Biology subjects

Martin, R. M.

Publications and source records attributed to Martin, R. M..

At least 19 recordsLinked to original sources

bioRxiv2026

The diel light cycle modulates microcystin content in continuous cultures and natural communities of Microcystis: Implications for bloom monitoring

Harmful algal blooms dominated by Microcystis spp. threaten fisheries, recreation, and drinking-water supplies because many strains produce the hepatotoxin microcystin. Monitoring programs compare microcystin concentrations among samples collected at different times of day, yet the extent that diel variation affects these estimates remains poorly resolved. We tested whether microcystin concentrations varied over a diel cycle under laboratory conditions and evaluated the effect of short-term sunlight exposure on a natural bloom community. Axenic Microcystis aeruginosa PCC 7806 was maintained in cyclostats with controlled nutrients and temperature under a 16 h light:8 h dark cycle. Microcystin concentrations normalized to culture volume (g L-1) and biovolume (ag m-E-3 were significantly higher (p [≤] 0.05) at the end of the dark period (64 {+/-} 8 g MC L-1; 630 {+/-} 40 ag MC m-3) than at the end of the light period (45 {+/-} 7 g MC L-1; 390 {+/-} 60 ag MC m-3), and this pattern was reproducible across consecutive days. Cell abundance and photosynthetic efficiency remained constant, indicating variation was not explained by changes in growth or photosynthetic performance. In parallel, water from a Lake Erie Microcystis bloom was exposed to sunlight or paired dark controls, and microcystin concentrations declined ~19% after just 60 min of sunlight exposure (p = 0.048). Together, these results demonstrate that microcystin measurements can vary predictably across the diel cycle and that light contributes to daytime declines. Although the underlying mechanism(s) remain unresolved, time of day should be considered, or standardized, when monitoring microcystins.

microbiology↗

bioRxiv2026

Quantitative fluorescence lifetime imaging of protein microenvironments by genetically encoded compact benzodiazole probes

Quantitative fluorescence lifetime imaging microscopy (FLIM) is limited by a lack of probes that combine single-residue specificity, minimal steric perturbation, visible-light excitation, and strong environment-dependent lifetime contrast. We introduce benzodiazole-based non-canonical amino acids (BD-ncAAs) as compact, genetically encoded sensors for site-specific FLIM. Using an engineered pyrrolysyl-tRNA synthetase pair, we incorporate three different BD-ncAAs into proteins in living cells. Site-specific incorporation of BD-ncAAs into a nanobody at different positions preserved native structure and antigen binding. The lead probe, cyano-substituted CBDS, exhibits visible-light excitation, large Stokes shifts, and pronounced environment-dependent fluorescence lifetimes spanning 1 to 24 ns. Under wash-free, live-cell FLIM conditions, CBDS quantitatively resolves localized structural microenvironments and transmembrane hydration gradients, while also distinguishing distinct states during protein secretion in eukaryotes. BD-ncAAs present genetically encoded, minimally perturbing reporters for tracking target proteins, detecting interactions with binding partners, and quantifying site-specific solvent accessibility in living cells by quantitative FLIM.

biophysics↗

bioRxiv2025

A human arteriovenous differentiation roadmap reveals vein developmental mechanisms and vascular effects of viruses

Extracellular signals and cell-fate trajectories during vein development remain elusive, despite trailblazing insights into artery development. Here we exploit human pluripotent stem cell differentiation and mouse embryology to present a model that answers longstanding questions: vein endothelial cell (EC) differentiation unfolds in two steps driven by opposing extracellular signals. First, VEGF differentiates mesoderm into "primed" ECs, newly-defined progenitors that co-express certain arterial (SOX17) and venous (APLNR) markers. Second, primed ECs execute vein differentiation upon VEGF/ERK inhibition; however, upon VEGF activation they can instead form artery ECs. The arteriovenous plasticity of primed ECs was supported by intersectional lineage tracing. Future venous genes including NR2F2 harbor poised chromatin in primed ECs, but are only transcribed upon VEGF/ERK inhibition. SOXF transcription factors, including SOX17, confer primed ECs with vein differentiation competence. Collectively, this two-step vein differentiation model--entailing primed EC intermediates and VEGF/ERK inhibition to trigger vein differentiation--has implications for VEGF-modulating therapies.

