👤 PREOBE team

The development of glucagon-like peptide 1 (GLP1) receptor agonists, including semaglutide and tirzepatide, has transformed the clinical management of overweight and obesity. However, substantial inter-person variability exists in both weight loss efficacy and the incidence of side effects Show less

Food allergy (FA) arises from a complex interplay between an individual's genetic predisposition and environmental factors, and its prevalence is increasing. Genome-wide association studies to date have been hindered by small sample sizes and varying FA definitions. We sought to identify novel FA risk loci by conducting a genome-wide association study meta-analysis in children and adults by using a multiphenotype approach to ensure a good trade-off between sufficient sample size and valid FA definitions. Analyses were conducted separately in children and adults on the basis of the following FA phenotypes: self-report, doctor diagnosis, food-specific sensitization, and doctor diagnosis plus food-specific sensitization. A meta-analysis was performed of genome-wide association studies from up to 16 cohorts of people of European ancestry including 229,426 adults and 14,234 children. Models were adjusted for sex, age, principal components, and, if applicable, further study-specific confounders. Sensitivity models were additionally adjusted for hay fever. Replication was conducted in additional external cohorts and a validation in oral food challenge-defined FA cases. Thirty-seven single nucleotide polymorphisms met suggestive significance (P < 1 × 10 This study identified 37 single nucleotide polymorphisms suggestively associated with FA and demonstrated genetic differences across phenotypes. It highlights the need for a unified FA definition and sheds light on FA's shared genetic architecture with allergies. Show less

Clarifying relationships between amyloid, tau, and cognition is crucial to understanding dementia risk, but has been mainly performed in non-Hispanic White (NHW) participants. It is unknown whether findings are generalizable to other ethnoracial groups. We evaluated relationships between amyloid-β (Aβ) positivity, apolipoprotein E allele (APOE) ε4, tau-positron emission tomography (PET) Black (β = 0.28, p < 0.001) and Hispanic (β = 0.34, p < 0.001) participants had higher medial temporal lobe (MTL) tau than NHW participants; however, findings were attenuated when accounting for choroid plexus off-target binding. Hispanic participants showed higher tau in lateral temporal regions compared to NHW and Black participants; however, reducing meningeal off-target binding through erosion demonstrated similar lateral temporal tau across groups. Factors other than amyloid and tau may impact cognition in Black participants. PI2620 off-target ethnoracial differences should be investigated. Show less

Women show higher levels of Alzheimer's disease (AD) pathology than men, but the implications for cognitive decline remain unclear. Determining the extent to which tau burden differentially accelerates cognitive decline in men and women will provide critical insights into sex-specific pathways of disease progression. We leveraged tau positron emission tomography (PET), amyloid beta (Aβ) PET, apolipoprotein E (APOE) ε4 genotyping, and longitudinal cognitive data over approximately 8.6 (standard deviation [SD] = 3.8) years from 1007 cognitively unimpaired adults across three cohorts. Cognitive trajectories were modeled with linear mixed-effects regression including sex × tau × time interactions, and results were synthesized using random-effects meta-analysis. Higher tau burden in medial and lateral temporal regions was associated with faster cognitive decline in women than in men. High tau burden carries a disproportionately greater cognitive cost for women, underscoring the need for sex-specific approaches to early detection and therapeutic intervention in AD. A meta-analysis across three independent cohorts shows that female cognitive advantage at low tau shifts to vulnerability at higher tau. Sex differences in tau-related cognitive decline were consistent after accounting for amyloid burden. Sex-specific rates of cognitive decline should be considered in clinical trial design. Show less

