Disease Phenotype Research Articles

Cancer predisposition syndromes (CPS) with pediatric onset are the leading known cause of childhood malignancies and are increasingly guiding clinical strategies in pediatric oncology. CPS are placed under evolutionary negative selective pressure, but pediatric pancancer studies have so far failed to investigate genomic evolutionary metrics as a guide to predict penetrance and reveal novel CPS. Germline whole-genome sequencing was performed in a 5-year prospective, registry-validated, nationwide cohort of individuals diagnosed with cancer before age 18. Evolution-guided burden analysis of private germline variants in constrained genes was compared with 125,748 gnomAD exomes. Across a total of 1,127 participants, 16% carried a pathogenic variant in at least one CPS gene. After genotype-phenotype matching, 9% of children in the prospective cohort (n = 651) carried a variant considered causative, a rate deemed significantly higher than in previous studies [RR, 1.54, 95% confidence interval (CI), 1.37-1.75, P = 1 × 10-14]. As predicted for a disease subject to negative Darwinian selective pressure, compared with reference adults, we found a significant excess of loss-of-function (LoF) variants in the 1,500 most constrained genes (RR, 1.54, 99% CI, 1.21-1.95, P = 4 × 10-6). Surprisingly, this excess was greater than expected, leaving a significant residual enrichment of predicted LoF variants in genes evolutionarily considered the least tolerant to damage (RR, 1.41, 99% CI, 1.09-1.80, P = 4 × 10-4). The high frequency of LoF variants, including in known CPS, emphasizes the need for systematic and extensive germline genomic mapping as part of the diagnostic workup of patients with childhood cancer and the linkage of such data to disease and response phenotypes to guide future pediatric oncological care and ultimately pave the way for prediagnostic interventional measures.

BackgroundThis study evaluated observational and causal relationships between rheumatoid arthritis (RA) and cardiovascular disease and imaging phenotypes in the UK Biobank.MethodsRA was defined using linked hospital records, self-reported diagnostics, and medication data. Controls were participants without a record of RA. Cardiovascular diseases (CVDs) were defined using linked hospital records over an average of 14 years of prospective follow-up, including: ischaemic heart diseases (IHD), acute myocardial infarction (AMI), atrial fibrillation, any arrhythmia, non-ischaemic cardiomyopathies, pericardial disease, stroke, peripheral vascular disease, and venous thromboembolism. For participants with cardiovascular magnetic resonance (CMR) available as part of the UK Biobank Imaging Study, we considered measures of cardiac structure and function extracted using automated pipelines. Associations of RA with prevalent and incident CVDs were calculated using logistic and Cox regression. Linear regression was used to examine associations with CMR metrics. Models were adjusted for demographic, lifestyle, and clinical confounders. Causal associations were assessed using two-sample Mendelian randomisation. Genetic instruments for RA (22,350 cases and 74,823 controls), nine CVDs (FinnGen, n = 224,737), and 11 CMR phenotypes (UK Biobank) were extracted and associations assessed using inverse-variance weighting with pleiotropy adjustments and multiple testing corrections.ResultsThe analysis included 1,436 RA cases (mean age 59.9 years; 70.6% female) and 476,975 controls (mean age 56.5 years; 54.3% female). Participants with RA lived in more socioeconomically deprived areas (as per the Townsend Deprivation Index), had lower physical activity levels, were more likely to smoke, and had a higher baseline prevalence of CVDs. In fully adjusted models, participants with RA had a significantly higher hazard of multiple incident CVDs, with the greatest risks related to pericardial disease (HR 2.63 (1.85, 3.74)), heart failure (HR 1.68 (1.42, 1.99)), and AMI (HR 1.53 (1.20, 1.96)). Mendelian Randomisation analyses supported causal links between RA and AMI (OR 1.07 (1.02, 1.09), p = 0.009), arrhythmias (OR 1.05 (1.02, 1.06), p = 0.0007), and IHD (OR 1.05 (1.01, 1.06), p = 0.036). No significant associations were identified between RA and CMR phenotypes.ConclusionsPeople with RA have a heightened risk of multiple prevalent and incident CVDs, independent of shared risk factors, with suggestions of causal links with IHD, AMI, and arrhythmias.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12916-025-04431-1.

