Uromodulin in sepsis and severe pneumonia: a two-sample Mendelian randomization study.

The outcome for patients with sepsis-associated acute kidney injury in the intensive care unit (ICU) remains poor. Low serum uromodulin (sUMOD) protein levels have been proposed as a causal mediator of this effect. We investigated the effect of different levels of sUMOD on the risk of sepsis and severe pneumonia and outcomes in these conditions. A two-sample Mendelian randomization (MR) study was performed. Single-nucleotide polymorphisms (SNPs) associated with increased levels of sUMOD were identified and used as instrumental variables for association with outcomes. Data from different cohorts were combined based on disease severity and meta-analyzed. Five SNPs associated with increased sUMOD levels were identified and tested in six datasets from two biobanks. There was no protective effect of increased levels of sUMOD on the risk of sepsis [two cohorts, odds ratio (OR) 0.99 (95% confidence interval 0.95-1.03), P = 0.698, and OR 0.95 (0.91-1.00), P = 0.060, respectively], risk of sepsis requiring ICU admission [OR 1.04 (0.93-1.16), P = 0.467], ICU mortality in sepsis [OR 1.00 (0.74-1.37), P = 0.987], risk of pneumonia requiring ICU admission [OR 1.05 (0.98-1.14), P = 0.181], or ICU mortality in pneumonia [OR 1.17 (0.98-1.39), P = 0.079]. Meta-analysis of hospital-admitted and ICU-admitted patients separately yielded similar results [OR 0.98 (0.95-1.01), P = 0.23, and OR 1.05 (0.99-1.12), P = 0.86, respectively]. Among patients with sepsis and severe pneumonia, there was no protective effect of different levels of sUMOD. Results were consistent regardless of geographic origins and not modified by disease severity. NEW & NOTEWORTHY The presence of acute kidney injury in severe infections increases the likelihood of poor outcome severalfold. A decrease in serum uromodulin (sUMOD), synthetized in the kidney, has been proposed as a mediator of this effect. Using the Mendelian randomization technique, we tested the hypothesis that increased sUMOD is protective in severe infections. Analyses, however, showed no evidence of a protective effect of higher levels of sUMOD in sepsis or severe pneumonia.

Metabolomic pattern associated with physical sequelae in patients presenting with respiratory symptoms validates the aestivation concept in dehydrated patients.

Hypertonic dehydration is associated with muscle wasting and synthesis of organic osmolytes. We recently showed a metabolic shift to amino acid production and urea cycle activation in coronavirus-2019 (COVID-19), consistent with the aestivation response. The aim of the present investigation was to validate the metabolic shift and development of long-term physical outcomes in the non-COVID cohort of the Biobanque Québécoise de la COVID-19 (BQC19). We included 824 patients from BQC19, where 571 patients had data of dehydration in the form of estimated osmolality (eOSM = 2Na + 2K + glucose + urea), and 284 patients had metabolome data and long-term follow-up. We correlated the degree of dehydration to mortality, invasive mechanical ventilation, acute kidney injury, and long-term symptoms. As found in the COVID cohort, higher eOSM correlated with a higher proportion of urea and glucose of total eOSM, and an enrichment of amino acids compared with other metabolites. Sex-stratified analysis indicated that women may show a weaker aestivation response. More severe dehydration was associated with mortality, invasive mechanical ventilation, and acute kidney injury during the acute illness. Importantly, more severe dehydration was associated with physical long-term symptoms but not mental long-term symptoms after adjustment for age, sex, and disease severity. Patients with water deficit in the form of increased eOSM tend to have more severe disease and experience more physical symptoms after an acute episode of care. This is associated with amino acid and urea production, indicating dehydration-induced muscle wasting.NEW & NOTEWORTHY We have previously shown that humans exhibit an aestivation-like response where dehydration leads to a metabolic shift to urea synthesis, which is associated with long-term weakness indicating muscle wasting. In the present study, we validate this response in a new cohort and present a deeper metabolomic analysis and pathway analysis. Finally, we present a sex-stratified analysis suggesting weaker aestivation in women. However, women show less dehydration, so the association warrants further study.

