Papers by Ben Joe Francis
In a phase I clinical trial, the chimeric hemagglutinin (cHA) immunogen induced antibody response... more In a phase I clinical trial, the chimeric hemagglutinin (cHA) immunogen induced antibody responses against the conserved HA stalk domain. However, the landscape of the B cell specificities and subsets induced by this vaccine remain undetermined. Here, we paired single cell RNA-sequencing and B cell receptor repertoire sequencing to analyze the relationship between transcriptome and B cell specificity following cHA immunization. We show that the cHA inactivated vaccine with a squalene-based adjuvant induced a robust activated B cell and memory B cell phenotype against two broadly neutralizing epitopes of the stalk domain. The overall specificities of the acute plasmablast and memory B cell responses were distinct, with the plasmablast compartment largely targeting non-neutralizing epitopes of the HA stalk. Altogether, these data indicate the B cell landscape following cHA vaccination includes diverse B cell subsets that are differentially induced by distinct vaccine formulations, inc...
Epilepsia, 2022
We aimed to identify genes associated with genetic generalized epilepsy (GGE) by combining large ... more We aimed to identify genes associated with genetic generalized epilepsy (GGE) by combining large cohorts enriched with individuals with a positive family history. Secondarily, we set out to compare the association of genes independently with familial and sporadic GGE.
Brain Communications, 2021
Better drugs are needed for common epilepsies. Drug repurposing offers the potential of significa... more Better drugs are needed for common epilepsies. Drug repurposing offers the potential of significant savings in the time and cost of developing new treatments. In order to select the best candidate drug(s) to repurpose for a disease, it is desirable to predict the relative clinical efficacy that drugs will have against the disease. Common epilepsy can be divided into different types and syndromes. Different antiseizure medications are most effective for different types and syndromes of common epilepsy. For predictions of antiepileptic efficacy to be clinically translatable, it is essential that the predictions are specific to each form of common epilepsy, and reflect the patterns of drug efficacy observed in clinical studies and practice. These requirements are not fulfilled by previously published drug predictions for epilepsy. We developed a novel method for predicting the relative efficacy of drugs against any common epilepsy, by using its Genome-Wide Association Study summary sta...
Genes and environment, 2019
Background: The association of haplotype combinations of polymorphisms at positions 16 and 27 of ... more Background: The association of haplotype combinations of polymorphisms at positions 16 and 27 of the β2-adrenergic receptor (ADRB2) gene and the risk of asthma exacerbations among users of long-acting β2-agonists (LABA) is still unclear. Aim: We investigated the association between these haplotypes of the ADRB2 gene and asthma exacerbations in asthmatic patients using LABA and inhaled corticosteroids (ICS) from the multi-ethnic Pharmacogenomics in Childhood Asthma (PiCA) consortium. Methods: We conducted a meta-analysis of 880 children and young adults aged (4-21) with asthma treated with LABA and ICS. We extracted two polymorphisms; rs1042713 (16Arg>Gly) and rs1042714 (27Gln>Glu) in the ADRB2 gene. Asthma exacerbations were defined as prescribed courses of oral corticosteroids and/or asthma-related hospitalizations/emergency room visits in the past 6 or 12 months prior to the study visit. The association between the haplotypes and asthma exacerbations was performed by using the Haplo-Stats package adjusted for age and sex. A meta-analysis was performed using an inverse variance–weighted method assuming a random-effect. Results: Three haplotypes were determined; Gly16Glu27, Arg16Gln27 and Gly16Gln27. Compared to the Gly16Glu27 haplotype, the Arg16Gln27 haplotype was significantly associated with an increased risk of asthma exacerbations (OR:1.37, 95%CI;1.03-1.81, P=0.028, I2=0.0%). Conclusion: We found that the Arg haplotype (Arg16Gln27) in the ADRB2 gene increased the risk of exacerbations among users of LABA and ICS. Whether or not this argues against use of LABA in patients with this haplotype needs further research.