Novel mutations in MTERF3: First report of a new genetic cause in two Chinese patients with developmental delay, intermittent hypoglycemia and metabolic acidosis.

Abstract Introduction Childhood-onset systemic lupus erythematosus (cSLE) is a chronic, multi-system autoimmune disease, with variable clinical and immunological presentations. Disease phenotype and severity can vary significantly between patients. cSLE tends to be more severe and aggressive than adult-onset disease; yet early disease recognition and diagnosis can be challenging due to its heterogeneous presentation and overlap with other paediatric conditions. We report a case of cSLE in an 11-year-old boy, highlighting the diagnostic and treatment challenges faced. Our case demonstrates the importance of cross-specialty and multi-disciplinary team work to aide diagnosis and treatment choices, in order to limit damage accrual and improve outcomes. Case description 11-year-old, male, Pakistani heritage, UK-born, non-consanguineous parents PC • Admission to local hospital with 1-month history of daily fever (max 41 °C), loose stool, severe abdominal pain • Transferred to GOSH for multi-team review (Gastroenterology / Infectious Diseases / Haematology / Rheumatology) Initial differentials considered in context of PUO • Infection – Intestinal-TB, parasitic-enteric infection • Infiltration – Lymphoma (mainly Burkitt’s) • Inflammation – Inflammatory bowel disease (initial working diagnosis); Rheumatological (cSLE, Vasculitis) Relevant HPC Symptoms/signs evolved after admission to GOSH and included: • Lethargy / drowsiness • Malar rash • Macroscopic haematuria / pedal oedema • Left ankle pain/swelling • Testicular pain/swelling. Underwent exploration/fixation (Dx necrotic hydatid of Morgagni) Examination (on admission to GOSH) • Looked unwell, drowsy, combative, GCS 13/15 (E3, S4, M6) • Malar rash, mouth ulcer (hard palate) • Generalised abdominal tenderness, guarding, no rebound, BS present • Swollen left ankle • Pedal oedema Summary of key investigations • Anaemia, thrombocytopenia, lymphopenia • ANA1:2560 homogeneous • dsDNA>379IU/ml • ENA - anti-Ro/anti-La positive • Low C3/C4 • DAT positive • Triple positive anti-phospholipid antibodies • ADAMTS-13 activity: normal • Urine ACR>600 mg/mmol • ID screen(+CSF):negative Significant results of multi-organ review • Neurology – MRI Brain in keeping with CNS vasculitis +/-Macrophage activation syndrome (MAS) • Ophthalmology - Solitary cotton wool spot in the right eye • ENT – Nosebleeds • Cardiology - Small pericardial effusion with significant rise in troponin and pro-BNP (without haemodynamic compromise) • Respiratory – Bilateral pleural effusions • Renal - Class III LN with features of thrombotic microangiopathy on renal biopsy • Gastroenterology – CT abdomen with ascending colitis in CT • Genital - Necrotic hydatid of Morgani • Haematological - Antiphospholipid syndrome (triple positive antibody profile with PICC line clot) • Musculoskeletal – Arthritis • Dermatology – Malar rash • Other – Macrophage activation syndrome with evidence of CNS involvement Treatment summary • IV methylprednisolone pulses (4-sets, ranging from 3-5 days) – switched to low dose IVMP (equivalent to PO Prednisolone 2 mg/kg/day) • Rituximab • Cyclophosphamide as per systemic vasculitis protocol • Prophylactic fluconazole and trimethoprim/sulfamethoxazole • Subcutaneous enoxaparin • Amlodipine (management of hypertension) • MAS treatment - AnakinraàCiclosporin Discussion This was a complex case, demonstrating a severe presentation of cSLE with significant multi-system involvement. It highlights nicely the initial diagnostic challenges faced in such cases when children present with non-specific symptoms such as fever and abdominal pain. The three “I” approach to guide team reviews and investigations was applied, namely, to consider infection, infiltration (malignancy) and inflammation. Given the initial presentation, inflammatory bowel disease sat high on the list of differential diagnoses, whilst exclusion of infection (including abdominal TB) and malignancy (mainly Burkitt’s lymphoma) was important. In our patient, almost all organ systems were affected, and balancing treatment choices in terms of risk versus benefit required continual review and multi-team discussion. Some specific scenarios included consideration of plasma exchange in the context of triple antiphospholipid antibody positivity, features of TMA on renal biopsy (although multiple blood films were non-suggestive of TMA and ADAM-TS13 activity was normal) and severe multi-organ disease; alongside the anti-coagulation conundrum in view of evolving anti-phospholipid syndrome with an occlusive PICC line clot in a patient with down-trending platelet count and hypofibrinogenemia, and clinically a history of nosebleeds, macroscopic haematuria and a frank gastrointestinal bleed requiring blood cell transfusion. Key learning points 1. Diagnostic challenges faced in the context of multi-system presentation of disease 2. Importance of continual assessment and multi-specialty collaboration when there is initial diagnostic uncertainty and evolution of symptoms over time 3. Therapeutic challenges, highlighting the need to balance risk / benefit of treatment choices and importance of multi-team discussions to reach consensus management plans 4. Prophylactic treatment considerations in terms of opportunistic infection cover in a sick, immunosuppressed child; and limitation of secondary complications, both iatrogenic and secondary to disease features e.g. clot / bleeding risks

