these metabolites could be genetically influenced by metabolite quantitative trait loci and performed colocalisation analysis to identify genes affecting both metabolites and kidney function. Elevated levels of 61 lipids with long unsaturated fatty acid chains such as phosphatidylethanolamines, triacylglycerols, diacylglycerols, ceramides and deoxysphingolipids were prospectively associated with more rapid kidney function decline. In addition, elevated levels of seven amino acids and three lipids in the plasma were associated with a slower decline in eGFR. We also identified 15 metabolite quantitative trait loci associated with these metabolites, within which variants near TM6SF2, APOE and CPS1 could affect both metabolite levels and kidney functions. Our study identified plasma metabolites associated with prospective renal function decline, offering insights into the underlying mechanism by which the metabolite abnormalities due to fatty acid oversupply might reflect impaired β-oxidation and associate with future chronic kidney disease progression in individuals with diabetes. Show less

Acute respiratory distress syndrome (ARDS) is a common respiratory emergency, but current clinical treatment remains at the level of symptomatic support and there is a lack of effective targeted treatment measures. Our previous study confirmed that inhalation of hydrogen gas can reduce the acute lung injury of ARDS, but the application of hydrogen has flammable and explosive safety concerns. Drinking hydrogen-rich liquid or inhaling hydrogen gas has been shown to play an important role in scavenging reactive oxygen species and maintaining mitochondrial quality control balance, thus improving ARDS in patients and animal models. Coral calcium hydrogenation (CCH) is a new solid molecular hydrogen carrier prepared from coral calcium (CC). Whether and how CCH affects acute lung injury in ARDS remains unstudied. In this study, we observed the therapeutic effect of CCH on lipopolysaccharide (LPS) induced acute lung injury in ARDS mice. The survival rate of mice treated with CCH and hydrogen inhalation was found to be comparable, demonstrating a significant improvement compared to the untreated ARDS model group. CCH treatment significantly reduced pulmonary hemorrhage and edema, and improved pulmonary function and local microcirculation in ARDS mice. CCH promoted mitochondrial peripheral division in the early course of ARDS by activating mitochondrial thioredoxin 2 (Trx2), improved lung mitochondrial dysfunction induced by LPS, and reduced oxidative stress damage. The results indicate that CCH is a highly efficient hydrogen-rich agent that can attenuate acute lung injury of ARDS by improving the mitochondrial function through Trx2 activation. Show less

Tumor androgens in castration-resistant prostate cancer (CRPC) reflect We evaluated tumor growth and androgens in LuCaP35CR and LuCaP96CR xenografts in response to adrenalectomy (ADX). We assessed protein expression of key steroidogenic enzymes in 185 CRPC metastases from 42 patients. Adrenal glands of intact and castrated mice expressed CYP17A. Serum DHEA, androstenedione (AED), and testosterone (T) in castrated mice became undetectable after ADX (all Mice are appropriate for evaluating adrenal impact of steroidogenesis inhibitors. A subset of ADX-resistant CRPC tumors demonstrate Show less

A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10(-10)) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index. Show less

SUMO-modification of nuclear proteins has profound effects on gene expression. However, non-toxic chemical tools that modulate sumoylation in cells are lacking. Here, to identify small molecule sumoylation inhibitors we developed a cell-based screen that focused on the well-sumoylated substrate, human Liver Receptor Homolog-1 (hLRH-1, NR5A2). Our primary gene-expression screen assayed two SUMO-sensitive transcripts, APOC3 and MUC1, that are upregulated by SUMO-less hLRH-1 or by siUBC9 knockdown, respectively. A polyphenol, tannic acid (TA) emerged as a potent sumoylation inhibitor in vitro (IC50 = 12.8 µM) and in cells. TA also increased hLRH-1 occupancy on SUMO-sensitive transcripts. Most significantly, when tested in humanized mouse primary hepatocytes, TA inhibits hLRH-1 sumoylation and induces SUMO-sensitive genes, thereby recapitulating the effects of expressing SUMO-less hLRH-1 in mouse liver. Our findings underscore the benefits of phenotypic screening for targeting post-translational modifications, and illustrate the potential utility of TA for probing the cellular consequences of sumoylation. Show less

The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. Although little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlying mechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth and maturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P < 1.67 × 10(-8)) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased body mass index, reduced pubertal growth and earlier puberty. Whereas epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall, this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty and childhood obesity and provides new information to pinpoint processes linking these traits. Show less