developmental biology↗

bioRxiv2025

Lysogen formation governs colonies while lytic infection is more prevalent in single cells of the bloom-forming cyanobacterium, Microcystis

While the bloom-forming cyanobacterium Microcystis can exist as free-living single cells or within dense mucilaginous colonies, the drivers and consequences of colony formation remain unclear. Here, we integrated metatranscriptomic datasets from two Microcystis bloom events in Lake Taihu, China, to analyze and validate the functional differences between colonial and single-cell Microcystis. Our results confirmed colony expression profiles were disproportionately enriched in Microcystis transcripts (and functions) compared to other prokaryotic taxa. Concomitantly, viral infection strategies diverged by Microcystis community morphology: colony-associated cells expressed lysogeny-associated genes, while single cells exhibited increased signatures of lytic infection. These data are consistent with the hypothesis that Microcystis colonies foster conditions favorable to lysogen formation--likely due to local high cell densities and the resulting advantage of superinfection immunity--whereas solitary cells experience stronger lytic pressure. On a broader scale, our findings refine the understanding of bloom dynamics by identifying how community morphological states coincide with distinct host-virus interactions. Cumulatively, this work underscores the importance of colony formation in shaping Microcystis ecology and highlights the need for mechanistic studies that disentangle the interplay between phage infection modes, colony formation, and microbial community structure.

microbiology↗

bioRxiv2024

Mitomycin C eliminates cyanobacterial transcription without detectable lysogen induction in a Microcystis-dominated bloom in Lake Erie

Although evidence indicates that viruses are important in the ecology of Microcystis spp., many questions remain. For example, how does Microcystis exist at high, bloom-associated cell concentrations in the presence of viruses that infect it? The phenomenon of lysogeny and associated homoimmunity offer possible explanations to this question. Virtually nothing is known about lysogeny in Microcystis, but a metatranscriptomic study suggests that widespread, transient lysogeny is active during blooms. These observations lead us to posit that lysogeny is important in modulating Microcystis blooms. Using a classic mitomycin C-based induction study, we tested for lysogeny in a Microcystis-dominated community in Lake Erie in 2019. Treated communities were incubated with 1 mg L-1 mitomycin C for 48 h alongside unamended controls. We compared direct counts of virus-like-particles (VLPs) and examined community transcription for active infection by cyanophage. Mitomycin C treatment did not increase VLP count. Mitomycin C effectively eliminated transcription in the cyanobacterial community, while we detected no evidence of induction. Metatranscriptomic analysis demonstrated that the standard protocol of 1 mg L-1 was highly-toxic to the cyanobacterial population, which likely inhibited induction of any prophage present. Follow-up lab studies indicated that 0.1 mg L-1 may be more appropriate for use in freshwater cyanobacterial studies. These findings will guide future efforts to detect lysogeny in Microcystis blooms. ImportanceHarmful algal blooms dominated by Microcystis spp. occur throughout the worlds freshwater ecosystems leading to detrimental effects on ecosystem services that are well documented. After decades of research, the scientific community continues to struggle to understand the ecology of Microcystis blooms. The phenomenon of lysogeny offers an attractive, potential explanation to several ecological questions surrounding blooms. However, almost nothing is known about lysogeny in Microcystis. We attempted to investigate lysogeny in a Microcystis bloom in Lake Erie and found that the standard protocols used to study lysogeny in aquatic communities are inappropriate for use in Microcystis studies, and perhaps freshwater cyanobacterial studies more broadly. This work can be used to design better methods to study the viral ecology of Microcystis blooms.

microbiology↗

bioRxiv2023

Cyfip2 controls the acoustic startle threshold through FMRP, actin polymerization, and GABAB receptor function.

