Abstract Introduction Sleep and circadian disturbances are highly prevalent in autism spectrum disorder (ASD), yet the mechanisms linking ASD risk genes to human sleep/circadian physiology remain unclear. Advances in single-cell expression quantitative trait loci (eQTL) datasets now enable testing of gene and cell-type-specific relationships with sleep traits. Methods We intersected the SPARK/ClinGen list of 162 ASD risk genes with cell-type–specific cis-eQTLs (N=983), yielding 111 genes with suitable instruments across seven brain cell types and 24 neuronal and glial sub-classes. These cis-eQTLs were used as expression proxies in a drug-target Mendelian randomization (DTMR) framework to estimate causal relationships with UK Biobank sleep traits (chronotype, sleep duration, ease of getting up, snoring; N≤413,343) under multiple-testing correction. To further prioritize ASD sleep–circadian genes, we triangulated DTMR findings with (i) postmortem human dorsolateral prefrontal cortex (dlPFC) time-series transcriptomics, and (ii) Drosophila RNAi circadian phenotyping. Results Across sleep outcomes, 12 ASD risk genes exhibited Bonferroni-significant, cell-type–specific relationships, primarily for chronotype (11 genes) and ease of getting up (5 genes). BCL11A showed concordant and opposite-direction chronotype associations across excitatory neurons, interneurons, and oligodendrocyte progenitors. RELN demonstrated robust chronotype associations across five neuronal and glial subclasses, strongest in interneurons. MEF2C displayed large chronotype relationships in homeostatic microglia and opposite-direction getting-up effects in activated microglia. Several Bonferroni- or FDR-significant genes (ACTB, EHMT1, DNMT3A, SETBP1, SHANK2, MAGEL2, IRF2BPL, CACNA1C, MEIS2) also displayed rhythmic or clock-regulated expression in dlPFC cell types, supporting conserved circadian roles. Further, Drosophila homologs of ASD genes such as NBEA, PHF3, PSMD12, and RERE produced canonical circadian phenotypes with complementary human MR associations. Although no ASD gene was implicated across all three systems, several showed convergent evidence across human genetics, brain circadian regulation, and Drosophila screening. Conclusion Integrating human genetic, transcriptomic, and cross-species functional evidence reveals that ASD risk genes exert cell-type–specific impact on human sleep and circadian traits, especially chronotype, highlighting conserved molecular pathways linking ASD genetics to sleep–circadian biology. Support (if any) SFARI, Eagles Autism Foundation, NINDS R35NS132223 (RA, GW, BL)

Sleep is essential for health and regulated by genetic and environmental factors. We perform genome-wide association studies of device-measured sleep duration, efficiency, and accelerometer-derived rapid eye movement (REM) and non-rapid eye movement (NREM) sleep in 80,013 UK Biobank participants. We identify 20 autosomal loci, 12 of which have not been previously reported, including genome-wide significant associations for REM and NREM sleep duration. MEIS1 shows strong opposing effects on REM and NREM durations and is intolerant to loss-of-function mutations, suggesting an essential role in the regulation of REM/NREM sleep balance. Functional enrichment analysis identifies statistically significant pathways related to chromatin remodelling, lipid metabolism, and metal ion homeostasis while tissue enrichment analysis highlights significant signals in the hypothalamus and frontal cortex. Sex-stratified analyses identify distinct loci, including FOXP2 and NRXN3 in females and LRP1B, NPBWR2, and PABPC4 in males. Mendelian randomization supports associations between shorter sleep duration and higher cardiometabolic risk. These findings highlight sex- and phase-specific regulators of human sleep architecture, providing biological insights and potential therapeutic targets.

The circadian clock is an intrinsic molecular system that synchronises biological processes with daily environmental cycles. Under physiological conditions, cell-intrinsic clocks and systemic cues together regulate the circadian rhythmicity of immune activity, limiting immune responses to the appropriate time and intensity for optimal energy allocation and fitness. In chronic inflammation, by contrast, persistent and profound circadian alterations may cause a pro-inflammatory shift of homeostasis and hinder resolution. Circadian-based therapeutic strategies are emerging as promising approaches to overcome the limitations of conventional anti-inflammatory therapeutics and relieve treatment burden. This Review examines the bi-directional relationship between circadian regulation and chronic inflammation across immune-mediated, metabolic and infectious conditions. Circadian rhythms shape the timing, severity and tissue specificity of inflammatory responses, while inflammatory signals from diverse pathological settings converge on shared transcriptional nodes that interface with the clock, altering temporal organisation across multiple systems. We further highlight key future directions, including defining the molecular links between the circadian clock, inflammation and metabolism for precise target identification, restoring the intrinsic capacity for temporal homeostatic regulation through personalised circadian medicine, and integrating behavioural and environmental factors into the current framework. Together, they represent a path towards more precise, preventive and holistic management of chronic inflammatory diseases.

