Warrington Hospital is a health facility at Warrington in Cheshire, England. It is managed by Warrington & Halton Hospitals NHS Foundation Trust.
Abstract Inflammatory bowel diseases (IBD), principally Crohn’s disease (CD) and ulcerative colitis (UC), are common chronic disorders involving inflammation and often progressive tissue damage. Genome-wide association studies have mapped many risk signals, but the causal variants, effector genes and relevant cellular contexts remain difficult to resolve, limiting mechanistic interpretation and therapeutic translation. Here we performed a multi-ancestry GWAS meta-analysis of 125,992 individuals with IBD and more than 1.2 million controls, identifying 619 independent association signals (374 novel) at 420 IBD regions that account for 77–80% of SNP-based heritability. Fine-mapping resolved 81 high-confidence variants, 41 not previously reported. Although most signals were shared between CD and UC, 39% showed IBD subtype specificity, with UC signals showing stronger enrichment in functional annotations from intestinal epithelial, secretory and enteroendocrine cells, and CD showing stronger genetic correlations with circulating inflammatory biomarkers, including C-reactive protein and glycoprotein acetylation. Latent causal modelling supported a causal effect of decreased high-density lipoprotein on CD risk. By integrating bulk and single-cell eQTL and pQTL resources using colocalisation and Mendelian randomisation, together with coding-variant evidence from exome sequencing, we prioritised 664 candidate effector genes across 341 signals, including 390 newly implicated IBD genes, revealing new biological mechanisms and candidate therapeutic targets supported by human genetics.
Autoimmune polyglandular syndromes (APS) comprise a heterogeneous group of disorders characterized by the coexistence of multiple autoimmune endocrine diseases and, frequently, additional non-endocrine autoimmune manifestations. Adult-onset APS (types 2–4) often evolves over years through sequential glandular involvement, creating a prolonged preclinical phase during which predictive biomarkers may facilitate earlier recognition and individualized surveillance. This narrative review examines the immunogenetic mechanisms underlying adult APS, evaluates the diagnostic and predictive roles of autoantibodies, and discusses emerging risk-stratified screening considerations. The review was informed by a targeted PubMed literature search of English-language publications, with emphasis on recent clinical guidelines, systematic reviews, cohort studies, landmark investigations, and key original studies relevant to adult APS, immunogenetics, autoantibody biomarkers, and screening strategies. Current evidence indicates that organ-specific autoantibodies are among the earliest detectable markers of endocrine autoimmunity and may precede clinical disease by several years. Among the available biomarkers, 21-hydroxylase autoantibodies remain the most informative marker of autoimmune adrenal insufficiency, while glutamic acid decarboxylase (GAD65) and thyroid peroxidase antibodies contribute to identifying individuals at increased risk of autoimmune diabetes and thyroid disease. Multiplex autoantibody platforms further demonstrate the potential to integrate multiple biomarkers within a single assay, supporting comprehensive immunological profiling and future risk-stratified surveillance. However, evidence supporting routine predictive screening in adults remains limited by the absence of validated risk models, standardized surveillance intervals, and prospective outcome studies. Current evidence supports targeted, phenotype-guided surveillance in selected high-risk adults rather than universal screening. Emerging multiplex autoantibody approaches may enhance individualized risk stratification and targeted monitoring but require prospective validation, cost-effectiveness evaluation, and standardized implementation before broad clinical adoption.
Abstract Background Amyotrophic lateral sclerosis (ALS) is a rare, progressive neurodegenerative disorder, with a substantial proportion of cases attributed to genetic factors. Recent advances in gene discovery and genomic technologies have transformed ALS care by enabling genomic testing to inform prognosis, assess familial risk, and facilitate access to novel therapies. However, guidance on the delivery of genetic testing and counselling in ALS remains limited, leading to variability in clinical practice. In response, the Manchester Motor Neuron Disease (MND) Care Centre and the Manchester Centre for Genomic Medicine co-developed a structured genetic care pathway for ALS, drawing on real-world data, patient engagement, and multidisciplinary collaboration. Results A retrospective evaluation of 326 ALS patients at the Manchester MND Care Centre identified significant variability in genetic testing uptake, counselling practices, and record-keeping. Patient survey and engagement sessions revealed uncertainty regarding key genetic concepts and inconsistent recall of pre- and post-test discussions. Priorities for improvement included clearer communication, standardised discussions, and enhanced support for families following genetic findings. Consequently, the Greater Manchester ALS Genetic Testing Pathway was developed by a multidisciplinary team, incorporating consensus-based steps for patient identification, pre-test conversations, consent, testing, results disclosure, and post-test support. This pathway integrates genetic testing into routine ALS care, clarifies team responsibilities, and establishes a framework for ongoing evaluation using key performance indicators. Patient and staff feedback is used to support continuous improvement. Conclusions The co-developed ALS genetic testing pathway provides a scalable model for standardising genomic care in mainstream clinical settings. By establishing clear processes for genetics discussions, consent, and follow-up, the pathway seeks to improve equity, transparency, and person-centred care. Ongoing evaluation and collaboration with patients, clinicians, and genetic services are essential to ensure the pathway remains responsive to scientific advances and evolving patient needs. Wider adoption of structured genetic pathways may facilitate the integration of genomics into care for rare diseases across healthcare systems.
Heart failure (HF) is a major cause of morbidity and mortality worldwide and is frequently associated with dysfunction of other organs, including the liver. Hepatic congestion and impaired perfusion from cardiac dysfunction may lead to liver injury, described as cardiohepatic syndrome. Studies suggest that liver dysfunction markers, such as the Model for End-Stage Liver Disease (MELD) and MELD excluding international normalized ratio (MELD-XI) scores, may serve as prognostic indicators in HF patients. This systematic review and meta-analysis evaluated the relationship between liver dysfunction markers and mortality outcomes in HF patients. A systematic literature search was conducted. Studies evaluating the association between liver dysfunction markers (MELD or MELD-XI scores) and mortality outcomes in adult HF patients were included. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using the generic inverse variance method with a random-effects model in Review Manager (RevMan) version 5.4 (The Cochrane Collaboration, Copenhagen, Denmark). Subgroup analyses were performed by liver dysfunction marker type and HF phenotype. The primary outcome was all-cause mortality. Nine studies comprising over 32,000 HF patients were included. Elevated liver dysfunction markers were significantly associated with increased mortality risk (pooled HR = 1.12, 95% CI 1.06-1.18). Substantial heterogeneity was observed (I² = 91%). Subgroup analysis showed significant associations for both MELD-XI (HR = 1.09, 95% CI 1.04-1.14) and MELD scores (HR = 1.10, 95% CI 1.06-1.14). Analysis by HF type revealed significant associations in acute HF (HR = 1.07), chronic HF (HR = 1.23), and advanced HF (HR = 1.05). Sensitivity analyses confirmed the findings, with no substantial publication bias observed. Elevated liver dysfunction markers significantly correlate with increased mortality in HF patients. Both MELD and MELD-XI scores provide prognostic information across HF populations. These findings emphasize the importance of considering hepatic dysfunction in HF assessment and suggest liver dysfunction markers may aid risk stratification. Further prospective studies are needed to determine the role of these markers in clinical decision-making.