Animals process a constant stream of sensory input, and to survive they must detect and respond to dangerous stimuli while ignoring innocuous or irrelevant ones. Behavioral responses are elicited when certain properties of a stimulus such as its intensity or size reach a critical value, and such behavioral thresholds can be a simple and effective mechanism to filter sensory information. For example, the acoustic startle response is a conserved and stereotyped defensive behavior induced by sudden loud sounds, but dysregulation of the threshold to initiate this behavior can result in startle hypersensitivity that is associated with sensory processing disorders including schizophrenia and autism. Through a previous forward genetic screen for regulators of the startle threshold a nonsense mutation in Cytoplasmic Fragile X Messenger Ribonucleoprotein (FMRP)-interacting protein 2 (cyfip2) was found that causes startle hypersensitivity in zebrafish larvae, but the molecular mechanisms by which Cyfip2 establishes the acoustic startle threshold are unknown. Here we used conditional transgenic rescue and CRISPR/Cas9 to determine that Cyfip2 acts though both Rac1 and FMRP pathways, but not the closely related FXR1 or FXR2, to establish the acoustic startle threshold during early neurodevelopment. To identify proteins and pathways that may be downstream effectors of Rac1 and FMRP, we performed a candidate-based drug screen that indicated that Cyfip2 can also act acutely to maintain the startle threshold branched actin polymerization and N-methyl D-aspartate receptors (NMDARs). To complement this approach, we used unbiased discovery proteomics to determine that loss of Cyfip2 alters cytoskeletal and extracellular matrix components while also disrupting oxidative phosphorylation and GABA receptor signaling. Finally, we functionally validated our proteomics findings by showing that activating GABAB receptors, which like NMDARs are also FMRP targets, restores normal startle sensitivity in cyfip2 mutants. Together, these data reveal multiple mechanisms by which Cyfip2 regulates excitatory/inhibitory balance in the startle circuit to control the processing of acoustic information.

neuroscience↗

bioRxiv2023

Cool temperature acclimation in toxigenic Microcystis aeruginosa PCC 7806 and its non-toxigenic mutant

For Microcystis aeruginosa PCC 7806, temperature decreases from 26{degrees} C to 19{degrees} C double the microcystin quota per cell during growth in continuous culture. Here we tested whether this increase in microcystin provided M. aeruginosa PCC 7806 with a fitness advantage during colder-temperature growth by comparing cell concentration, cellular physiology, and the transcriptomics-inferred metabolism to a non-toxigenic mutant strain M. aeruginosa PCC 7806 {Delta}mcyB. Photo-physiological data combined with transcriptomic data revealed metabolic changes in the mutant strain during growth at 19{degrees} C, which included increased electron sinks and non-photochemical quenching. Increased gene expression was observed for a glutathione-dependent peroxiredoxin during cold treatment, suggesting compensatory mechanisms to defend against reactive oxygen species are employed in the absence of microcystin in the mutant. Our observations highlight the potential selective advantages of a longer-term defensive strategy in management of oxidative stress (i.e., making microcystin) vs the shorter-term proactive strategy of producing cellular components to actively dissipate or degrade oxidative stress agents. ImportanceThrough comparisons of a microcystin-producing wildtype strain M. aeruginosa PCC 7806 and a non microcystin-producing mutant, M. aeruginosa PCC 7806{Delta} mcyB, our observations highlight defensive (microcystin production) vs active (production of degradation enzymes and increased electron sinks) strategies for dealing with cold-temperature induced oxidative stress as well as associated physiological changes. This work increases our understanding of microcystins intracellular function, and the role it may play in bloom ecology. In combination with other studies, this work begins to experimentally establish a mechanistic foundation to better understand cold-to-warm seasonal transitions from toxigenic to non-toxigenic strains frequently observed in situ.