Cognitive resilience, the ability to maintain better than expected cognitive function despite neuropathological burden, is a key contributor to clinical outcomes in Alzheimer's disease (AD), though the underlying neurobiological mechanisms remain poorly understood. To determine whether hippocampal volume and microstructure moderate the relationship between early tau pathology and cognitive performance, thereby serving as potential markers of cognitive resilience. Cross-sectional observational study. Participant data was obtained from the longitudinal BIOCARD Study, a volunteer-based research cohort. The sample included 190 dementia-free adults (mean age = 68 years), comprising 176 cognitively unimpaired individuals and 14 with mild cognitive impairment (MCI). Hippocampal volume and microstructure (mean diffusivity (MD)) were measured using structural magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI), respectively. Tau pathology was measured using FMK-6240 tau PET imaging across Braak stages I-III. Cognitive performance was indexed using global and domain-specific composite scores. Regression models tested the interactions between hippocampal volume or MD and tau burden, adjusting for demographics, APOE genotype, amyloid status, and diagnostic status. Lower hippocampal MD (indicative of better microstructural integrity) attenuated the negative association between tau burden in Braak stages II-III and both global cognition and episodic memory (ps < 0.010). Logistic regression models indicated that lower hippocampal MD was associated with a weaker relationship between tau burden in Braak stages II-III and the likelihood of MCI diagnosis (ps < 0.050). In contrast, hippocampal volume did not moderate the relationship between tau and any cognitive outcome (ps > 0.250). Hippocampal MD may serve as a promising imaging marker of cognitive resilience to early tau pathology, with potential utility for risk stratification and as a target for preventive interventions in AD. Show less

Cardiometabolic risks affect cognition during aging, yet genetic basis for both remain understudied in Indians. This study constructs an ancestry-matched Indian haplotype reference panel for genotype imputation of 5111 rural Indians. Single-locus, gene-based, conditional genome-wide association analyses are performed on 20 cognitive and 10 cardiometabolic traits, with subsequent follow-up of identified associations through multimodal functional annotation. Furthermore, causal interrelationships between cardiometabolic and cognitive phenotypes by Mendelian randomization are investigated. One novel memory-associated and 17 novel cardiometabolic phenotypes-associated (high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], triglycerides [TG], total cholesterol [TC], TG:HDL, and visceral adiposity index [VAI]) genome-wide significant loci, and multiple genes are identified. AMIGO1 (delayed-recall) and ZPR1-APOA5 (metabolic syndrome) exhibit distinct haplotype structure compared to other populations. Causal roles of cardiometabolic traits on various cognitive domains are identified via genetic instruments in APOC3-APOA4-APOA5-ZPR1-BUD13 among others. These findings illustrate the impact of cardiometabolic factors on cognition in a rural socioeconomically disadvantaged population, advancing efforts to address health disparities. Our newly constructed ancestry-matched haplotype reference panel gives better genotype imputation accuracy for the Indian population. One and 17 novel genome-wide significant single-loci were identified to be associated with cognitive and cardiometabolic traits, respectively. Several subgenome-wide hits for all phenotypes were identified. Collapsing protein truncating variants (PTVs), there were two genes identified to be associated with cardiometabolic traits at a genome-wide level of significance, correcting for multiple phenotypes tested. Haplotypic differences were identified compared to 1000 Genomes superpopulations for genes influencing delayed recall and metabolic syndrome. Adverse causal roles of cardiometabolic traits on cognition were uncovered via genetic instruments in APOC3-APOA4-APOA5-ZPR1-BUD13, among others, through Mendelian randomization. Show less

Patients with inflammatory breast cancer (IBC) have aggressive biology and relatively inferior responses to standard-of-care (SOC) therapies. Understanding the efficacy of SOC therapies in IBC is critical to optimize outcomes. Our objective was to assess the progression-free survival (PFS) of metastatic hormone receptor-positive HER2-negative/low (HR+HER2-) IBC patients treated with CDK4/6 inhibitors (CDKIs) and hormonal therapy (HT). Data from 58 IBC patients with metastatic HR + /HER2- IBC from a single institution were reviewed. The medians (95% confidence intervals) of overall survival (OS), PFS, and time on treatment (ToT) from the time of CDKI initiation were reported via the Kaplan‒Meier method. Differences were tested by the log-rank test. We identified 58 patients (including 16 with de novo stage IV disease). The median OS, PFS, and ToT in the total cohort were 26 (16, 37), 7 (5, 10), and 7 (5, 10) months (mos), respectively. No differences were observed between pre-menopausal patients and postmenopausal patients. The OS, PFS, and ToT rates at the initial diagnosis of Stage III later developing metastatic breast cancer (MBC, N = 42) and de novo IV (N = 16) patients were 19 (15, 34) vs 34 (21, NR), 7 (5, 14) vs 9 (6, NR), and 6 (5, 10) vs 9 (4, NR) mos, respectively (ns). OS, PFS, and ToT in patients receiving CDKI in the first-line vs second-line metastatic setting were 27 (19, 44) vs 17 (12, 39), 7 (5, 15) vs 6 (3, NR), and 7 (5, 15) vs 6 (3, 20) mos, respectively (ns). Among the patients initially diagnosed with stage III disease later progressing to MBC, brain metastases were observed in 12/42 patients. Thirty-eight patients underwent genomic testing either before CDKI treatment (N = 21) or at progression (N = 17). Among the 38 patients who underwent genomic testing, 34 had mutations, most commonly in TP53, PIK3CA, FGFR1, CCND1, and ARID1A. ESR1 mutations were present in 0% of the samples tested prior to CDKI treatment, and 29% of the samples tested at progression. Patients with metastatic HR+HER2- IBC demonstrated a shorter time on treatment suggesting shorter duration of response on CDKI + HT, which is markedly inferior to reported data for non-IBC patients from phase III trials. Show less