Translational Psychiatry, 2020
Clozapine is the most effective antipsychotic drug for schizophrenia, yet it can cause life-threa... more Clozapine is the most effective antipsychotic drug for schizophrenia, yet it can cause life-threatening adverse drug reactions, including myocarditis. The aim of this study was to determine whether schizophrenia patients with clozapine-induced myocarditis have a genetic predisposition compared with clozapine-tolerant controls. We measured different types of genetic variation, including genome-wide single-nucleotide polymorphisms (SNPs), coding variants that alter protein expression, and variable forms of human leucocyte antigen (HLA) genes, alongside traditional clinical risk factors in 42 cases and 67 controls. We calculated a polygenic risk score (PRS) based on variation at 96 different genetic sites, to estimate the genetic liability to clozapine-induced myocarditis. Our genome-wide association analysis identified four SNPs suggestive of increased myocarditis risk (P < 1 × 10−6), with odds ratios ranging 5.5–13.7. The SNP with the lowest P value was rs74675399 (chr19p13.3, P =...
Clinical Pharmacology & Therapeutics, 2019
Statins can be associated with myopathy. We have undertaken a genomewide association study (GWAS)... more Statins can be associated with myopathy. We have undertaken a genomewide association study (GWAS) to discover and validate genetic risk factors for statin-induced myopathy in a "real-world" setting. One hundred thirtyfive patients with statin myopathy recruited via the UK Clinical Practice Research Datalink were genotyped using the Illumina OmniExpress Exome version 1.0 Bead Chip and compared with the Wellcome Trust Case-Control Consortium (n = 2,501). Nominally statistically significant single nucleotide polymorphism (SNP) signals in the GWAS (P < 5 × 10 −5) were further evaluated in several independent cohorts (comprising 332 cases and 449 drug-tolerant controls). Only one (rs4149056/c.521C>T in the SLCO1B1 gene) SNP was genomewide significant in the severe myopathy (creatine kinase > 10 × upper limit of normal or rhabdomyolysis) group (P = 2.55 × 10 −9 ; odds ratio 5.15; 95% confidence interval 3.13-8.45). The association with SLCO1B1 was present for several statins and replicated in the independent validation cohorts. The data highlight the role of SLCO1B1 c.521C>T SNP as a replicable genetic risk factor for statin myopathy. No other novel genetic risk factors with a similar effect size were identified. The 3-hydroxy-3-methyl-glutaryl-coenzyme A inhibitors, or statins, are a widely prescribed class of drugs for the treatment of hyperlipidemia. Although generally well tolerated, a small proportion of patients can develop muscle-related adverse effects. 1 These can range from mild muscle pain without creatine kinase (CK) elevation, where causality can be difficult to assess,
Nature Communications, 2018
The epilepsies affect around 65 million people worldwide and have a substantial missing heritabil... more The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these find...
Pharmacogenomics and Personalized Medicine
Bisoprolol is a widely used beta-blocker in patients with cardiovascular diseases. As with other ... more Bisoprolol is a widely used beta-blocker in patients with cardiovascular diseases. As with other beta-blockers, there is variability in response to bisoprolol, but the underlying reasons for this have not been clearly elucidated. Our aim was to investigate genetic factors that affect bisoprolol pharmacokinetics (PK) and pharmacodynamics (PD), and potentially the clinical outcomes. Patients and Methods: Patients with non-ST elevation acute coronary syndrome were recruited prospectively on admission to hospital and followed up for up to 2 years. Patients from this cohort who were on treatment with bisoprolol, at any dose, had bisoprolol adherence data and a plasma sample, one month after discharge from index hospitalisation were included in the study. Individual bisoprolol clearance values were estimated using population pharmacokinetic modeling. Genome-wide association analysis after genotyping was undertaken using an Illumina HumanOmniExpressExome-8 v1.0 BeadChip array, while CYP2D6 copy number variations were determined by PCR techniques and phenotypes for CYP2D6 and CYP3A were inferred from the genotype. GWAS significant SNPs were analysed for heart rate response to bisoprolol in an independent cohort of hypertensive subjects. Results: Six hundred twenty-two patients on bisoprolol underwent both PK and genome wide analysis. The mean (IQR) of the estimated clearance in this population was 13.6 (10.0-18.0) L/h. Bisoprolol clearance was associated with rs11029955 (p=7.17×10 −9) mapped to the region of coiled-coil domain containing 34 region (CCDC34) on chromosome 11, and with rs116702638 (p=2.54×10 −8). Each copy of the minor allele of rs11029955 was associated with 2.2 L/h increase in clearance. In an independent cohort of hypertensive subjects, rs11029955 was associated with 24-hour heart rate response to 4-week treatment with bisoprolol (p= 9.3×10 −5), but not with rs116702638. Conclusion: A novel locus on the chromosomal region 11p14.1 was associated with bisoprolol clearance in a real-world cohort of patients and was validated in independent cohort with a pharmacodynamic association.