microbiology↗

bioRxiv2023

Declines in ice cover induce light limitation in freshwater diatoms

The rediscovery of diatom blooms embedded within and beneath Lake Erie ice cover (2007-2012) ignited an intense interest in psychrophilic adaptations and winter limnology. Subsequent studies determined ice plays a vital role in winter diatom ecophysiology, as diatoms partition to the underside of ice thereby fixing their location within the photic zone. Yet, climate change has led to widespread ice decline across the Great Lakes, with Lake Erie presenting a nearly ice-free state in several recent winters. It has been hypothesized the resultant turbid, isothermal water column will induce light limitation amongst winter diatoms, serving as a detrimental competitive disadvantage. Here, we conducted a physiochemical and metatranscriptomic survey of the winter Lake Erie water column (2019-2020) that spanned spatial, temporal, and climatic gradients to investigate this hypothesis. We determined ice-free conditions decreased diatom bloom magnitude and altered diatom community composition. Diatoms increased the expression of various photosynthetic genes and iron transporters, suggesting they are attempting to increase their quantity of photosystems and light-harvesting components (a well-defined indicator of light limitation). Notably, we identified two gene families which serve to increase diatom fitness in the turbid ice-free water column: proton-pumping rhodopsins (a second means of light-driven energy acquisition) and fasciclins (a means to "raft" together to increase buoyancy and co-locate to the surface to optimize light acquisition). With large-scale climatic changes already underway, our observations provide insight into how diatoms respond to the dynamic ice conditions of today and shed light on how they will fare in a climatically altered tomorrow.

ecology↗

bioRxiv2022

Epigenetic markers of adverse lifestyle identified among night shift workers

BackgroundEpigenetic changes in the form of DNA methylation (DNAm) may act as biological markers of risk factors or adverse health states. We investigated associations between night shift work and established DNAm predictors of lifestyle, and compared them with those observed between night shift work and self-reported or conventionally-measured phenotypes. MethodsIn two cohort studies, Generation Scotland (GS) (n=7,028) and Understanding Society (UKHLS) (n=1,175), we evaluated associations between night shift work and four lifestyle factors (body mass index, smoking, alcohol, education) using both conventionally-measured phenotypes and DNA methylation-based scores proxying the phenotypes. DNA methylation-based measures of biological ageing were also generated using six established "epigenetic clocks". Meta-analysis of GS and UKHLS results was conducted using inverse-variance weighted fixed effects. ResultsNight shift work was associated with higher BMI (0.79; 95%CI 0.02, 1.56; p=0.04) and lower education (-0.18; -0.30, -0.07; p=0.002). There was weak evidence of association between night shift work and DNAm scores for smoking (0.06, -0.03, 0.15; p=0.18) and education (-0.24; -0.49, 0.01; p=0.06) in fully adjusted models. Two of the epigenetic age measures demonstrated higher age acceleration among night shift workers (0.80; 0.42, 1.18; p<0.001 for GrimAge and 0.46; 0.00, 0.92; p=0.05 for PhenoAge). ConclusionsNight shift work is associated with phenotypic and DNAm-based measures of lower education. Night shift work was also related to DNAm predictors of smoking and ageing.

genetics↗

bioRxiv2021

The cyanotoxin 2,4-DAB enhances mortality and causes behavioral and molecular dysfunctions associated with neurodegeneration in larval zebrafish

Exposure to cyanotoxins has been linked to neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimers, and Parkinsons disease. While the cyanotoxin {beta}-methylamino-L-alanine (BMAA) has received much attention, cyanobacteria produce many cyanotoxic compounds, several of which have been detected in nature alongside BMAA including 2,4-diaminobutyric acid (2,4-DAB), and N-(2-aminoethyl)glycine (AEG). Thus, the question of whether DAB and AEG also cause neurotoxic effects in vivo is of great interest, as is the question of whether they interact to enhance toxicity. Here, we evaluate the toxic and neurotoxic effects of these cyanotoxins alone or in combination by measuring zebrafish larval viability and behavior after exposure. 2,4-DAB was the most potent cyanotoxin as it decreased larval viability by approximately 50% at 6 days post fertilization, while BMAA and AEG decreased viability by just 16% and 8%, respectively. Although we only observed minor neurotoxic effects on spontaneous locomotion, BMAA and AEG enhanced acoustic startle sensitivity, and they interacted in an additive manner to exert their effects. 2,4-DAB, however, only modulated the startle kinematics, an indication of motor dysfunction. To investigate the mechanisms of 2,4-DABs effects, we analyzed the protein profile of larval zebrafish exposed to 500M 2,4-DAB at two time points and identified molecular signatures consistent with neurodegeneration, including disruption of metabolic pathways and downregulation of the ALS-associated genes SOD1 and UBQLN4. Together, our data demonstrate that BMAA and its isomers AEG and 2,4-DAB cause neurotoxic effects in vivo, with 2,4-DAB as the most potent of the three in the zebrafish model.

