👤 Joseph S K Au

A signature of 16 serum proteins that were previously profiled using the aptamer-based Somascan technology highlighted the roles of the e2 allele of APOE in lipid regulation via apolipoprotein B (APOB) and apolipoprotein E (APOE) and in inflammation. Here, the serum protein signature of APOE is validated and expanded using a combination of mass-spectrometry, ELISA, Luminex, blood transcriptomics, and antibody-based Olink serum proteomics. Some of the findings were replicated in the UK Biobank using antibody-based Olink serum proteomics. This analysis replicated the association between APOB and the e2 allele of APOE, detected a new, robust pattern of association between APOE genotypes and the serum level of APOE, and discovered new associations between APOE genotypes and the complex of apolipoproteins APOC1, APOC2, APOC3, APOC4, APOE, APOF, and APOL1. In addition, 13 new proteins correlated with APOE genotypes. This extended signature includes granule proteins CAMP, CTSG, DEFA3, and MPO secreted from neutrophils and points to olfactomedin 4 (OLFM4) as a new target for the prevention of Alzheimer's disease. Show less

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

We previously identified a signature of 16 serum proteins that highlighted a role of the e2 allele of APOE in lipid regulation via apolipoprotein B (APOB) and apolipoprotein E (APOE), and in inflammation. The serum proteins were profiled using the aptamer-based Somalogic technology. Here, we validate and expand the serum protein signature of APOE using a combination of mass-spectrometry, ELISA, Luminex, antibody-based Olink proteomics, and blood transcriptomics. We replicate the association between APOB and the e2 allele of APOE, we correct the pattern of association between APOE genotypes and serum level of APOE, and we detect new associations between APOE genotypes and the complex of apolipoproteins APOC1, APOC4, APOC2, APOC3, APOE, APOF and APOL1. In addition, we discover 13 new proteins that correlate with APOE genotypes. This extended signature includes granule proteins CAMP, CTSG, DEFA3, and MPO secreted from neutrophils and points to olfactomedin 4 (OLFM4) as a new target for the prevention of Alzheimer's disease. Show less

Leukaemia of various subtypes are driven by distinct chromosomal rearrangement or genetic abnormalities. The leukaemogenic fusion transcripts or genetic mutations serve as molecular markers for minimal residual disease (MRD) monitoring. The current study evaluated the applicability of several droplet digital PCR assays for the detection of these targets at RNA and DNA levels (atypical BCR::ABL1 e19a2, e23a2ins52, e13a2ins74, rare types of CBFB::MYH11 (G and I), PCM1::JAK2, KMT2A::ELL2, PICALM::MLLT10 fusion transcripts and CEBPA frame-shift and insertion/duplication mutations) with high sensitivity. The analytical performances were assessed by the limit of blanks, limit of detection, limit of quantification and linear regression. Our data demonstrated serial MRD monitoring for patients at molecular level could become "digitalized", which was deemed important to guide clinicians in treatment decision for better patient care. Show less

Our objective was to examine differences in cytokine/chemokine response in chronic hepatitis B(CHB) patients to understand the immune mechanism of HBsAg loss (functional cure) during antiviral therapy. We used an unbiased machine learning strategy to unravel the immune pathways in CHB nucleo(t)side analogue-treated patients who achieved HBsAg loss with peg-interferon-α(peg-IFN-α) add-on or switch treatment in a randomised clinical trial. Cytokines/chemokines from plasma were compared between those with/without HBsAg loss, at baseline, before and after HBsAg loss. Peg-IFN-α treatment resulted in higher levels of IL-27, IL-12p70, IL-18, IL-13, IL-4, IL-22 and GM-CSF prior to HBsAg loss. Probabilistic network analysis of cytokines, chemokines and soluble factors suggested a dynamic dendritic cell driven NK and T cell immune response associated with HBsAg loss. Bayesian network analysis showed a dominant myeloid-driven type 1 inflammatory response with a MIG and I-TAC central module contributing to HBsAg loss in the add-on arm. In the switch arm, HBsAg loss was associated with a T cell activation module exemplified by high levels of CD40L suggesting T cell activation. Our findings show that more than one immune pathway to HBsAg loss was found with peg-IFN-α therapy; by myeloid-driven Type 1 response in one instance, and T cell activation in the other. Show less

Genetic studies have been reported on the association between APOA5, APOB, APOC3 and ABCA1 gene polymorphisms and ischemic stroke, but results remain controversial. Hence, this meta-analysis aimed to infer the causal relationships of APOA5 (rs662799, rs3135506), APOB (rs693, rs1042031, rs1801701), APOC3 (rs4520, rs5128, rs2854116, rs2854117) and ABCA1 rs2230806 with ischemic stroke risk. A systematic review was performed for all the articles retrieved from multiple databases, up until March 2017. Data were extracted from all eligible studies, and meta-analysis was carried out using RevMan 5.3 and R package 3.2.1. The strength of association between each studied polymorphism and ischemic stroke risk was measured as odds ratios (ORs) and 95% confidence intervals (CIs), under fixed- and random-effect models. A total of 79 studies reporting on the association between the studied polymorphisms and ischemic stroke risk were identified. The pooled data indicated that all genetic models of APOA5 rs662799 (ORs = 1.23-1.43), allelic and over-dominant models of APOA5 rs3135506 (ORs = 1.77-1.97), APOB rs1801701 (ORs = 1.72-2.13) and APOB rs1042031 (ORs = 1.66-1.88) as well as dominant model of ABCA1 rs2230806 (OR = 1.31) were significantly associated with higher risk of ischemic stroke. However, no significant associations were observed between ischemic stroke and the other five polymorphisms, namely ApoB (rs693) and APOC3 (rs4520, rs5128, rs2854116 and rs2854117), under any genetic model. The present meta-analysis confirmed a significant association of APOA5 rs662799 CC, APOA5 rs3135506 CG, APOB rs1801701 GA, APOB rs1042031 GA and ABCA1 rs2230806 GG with increased risk of ischemic stroke. Show less