APS Meeting …, 2010
We describe a system wherein the lock of trapping, ionizing, and ion resonance lasers for a Sr ex... more We describe a system wherein the lock of trapping, ionizing, and ion resonance lasers for a Sr experiment are bootstrapped together in a single neutral atom vapor cell. This is done by overlapping beams to optically pump the atoms into the necessary states.
Forests
There is considerable uncertainty surrounding the future availability of hardwood timber from sta... more There is considerable uncertainty surrounding the future availability of hardwood timber from state-owned native forests in southern Queensland. The timber industry is becoming increasingly reliant on private native forests, where much is on properties primarily managed for beef cattle grazing. Historically, these forests have been periodically high-grade harvested without silvicultural treatment or cleared to increase pasture production where landholders have the right to do so. This study compares these traditional forest management practices at four case study properties against silvopastoral system alternatives. Merchantable timber, pasture and cattle production was estimated for each management scenario with a native forest silvicultural treatment response model. The net present value of each scenario was estimated over a 20-year management period. For all case study properties, the worst-performing forest management scenario was to clear forest for grazing. Investment in silvo...
Environmental Microbiome, 2021
Background The planktonic bacterial community associated with spring phytoplankton blooms in the ... more Background The planktonic bacterial community associated with spring phytoplankton blooms in the North Sea is responsible for a large amount of carbon turnover in an environment characterised by high primary productivity. Individual clades belonging to the Gammaproteobacteria have shown similar population dynamics to Bacteroidetes species, and are thus assumed to fill competing ecological niches. Previous studies have generated large numbers of metagenome assembled genomes and metaproteomes from these environments, which can be readily mined to identify populations performing potentially important ecosystem functions. In this study we attempt to catalogue these spring bloom-associated Gammaproteobacteria, which have thus far attracted less attention than sympatric Alphaproteobacteria and Bacteroidetes. Methods We annotated 120 non-redundant species-representative gammaproteobacterial metagenome assembled genomes from spring bloom sampling campaigns covering the four years 2010–2012 ...
Platelets, 2021
A multi-center prospective cross-sectional and genome-wide association study (GWAS) recruited pre... more A multi-center prospective cross-sectional and genome-wide association study (GWAS) recruited pregnant women taking low dose aspirin. Objectives were to (i) develop pregnancy-specific 95% reference intervals for a range of laboratory based platelet function tests (PFTs); (ii) select an optimal and acceptable PFT that reflected aspirin's COX-1 inhibition in women with confirmed aspirin adherence in pregnancy; and (iii) identify genomic variants that may influence pregnant women's platelet response to aspirin.The study included two independent cohorts of pregnant women. A range of PFTs and matched phenotyping with urinary 11-dehydrothromboxane B2 (11DTXB2) and nuclear magnetic resonance (NMR) spectroscopy detection of urinary salicyluric acid as a measure of aspirin adherence were performed. Genome-wide data was acquired from the UK Biobank Axiom® (Thermo Fisher Scientific). 11DTXB2 in combination with adherence testing with NMR salicyluric acid was an accurate and acceptable testing strategy for detecting biochemical aspirin responsiveness in pregnant women, with the provision of relevant reference ranges. GWAS meta-analysis found no significant single nucleotide polymorphisms in association with response to aspirin in pregnancy. Further evaluation in relation to effective dosing of aspirin in pregnancy and optimizing the benefits to specific subgroups should now be a priority for future research.