Predicting ExWAS findings from GWAS data: a shorter path to causal genes.

GWAS has identified thousands of loci associated with disease, yet the causal genes within these loci remain largely unknown. Identifying these causal genes would enable deeper understanding of the disease and assist in genetics-based drug development. Exome-wide association studies (ExWAS) are more expensive but can pinpoint causal genes offering high-yield drug targets, yet suffer from a high false-negative rate. Several algorithms have been developed to prioritize genes at GWAS loci, such as the Effector Index (Ei), Locus-2-Gene (L2G), Polygenic Prioritization score (PoPs), and Activity-by-Contact score (ABC) and it is not known if these algorithms can predict ExWAS findings from GWAS data. However, if this were the case, thousands of associated GWAS loci could potentially be resolved to causal genes. Here, we quantified the performance of these algorithms by evaluating their ability to identify ExWAS significant genes for nine traits. We found that Ei, L2G, and PoPs can identify ExWAS significant genes with high areas under the precision recall curve (Ei: 0.52, L2G: 0.37, PoPs: 0.18, ABC: 0.14). Furthermore, we found that for every unit increase in the normalized scores, there was an associated 1.3-4.6-fold increase in the odds of a gene reaching exome-wide significance (Ei: 4.6, L2G: 2.5, PoPs: 2.1, ABC: 1.3). Overall, we found that Ei, L2G, and PoPs can anticipate ExWAS findings from widely available GWAS results. These techniques are therefore promising when well-powered ExWAS data are not readily available and can be used to anticipate ExWAS findings, allowing for prioritization of genes at GWAS loci.

Colocalization of expression transcripts with COVID-19 outcomes is rare across cell states, cell types and organs.

Identifying causal genes at GWAS loci can help pinpoint targets for therapeutic interventions. Expression studies can disentangle such loci but signals from expression quantitative trait loci (eQTLs) often fail to colocalize-which means that the genetic control of measured expression is not shared with the genetic control of disease risk. This may be because gene expression is measured in the wrong cell type, physiological state, or organ. We tested whether Mendelian randomization (MR) could identify genes at loci influencing COVID-19 outcomes and whether the colocalization of genetic control of expression and COVID-19 outcomes was influenced by cell type, cell stimulation, and organ. We conducted MR of cis-eQTLs from single cell (scRNA-seq) and bulk RNA sequencing. We then tested variables that could influence colocalization, including cell type, cell stimulation, RNA sequencing modality, organ, symptoms of COVID-19, and SARS-CoV-2 status among individuals with symptoms of COVID-19. The outcomes used to test colocalization were COVID-19 severity and susceptibility as assessed in the Host Genetics Initiative release 7. Most transcripts identified using MR did not colocalize when tested across cell types, cell state and in different organs. Most that did colocalize likely represented false positives due to linkage disequilibrium. In general, colocalization was highly variable and at times inconsistent for the same transcript across cell type, cell stimulation and organ. While we identified factors that influenced colocalization for select transcripts, identifying 33 that mediate COVID-19 outcomes, our study suggests that colocalization of expression with COVID-19 outcomes is partially due to noisy signals even after following quality control and sensitivity testing. These findings illustrate the present difficulty of linking expression transcripts to disease outcomes and the need for skepticism when observing eQTL MR results, even accounting for cell types, stimulation state and different organs.

Efficacy of antihyperglycemic therapies on cardiovascular and heart failure outcomes: an updated meta-analysis and meta-regression analysis of 35 randomized cardiovascular outcome trials.