neuroscience↗

bioRxiv2021

Comparing optimized exoskeleton assistance of the hip, knee, and ankle in single and multi-joint configurations

Exoskeletons that assist the hip, knee, and ankle joints have begun to improve human mobility, particularly by reducing the metabolic cost of walking. However, direct comparisons of optimal assistance of these joints, or their combinations, have not yet been possible. Assisting multiple joints may be more beneficial than the sum of individual effects, because muscles often span multiple joints, or less effective, because single-joint assistance can indirectly aid other joints. In this study, we used a hip-knee-ankle exoskeleton emulator paired with human-in-the-loop optimization to find single-joint, two-joint, and whole-leg assistance that maximally reduced the metabolic cost of walking for three participants. Hip-only and ankle-only assistance reduced the metabolic cost of walking by 26% and 30% relative to walking in the device unassisted, confirming that both joints are good targets for assistance. Knee-only assistance reduced the metabolic cost of walking by 13%, demonstrating that effective knee assistance is possible. Two-joint assistance reduced the metabolic cost of walking by between 34% and 42%, with the largest improvements coming from hip-ankle assistance. Assisting all three joints reduced the metabolic cost of walking by 50%, showing that at least half of the metabolic energy expended during walking can be saved through exoskeleton assistance. Changes in kinematics and muscle activity indicate that single-joint assistance indirectly assisted muscles at other joints, such that the improvement from whole-leg assistance was smaller than the sum of its single-joint parts. Exoskeletons can assist the entire limb for maximum effect, but a single well-chosen joint can be more efficient when considering additional factors such as weight and cost.

bioengineering↗

bioRxiv2020

Gene replacement of α-globin with β-globin restores hemoglobin balance in β-thalassemia-derived hematopoietic stem and progenitor cells

{beta}-thalassemia pathology is not only due to loss of {beta}-globin (HBB), but also erythrotoxic accumulation and aggregation of the {beta}-globin binding partner, -globin (HBA1/2). Here we describe a Cas9/AAV6-mediated genome editing strategy that can replace the entire HBA1 gene with a full-length HBB transgene in {beta}-thalassemia-derived hematopoietic stem and progenitor cells (HSPCs), which is sufficient to normalize {beta}-globin:-globin mRNA and protein ratios and restore functional adult hemoglobin tetramers in patient-derived red blood cells. Edited HSPCs were capable of long-term and bi-lineage hematopoietic reconstitution in mice, establishing proof-of-concept for replacement of HBA1 with HBB as a novel therapeutic strategy for curing {beta}-thalassemia.

molecular biology↗

bioRxiv2020

Coffee consumption and risk of breast cancer: a Mendelian Randomization study

BackgroundObservational studies have reported either null or weak protective associations for coffee consumption and risk of breast cancer. MethodsWe conducted a two-sample Mendelian randomization randomization (MR) analysis to evaluate the relationship between coffee consumption and breast cancer risk using 33 single-nucleotide polymorphisms (SNPs) associated with coffee consumption from a genome-wide association (GWA) study on 212,119 female UK Biobank participants of White British ancestry. Risk estimates for breast cancer were retrieved from publicly available GWA summary statistics from the Breast Cancer Association Consortium (BCAC) on 122,977 cases (of which 69,501 were estrogen receptor (ER)-positive, 21,468 ER-negative) and 105,974 controls of European ancestry. Random-effects inverse variance weighted (IVW) MR analyses were performed along with several sensitivity analyses to assess the impact of potential MR assumption violations. ResultsOne cup per day increase in genetically predicted coffee consumption in women was not associated with risk of total (IVW random-effects; odds ratio (OR): 0.91, 95% confidence intervals (CI): 0.80-1.02, P: 0.12, P for instrument heterogeneity: 7.17e-13), ER-positive (OR=0.90, 95% CI: 0.79-1.02, P: 0.09) and ER-negative breast cancer (OR: 0.88, 95% CI: 0.75-1.03, P: 0.12). Null associations were also found in the sensitivity analyses using MR-Egger (total breast cancer; OR: 1.00, 95% CI: 0.80-1.25), weighted median (OR: 0.97, 95% CI: 0.89-1.05) and weighted mode (OR: 1.00, CI: 0.93-1.07). ConclusionsThe results of this large MR study do not support an association of genetically predicted coffee consumption on breast cancer risk, but we cannot rule out existence of a weak inverse association.