Rationale Focal epilepsy is the most frequent form of epilepsy in adults. Several pharmacogenomic... more Rationale Focal epilepsy is the most frequent form of epilepsy in adults. Several pharmacogenomic studies have already interrogated factors associated with treatment response in newly diagnosed epilepsy, but there are no large scale GWAS in newly diagnosed focal epilepsy. Here we report results of a GWAS performed for an early remission after application of the first well tolerated anticonvulsant. Methods Our research cohort was created as a part of EpiPGX study, which was an EU funded collaborative Europe wide epilepsy pharmacogenomics study. It included retrospective and prospective historical cohorts from Glasgow, the UK-wide SANAD trial and Melbourne. Results In total 935 cases were included. GWAS was performed with and without adjustment for significant clinical factors established by a prior logistic regression. There were no SNPs with genome-wide significant association, but 45 SNPs had genome-wide suggestive p-values in the univariate analysis and 37 SNPs in the adjusted ana...
The Lancet, Feb 1, 2017
Background Carbamazepine (CBZ) therapy is associated with hypersensitivity reactions, which can b... more Background Carbamazepine (CBZ) therapy is associated with hypersensitivity reactions, which can be multisystemic and sometimes fatal. The pathogenesis of these reactions is incompletely understood but heterologous immunity generated to viral antigens has been proposed as a potential mechanism. Our aim was to investigate changes in gene expression profi les of peripheral blood mononuclear cells (PBMCs) from patients with CBZ hypersensitivity to characterise the pathways involved in immune activation. Methods PBMCs were isolated from fi ve individuals with a history of hypersensitivity to CBZ. The PBMCs were incubated for 24 h with CBZ, carbamazepine 10,11-epoxide (CBZE), cell culture medium, or tetanus toxoid. Expression profi les for mRNA and microRNA were generated with microarrays (Aff ymetrix, Santa Clara, CA, USA). Diff erential gene expression was undertaken by limma analysis in the R statistical software. Ingenuity pathway analysis (IPA) was used to defi ne the molecular mechanisms in development of CBZ hypersensitivity. Findings Incubation of PBMCs with CBZ, CBZE, and tetanus toxoid led to signifi cant diff erential expression (log 2-fold change >1 or <-1, p<0•05) of multiple mRNA (n=204) and microRNA (n=148) transcripts with little overlap between the diff erent incubation conditions. The top diff erentially expressed genes for CBZ-treated and CBZE-treated cells identifi ed in IPA analysis were COX8A,
Journal of Allergy and Clinical Immunology, 2018
Paediatric asthma and allergy, 2019
Introduction: Inhaled corticosteroids (ICS) are the most effective medication for control of asth... more Introduction: Inhaled corticosteroids (ICS) are the most effective medication for control of asthma symptoms. However, a proportion of patients do not respond to this medication and suffer exacerbations, due to a combination of environmental and genetic factors. We performed a meta- genome-wide association study (GWAS) to identify genes associated with ICS response in European children. Methods: A GWAS meta-analysis of asthma exacerbations was performed across eight European studies from the Pharmacogenomics in Childhood Asthma (PiCA) consortium including 2,704 asthmatic children and young adults treated with ICS. Imputation of genetic variants was carried out using the Haplotype Reference Consortium as reference panel and association testing was performed by means of logistic regression models. A total of 8.1 million genetic variants with minor allele frequency ≥1% were meta-analyzed. Results: Nineteen polymorphisms were suggestively associated with asthma exacerbations despite use of ICS (p≤5x10-6). These variants were located at 10 segregating sites (minimum p=6.7x10-7). Novel associations were revealed in biologically plausible genes involved in drug metabolism (AOX1) and previously associated with lung function measurements (WNT5A and CNTNAP5). Moreover, variants located at CNTNAP5 were also nominally associated with a change in FEV1 after ICS treatment in SLOVENIA (minimum p=0.025). Conclusions: We revealed genes suggestively associated with asthma exacerbations in children and young adults despite the use of ICS. Replication will be performed in further independent studies. Study supported by Instituto de Salud Carlos III (AC15/00015) and ERACoSysMed 1st Joint Transnational Call (SysPharmPedia).
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Papers by Ben Joe Francis