BACKGROUND: Effects of antihyperglycemic therapies on cardiovascular and heart failure (HF) risks have varied widely across cardiovascular outcome trials (CVOTs), and underlying factors remain incompletely understood. We aimed to determine the relationships of glycated hemoglobin (HbA1c) or bodyweight changes with these outcomes in all CVOTs of antihyperglycemic therapies. METHODS: We searched PubMed and EMBASE up to 25 January 2023 for all randomized controlled CVOTs of antihyperglycemic therapies reporting both major adverse cardiovascular events (MACE) and HF outcomes in patients with type 2 diabetes or prediabetes. We performed meta-regression analyses following random-effects meta-analyses to evaluate the effects of HbA1c or bodyweight reductions on each outcome. RESULTS: Thirty-five trials comprising 256,524 patients were included. Overall, antihyperglycemic therapies reduced MACE by 9% [risk ratio (RR): 0.91; 95% confidence interval (CI) 0.88-0.94; P < 0.001; I2 = 36.5%]. In meta-regression, every 1% greater reduction in HbA1c was associated with a 14% reduction in the RR of MACE (95% CI 4-24; P = 0.010), whereas bodyweight change was not associated with the RR of MACE. The magnitude of the reduction in MACE risk associated with HbA1c reduction was greater in trials with a higher baseline prevalence of atherosclerotic cardiovascular disease. On the other hand, antihyperglycemic therapies showed no overall significant effect on HF (RR: 0.95; 95% CI 0.87-1.04; P = 0.28; I2 = 75.9%). In a subgroup analysis based on intervention type, sodium-glucose cotransporter-2 inhibitors (SGLT2i) conferred the greatest HF risk reduction (RR: 0.68; 95% CI 0.62-0.75; P < 0.001; I2 = 0.0%). In meta-regression, every 1 kg bodyweight reduction, but not HbA1c reduction, was found to reduce the RR of HF by 7% (95% CI 4-10; P < 0.001); however, significant residual heterogeneity (P < 0.001) was observed, and SGLT2i reduced HF more than could be explained by HbA1c or bodyweight reductions. CONCLUSIONS: Antihyperglycemic therapies reduce MACE in an HbA1c-dependent manner. These findings indicate that HbA1c can be a useful marker of MACE risk reduction across a wide range of antihyperglycemic therapies, including drugs with pleiotropic effects. In contrast, HF is reduced not in an HbA1c-dependent but in a bodyweight-dependent manner. Notably, SGLT2i have shown class-specific benefits for HF beyond HbA1c or bodyweight reductions.

Stabilization of kidney function and reduction in heart failure events with sodium-glucose co-transporter 2 inhibitors: A meta-analysis and meta-regression analysis.

AIMS: Sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of heart failure (HF) events regardless of diabetes status. However, factors associated with their efficacy in HF reduction remain unknown. This study aims to identify clinically relevant markers for the efficacy of SGLT2 inhibitors in HF risk reduction. MATERIALS AND METHODS: We searched PubMed/MEDLINE and EMBASE for randomized placebo-controlled trials of SGLT2 inhibitors reporting a composite of HF hospitalization or cardiovascular death in participants with or without type 2 diabetes published until 28 February 2023. Random-effects meta-analysis and mixed-effects meta-regression were conducted to evaluate the association between the outcomes and clinical variables, including changes in glycated haemoglobin, body weight, systolic blood pressure, haematocrit and overall/chronic estimated glomerular filtration rate (eGFR) slope. RESULTS: Thirteen trials with 90 413 participants were included. SGLT2 inhibitors reduced the hazard ratio of the composite of HF hospitalization or cardiovascular death (hazard ratio 0.77; 95% confidence interval, 0.74-0.81; p < .0001). In meta-regression analysis, chronic eGFR slope (eGFR change after the initial dip) was significantly associated with the composite outcome (p = .017), and each 1 ml/min/1.73 m2 /year improvement in chronic eGFR slope led to a 14% reduction in the composite outcome. By contrast, changes in the other parameters showed no significant associations. CONCLUSIONS: Improvement in chronic eGFR slope, which reflects the stabilization of kidney function, is significantly associated with the efficacy of the SGLT2 inhibitor in HF, highlighting the cardiorenal axis role in the beneficial effects on HF. The chronic eGFR slope can be a surrogate marker of the effects of SGLT2 inhibitors on HF reduction.

Effects of glucagon-like peptide-1 receptor agonists on cardiovascular and renal outcomes: A meta-analysis and meta-regression analysis.