P028 Crowned dens syndrome: a rare yet important-to-recognise phenotype of calcium pyrophosphate crystal deposition disease

Multiple risk factors for asthma severity have been identified by epidemiological studies. Yet, the pathophysiological mechanisms driving the severity of clinical asthma manifestations remain incompletely understood. In asthmatic children, Notch4 expression on circulating Treg cells and levels of circulating GDF15 have been shown to be increased as a function of disease severity, suggesting a contribution of Treg dysfunction to disease phenotype. 126 children with asthma (intermittent = 40; mild persistent = 43; moderate persistent = 29, and severe persistent = 14) and 83 non-asthmatic controls were recruited in the Allergy clinic at Boston Children's Hospital and from asthma cohorts. Untargeted metabolomic analysis and cytokine profiling were performed in plasma and results correlated with disease severity, Notch4 expression, and presence of other atopic comorbidities. Children with moderate/severe asthma had higher levels of select lipids (triglycerides, ceramides) and carboxylic acids (lactic acid, aconitic acid) and lower levels of amino acids (sarcosine and arginine) and of IFNλ 2/3 compared to children with intermittent/mild asthma. Treg Notch4 expression and GDF15 levels, which increase with disease severity, correlated positively with lactic acid and xanthine levels and inversely with sarcosine and arginine. The concomitant presence of food allergy was associated with alterations in microbiome-related metabolites and allergic rhinitis with marked triglyceride dysregulation. Untargeted metabolomic profiling identified both shared and unique pathways associated with known asthma severity contributors, Notch4 dysregulation and GDF15 elevation, suggesting that different mechanisms may both converge or independently contribute to determining clinical manifestations of asthma severity in asthmatic children.

Prenatal exposure to dietary levels of glyphosate disrupts metabolic, immune, and behavioral markers across generations in mice.

Gut microbiota-based metabolism contributes to the protection of pseudolaric acid B against MAFLD.

ABSTRACTEndothelial colony forming cells (ECFCs) derived from peripheral blood have been shown to retain disease phenotype in several conditions thus possessing great translational potential for regenerative medicine. Hyperglycaemia may alter the phenotype of ECFCs yet the characteristics of ECFCs isolated from people with type 1 diabetes (T1D) have not been described. Here, we establish whether ECFCs can be successfully isolated from donors with T1D and we characterize their functional properties. Human ECFCs were isolated from peripheral blood of up to 9 control and T1D donors. Expression of cell markers and cytokines was analyzed using immunocytochemistry, RT‐PCR and ELISA. Ca2+ signaling and contraction were studied using Fluo‐4‐AM in cells treated with serial concentrations of histamine (1 × 10−7‐1 × 10−4M). T1D ECFCs showed robust endothelial marker expression and displayed normal morphology but had a reduced size compared to those from control donors. In response to inflammatory stimuli, T1D ECFCs exhibited exaggerated pro‐atherogenic/pro‐inflammatory cytokine (IL‐6 and MCP‐1) and adhesion molecule gene induction (VCAM‐1 and ICAM‐1) but suppressed induction of interferon signaling markers (IP‐10). Histamine stimulated a concentration‐dependent increase in Ca2+ influx in ECFCs which was significantly reduced in ECFCs from T1D donors, independent of differences in H1 receptor expression levels. Histamine‐induced contraction was significantly enhanced in T1D ECFCs. ECFCs from control and T1D donors exhibit distinct phenotypic differences redolent of the vascular pathologies associated with T1D. This establishes the utility of T1D ECFCs for modeling vascular complications but also highlights the need to understand the potential limitations of autologous ECFCs to treat diabetic complications.