cancer biology↗

bioRxiv2020

Exposure to a mixture of BMAA and MCLR synergistically modulates behavior in larval zebrafish while exacerbating molecular changes related to neurodegeneration.

Exposure to toxins produced by cyanobacteria (i.e., cyanotoxins) is an emerging health concern due to their increased occurrence and previous associations with neurodegenerative disease including amyotrophic lateral sclerosis (ALS). The objective of this study was to evaluate the neurotoxic effects of a mixture of two co-occurring cyanotoxins, {beta}-methylamino-L-alanine (BMAA) and microcystin leucine and arginine (MCLR), using the larval zebrafish model. We combined high-throughput behavior based toxicity assays with discovery proteomic techniques to identify behavioral and molecular changes following 6 days of exposure. While neither toxin caused mortality, morphological defects, or altered general locomotor behavior in zebrafish larvae, both toxins increased acoustic startle sensitivity in a dose-dependent manner by at least 40% (p<0.0001). Furthermore, startle sensitivity was enhanced by an additional 40% in larvae exposed to the BMAA/MCLR mixture relative to those exposed to the individual toxins. Supporting these behavioral results, our proteomic analysis revealed a 4-fold increase in the number of differentially expressed proteins (DEPs) in the mixture exposed group. Additionally, prediction analysis reveals activation and/or inhibition of 8 enriched canonical pathways (enrichment p-value<0.01; z-score[≥]|2|), including ILK, Rho Family GTPase, RhoGDI, and calcium signaling pathways, which have been implicated in neurodegeneration. We also found that expression of TDP-43, of which cytoplasmic aggregates are a hallmark of ALS pathology, was significantly upregulated by 5.7-fold following BMAA/MCLR mixture exposure. Together, our results emphasize the importance of including mixtures of cyanotoxins when investigating the link between environmental cyanotoxins and neurodegeneration as we reveal that BMAA and MCLR interact in vivo to enhance neurotoxicity.

pharmacology and toxicology↗

bioRxiv2019

Mendelian randomisation study exploring the associations of serum folate with pan and site-specific cancers