AIM: To evaluate the cardiovascular and renal outcomes of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and the associations between these outcomes and HbA1c or weight reduction. MATERIALS AND METHODS: We searched PubMed/MEDLINE, EMBASE, and CENTRAL databases for randomized, placebo-controlled trials of GLP-1 RAs reporting major adverse cardiovascular events (MACE; a composite of cardiovascular mortality, stroke, and myocardial infarction) as the primary outcome. We conducted a meta-regression analysis of primary and secondary outcomes with HbA1c or weight reduction following a meta-analysis with a random-effects model for these outcomes. RESULTS: We extracted data of 60 800 individuals from eight eligible studies (ELIXA, LEADER, SUSTAIN-6, EXSCEL, HARMONY, PIONEER 6, REWIND, and AMPLITUDE-O). GLP-1 RAs reduced MACE (hazard ratio [HR] 0.86; 95% CI: 0.80-0.93; P < .001) and secondary outcomes including the composite renal outcome (0.80; 0.73-0.87; P < .001). In meta-regression analysis, every 1% reduction in HbA1c was associated with 26% and 35% decreases in the logarithm of HR of MACE (P = .044; R2  = 0.65) and the composite renal outcome (P = .040; R2  = 0.85), respectively. On the contrary, weight reduction was not associated with any outcome, including MACE (P = .390). CONCLUSIONS: The reduction in HbA1c, but not body weight, is associated with cardiovascular and renal outcomes. The magnitude of HbA1c reduction can be a surrogate for the cardiovascular and renal benefits of treatment with GLP-1 RAs.

Dehydration is associated with production of organic osmolytes and predicts physical long-term symptoms after COVID-19: a multicenter cohort study.

BACKGROUND: We have previously shown that iatrogenic dehydration is associated with a shift to organic osmolyte production in the general ICU population. The aim of the present investigation was to determine the validity of the physiological response to dehydration known as aestivation and its relevance for long-term disease outcome in COVID-19. METHODS: The study includes 374 COVID-19 patients from the Pronmed cohort admitted to the ICU at Uppsala University Hospital. Dehydration data was available for 165 of these patients and used for the primary analysis. Validation was performed in Biobanque Québécoise de la COVID-19 (BQC19) using 1052 patients with dehydration data. Dehydration was assessed through estimated osmolality (eOSM = 2Na + 2 K + glucose + urea), and correlated to important endpoints including death, invasive mechanical ventilation, acute kidney injury, and long COVID-19 symptom score grouped by physical or mental. RESULTS: Increasing eOSM was correlated with increasing role of organic osmolytes for eOSM, while the proportion of sodium and potassium of eOSM were inversely correlated to eOSM. Acute outcomes were associated with pronounced dehydration, and physical long-COVID was more strongly associated with dehydration than mental long-COVID after adjustment for age, sex, and disease severity. Metabolomic analysis showed enrichment of amino acids among metabolites that showed an aestivating pattern. CONCLUSIONS: Dehydration during acute COVID-19 infection causes an aestivation response that is associated with protein degradation and physical long-COVID. TRIAL REGISTRATION: The study was registered à priori (clinicaltrials.gov: NCT04316884 registered on 2020-03-13 and NCT04474249 registered on 2020-06-29).

Circulating Metabolite Abundances Associated With Risks of Bipolar Disorder, Schizophrenia, and Depression: A Mendelian Randomization Study.