STUDY OBJECTIVES:Our study introduced the 2023 UK Biobank sleep questionnaire and described variation in sleep health dimensions and the prevalence of disordered sleep. METHODS:A questionnaire comprising validated measures and bespoke items was developed to capture key self-reported domains of sleep health and symptoms of sleep disorders. We quantified cohort prevalence of operationally defined sleep disorders and assessed the patterning of sleep health dimensions across key sociodemographic and clinically relevant variables. RESULTS:A total of 183 704 individuals completed at least one module of the questionnaire after email invitation (representing 56 per cent of those with an active email address), and an additional 1352 individuals completed via the participant website. In total 185 056 individuals were included in the analysis. Respondents were predominantly from a White ethnic background (96.8%), had a mean age of 69.9 (SD, 7.5) years, 57.9 per cent were female, and 25.5 per cent were in employment. Compared to non-respondents, respondents were more likely to be female, tended to be better educated, healthier, and exhibit lower levels of socioeconomic deprivation, although baseline sleep variables were similar between respondents and non-respondents. Around 40 per cent of respondents reported sleep duration less than 7 h, and 49 per cent reported poor sleep quality (Pittsburgh Sleep Quality Index >5). Approximately one-quarter (25.2%) met the criteria for at least one operationally defined sleep disorder, with insomnia being the most common (14.4%) followed by obstructive sleep apnea (8.0%), restless legs syndrome (4.1%), and frequent nightmares (3.7%). Sleep disorders were associated with higher levels of anxiety, depression, fatigue, and cognitive complaints. CONCLUSIONS:Poor sleep quality and operationally defined sleep disorders are common in the UK Biobank cohort. Sleep questionnaire data can now be integrated with a range of biomedical information to advance understanding of sleep.

BACKGROUND & AIMS:Fibroblast growth factor 21 (FGF21) analogs are in development for metabolic dysfunction-associated steatotic liver disease (MASLD), but their impact on problematic alcohol use (PAU), alcohol use disorder, binge drinking, and alcohol-related liver disease (ALD) is unknown. METHODS:We leveraged genome-wide association study data from the UK Biobank, FinnGen, Million Veterans Program, and GenomALC for PAU, alcohol use disorder, binge drinking, weekly drinks, and ALD. Our four-tier evaluation included: (1) multivariable Mendelian randomization (MR) and mediation with circulating FGF21 levels; (2) comparative MR of MASLD and ALD targets (PNPLA3, TM6SF2, HSD17B13) using liver fat and expression instruments; (3) receptor-focused MR of β-Klotho (KLB) and FGFR1/2/3 incorporating brain-region expression; and (4) a phenome-wide MR across 1,022 traits to assess safety. RESULTS:Genetically higher FGF21 protein levels were associated with lower PAU (β = -0.097, 95% CI -0.135 to -0.059, p = 6.13 × 10-7), fewer binge episodes, reduced drinking, and lower ALD risk (odds ratio [OR] = 0.79, 95% CI 0.638-0.987, p = 0.038). Multivariable MR and mediation attributed these effects entirely to behavioral pathways (reduced drinking, improved diet) and increased basal metabolic rate. In comparative MR, FGF21 - unlike PNPLA3, or HSD17B13 - reduced alcohol outcomes: a 1-SD rise in hepatic FGF21 expression reduced PAU (β = -0.245, 95% CI -0.409 to -0.082, p = 0.003) and ALD (OR = 0.54, 95% CI 0.417-0.697, p = 2.44×10-6) risk. Receptor analyses implicated hippocampal FGFR3 (OR = 0.909, 95% CI 0.876-0.943, p = 4.28 × 10-7) and basal ganglia KLB expression, supporting a liver-brain axis. Phenome-wide MR uncovered 28 Bonferroni-significant protective associations with higher FGF21 (e.g. gout). Hepatic FGF21 expression showed fewer on-target liabilities than HSD17B13 or PNPLA3. CONCLUSIONS:Human genetic evidence indicates that FGF21 analogs mitigate hazardous drinking and ALD via both behavioral and metabolic pathways. These findings distinguish FGF21 from other MASLD targets and highlight its potential for precision treatment of alcohol-related disorders. IMPACT AND IMPLICATIONS:This study leverages human genetic evidence to validate FGF21 - a liver-derived hormone currently in clinical trials for fatty liver disease - as a dual-action therapeutic that both curbs harmful drinking behaviors and protects against alcohol-related liver injury, addressing a critical therapeutic gap with limited existing pharmacotherapies. The results are important for clinicians and researchers seeking precision medicine strategies for alcohol use disorder and liver disease, as well as for patients who currently face limited treatment options. By pinpointing FGF21's behavioral and metabolic pathways and demonstrating a favorable safety profile, our findings support the repurposing of FGF21 analogs in clinical trials of alcohol use disorder and alcohol-related liver disease and suggest that genetic stratification could optimize patient selection for therapy. While these conclusions rely on European-ancestry genetic data and Mendelian randomization assumptions, they help inform future clinical studies, biomarker development, and policy efforts aimed at expanding treatment options for alcohol-related conditions.

The basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) proteins BMAL1 and CLOCK heterodimerize to form the master transcription factor governing rhythmic gene expression. Owing to connections between circadian regulation and numerous physiological pathways, targeting the BMAL1-CLOCK complex pharmacologically is an attractive entry point for intervening in circadian-related processes. In this study, we developed a small molecule, Core Circadian Modulator (CCM), that targets the cavity in the PASB domain of BMAL1, causing it to expand, leading to conformational changes in the PASB domain and altering the functions of BMAL1 as a transcription factor. Biochemical, structural and cellular investigations validate the high level of selectivity of CCM in engaging BMAL1, enabling direct access to BMAL1-CLOCK cellular activities. CCM induces dose-dependent alterations in PER2-Luc oscillations and orchestrates the downregulation of inflammatory and phagocytic pathways in macrophages. These findings collectively reveal that the BMAL1 protein architecture is inherently configured to enable the binding of chemical ligands for functional modulation.

Rationale:Asthma is more common in females and more common in night shift workers. Since increasing numbers of females are becoming shift workers, it is important to determine if the risk of shift work-associated asthma is higher in females. The objective of the present study was to determine if increasing frequency of shift work is more strongly related to prevalent asthma in females than in males. Method:We used cross-sectional data from >280 000 UK Biobank participants and logistic regression models adjusted for demographic and lifestyle factors to describe sex differences in prevalent asthma phenotypes related to shift work frequency. To obtain mechanistic insights, we explored associations with chronotype, sex hormones and menopause. Results:Female permanent night shift workers had higher covariate-adjusted odds of moderate-severe asthma (odds ratio (OR) 1.50, 95% confidence interval (CI) 1.18-1.91) than female dayworkers, but there was no corresponding relationship among males (OR 0.95, 95% CI 0.72-1.26; sex interaction p-value=0.01). Similar relationships were observed for "all asthma" and for "wheeze or whistling in the chest". Female shift work-related asthma was driven by relationships in postmenopausal women not using hormone replacement therapy (HRT) (adjusted OR 1.89 (95% CI 1.24-2.87) for moderate-severe asthma; sex interaction p-value=0.02 in permanent night shift workers, compared with dayworkers), but these relationships attenuated to the null in postmenopausal women using HRT. Conclusion:Our finding that increasing shift work frequency is more strongly related to asthma in females than in males could have public health implications. Intervention studies should determine if modifying shift work schedules or using HRT can reduce asthma risk in females.

Shift work can result in sleepiness, increasing risks of accidents, absenteeism and illness. Systematic reviews have examined individually-directed non-pharmacological interventions (e.g., light therapy, napping) for shift workers, but the diversity of interventions, settings and review conclusions make it difficult to determine which interventions work. We conducted a systematic review of systematic reviews to appraise evidence for such interventions to improve sleep or reduce sleepiness in shift workers. Six databases were searched and screened with good reliability. Two reviewers independently extracted data from all identified reviews, and a narrative synthesis was conducted. Twenty-eight systematic reviews were included, containing 69 primary studies involving 4947 participants. Twenty-three reviews were critically low-quality. The most-investigated interventions were light therapy (n = 8 reviews) and napping (n = 7 reviews). High-quality reviews suggested inconclusive evidence for which interventions improved sleep quality, sleep quantity and subjective sleepiness in shift workers, although lower quality reviews indicated light therapy, napping, physical activity, dietary supplements, mobile health apps and mindfulness may be effective. We have identified several promising interventions to improve sleep or reduce sleepiness in shift workers, although none met high-quality thresholds. More rigorous and high-quality trials should focus on these promising interventions.