Persistent monocyte activation and altered cytokine responses are reported in PWH despite ART. How prior HIV-1 infection status and timing of ART initiation relate to monocyte pattern-recognition receptor crosstalk between TLR8 and RLRs remains uncertain. We conducted a comparative cohort study in adult males enrolled from two Dutch HIV-cohorts. Participants included HIV-negative participants, PWH who initiated ART during chronic HIV infection, and PWH who initiated ART during acute HIV infection, with sampling at 24 and 156 weeks after ART initiation for the acute group. PBMCs were stimulated with an RLR agonist, a TLR8 agonist, or both. Monocyte surface markers were assessed by flow cytometry and pro-inflammatory cytokines were analysed with qPCR and ELISA. Across groups, RLR stimulation induced IL-12p70 and IL-27, TLR8 stimulation induced IL-6 and IL-12p70 and combined TLR8 + RLR co-stimulation synergistically increased IL-12p70 and IL-27 while restricting IL-6. Compared with controls, CHI showed reduced IL-12p70 and IL-27 and higher IL-6. In AHI at 24 weeks, cytokine patterns and co-stimulation effects resembled HIV-negative participants; by 156 weeks, responses were attenuated and approximated CHI. In this male cohort, TLR8-RLR crosstalk was preserved early after ART initiation during acute infection but diminished over time, approaching profiles observed in chronically treated infection. These observations emphasise a potential early window after ART initiation for interventions aiming to preserve monocyte function and motivate studies to characterise underlying mechanisms. Funding for this study was obtained through a ZonMW/Aidsfonds grant NL4Cure: Bridging shock and kill strategies (446002508). Show less

SARS-CoV-2's continued global health impact underscores the importance of ongoing pathogenesis research. Insights into the host's first line of defense against severe COVID-19 identify actionable biomarkers, informing disease management or therapeutics. Yet, the innate immune response, including cytokines, chemokines, adenosine deaminases (ADAs) and Toll-like receptors (TLRs), relevant to COVID-19 remain incompletely characterized. Peripheral blood was longitudinally collected between May 2020 and March 2021 from COVID-19 hospitalized adults (N = 79) and healthy controls (HCs) (N = 14; not tested, assumed COVID-negative, no viral exposure or symptoms). Heparinized blood was fractionated for plasma cryopreservation and in vitro whole blood TLR-stimulation employing TLR-3, -4, and -7/8 agonists. Post-stimulation culture supernatants were analyzed using multiplex and enzymatic assays. Upon hospitalization, plasma concentrations of IFNγ, IL-6, CXCL10, and ADAs were significantly upregulated compared to convalescent time points and HCs. Participants with fatal COVID-19 exhibited higher IL-27, CXCL10, and ADAs concentrations upon admission. Plasma cytokines, chemokines, and ADAs were positively correlated and associated with distinct temporal patterns. TLR-stimulated cell cultures from patients produced reduced IFNα2, IFNγ, IL-12p40, and IL-12p70 compared to HCs or later time points. Higher plasma concentrations of IL-27, CXCL10, and ADAs at admission were associated with severe COVID-19 and mortality. Reduced TLR-mediated IFNα2, IFNγ, and IL-12p70 production suggests COVID dampens Th1-polarizing innate immune responses, providing insight into immunological sequelae of SARS-CoV-2 infection. Show less