BACKGROUND: Preventive measures and treatments for psychiatric disorders are limited. Circulating metabolites are potential candidates for biomarker and therapeutic target identification, given their measurability and essential roles in biological processes. METHODS: Leveraging large-scale genome-wide association studies, we conducted Mendelian randomization analyses to assess the associations between circulating metabolite abundances and the risks of bipolar disorder, schizophrenia, and depression. Genetic instruments were selected for 94 metabolites measured in the Canadian Longitudinal Study on Aging cohort (N = 8299). We repeated Mendelian randomization analyses based on the UK Biobank, INTERVAL, and EPIC (European Prospective Investigation into Cancer)-Norfolk studies. RESULTS: After validating Mendelian randomization assumptions and colocalization evidence, we found that a 1 SD increase in genetically predicted circulating abundances of eicosapentaenoate and docosapentaenoate was associated with odds ratios of 0.72 (95% CI, 0.65-0.79) and 0.63 (95% CI, 0.55-0.72), respectively, for bipolar disorder. Genetically increased Ω-3 unsaturated fatty acids abundance and Ω-3-to-total fatty acids ratio, as well as genetically decreased Ω-6-to-Ω-3 ratio, were negatively associated with the risk of bipolar disorder in the UK Biobank. Genetically increased circulating abundances of 3 N-acetyl-amino acids were associated with an increased risk of schizophrenia with a maximum odds ratio of 1.31 (95% CI, 1.18-1.44) per 1 SD increase. Furthermore, a 1 SD increase in genetically predicted circulating abundance of hypotaurine was associated with an odds ratio of 0.85 (95% CI, 0.78-0.93) for depression. CONCLUSIONS: The biological mechanisms that underlie Ω-3 unsaturated fatty acids, NAT8-catalyzed N-acetyl-amino acids, and hypotaurine warrant exploration to identify new biomarkers and potential therapeutic targets.

Vitamin D, Cognition, and Alzheimer's Disease: Observational and Two-Sample Mendelian Randomization Studies.

Background: Observational studies have found that vitamin D supplementation is associated with improved cognition. Further, recent Mendelian randomization (MR) studies have shown that higher vitamin D levels, 25(OH)D, may protect against Alzheimer's disease. Thus, it is possible that 25(OH)D may protect against Alzheimer's disease by improving cognition. Objective: We assessed this hypothesis, by examining the relationship between 25(OH)D levels and seven cognitive measurements. Methods: To mitigate bias from confounding, we performed two-sample MR analyses. We used instruments from three publications: Manousaki et al. (2020), Sutherland et al. (2022), and the Emerging Risk Factors Collaboration/EPIC-CVD/Vitamin D Studies Collaboration (2021). Results: Our observational studies suggested a protective association between 25(OH)D levels and cognitive measures. An increase in the natural log of 25(OH)D by 1 SD was associated with a higher PACC score (BetaPACC score = 0.06, 95% CI = (0.04-0.08); p = 1.8×10-10). However, in the MR analyses, the estimated effect of 25(OH)D on cognitive measures was null. Specifically, per 1 SD increase in genetically estimated natural log of 25(OH)D, the PACC scores remained unchanged in the overall population, (BetaPACC score = -0.01, 95% CI (-0.06 to 0.03); p = 0.53), and amongst individuals aged over 60 (BetaPACC score = 0.03, 95% CI (-0.028 to 0.08); p = 0.35). Conclusions: In conclusion, our MR study found no clear evidence to support a protective role of increased 25(OH)D concentrations on cognitive performance in European ancestry individuals. However, our study cannot entirely dismiss the potential beneficial effect on PACC for individuals over the age of 60.

The influence of trinucleotide repeats in the androgen receptor gene on androgen-related traits and diseases.

CONTEXT: Trinucleotide repeats in the androgen receptor have been proposed to influence testosterone signaling in men, but the clinical relevance of these trinucleotide repeats remains controversial. OBJECTIVE: To examine how androgen receptor trinucleotide repeat lengths affect androgen-related traits and disease risks and whether they influence the clinical importance of circulating testosterone levels. METHODS: We quantified CAG and GGC repeat lengths in the androgen receptor (AR) gene of European-ancestry male participants in UK Biobank from whole-genome and whole-exome sequence data using ExpansionHunter, and tested associations with androgen-related traits and diseases. We also examined whether the associations between testosterone levels and these outcomes were affected by adjustment for the repeat lengths. RESULTS: We successfully quantified the repeat lengths from whole-genome and/or whole-exome sequence data in 181,217 males. Both repeat lengths were shown to be positively associated with circulating total testosterone level and bone mineral density, whereas CAG repeat length was negatively associated with male-pattern baldness, but their effects were relatively small and were not associated with most of the other outcomes. Circulating total testosterone level was associated with various outcomes, but this relationship was not affected by adjustment for the repeat lengths. CONCLUSION: In this large-scale study, we found that longer CAG and GGC repeats in the AR gene influence androgen resistance, elevate circulating testosterone level via a feedback loop and play a role in some androgen-targeted tissues. Generally, however, circulating testosterone level is a more important determinant of androgen action in males than repeat lengths.