Incomplete penetrance, or absence of disease phenotype in an individual with a disease-associated variant, is a major challenge in variant interpretation. Studying individuals with apparent incomplete penetrance can shed light on underlying drivers of altered phenotype penetrance. Here, we investigate clinically relevant variants from ClinVar in 807,162 individuals from the Genome Aggregation Database (gnomAD), demonstrating improved representation in gnomAD version 4. We then conduct a comprehensive case-by-case assessment of 734 predicted loss of function variants in 77 genes associated with severe, early-onset, highly penetrant haploinsufficient disease. Here, we identify explanations for the presumed lack of disease manifestation in 701 of 734 variants (95%). Individuals with unexplained lack of disease manifestation in this set of disorders are rare, underscoring the need and power of deep case-by-case assessment presented here to minimize false assignments of disease risk, particularly in unaffected individuals with higher rates of secondary properties that result in rescue.

Inflammatory bowel disease (IBD), which encompasses ulcerative colitis (UC) and Crohn's disease (CD), is a chronic condition characterized by recurrent intestinal inflammation and complications. Despite extensive research on bacterial dysbiosis in IBD, the role of the gut mycobiome remains largely unexplored, particularly in surgical tissue specimens. In this study, we performed a comprehensive analysis of the intestinal fungal communities in surgical resections obtained from 20 patients with UC and 30 patients with CD, with non-IBD resections serving as controls. Fungal DNA was extracted and the internal transcribed spacer (ITS) region was amplified and sequenced using high-throughput Illumina technology. RNA from surgical resections from both non-IBD and IBD patients was obtained and the expression of pro-inflammatory and profibrotic genes was analyzed by real-time quantitative polymerase chain reaction. Bioinformatic analysis revealed modest changes in fungal diversity in UC resections compared with those from controls. However, CD specimens exhibited significant alterations in mycobiome composition, including an increased abundance of Malassezia, specifically Malassezia globose, alongside a reduction in Yarrowia lipolytica. Moreover, stratification of CD into complicated phenotypes (B2 stricturing vs B3 penetrating) identified distinct fungal signatures capable of discriminating between these clinical phenotypes. Correlation analyses revealed a direct association between the mycobiome and intestinal inflammation and fibrosis, in parallel with several interactions between fungal and bacterial species, further reporting interkingdom interactions between both microbial communities. These results underscore the potential of fungal biomarkers in elucidating IBD pathogenesis and its associated complications, which opens up promising avenues for targeted therapeutic strategies.

Holistic modulation of TLR4, MAPK, and apoptosis Signalings and gut microbiota by Sihuangzhili granule: A herbal strategy against avian colibacillosis.

Significance of integrated clinical and proteomic characteristics analysis for pathogenesis and management of Crohn's disease with concomitant psoriasis.

Inflammation plays a complex role in the pathophysiology of both acute coronary syndrome (ACS) and acute stroke (AS). Erythrocyte aggregation is a physiological phenomenon. Its initial kinetics (EAK), measured at the point of care in 20s, is a powerful marker of inflammation accelerated early in the inflammation process. Inflammation is highly suspected when EAK during the first 5 s (EAK5s) has a half-life less than 1.86s. EAK5s is the first marker of the vascular phase of inflammation, activated when systemic infection is present. We conducted two clinical studies in patients in whom either ACS (n = 34) or AS (n = 247) was suspected. We show that EAK is accelerated in many, but not all the patients: EAK5s variation coefficients ranged 6.9–37% across disease groups. EAK5s failed to identify ACS and AS patients among those in whom either condition was suspected. However, EAK5s may identify disease phenotypes such as no-ST elevation myocardial infarction (NSTEMI) or epilepsy in which the vascular phase of inflammation is activated: ROC areas under the curve 0.81 (95% CI 0.66–0.96) and 0.68 (95% CI 0.55–0.82) respectively. Besides other mechanisms, EAK, now easily measured, can be used to better understand the complex role of inflammation and its vascular phase in cardiovascular diseases.