Prior studies have demonstrated the existence of cognitively-defined subgroups among dementia free older adults, however, it is unclear whether such subgroups are characterized by distinct neuroimaging measures of brain function and structure. To address this gap, the current study used latent profile analysis (LPA) to identify cognitively-defined subgroups in a sample of 167 (mean age = 69 years) dementia-free older adults with cognitive testing, amyloid PET, and multimodal brain MRI scans. The cognitive test scores covered the domains of episodic memory, executive function, language, and visuospatial processing. Linear regression models tested the associations between subgroup membership and neuroimaging measures, adjusting for age, sex, and years of education. Based on the LPA, three cognitive subgroups were identified: (1) high-average cognition (n = 61, 36%), (2) average cognition (n = 88, 53%), and low-average cognition (n = 18, 11%). Compared to the high-average group, the low-average group had lower volumes in cortical regions sensitive to Alzheimer's disease, lower global white matter microstructural integrity measured by diffusion tensor imaging, and higher global white matter hyperintensity burden. There were no group differences in global PET amyloid burden. Additionally, the high-average group tended to have higher resting-state functional connectivity within large-scale cognitive networks than the other two groups. These results suggest that cognitively-defined subgroups among older adults without dementia are associated with several measures of brain structure and function. Evaluating brain structure/function differences among dementia-free older adults may help identify individuals at greatest risk for future cognitive decline. Show less

Is there an increased risk of immunological diseases among endometriosis patients, and does a shared genetic basis contribute to this risk? Endometriosis patients show a significantly increased risk of autoimmune, autoinflammatory, and mixed-pattern diseases, including rheumatoid arthritis, multiple sclerosis, coeliac disease, osteoarthritis, and psoriasis, with genetic correlations between endometriosis and osteoarthritis, rheumatoid arthritis, and multiple sclerosis, and a potential causal link to rheumatoid arthritis. The epidemiological evidence for an increased risk of immunological diseases among women with endometriosis is limited in scope and has varied in robustness due to the opportunity for biases. The presence of a biological basis for increased comorbidity across immunological conditions has not been investigated. Here we investigate the phenotypic and genetic association between endometriosis and 31 immune conditions in the UK Biobank. Phenotypic analyses between endometriosis and immune conditions (17 classical autoimmune, 10 autoinflammatory, and 4 mixed-pattern diseases) were conducted using two approaches (8223 endometriosis, 64 620 immunological disease cases): (i) retrospective cohort study design to incorporate temporality between diagnoses and (ii) cross-sectional analysis for simple association. Genome-wide association studies (GWAS) and meta-analyses for those immune conditions that showed phenotypic association with endometriosis (1493-77 052 cases) were conducted. Comprehensive phenotypic association analyses were conducted in females in the UK Biobank. GWAS for immunological conditions were conducted in females-only and sex-combined study populations in UK Biobank and meta-analysed with existing largest available GWAS results. Genetic correlation and Mendelian randomization (MR) analyses were conducted to investigate potential causal relationships. Those immune conditions with significant genetic correlation with endometriosis were included in multi-trait analysis of GWAS to boost discovery of novel and shared genetic variants. These shared variants were functionally annotated to identify affected genes utilizing expression quantitative trait loci (eQTL) data from GTEx and eQTLGen databases. Biological pathway enrichment analysis was conducted to identify shared underlying biological pathways. In both retrospective cohort and cross-sectional analyses, endometriosis patients were at significantly increased (30-80%) risk of classical autoimmune (rheumatoid arthritis, multiple sclerosis, coeliac disease), autoinflammatory (osteoarthritis), and mixed-pattern (psoriasis) diseases. Osteoarthritis (genetic correlation (rg) = 0.28, P = 3.25 × 10-15), rheumatoid arthritis (rg = 0.27, P = 1.5 × 10-5) and multiple sclerosis (rg = 0.09, P = 4.00 × 10-3) were significantly genetically correlated with endometriosis. MR analysis suggested a causal association between endometriosis and rheumatoid arthritis (OR = 1.16, 95% CI = 1.02-1.33). eQTL analyses highlighted genes affected by shared risk variants, enriched for seven pathways across all four conditions, with three genetic loci shared between endometriosis and osteoarthritis (BMPR2/2q33.1, BSN/3p21.31, MLLT10/10p12.31) and one with rheumatoid arthritis (XKR6/8p23.1). We conducted the first female-specific GWAS analyses for immune conditions. Given the novelty of these analyses, the sample sizes from which results were derived were limited compared to sex-combined GWAS meta-analyses, which limited the power to use female-specific summary statistics to uncover the shared genetic basis with endometriosis in follow-up analyses. Secondly, the 39 genome-wide significant endometriosis-associated variants used as instrumental variables in the MR analysis explained approximately 5% of disease variation, which may account for the nominal or non-significant MR results. Endometriosis patients have a moderately increased risk for osteoarthritis, rheumatoid arthritis, and to a lesser extent, multiple sclerosis, due to underlying shared biological mechanisms. Clinical implications primarily involve the need for increased awareness and vigilance. The shared genetic basis opens up opportunities for developing new treatments or repurposing therapies across these conditions. We thank all the UK Biobank and 23andMe participants. Part of this research was conducted using the UK Biobank Resource under Application Number 9637. N.R. was supported by a grant from the Wellbeing of Women UK (RG2031) and the EU Horizon 2020 funded project FEMaLe (101017562). A.P.M. was supported in part by Versus Arthritis (grant 21754). H.F. was supported by the National Natural Science Foundation of China (grant 32170663). N.R., S.A.M., and K.T.Z. were supported in part by a grant from CDMRP DoD PRMRP (W81XWH-20-PRMRP-IIRA). K.T.Z. and C.M.B. reported grants in 3 years prior, outside the submitted work, from Bayer AG, AbbVie Inc., Volition Rx, MDNA Life Sciences, PrecisionLife Ltd., and Roche Diagnostics Inc. S.A.M. reports grants in the 3 years prior, outside this submitted work, from AbbVie Inc. N.R. is a consultant for Endogene.bio, outside this submitted work. The other authors have no conflicts of interest to declare. N/A. Show less