Proteome- and Transcriptome-Wide Genetic Analysis Identifies Biological Pathways and Candidate Drug Targets for Preeclampsia.

BACKGROUND: Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality. However, the current understanding of its underlying biological pathways remains limited. METHODS: In this study, we performed a cross-platform proteome- and transcriptome-wide genetic analysis aimed at evaluating the causal relevance of >2000 circulating proteins with preeclampsia, supported by data on the expression of over 15 000 genes across 36 tissues leveraging large-scale preeclampsia genetic association data from women of European ancestry. RESULTS: We demonstrate genetic associations of 18 circulating proteins with preeclampsia (SULT1A1 [sulfotransferase 1A1], SH2B3 [SH2B adapter protein 3], SERPINE2 [serpin family E member 2], RGS18 [regulator of G-protein signaling 18], PZP [pregnancy zone protein], NOTUM [notum, palmitoleoyl-protein carboxylesterase], METAP1 [methionyl aminopeptidase 1], MANEA [mannosidase endo-alpha], jun-D [JunD proto-oncogene], GDF15 [growth differentiation factor 15], FGL1 [fibrinogen like 1], FGF5 [fibroblast growth factor 5], FES [FES proto-oncogene], APOBR [apolipoprotein B receptor], ANP [natriuretic peptide A], ALDH-E2 [aldehyde dehydrogenase 2 family member], ADAMTS13 [ADAM metallopeptidase with thrombospondin type 1 motif 13], and 3MG [N-methylpurine DNA glycosylase]), among which 11 were either directly or indirectly supported by gene expression data, 9 were supported by Bayesian colocalization analyses, and 5 (SERPINE2, PZP, FGF5, FES, and ANP) were supported by all lines of evidence examined. Protein interaction mapping identified potential shared biological pathways through natriuretic peptide signaling, blood pressure regulation, immune tolerance, and thrombin activity regulation. CONCLUSIONS: This investigation identified multiple targetable proteins linked to cardiovascular, inflammatory, and coagulation pathways, with SERPINE2, PZP, FGF5, FES, and ANP identified as pivotal proteins with likely causal roles in the development of preeclampsia. The identification of these potential targets may guide the development of targeted therapies for preeclampsia.

Dose-dependent Association of Alcohol Consumption With Obesity and Type 2 Diabetes: Mendelian Randomization Analyses.

CONTEXT: Effects of modest alcohol consumption remain controversial. Mendelian randomization (MR) can help to mitigate biases due to confounding and reverse causation in observational studies, and evaluate the potential causal role of alcohol consumption. OBJECTIVE: This work aimed to evaluate dose-dependent effect of alcohol consumption on obesity and type 2 diabetes. METHODS: Assessing 408 540 participants of European ancestry in the UK Biobank, we first tested the association between self-reported alcohol intake frequency and 10 anthropometric measurements, obesity, and type 2 diabetes. We then conducted MR analyses both in the overall population and in subpopulations stratified by alcohol intake frequency. RESULTS: Among individuals having more than 14 drinks per week, a 1-drink-per-week increase in genetically predicted alcohol intake frequency was associated with a 0.36-kg increase in fat mass (SD = 0.03 kg), a 1.08-fold increased odds of obesity (95% CI, 1.06-1.10), and a 1.10-fold increased odds of type 2 diabetes (95% CI, 1.06-1.13). These associations were stronger in women than in men. Furthermore, no evidence was found supporting the association between genetically increased alcohol intake frequency and improved health outcomes among individuals having 7 or fewer drinks per week, as MR estimates largely overlapped with the null. These results withstood multiple sensitivity analyses assessing the validity of MR assumptions. CONCLUSION: As opposed to observational associations, MR results suggest there may not be protective effects of modest alcohol consumption on obesity traits and type 2 diabetes. Heavy alcohol consumption could lead to increased measures of obesity as well as increased risk of type 2 diabetes.