BACKGROUND:Asthma demonstrates a robust daily rhythm, with airflow obstruction and airway inflammation peaking overnight. Aligning the timing of drug administration with rhythms in disease (chronotherapy) may improve therapeutic efficacy. We aimed to evaluate the impact of dosage timing for inhaled corticosteroids in asthma. METHODS:This is a randomised three-way crossover trial. Participants with mild to moderate atopic asthma were randomised to beclometasone dipropionate: (1) 400 µg once daily between 08:00 and 09:00 (ODAM); (2) 400 µg once daily between 15:00 and 16:00 (ODPM); and (3) 200 µg twice daily between 08:00 and 09:00 and between 20:00 and 21:00 (BD) for 28 days, with a 2 week washout period in between treatment periods. Six-hourly spirometry and biomarkers were measured over 24 hours following the run-in period and at the end of each treatment period. RESULTS:Of 25 participants, 21 completed all regimens. ODPM was superior in improving 22:00 FEV1 (median (IQR): +160 (+70, +270) ml) compared with ODAM (-20 (-80, +230) ml) and BD (+80 (-20, +200) ml). ODPM resulted in better overnight (22:00 and 04:00) suppression in blood eosinophil counts compared with BD and ODAM. All regimens improved asthma control and reduced fractional exhaled nitric oxide and serum cortisol levels with no difference among dosing regimens. CONCLUSION:ODPM better suppresses the nocturnal dip in lung function and peak of blood eosinophil counts compared with BD and ODAM; this was without an increase in adverse events. Future trials are warranted to validate these findings in real-life settings and to determine which population may best benefit from chronotherapy.

ABSTRACT The prevalence of type 2 diabetes (T2D) varies among populations of different race/ethnicity. The influence of genetically-proxied lipoprotein cholesterol (LDL-C) lowering through proprotein convertase subtilisin/kexin 9 (PCSK9) and HMG-CoA Reductase (HMGCR) on T2D in non-European populations is not well established.A drug-target Mendelian randomization (MR) approach was used to assess the effects of PCSK9 and HMGCR inhibition on T2D risk and glycemic traits in five populations: East Asian (EAS), South Asian (SAS), Hispanic (HISP), African (AFR), and European (EUR). Our study did not find relationships between genetically-proxied PCSK9 inhibition and T2D risk in EAS (odds ratio [OR]=1.02, [0.95-1.10]), SAS (OR=1.05, [0.97-1.14]), HISP (OR=1.03, [0.94-1.12]), or EUR (OR=1.04, [0.98-1.11]). However, in AFR, primary analyses suggested an increased risk of T2D due to PCSK9 inhibition (OR=1.53, [1.058-2.22], P-value=0.024), although this was not supported in sensitivity analyses. Genetically-proxied HMGCR inhibition was associated with an increased risk of T2D in SAS (OR=1.44, [1.30-1.61], P-value=9.8×10-12), EAS (OR=1.36, [1.22-1.51], P-value=4.2×10-10), and EUR (OR=1.52, [1.21-1.90], P-value=3.3×10-4). These results were consistent across various sensitivity analyses, including colocalization, indicating a robust finding. The findings indicate a neutral impact of long-term PCSK9 inhibition on T2D and glycemic markers in most non-European populations, with a potential increased risk in AFR cohorts. By contrast, HMGCR inhibition increased the risk of T2D in South Asian, East Asian, and European cohorts, underscoring the need to consider diversity in genetic research on metabolic diseases. ARTICLE HIGHLIGHTS o This study investigates the impact of lipid-lowering therapies, specifically PCSK9 and HMGCR inhibition, on type 2 diabetes (T2D) risk across diverse populations using Mendelian randomization (MR) analyses. o We found no adverse effect of PCSK9 inhibition on T2D risk in EAS, SAS, HISP, or EUR populations, though weak evidence of increased risk was seen in AFR, which was not robust in sensitivity analyses. o HMGCR inhibition was associated with a slight increase in T2D risk, consistent with previous findings, but the cardiovascular benefits of statin therapy likely outweigh this risk.