BackgroundEpidemiological studies report evidence for an association between folate and the risk of several common cancers. However, both protective and harmful effects have been reported, and effects may differ by cancer site. Using Mendelian randomisation (MR), we investigated the causal relationships of genetically predicted serum folate with pan-cancer risk (all cancers excluding non-melanoma skin cancers); breast, prostate, ovarian, lung, and colorectal cancers; and malignant melanoma. MethodsWe conducted a two-sample MR analysis, using genetic instruments for serum folate to appraise the possible causal role on risk of pan-cancer and six site-specific cancers using summary statistics available from large consortia and the population-based cohort study UK Biobank (UKBB). ResultsThere was little evidence that genetically elevated serum folate was causally associated with risk of pan-cancer or six site-specific cancers. Meta-analysis showed odds ratios (OR) per SD increase in log serum folate of 0.93 (95% CI 0.78-1.11) for breast cancer, 0.87 (95% CI 0.71-1.06) for prostate cancer, 0.84 (95% CI 0.59-1.20) for ovarian cancer, and 0.87 (95% CI 0.57-1.32) for lung cancer. The OR for colorectal cancer was 1.18 (95% CI 0.64-2.18) in large consortia analysis, while ORs for pan-cancers and malignant melanoma in UKBB were 0.88 (95% CI 0.73-1.06) and 0.56 (95% CI 0.29-1.08) respectively. The results were powered to detect modest effect sizes (>90% power ( 0.05) to detect ORs 1.2 (0.8) for the GWAS consortia) and were consistent between the two statistical approaches used (inverse variance weighted (IVW) and likelihood-based). ConclusionsThere is little evidence that genetically elevated serum folate may affect the risk of pan-cancer and six site-specific cancers. However, we may still be underpowered to detect clinically relevant but smaller magnitude effects. Our results provide some evidence that increasing levels of circulating folate through widespread supplementation or deregulation of fortification of foods with folic acid is unlikely to lead to moderate unintended population-wide increase in cancer risk. Key MessagesO_LIObservational studies have identified associations between folate (both intake and circulating levels) and risk of developing site-specific cancers. However, these studies are liable to biases such as confounding, measurement error, and reverse causation. C_LIO_LIUsing Mendelian randomisation, we appraised the causal relationships between genetically influenced serum folate levels and pan-cancer risk (all cancers excluding non-melanoma skin cancers); breast, prostate, ovarian, lung, and colorectal cancers; and malignant melanoma. C_LIO_LIOverall findings suggest that there is little evidence for the causal associations between genetically influenced serum folate and risk of pan-cancer and six site-specific cancers. C_LIO_LIWe provide some evidence that increasing levels of circulating folate through widespread supplementation or deregulation of fortification of foods with folic acid is unlikely to lead to moderate unintended population-wide increase in cancer risk. C_LI

genomics↗

bioRxiv2019

Appraising causal relationships of dietary, nutritional and physical-activity exposures with overall and aggressive prostate cancer: two-sample Mendelian randomization study based on 79,148 prostate cancer cases and 61,106 controls

BackgroundProstate cancer is the second most common male cancer worldwide, but there is substantial geographical variation suggesting a potential role for modifiable risk factors in prostate carcinogenesis.\n\nMethodsWe identified previously reported prostate cancer risk factors from the World Cancer Research Funds (WCRF) systematic appraisal of the global evidence (2018). We assessed whether each identified risk factor was causally associated with risk of overall (79,148 cases and 61,106 controls) or aggressive (15,167 cases and 58,308 controls) prostate cancer using Mendelian randomization (MR) based on genome wide association study (GWAS) summary statistics from the PRACTICAL and GAME-ON/ELLIPSE consortia. We assessed evidence for replication in UK Biobank (7,844 prostate cancer cases and 204,001 controls).\n\nFindingsWCRF identified 57 potential risk factors, of which 22 could be instrumented for MR analyses using single nucleotide polymorphisms (SNPs). In MR analyses for overall prostate cancer, we identified evidence compatible with causality for the following risk factors (odds ratio [OR] per standard deviation increase; 95% confidence interval): accelerometer-measured physical-activity, OR=0.49 (0.33-0.72; p=0.0003); serum iron, OR=0.92 (0.86-0.98; p=0.007); body mass index (BMI), OR=0.90 (0.84-0.97; p=0.003); and mono-unsaturated fat, OR=1.11 (1.02-1.20; p=0.02). Findings in our replication analyses in UK Biobank were compatible with our main analyses (albeit with wide confidence intervals). In MR analysis, height was positively associated with aggressive prostate cancer risk: OR=1.07 (1.01-1.15; p=0.03).\n\nInterpretationThe results for physical-activity, serum iron, BMI, mono-unsaturated fat and height are compatible with causality for prostate cancer but more research is needed to rule out violations of MR assumptions for some risk factors. The results suggest that interventions aimed at increasing physical activity may reduce prostate cancer risk, but the direction of effects of BMI, and iron are at odds with their effects on other diseases, so the overall public health impact of intervening on these need to be considered.\n\nFundingWorld Cancer Research Fund International (2015/1421), Cancer Research UK program grant (C18281/A19169), National Institute for Health Research, Bristol Biomedical Research Centre, and Victorian Cancer Agency (MCRF18005).