A phenome-wide association study (PheWAS) to identify the health impacts of 4-cresol sulfate in the Nagahama Study.

Gut-microbiota derived metabolites are important regulators of host biology and metabolism. To understand the impacts of the microbial metabolite 4-cresol sulfate (4-CS) on four chronic diseases [type 2 diabetes mellitus, metabolic syndrome (MetS), non-alcoholic fatty liver disease, and chronic kidney disease (CKD)], we conducted association analyses of plasma 4-CS quantified by liquid chromatography coupled to mass spectrometry (LC-MS) in 3641 participants of the Nagahama study. Our results validated the elevation of 4-CS in CKD and identified a reducing trend in MetS. To delineate the holistic effects of 4-CS, we performed a phenome-wide association analysis (PheWAS) with 937 intermediate biological and behavioral traits. We detected associations between 4-CS and 39 phenotypes related to blood pressure regulation, hepatic and renal functions, hematology, sleep quality, intraocular pressure, ion regulation, ketone and fatty acid metabolisms, disease history and dietary habits. Among them, 19 PheWAS significant traits, including fatty acids and 14 blood pressure indices, were correlated with MetS, suggesting that 4-CS is a potential biomarker for MetS. Consistent associations of this gut microbial-derived metabolite on multiple endophenotypes underlying distinct etiopathogenesis support its role in the overall host health, with prospects of probiotic-based therapeutic solutions in chronic diseases.

Increasing serum iron levels and their role in the risk of infectious diseases: a Mendelian randomization approach.

OBJECTIVES: Increased iron stores have been associated with elevated risks of different infectious diseases, suggesting that iron supplementation may increase the risk of infections. However, these associations may be biased by confounding or reverse causation. This is important, since up to 19% of the population takes iron supplementation. We used Mendelian randomization (MR) to bypass these biases and estimate the causal effect of iron on infections. METHODS: As instrumental variables, we used genetic variants associated with iron biomarkers in two genome-wide association studies (GWASs) of European ancestry participants. For outcomes, we used GWAS results from the UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative or 23andMe, for seven infection phenotypes: 'any infections', combined, COVID-19 hospitalization, candidiasis, pneumonia, sepsis, skin and soft tissue infection (SSTI) and urinary tract infection (UTI). RESULTS: Most of our analyses showed increasing iron (measured by its biomarkers) was associated with only modest changes in the odds of infectious outcomes, with all 95% odds ratios confidence intervals within the 0.88 to 1.26 range. However, for the three predominantly bacterial infections (sepsis, SSTI, UTI), at least one analysis showed a nominally elevated risk with increased iron stores (P <0.05). CONCLUSION: Using MR, we did not observe an increase in risk of most infectious diseases with increases in iron stores. However for bacterial infections, higher iron stores may increase odds of infections. Hence, using genetic variation in iron pathways as a proxy for iron supplementation, iron supplements are likely safe on a population level, but we should continue the current practice of conservative iron supplementation during bacterial infections or in those at high risk of developing them.

Genomic atlas of the plasma metabolome prioritizes metabolites implicated in human diseases.

Metabolic processes can influence disease risk and provide therapeutic targets. By conducting genome-wide association studies of 1,091 blood metabolites and 309 metabolite ratios, we identified associations with 690 metabolites at 248 loci and associations with 143 metabolite ratios at 69 loci. Integrating metabolite-gene and gene expression information identified 94 effector genes for 109 metabolites and 48 metabolite ratios. Using Mendelian randomization (MR), we identified 22 metabolites and 20 metabolite ratios having estimated causal effect on 12 traits and diseases, including orotate for estimated bone mineral density, α-hydroxyisovalerate for body mass index and ergothioneine for inflammatory bowel disease and asthma. We further measured the orotate level in a separate cohort and demonstrated that, consistent with MR, orotate levels were positively associated with incident hip fractures. This study provides a valuable resource describing the genetic architecture of metabolites and delivers insights into their roles in common diseases, thereby offering opportunities for therapeutic targets.