OBJECTIVE:Shift work is common across most societies but poses significant risks to the health of shift workers. In part, this risk is due to the disruption of healthy sleep-wake schedules. This systematic review identified qualitative research on shift workers' experiences of sleep disturbance, fatigue and healthy behaviors. METHODS:We conducted a systematic search of four databases (CINAHL, EMBASE, MEDLINE, PsycINFO) and identified 28 eligible studies involving 1519 participants. We appraised the studies using an adapted Critical Appraisal Skills Programme (CASP) checklist, and confidence in the review findings was formally assessed using the Grading of Recommendations Assessment, Development and Evaluation-Confidence in the Evidence from Reviews of Qualitative research (GRADE-CERQual) approach. Data were thematically synthesized. RESULTS:Three analytical themes were generated. 'Inevitability of fatigue and tiredness' outlines how shift workers experience a culture where they feel "peer pressure to soldier through" their shifts regardless of fatigue. 'Balancing sleep needs with competing responsibilities' highlights how shift workers struggle to balance the need for daytime sleep with family, leisure, and work responsibilities, often prioritizing family needs over their own sleep. 'Obstacles to engaging in healthy behaviors' describes how shift workers often know which actions would benefit their health and reduce fatigue but find it challenging to translate this knowledge into behavior due to fatiguing and stressful work environments. For the purposes of the GRADE-CERQual assessment, short summary statements were developed to describe 22 review findings: there was moderate or high confidence in all but one of these findings. CONCLUSION:This review suggests that sleep education alone is unlikely to be effective. Interventions should focus on helping shift workers self-regulate their behaviors, thoughts, and emotions to better manage sleep and fatigue.

Dosage timings of inhaled corticosteroids and time of day are both important confounders for exhaled VOC levels in asthma. These factors must be appropriately accounted for at the biomarker discovery stage, allowing for external validation of findings. https://bit.ly/435BQtt.

Using 13C6 glucose labeling coupled to gas chromatography-mass spectrometry and 2D 1H-13C heteronuclear single quantum coherence NMR spectroscopy, we have obtained a comparative high-resolution map of glucose fate underpinning β cell function. In both mouse and human islets, the contribution of glucose to the tricarboxylic acid (TCA) cycle is similar. Pyruvate fueling of the TCA cycle is primarily mediated by the activity of pyruvate dehydrogenase, with lower flux through pyruvate carboxylase. While the conversion of pyruvate to lactate by lactate dehydrogenase (LDH) can be detected in islets of both species, lactate accumulation is 6-fold higher in human islets. Human islets express LDH, with low-moderate LDHA expression and β cell-specific LDHB expression. LDHB inhibition amplifies LDHA-dependent lactate generation in mouse and human β cells and increases basal insulin release. Lastly, cis-instrument Mendelian randomization shows that low LDHB expression levels correlate with elevated fasting insulin in humans. Thus, LDHB limits lactate generation in β cells to maintain appropriate insulin release.