Hyposmia (decreased smell function) is a common early symptom of Parkinson's disease (PD). The shared genetic architecture between hyposmia and PD is unknown. We leveraged genome-wide association study (GWAS) results for self-assessment of 'ability to smell' and PD diagnosis to determine shared genetic architecture between the two traits. Linkage disequilibrium score (LDSC) regression found that the sense of smell negatively correlated at a genome-wide level with PD. Local Analysis of [co]Variant Association (LAVA) found negative correlations in four genetic loci near GBA1, ANAPC4, SNCA, and MAPT, indicating shared genetic liability only within a subset of prominent PD risk genes. Using Mendelian randomization, we found evidence for a strong causal relationship between PD and liability towards poorer sense of smell, but weaker evidence for the reverse direction. This work highlights the heritability of olfactory function and its relationship with PD heritability and provides further insight into the association between PD and hyposmia. Show less

Pregnancy is a risk factor for increased severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other respiratory infections, but the mechanisms underlying this risk are poorly understood. To gain insight into the role of pregnancy in modulating immune responses at baseline and upon SARS-CoV-2 infection, we collected peripheral blood mononuclear cells and plasma from 226 women, including 152 pregnant individuals and 74 non-pregnant women. We find that SARS-CoV-2 infection is associated with altered T cell responses in pregnant women, including a clonal expansion of CD4-expressing CD8 Show less

Pregnancy is a risk factor for increased severity of SARS-CoV-2 and other respiratory infections. The mechanisms underlying this risk have not been well-established, partly due to a limited understanding of how pregnancy shapes immune responses. To gain insight into the role of pregnancy in modulating immune responses at steady state and upon perturbation, we collected peripheral blood mononuclear cells (PBMC), plasma, and stool from 226 women, including 152 pregnant individuals (n = 96 with SARS-CoV-2 infection and n = 56 healthy controls) and 74 non-pregnant women (n = 55 with SARS-CoV-2 and n = 19 healthy controls). We found that SARS-CoV-2 infection was associated with altered T cell responses in pregnant compared to non-pregnant women. Differences included a lower percentage of memory T cells, a distinct clonal expansion of CD4-expressing CD8 Show less