epidemiology↗

bioRxiv2019

A genetic hazard score to personalize prostate cancer screening, applied to population data

BackgroundGenetic risk stratification may inform decisions of whether--and when--a man should undergo prostate cancer (PCa) screening. We previously validated a polygenic hazard score (PHS), a weighted sum of 54 single-nucleotide polymorphism genotypes, for accurate prediction of age of onset of aggressive PCa and improved screening performance. We now assess the potential impact of PHS-informed screening.\n\nMethodsUnited Kingdom population data were fit to a continuous model of age-specific PCa incidence. Using hazard ratios estimated from ProtecT trial data, age-specific incidence rates were calculated for percentiles of genetic risk. Incidence of higher-grade PCa (Gleason[≥]7) was estimated from age-specific data from the linked CAP trial. PHS and incidence data were combined to give a risk-equivalent age, when a man with a given PHS percentile will have risk of higher-grade PCa equivalent to that of a typical man at age 50 (50-years standard). Positive predictive value (PPV) of PSA testing was calculated using PHS-adjusted (PCa-risk-equivalent age) groups identified from ProtecT.\n\nResultsExpected age of onset of higher-grade PCa is modulated by 19 years between the 1st and 99th PHS percentiles. A man with PHS in the 99th percentile reaches 50-years-standard risk at age 41; conversely, a man in the 1st percentile reaches this risk at age 60. PPV of PSA was higher for men with higher PHS-adjusted age.\n\nConclusionsPHS informs PCa screening strategies with individualized estimates of risk-equivalent age for higher-grade PCa. Screening initiation could be adjusted according to a mans genetic hazard score, improving PPV of PSA screening.

genetics↗

bioRxiv2018

Repurposing antihypertensive drugs for the prevention of Alzheimer’s disease: a Mendelian Randomization study

BackgroundEvidence concerning the potential repurposing of antihypertensives for Alzheimers disease prevention is inconclusive. We used Mendelian randomization, which can be more robust to confounding by indication and patient characteristics, to investigate the effects of lowering systolic blood pressure (SBP), via different antihypertensive drug classes, on Alzheimers disease.\n\nMethodsWe used summary statistics from genome wide association studies of SBP (from UK Biobank) and Alzheimers disease (from the International Genomics of Alzheimers Project) in a two-sample Mendelian randomization analysis. We identified single nucleotide polymorphisms (SNPs) that mimic the action of antihypertensive targets and estimated the effect of lowering SBP, via antihypertensive drug classes, on Alzheimers disease. We also report the effect of lowering SBP on Alzheimers disease by combining all drug targets and without consideration of the associated drugs.\n\nResultsThere was limited evidence that lowering SBP, via antihypertensive drug classes, affected Alzheimers disease risk. For example, calcium channel blockers had an odds ratio (OR) per 10mmHg lower SBP of 1.53 (95% confidence interval (CI): 0.94 to 2.49; p=0.09; SNPs=17). We also found limited evidence for an effect of lowering SBP on Alzheimers disease when combining all drug targets (OR per 10mmHg lower SBP: 1.14; 95%CI: 0.83 to 1.56; p=0.41; SNPs=59) and without consideration of the associated drug targets (OR per 10mmHg lower SBP: 1.04; 95%CI: 0.95 to 1.13; p=0.45; SNPs=153).\n\nConclusionsLowering SBP itself is unlikely to affect risk of developing Alzheimers disease. Consequently, if specific antihypertensive drug classes do affect risk of Alzheimers disease, they are unlikely to do so via SBP.\n\nKEY MESSAGESO_LIThis is the first study to use Mendelian randomization to estimate the effects of the twelve most common antihypertensive drug classes on Alzheimers disease.\nC_LIO_LILowering systolic blood pressure itself is unlikely to affect risk of developing Alzheimers disease.\nC_LIO_LIIf specific antihypertensive drug classes do affect Alzheimers disease risk, they are unlikely to do so via systolic blood pressure.\nC_LI

genetics↗