HomeCirculation: Genomic and Precision MedicineVol. 17, No. 1Evaluating the Cardiovascular Impact of Genetically Proxied PCSK9 and HMGCR Inhibition in East Asian and European Populations: A Drug-Target Mendelian Randomization Study No AccessResearch ArticleRequest AccessFull TextAboutView Full TextView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toNo AccessResearch ArticleRequest AccessFull TextEvaluating the Cardiovascular Impact of Genetically Proxied PCSK9 and HMGCR Inhibition in East Asian and European Populations: A Drug-Target Mendelian Randomization Study Daniel B. Rosoff, Andrew S. Bell, Lucas A. Mavromatis, Ali Hamandi, Lauren Park, Jeesun Jung, Josephin Wagner, Pal Pacher, David Ray, George Davey Smith and Falk W. Lohoff Daniel B. RosoffDaniel B. Rosoff https://orcid.org/0000-0002-5718-7668 Section on Clinical Genomics and Experimental Therapeutics (D.B.R., A.S.B., L.A.M., A.H., L.P., J.J., J.W., F.W.L.), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health (NIH), Bethesda, MD. NIH-Oxford-Cambridge Scholars Program, University of Oxford, United Kingdom (D.B.R.). Medical Research Council Integrative Epidemiology Unit, University of Bristol, United Kingdom (D.B.R., G.D.S.). , Andrew S. BellAndrew S. Bell https://orcid.org/0000-0003-2497-9420 Section on Clinical Genomics and Experimental Therapeutics (D.B.R., A.S.B., L.A.M., A.H., L.P., J.J., J.W., F.W.L.), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health (NIH), Bethesda, MD. , Lucas A. MavromatisLucas A. Mavromatis https://orcid.org/0000-0003-2921-4654 Section on Clinical Genomics and Experimental Therapeutics (D.B.R., A.S.B., L.A.M., A.H., L.P., J.J., J.W., F.W.L.), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health (NIH), Bethesda, MD. , Ali HamandiAli Hamandi Section on Clinical Genomics and Experimental Therapeutics (D.B.R., A.S.B., L.A.M., A.H., L.P., J.J., J.W., F.W.L.), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health (NIH), Bethesda, MD. , Lauren ParkLauren Park https://orcid.org/0009-0003-6958-2539 Section on Clinical Genomics and Experimental Therapeutics (D.B.R., A.S.B., L.A.M., A.H., L.P., J.J., J.W., F.W.L.), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health (NIH), Bethesda, MD. , Jeesun JungJeesun Jung https://orcid.org/0000-0002-2668-5541 Section on Clinical Genomics and Experimental Therapeutics (D.B.R., A.S.B., L.A.M., A.H., L.P., J.J., J.W., F.W.L.), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health (NIH), Bethesda, MD. , Josephin WagnerJosephin Wagner https://orcid.org/0000-0002-8880-5721 Section on Clinical Genomics and Experimental Therapeutics (D.B.R., A.S.B., L.A.M., A.H., L.P., J.J., J.W., F.W.L.), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health (NIH), Bethesda, MD. , Pal PacherPal Pacher https://orcid.org/0000-0001-7036-8108 Laboratory of Cardiovascular Physiology and Tissue Injury (P.P.), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health (NIH), Bethesda, MD. , David RayDavid Ray https://orcid.org/0000-0002-4739-6773 Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, United Kingdom (D.R.). National Institute for Health and Care Research Oxford Biomedical Research Centre, John Radcliffe Hospital, United Kingdom (D.R.). , George Davey SmithGeorge Davey Smith https://orcid.org/0000-0002-1407-8314 Medical Research Council Integrative Epidemiology Unit, University of Bristol, United Kingdom (D.B.R., G.D.S.). and Falk W. LohoffFalk W. Lohoff Correspondence to: Falk W. Lohoff, MD, Section on Clinical Genomics and Experimental Therapeutics, Lasker Clinical Research Scholar, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 10 Center Dr (10CRC/2-2352), Bethesda, MD 20892. Email E-mail Address: [email protected] https://orcid.org/0000-0002-0480-7755 Section on Clinical Genomics and Experimental Therapeutics (D.B.R., A.S.B., L.A.M., A.H., L.P., J.J., J.W., F.W.L.), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health (NIH), Bethesda, MD. Originally published23 Jan 2024https://doi.org/10.1161/CIRCGEN.122.004224Circulation: Genomic and Precision Medicine. 2024;17FootnotesFor Sources of Funding and Disclosures, see page 62.Correspondence to: Falk W. Lohoff, MD, Section on Clinical Genomics and Experimental Therapeutics, Lasker Clinical Research Scholar, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 10 Center Dr (10CRC/2-2352), Bethesda, MD 20892. Email falk.lohoff@nih.govREFERENCES1. Meadows TA, Bhatt DL, Cannon CP, Gersh BJ, Röther J, Goto S, Liau CS, Wilson PWF, Salette G, Smith SC, et al; REACH Registry Investigators. Ethnic differences in cardiovascular risks and mortality in atherothrombotic disease: insights from the Reduction of Atherothrombosis for Continued Health (REACH) registry.Mayo Clin Proc. 2011; 86:960–967. doi: 10.4065/mcp.2011.0010CrossrefMedlineGoogle Scholar2. Clark LT, Watkins L, Piña IL, Elmer M, Akinboboye O, Gorham M, Jamerson B, McCullough C, Pierre C, Polis AB, et al. Increasing diversity in clinical trials: overcoming critical barriers.Curr Probl Cardiol. 