Hyposmia (loss of smell) is a common early symptom of Parkinson's disease (PD). The shared genetic architecture between hyposmia and PD is unknown. We leveraged genome-wide association study (GWAS) results for self-assessment of 'ability to smell' and PD diagnosis. Linkage disequilibrium score regression (LDSC) and Local Analysis of [co]Variant Association (LAVA) were used to identify genome-wide and local genetic correlations. Mendelian randomization was used to identify potential causal relationships. LDSC found that sense of smell negatively correlated at a genome-wide level with PD. LAVA found negative correlations in four genetic loci near Hyposmia and PD share genetic liability in only a subset of the major PD risk genes. While there was definitive evidence that PD can lower the sense of smell, there was only suggestive evidence for the reverse. This work highlights the heritability of olfactory function and its relationship with PD heritability and provides further insight into the association between PD and hyposmia. Show less

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention. Show less

Depression is the most prevalent mental disorder with substantial morbidity and mortality. Although genome-wide association studies (GWASs) have identified multiple risk variants for depression, due to the complicated gene regulatory mechanisms and complexity of linkage disequilibrium (LD), the biological mechanisms by which the risk variants exert their effects on depression remain largely unknown. Here, we perform a transcriptome-wide association study (TWAS) of depression by integrating GWAS summary statistics from 807,553 individuals (246,363 depression cases and 561,190 controls) and summary-level gene-expression data (from the dorsolateral prefrontal cortex (DLPFC) of 1003 individuals). We identified 53 transcriptome-wide significant (TWS) risk genes for depression, of which 23 genes were not implicated in risk loci of the original GWAS. Seven out of 53 risk genes (B3GALTL, FADS1, TCTEX1D1, XPNPEP3, ZMAT2, ZNF501 and ZNF502) showed TWS associations with depression in two independent brain expression quantitative loci (eQTL) datasets, suggesting that these genes may represent promising candidates. We further conducted conditional analyses and identified the potential risk genes that driven the TWAS association signal in each locus. Finally, pathway enrichment analysis revealed biologically pathways relevant to depression. Our study identified new depression risk genes whose expression dysregulation may play a role in depression. More importantly, we translated the GWAS associations into risk genes and relevant pathways. Further mechanistic study and functional characterization of the TWS depression risk genes will facilitate the diagnostics and therapeutics for depression. Show less

CD38, a druggable ectoenzyme, is involved in the generation of adenosine, which is implicated in tumour immune evasion. Its expression and role in prostate tumour-infiltrating immune cells (TIICs) have not been elucidated. To characterise CD38 expression on prostate cancer (PC) epithelial cells and TIICs, and to associate this expression with clinical outcomes. RNAseq from 159 patients with metastatic castration-resistant prostate cancer (mCRPC) in the International Stand Up To Cancer/Prostate Cancer Foundation (SU2C/PCF) cohort and 171 mCRPC samples taken from 63 patients in the Fred Hutchinson Cancer Research Centre cohort were analysed. CD38 expression was immunohistochemically scored by a validated assay on 51 castration-resistant PC (CRPC) and matching, same-patient castration-sensitive PC (CSPC) biopsies obtained between 2016 and 2018, and was associated with retrospectively collected clinical data. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: mCRPC transcriptomes were analysed for associations between CD38 expression and gene expression signatures. Multiplex immunofluorescence determined CD38 expression in PC biopsies. Differences in CD38 CD38 mRNA expression in mCRPC was most significantly associated with upregulated immune signalling pathways. CD38 mRNA expression was associated with interleukin (IL)-12, IL-23, and IL-27 signalling signatures as well as immunosuppressive adenosine signalling and T cell exhaustion signatures. CD38 protein was frequently expressed on phenotypically diverse TIICs including B cells and myeloid cells, but largely absent from tumour epithelial cells. CD38 CD38 CD38 is expressed on the surface of white blood cells surrounding PC cells. These cells may impact PC growth and treatment resistance. Patients with PC with more CD38-expressing white blood cells are more likely to die earlier. Show less