The aim of our study was to identify routine serum biomarkers that may be related to alpha-1 antitrypsin deficiency (AATD) lung disease phenotypes and severity. Observational, cross sectional, multicentre study conducted in patients with a Pi*ZZ genotype. Serum biomarkers, including neutrophil/lymphocyte ratio (NLR), eosinophil/lymphocyte ratio (ELR) and platelet/lymphocyte ratio (PLR), were calculated. Data were analysed to establish possible associations between biomarkers and lung function and lung phenotypes. Among the 897 patients included, 48.4% were men with a mean age of 53.9 (SD 14.7) years. Patients with COPD (n = 337) had higher haemoglobin levels (15.3 mg/dl vs. 13.9 mg/dl, p<0.001), gamma-glutamyl transferase (GGT) (50.1 IU/L vs. 35.7 IU/L, p<0.001), eosinophils (0.22 10^9/L vs. 0.19 10^9/L, p<0.001), NRL (2.55 vs. 1.86), PLR (132.6 vs. 119.8) and ELR 0.12 vs. 0.1) compared to those without COPD. In multivariate analysis, older age, male sex, higher haematocrit, elevated alanine transaminase (ALT) and GGT levels, and a higher NRL and PLR were associated with a worse FEV1(%). A higher Charlson score, elevated haematocrit and white cell count, as well as increased levels of AAT, aspartate aminotransferase (AST), GGT, and PLR were associated with worse carbon monoxide transfer coefficient (KCO)(%). Exacerbations were associated with female sex, and a higher PLR. Some blood biomarkers are increased in patients worse lung function. However, the correlations between these biomarkers and the different measures of lung function are weak, and thus, identifying a single routine biomarker that accurately predicts disease severity and progression is challenging.

ObjectiveThis study evaluated associations between several obesity indicators and the risks of Crohn’s disease (CD) and ulcerative colitis (UC), the two principal clinical phenotypes of inflammatory bowel disease (IBD).MethodsData from 479,590 UK Biobank participants (mean age ± standard deviation: 56.5 ± 8.09 years; 54.5% female) were analyzed. Participants were classified based on waist circumference (WC). Cox proportional hazards models were used to quantify associations between multiple adiposity measures and incident CD and UC, adjusting for demographic, behavioral, and clinical covariates.ResultsDuring a median observation period of 12.5 years (maximum 15.6 years), 1,518 incident CD cases and 2,957 incident UC cases were identified. Taking into account demographic variables (age, sex, and ethnic background), lifestyle indicators (including smoking, alcohol intake, sleep, diet, physical exercise, and employment), socioeconomic status measured by the Townsend Deprivation Index(TDI), coexisting conditions (hypertension and diabetes), inflammatory status (C-reactive protein), and nonsteroidal anti-inflammatory drug consumption, waist-to-hip ratio (WHR)–defined central adiposity was found to elevate the risk of CD (hazard ratio [HR] 1.18; 95% confidence interval [CI] 1.05–1.34). However, WC-defined central obesity did not demonstrate a statistically significant link to CD risk (HR 1.11, 95% CI 0.97–1.27). In minimally adjusted models, WHR-defined central obesity was associated with an increased hazard of UC (HR 1.13; 95% CI 1.05–1.23); this association attenuated to non-significance after full covariate adjustment (HR 1.03; 95% CI 0.95–1.13). Obesity defined by BMI ≥ 30 showed no relation to CD, whereas it was associated with a lower hazard of UC (HR 0.86; 95% CI 0.78–0.95). Similarly, higher body-fat percentage (BFP: male > 25%, female > 35%) was associated with a modestly lower hazard of CD (HR 0.92; 95% CI 0.85–0.99). Excluding incident IBD events that occurred during the first 24 months of follow-up, the WHR–CD association persisted (HR 1.19; 95% CI 1.04–1.36). Additionally, individuals in the highest third of WHR-for-BMI residuals (> 66th percentile) exhibited a markedly elevated risk of CD (HR 1.26; 95% CI 1.10–1.44).ConclusionsCentral obesity, assessed by WHR, independently predicts the risk of CD, with a particularly pronounced effect in females, irrespective of BMI or other metabolic confounders. Conversely, higher BMI and BFP were inversely associated with UC risk.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12944-025-02763-8.