Genome-wide association studies (GWAS) on Parkinson's disease (PD) have mostly been done in Europeans and Japanese. No study has been done in Han Chinese, which make up nearly a fifth of the world population. We conducted the first Han Chinese GWAS analysing a total of 22,729 subjects (5,125 PD cases and 17,604 controls) from Singapore, Hong Kong, Malaysia, Korea, mainland China and Taiwan. We performed imputation, merging and logistic regression analyses of 2,402,394 SNPs passing quality control filters in 779 PD cases, 13,227 controls, adjusted for the first three principal components. 90 SNPs with association P < 10-4 were validated in 9 additional sample collections and the results were combined using fixed-effects inverse-variance meta-analysis. We observed strong associations reaching genome-wide significance at SNCA, LRRK2 and MCCC1, confirming their important roles in both European and Asian PD. We also identified significant (P < 0.05) associations at 5 loci (DLG2, SIPA1L2, STK39, VPS13C and RIT2), and observed the same direction of associations at 9 other loci including BST1 and PARK16. Allelic heterogeneity was observed at LRRK2 while European risk SNPs at 6 other loci including MAPT and GBA-SYT11 were non-polymorphic or very rare in our cohort. Overall, we replicate associations at SNCA, LRRK2, MCCC1 and 14 other European PD loci but did not identify Asian-specific loci with large effects (OR > 1.45) on PD risk. Our results also demonstrate some differences in the genetic contribution to PD between Europeans and Asians. Further pan-ethnic meta-analysis with European GWAS cohorts may unravel new PD loci. Show less

Fibroblast growth factor 21 (FGF21) is increasingly recognized as an important metabolic regulator of glucose homeostasis. Here, we conducted an exome-chip association analysis by genotyping 5,169 Chinese individuals from a community-based cohort and two clinic-based cohorts. A custom Asian exome-chip was used to detect genetic determinants influencing circulating FGF21 levels. Single-variant association analysis interrogating 70,444 single nucleotide polymorphisms identified a novel locus, Show less

Reactive oxygen species (ROS) have been commonly accepted as inducers of autophagy, and autophagy in turn is activated to relieve oxidative stress. Yet, whether and how oxidative stress, generated in various human pathologies, regulates autophagy remains unknown. Here, we mechanistically studied the role of TRPM2 (transient receptor potential cation channel subfamily M member 2)-mediated Ca(2+) influx in oxidative stress-mediated autophagy regulation. On the one hand, we demonstrated that oxidative stress triggered TRPM2-dependent Ca(2+) influx to inhibit the induction of early autophagy, which renders cells more susceptible to death. On the other hand, oxidative stress induced autophagy (and not cell death) in the absence of the TRPM2-mediated Ca(2+) influx. Moreover, in response to oxidative stress, TRPM2-mediated Ca(2+) influx activated CAMK2 (calcium/calmodulin dependent protein kinase II) at levels of both phosphorylation and oxidation, and the activated CAMK2 subsequently phosphorylated BECN1/Beclin 1 on Ser295. Ser295 phosphorylation of BECN1 in turn decreased the association between BECN1 and PIK3C3/VPS34, but induced binding between BECN1 and BCL2. Clinically, acetaminophen (APAP) overdose is the most common cause of acute liver failure worldwide. We demonstrated that APAP overdose also activated ROS-TRPM2-CAMK2-BECN1 signaling to suppress autophagy, thereby causing primary hepatocytes to be more vulnerable to death. Inhibiting the TRPM2-Ca(2+)-CAMK2 cascade significantly mitigated APAP-induced liver injury. In summary, our data clearly demonstrate that oxidative stress activates the TRPM2-Ca(2+)-CAMK2 cascade to phosphorylate BECN1 resulting in autophagy inhibition. Show less

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C. Show less

Essential tremor (ET) is characterized by postural and action tremor.(1-3) A genome-wide association study (GWAS) identified a LINGO1 gene variant to be associated with ET.(4) Subsequent GWAS further identified an intronic variant (rs3794087) of the main glial glutamate transporter (SLC1A2) gene to be associated with ET with an odds ratio (OR) of approximately 1.4.(5) We conducted a case-control study to examine the SLC1A2 gene variant in an Asian cohort of ET. In addition, we also investigated the variant in patients with Parkinson disease (PD) because the GWAS LINGO1 variant has been implicated in both ET and PD and etiologic links between the conditions have been suggested.(6.) Show less