Daytime napping is a common, heritable behavior, but its genetic basis and causal relationship with cardiometabolic health remain unclear. Here, we perform a genome-wide association study of self-reported daytime napping in the UK Biobank (n = 452,633) and identify 123 loci of which 61 replicate in the 23andMe research cohort (n = 541,333). Findings include missense variants in established drug targets for sleep disorders (HCRTR1, HCRTR2), genes with roles in arousal (TRPC6, PNOC), and genes suggesting an obesity-hypersomnolence pathway (PNOC, PATJ). Association signals are concordant with accelerometer-measured daytime inactivity duration and 33 loci colocalize with loci for other sleep phenotypes. Cluster analysis identifies three distinct clusters of nap-promoting mechanisms with heterogeneous associations with cardiometabolic outcomes. Mendelian randomization shows potential causal links between more frequent daytime napping and higher blood pressure and waist circumference. Show less

Blood pressure (BP) was inconsistently associated with migraine and the mechanisms of BP-lowering medications in migraine prophylaxis are unknown. Leveraging large-scale summary statistics for migraine (N Show less

The aims of the NYU Children's Health and Environment Study (CHES) are to evaluate influences of prenatal non-persistent chemical exposures on fetal and postnatal growth and pool our data with the US National Institutes of Health Environmental influences on Child Health Outcomes (ECHO) Program to answer collaborative research questions on the impact of the preconceptual, prenatal, and postnatal environment on childhood obesity, neurodevelopment, pre/peri/postnatal outcomes, upper and lower airway outcomes, and positive health. Eligible women were ≥ 18 years old, < 18 weeks pregnant, had a pregnancy that is not medically threatened, and planned to deliver at NYU Langone Hospital-Manhattan, Bellevue Hospital, or NYU Langone Hospital-Brooklyn. Between March 22, 2016 and April 15, 2019, we recruited 2469 pregnant women, from whom 2193 completed an initial questionnaire and continued into NYU CHES. Of the 2193, 88 miscarried, 28 terminated, and 20 experienced stillbirth, while 57 were lost to follow up. We report here demographic and other characteristics of the 2000 live deliveries (2037 children), from whom 1624 (80%) consented to postnatal follow-up. Data collection in pregnancy was nested in clinical care, with questionnaire and specimen collection conducted during routine prenatal visits at < 18, 18-25, and > 25 weeks gestation. These have been followed by questionnaire and specimen collection at birth and regular postpartum intervals. Show less

A recent genome-wide association study (GWAS) identified 99 loci that contain genetic risk variants shared between asthma, hay fever, and eczema. Many more risk loci shared between these common allergic diseases remain to be discovered, which could point to new therapeutic opportunities. We sought to identify novel risk loci shared between asthma, hay fever, and eczema by applying a gene-based test of association to results from a published GWAS that included data from 360,838 subjects. We used approximate conditional analysis to adjust the results from the published GWAS for the effects of the top risk variants identified in that study. We then analyzed the adjusted GWAS results with the EUGENE gene-based approach, which combines evidence for association with disease risk across regulatory variants identified in different tissues. Novel gene-based associations were followed up in an independent sample of 233,898 subjects from the UK Biobank study. Of the 19,432 genes tested, 30 had a significant gene-based association at a Bonferroni-corrected P value of 2.5 × 10 Using a gene-based approach, we identified 11 risk loci for allergic disease that were not reported in previous GWASs. Functional studies that investigate the contribution of the 19 associated genes to the pathophysiology of allergic disease and assess their therapeutic potential are warranted. Show less

Variants in the human genes of fatty acid (FA) desaturase 1 (FADS1), 2 (FADS2) and 3 (FADS3) are associated with PUFA blood levels. We explored if maternal prenatal supplementation and children's genetic variation in seventeen SNP of the FADS1, FADS2 and FADS3 gene cluster influence twenty-one of the most relevant cheek cells' derived FA in glycerophospholipids (GPL-FA). The study was conducted in 147 Spanish and German mother-children pairs participating in the Nutraceuticals for a Healthier Life (NUHEAL) study at 8, 9 and 9·5 years. Linear and mixed model longitudinal regression analyses were performed. Maternal fish-oil (FO) or FO+5-methyltetrahydrofolate (5-MTHF) supplementation during pregnancy was associated with a significant decrease of arachidonic acid (AA) concentrations in cheek cell GPL in the offspring, from 8 to 9·5 years; furthermore, maternal FO+5-MTHF supplementation was associated with higher n-6 docosapentaenoic acid concentrations in their children at age 8 years. FADS1 rs174556 polymorphism and different FADS2 genotypes were associated with higher concentrations of linoleic and α-linolenic acids in children; moreover, some FADS2 genotypes determined lower AA concentrations in children's cheek cells. It is suggested an interaction between type of prenatal supplementation and the offspring genetic background driving GPL-FA levels at school age. Prenatal FO supplementation, and/or with 5-MTHF, seems to stimulate n-3 and n-6 FA desaturation in the offspring, increasing long-chain PUFA concentrations at school age, but depending on children's FADS1 and FADS2 genotypes. These findings suggest potential early nutrition programming of FA metabolic pathways, but interacting with children's FADS polymorphisms. Show less