2019; 44:148–172. doi: 10.1016/j.cpcardiol.2018.11.002CrossrefMedlineGoogle Scholar3. Michos ED, Reddy TK, Gulati M, Brewer LC, Bond RM, Velarde GP, Bailey AL, Echols MR, Nasser SA, Bays HE, et al. Improving the enrollment of women and racially/ethnically diverse populations in cardiovascular clinical trials: an ASPC practice statement.Am J Prev Cardiol. 2021; 8:100250. doi: 10.1016/j.ajpc.2021.100250CrossrefMedlineGoogle Scholar4. Schmidt AF, Finan C, Gordillo-Marañón M, Asselbergs FW, Freitag DF, Patel RS, Tyl B, Chopade S, Faraway R, Zwierzyna M, et al. Genetic drug target validation using Mendelian randomisation.Nat Commun. 2020; 11:3255–3255. doi: 10.1038/s41467-020-16969-0CrossrefMedlineGoogle Scholar5. Da Dalt L, Castiglioni L, Baragetti A, Audano M, Svecla M, Bonacina F, Pedretti S, Uboldi P, Benzoni P, Giannetti F, et al. PCSK9 deficiency rewires heart metabolism and drives heart failure with preserved ejection fraction.Eur Heart J. 2021; 42:3078–3090. doi: 10.1093/eurheartj/ehab431CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. 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Abstract Human genetic and transgenic mouse studies have highlighted a potential liver-adipose tissue endocrine axis, involving activin C (Act-C) and/or Act-E and ALK7, influencing fat distribution and systemic metabolism. We investigated the bidirectional effects between circulating INHBC, which homodimerizes into Act-C, and adiposity traits, insulin resistance, inflammation, and cardiometabolic disease risk. Additionally, we examined if Act-C is an ALK7 ligand in human adipocytes. We used Mendelian randomization and in vitro studies in immortalized human abdominal and gluteal adipocytes. Circulating INHBC was causally linked to reduced lower-body fat, dyslipidaemia, and increased risks of coronary artery disease (CAD) and non-alcoholic fatty liver disease (NAFLD). Conversely, upper-body fat distribution, obesity, hypertriglyceridemia, subclinical inflammation, and type 2 diabetes positively impacted plasma INHBC levels. Mechanistically, an atherogenic lipid profile may partly explain the INHBC-CAD link, while inflammation and hypertriglyceridemia may partly explain how adiposity traits affect circulating INHBC. Phenome-wide Mendelian randomization showed weak causal relationships between higher plasma INHBC and impaired kidney function and higher gout risk. In human adipocytes, recombinant Act-C activated SMAD2/3 signaling via ALK7 and suppressed lipolysis. In summary, INHBC influences systemic metabolism by activating ALK7 in adipose tissue and may serve as a drug target for atherogenic dyslipidemia, CAD, and NAFLD. Article Highlights · We explored the bidirectional relationships between circulating INHBC and cardiometabolic traits and diseases, and investigated whether activin C, an INHBC homodimer, acts as an ALK7 ligand in human adipocytes. · Elevated circulating INHBC was linked to dyslipidemia, increased coronary artery disease and non-alcoholic fatty liver disease risk. Conversely, upper-body obesity, hypertriglyceridemia, inflammation, and diabetes increased circulating INHBC, potentially creating a vicious cycle. Activin C activated ALK7 signaling in adipocytes and suppressed lipolysis. · INHBC is a novel hepatokine influencing systemic metabolism and a potential drug target for cardiometabolic diseases.

Rheumatoid arthritis is a chronic inflammatory disease that shows characteristic diurnal variation in symptom severity, where joint resident fibroblast-like synoviocytes (FLS) act as important mediators of arthritis pathology. We investigate the role of FLS circadian clock function in directing rhythmic joint inflammation in a murine model of inflammatory arthritis. We demonstrate FLS time-of-day-dependent gene expression is attenuated in arthritic joints, except for a subset of disease-modifying genes. The deletion of essential clock gene Bmal1 in FLS reduced susceptibility to collagen-induced arthritis but did not impact symptomatic severity in affected mice. Notably, FLS Bmal1 deletion resulted in loss of diurnal expression of disease-modulating genes across the joint, and elevated production of MMP3, a prognostic marker of joint damage in inflammatory arthritis. This work identifies the FLS circadian clock as an influential driver of daily oscillations in joint inflammation, and a potential regulator of destructive pathology in chronic inflammatory arthritis.