Clonal hematopoiesis (CH) is characterized by the expansion of hematopoietic stem and progenitor cells harboring somatic mutations, which confers an increased risk of hematologic malignancies and cardiovascular disease. Among CH-associated mutations, mutations affecting splicing factors (SFs), including splicing factor 3b subunit 1 (SF3B1), serine/arginine-rich splicing factor 2 (SRSF2), U2 small nuclear RNA auxiliary factor 1 (U2AF1), and zinc finger CCCH-type, RNA binding motif and serine/arginine rich 2 (ZRSR2), play a unique role in promoting clonal expansion and leukemogenesis. In this review, we summarize recent findings on the role of SF mutations in CH progression, their interplay with other mutations (e.g., DNA methyltransferase 3 alpha (DNMT3A), ten-eleven translocation methylcytosine dioxygenase 2 (TET2) and isocitrate dehydrogenase 2 (IDH2)), and their impact on hematopoietic homeostasis. Epidemiological studies have demonstrated that SF-mutant CH exhibits an accelerated clonal expansion compared to other CH clones. Furthermore, murine models suggest that SF mutations alone do not inherently confer a growth advantage for clonal expansion but rather enhance disease phenotypes when co-existing with epigenetic mutations, such as IDH2 and TET2. These findings suggest that SF mutations contribute to CH expansion and malignant transformation through a synergistic interplay with other mutations and external factors such as inflammation. Given the clinical significance of SF mutations, ongoing research is focused on developing targeted therapies that modulate aberrant RNA splicing and prevent CH-driven leukemogenesis. Understanding the mechanisms underlying mutant spliceosome-mediated CH expansion may provide novel insights into early detection, risk stratification, and therapeutic interventions in hematologic malignancies.

BACKGROUND: β-thalassaemia has heterogeneous disease severities ranging from mild to trait, and major. Long noncoding RNAs (lncRNAs) are known to regulate microRNAs (miRNAs) and genes, possibly modifying the disease phenotypes. However, limited data exist on the lncRNAs in β-thalassaemia, and no study has yet addressed this gap in Malaysia. Therefore, this study aimed to identify the expression profile of lncRNAs in β-thalassaemia major and trait among Malaysians.METHODS: Case-control study was conducted in two phases at Tunku Azizah Women and Children's Hospital and the Institute of Medical Research, from September 2019 to November 2021. Total of 141 individuals were recruited, comprising β-thalassemia major (MAJOR, n=11), β-thalassemia trait (TRAIT, n=17), and healthy controls (CON, n=113). All participants were genotyped for thalassaemia and assessed for their haemoglobin and red blood cells (RBC) indices. In the first phase, discovery of lncRNA was performed using microarray, and differential expression of lncRNAs (DEL) in MAJOR, TRAIT, and CON groups was identified. Significant lncRNAs were subjected to lncRNA-miRNA prediction, and gene ontology and biological pathway were analyzed. In validation phase, six potential lncRNAs were further validated via using lncRNA polymerase chain reaction (PCR) custom array.RESULTS: Total of 364 DELs were identified in MAJOR group, and 128 DELs were identified in TRAIT group. Between the MAJOR and TRAIT groups, 100 DELs were dysregulated in MAJOR group. Two molecular networks comprising the lncRNA interactions with miRNAs were identified and associated with traits and major phenotypes, resulting in six potential lncRNAs for validation. Among these six lncRNAs, three lncRNAs (TYMSOS, VASH1-AS1, and LINC01001) were reduced in the MAJOR group (fold change (FC)=-6.67, p=0.026; FC=-8.33, p=0.022; and FC=-8.33, p=0.021, respectively).CONCLUSION: Expressions of TYMSOS, VASH1-AS1, and LINC01001 lncRNAs were altered differently between β-thalassaemia major and trait patients. Therefore these lncRNAs may serve as novel biomarkers for β-thalassaemia disease severity in Malaysian population.KEYWORDS: β-thalassaemia, lncRNAs, miRNAs, severity, major, trait, molecular network