Single nucleotide polymorphisms (SNPs) in the genes encoding the fatty acid desaturase (FADS) and elongase (ELOVL) enzymes affect long-chain polyunsaturated fatty acid (LC-PUFA) production. We aimed to determine if these SNPs are associated with body mass index (BMI) or affect fatty acids (FAs) in pregnant women. Participants (n = 180) from the PREOBE cohort were grouped according to pre-pregnancy BMI: normal-weight (BMI = 18.5-24.9, n = 88) and overweight/obese (BMI≥25, n = 92). Plasma samples were analyzed at 24 weeks of gestation to measure FA levels in the phospholipid fraction. Selected SNPs were genotyped (7 in FADS1, 5 in FADS2, 3 in ELOVL2 and 2 in ELOVL5). Minor allele carriers of rs174545, rs174546, rs174548 and rs174553 (FADS1), and rs1535 and rs174583 (FADS2) were nominally associated with an increased risk of having a BMI≥25. Only for the normal-weight group, minor allele carriers of rs174537, rs174545, rs174546, and rs174553 (FADS1) were negatively associated with AA:DGLA index. Normal-weight women who were minor allele carriers of FADS SNPs had lower levels of AA, AA:DGLA and AA:LA indexes, and higher levels of DGLA, compared to major homozygotes. Among minor allele carriers of FADS2 and ELOVL2 SNPs, overweight/obese women showed higher DHA:EPA index than the normal-weight group; however, they did not present higher DHA concentrations than the normal-weight women. In conclusion, minor allele carriers of FADS SNPs have an increased risk of obesity. Maternal weight changes the effect of genotype on FA levels. Only in the normal-weight group, minor allele carriers of FADS SNPs displayed reduced enzymatic activity and FA levels. This suggests that women with a BMI≥25 are less affected by FADS genetic variants in this regard. In the presence of FADS2 and ELOVL2 SNPs, overweight/obese women showed higher n-3 LC-PUFA production indexes than women with normal weight, but this was not enough to obtain a higher n-3 LC-PUFA concentration. Show less

Delta-5 and delta-6 desaturases (D5D and D6D) are key enzymes in endogenous synthesis of long-chain PUFAs. In this sample of healthy subjects (n = 310), genotypes of single nucleotide polymorphisms (SNPs) rs174537, rs174561, and rs3834458 in the FADS1-FADS2 gene cluster were strongly associated with proportions of LC-PUFAs and desaturase activities estimated in plasma and erythrocytes. Minor allele carriage associated with decreased activities of D5D (FADS1) (5.84 × 10(-19) ≤ P ≤ 4.5 × 10(-18)) and D6D (FADS2) (6.05 × 10(-8) ≤ P ≤ 4.20 × 10(-7)) was accompanied by increased substrate and decreased product proportions (0.05 ≤ P ≤ 2.49 × 10(-16)). The significance of haplotype association with D5D activity (P = 2.19 × 10(-17)) was comparable to that of single SNPs, but haplotype association with D6D activity (P = 3.39 × 10(-28)) was much stronger. In a randomized controlled dietary intervention, increasing eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) intake significantly increased D5D (P = 4.0 × 10(-9)) and decreased D6D activity (P = 9.16 × 10(-6)) after doses of 0.45, 0.9, and 1.8 g/day for six months. Interaction of rs174537 genotype with treatment was a determinant of D5D activity estimated in plasma (P = 0.05). In conclusion, different sites at the FADS1-FADS2 locus appear to influence D5D and D6D activity, and rs174537 genotype interacts with dietary EPA+DHA to modulate D5D. Show less