HLA allele-calling using multi-ancestry whole-exome sequencing from the UK Biobank identifies 129 novel associations in 11 autoimmune diseases.

The human leukocyte antigen (HLA) region on chromosome 6 is strongly associated with many immune-mediated and infection-related diseases. Due to its highly polymorphic nature and complex linkage disequilibrium patterns, traditional genetic association studies of single nucleotide polymorphisms do not perform well in this region. Instead, the field has adopted the assessment of the association of HLA alleles (i.e., entire HLA gene haplotypes) with disease. Often based on genotyping arrays, these association studies impute HLA alleles, decreasing accuracy and thus statistical power for rare alleles and in non-European ancestries. Here, we use whole-exome sequencing (WES) from 454,824 UK Biobank (UKB) participants to directly call HLA alleles using the HLA-HD algorithm. We show this method is more accurate than imputing HLA alleles and harness the improved statistical power to identify 360 associations for 11 auto-immune phenotypes (at least 129 likely novel), leading to better insights into the specific coding polymorphisms that underlie these diseases. We show that HLA alleles with synonymous variants, often overlooked in HLA studies, can significantly influence these phenotypes. Lastly, we show that HLA sequencing may improve polygenic risk scores accuracy across ancestries. These findings allow better characterization of the role of the HLA region in human disease.

Proteome-wide Mendelian randomization implicates nephronectin as an actionable mediator of the effect of obesity on COVID-19 severity.

Obesity is a major risk factor for Coronavirus disease (COVID-19) severity; however, the mechanisms underlying this relationship are not fully understood. As obesity influences the plasma proteome, we sought to identify circulating proteins mediating the effects of obesity on COVID-19 severity in humans. Here, we screened 4,907 plasma proteins to identify proteins influenced by body mass index using Mendelian randomization. This yielded 1,216 proteins, whose effect on COVID-19 severity was assessed, again using Mendelian randomization. We found that an s.d. increase in nephronectin (NPNT) was associated with increased odds of critically ill COVID-19 (OR = 1.71, P = 1.63 × 10-10). The effect was driven by an NPNT splice isoform. Mediation analyses supported NPNT as a mediator. In single-cell RNA-sequencing, NPNT was expressed in alveolar cells and fibroblasts of the lung in individuals who died of COVID-19. Finally, decreasing body fat mass and increasing fat-free mass were found to lower NPNT levels. These findings provide actionable insights into how obesity influences COVID-19 severity.

Year-long effects of COVID-19 restrictions on glycemic control and body composition in patients with glucose intolerance in Japan: A single-center retrospective study.

AIMS/INSTRUCTION: During the coronavirus disease 2019 (COVID-19) pandemic, the lockdowns in Europe raised concerns about negative effects on glycemic control and body composition in patients with diabetes. In Japan, voluntary-based restrictions were imposed as the declaration of a state of emergency (DSE), whose metabolic consequences have not been fully investigated. We carried out a single-center retrospective study to evaluate changes in glycemic control and body composition in outpatients with glucose intolerance after the DSE. MATERIALS AND METHODS: We enrolled outpatients with glucose intolerance: (i) for whom longitudinal data about body composition were available; (ii) who participated in dietary follow up with nutritionists; and (iii) whose laboratory data included glycated hemoglobin (HbA1c) levels before and after the DSE. RESULTS: Among 415 patients, we found no significant changes in HbA1c overall after the DSE. Bodyweight and fat mass increased significantly, whereas skeletal mass decreased significantly. HbA1c changes after the DSE were significantly correlated with changes in bodyweight and fat mass. In 128 patients whose HbA1c levels increased ≥0.3%, changes in bodyweight and fat mass were significantly larger than those in the other 287 patients. With regard to lifestyle changes, increased snacking was likely to worsen glycemic control (odds ratio 1.76, P = 0.036). CONCLUSIONS: COVID-19 restrictions in Japan had unfavorable metabolic consequences for patients with glucose intolerance, highlighted by increased bodyweight and body fat, and decreased skeletal muscle. In addition, lifestyle changes, such as increased snacking, might worsen glycemic control. Clinical attention and interventions are required to prevent such metabolic changes.