BackgroundAnti-C1q autoantibodies can disrupt normal complement function, contributing to the formation of pathogenic immune complexes and end-organ damage. Although their role in SLE is well-established, their detection rate and clinical relevance across a broader spectrum of diseases remain insufficiently characterised. This study aimed to investigate the distribution of abnormal anti-C1q levels in the population and examine their associations with age, sex and specific clinical subtypes.MethodsThis retrospective study included patients who underwent anti-C1q testing at our hospital between September 2020 and September 2023. The primary outcome was the detection rate of abnormal anti-C1q levels (>10 U/mL) categorised by patient sex, age and disease diagnosis. One-way and two-way fixed-effect models were used to assess associations between odds of abnormal antibody levels and demographic factors. Multivariate logistic regression was performed to identify disease-specific correlates.ResultsAmong 15 363 patients (median (IQR) age, 38 (28–53) years; 79.02% female; 52.19% aged <40 years) representing 67 distinct diagnoses, 7.88% showed abnormal anti-C1q levels. Female sex and younger age showed higher median anti-C1q levels and a greater proportion of abnormal results. SLE subtypes showed the highest detection rate of abnormal anti-C1q levels, with SLE without severe complications (853 of 3760, 22.69%) and lupus nephritis (88 of 294, 29.93%) being the most obvious. Lupus haematological and encephalopathic manifestations were associated with elevated antibody levels. Additionally, autoimmune cirrhosis (7 of 59, 11.86%) and systemic sclerosis (19 of 165, 11.52%) also showed high detection rates of abnormal anti-C1q levels. Both univariate and multivariate analyses indicated that male sex and younger age were significantly associated with increased odds of abnormal anti-C1q levels.ConclusionElevations in anti-C1q levels extend beyond SLE and are influenced by both demographic factors and specific disease phenotypes. Male sex and younger age emerged as significant predictors of abnormal anti-C1q status. Our findings underscore the potential utility of anti-C1q testing for improving diagnostic precision and risk stratification across a wide range of clinical conditions.

Genetic factors, including single-nucleotide variants (SNVs), may modulate disease course and therapeutic efficacy in patients with inflammatory bowel disease (IBD). We investigated the association between four SNVs in cytokine genes and clinical phenotype as well as the response to molecular-targeted drugs in patients with IBD. A total of 197 IBD patients (142 Crohn's disease [CD], 55 ulcerative colitis [UC]) undergoing targeted treatment were enrolled. The SNVs analysed were: TNFA rs1800629 (-308 G>A), TGFB rs1800471 (-codon 10 C>T), IL6 rs1800795 (-174 G>C), and IL10 rs1800896 (-1082 G>A). Biochemical response at 12 months (T12) was defined as C-reactive protein < 5.0 mg/L and faecal calprotectin < 250 μg/g at T12, in the absence of ongoing corticosteroid therapy. Among the SNVs analysed, the IL6 rs1800795 C allele was significantly associated with a younger age at diagnosis (p = 0.049), while the TNFA rs1800629 A allele was more frequently observed in patients with CD than in UC (p = 0.036). Regarding treatment response, 134 patients completed 12 months of molecular-targeted therapy and were included in the per-protocol analysis; 41.0% achieved biochemical remission at T12. The IL10 rs1800896 variant allele was significantly associated with remission (OR = 2.15, 95% CI: 1.03-4.44; p = 0.041). This association remained significant in multivariate analysis (aOR = 4.15, 95% CI: 1.49-11.56; p = 0.007), independently of clinical and treatment-related variables. In conclusion, genotyping of cytokine-related SNVs may help identify patients with a more aggressive disease phenotype and guide personalised treatment strategies in patients with IBD.