bluuebunny/crossref_metadata_2025_split huggingface dataset:
P1167 Inflammatory Bowel Disease: a phenome-wide pre- and post-diagnostic association study
Authors: Ebert A , Elmahdi R , Poulsen G , Bøgsted M , Verstockt B , Lees C , Jess T 
Published: January 2024

Abstract

Background
Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is known to be associated with various extra-intestinal manifestations, impacting organ systems beyond the gastrointestinal tract. Identifying comorbidities in IBD and the timing of their development can provide valuable insight into the mechanisms underlying IBD development.

Methods
We conducted the first population- and disease-wide phenomic association study in IBD, using &gt;6 million ICD-10 coded healthcare contacts from 10 years before and up to 17 years after IBD diagnosis to investigate associations with 1583 diseases. To explore co-morbidities with potential aetiological significance with IBD, we additionally assessed the strength of association with all diseases in the pre-diagnostic compared with the post-diagnostic period. To correct for multiple testing, we adjust our significance threshold (p&lt;0.05) with the Bonferroni correction, resulting in an adjusted p-value of 7.90×10, which we refer to as disease-wide statistical significance.

Results
We identified 312 disease-wide statistically significant associations with 125 of these diseases appearing up to 10 years before diagnosis. The risk of immune-mediated diseases and extra-intestinal manifestations are among those diseases increased up to 10 years prior to IBD diagnosis (psoriasis: CD-RR: 2.57, 95% CI: 2.00-3.29; UC-RR: 1.54, 95% CI: 1.25-1.87; enteropathic arthropathies: CD-RR: 3.57, 95% CI: 2.65-4.78; UC-RR: 1.8, 95% CI: 1.38-2.32). This was also the case for gastroenterological and liver disorders (gall stones: CD-RR: 1.82, 95% CI: 1.62-2.04; UC-RR: 1.26, 95% CI: 1.15-1.37; acute pancreatitis: CD-RR: 1.83, 95% CI: 1.30- 2.53; UC-RR: 2.27, 95% CI: 1.84-2.79). The risk of cardiometabolic diseases and neuropsychological disorders had increased disease-wide statistical significance both pre- and post-diagnostically, whereas potential sequelae of treatment, such as osteoporosis (CD-HR: 2.56, 95% CI: 2.30-2.86; UC-HR: 1.92, 95% CI: 1.79-2.07) or herpes simplex infections (CD-HR: 4.04, 95% CI: 2.76-5.91; UC-HR: 1.69, 95% CI: 1.2-2.38) were primarily seen post-diagnostically. Of potential aetiological importance to CD, diagnosis with infectious mononucleosis (RR: 1.87, 95% CI: 1.37-2.52) was significantly associated with the pre- compared to the post-diagnostic period.

Conclusion
Our results demonstrate IBD as an essentially multisystemic disease, particularly manifesting as gastrointestinal, metabolic, immune, and neuropsychological disorders, present up to 10 years prior to IBD diagnosis. Infectious diseases of aetiological interest identified warrant further investigation.
P1168 Anthropometric trajectories prior to the development of inflammatory bowel disease in Danish school-aged children and adolescents from 1997 to 2017
Authors: Brusco De Freitas M , Juul Poulsen G , Jess T 
Published: January 2024

Abstract

Background
Compromised nutritional status during the disease course can be a major clinical challenge in children diagnosed with inflammatory bowel disease (IBD). However, a key question is knowing how long these changes precede the disease; to this end, the impact of childhood-onset IBD on mean Z-scores for length/height (HAZ), weight (WAZ) and body mass index (BAZ) before and after IBD diagnosis will be evaluated.

Methods
The study used a nationwide children's database that collects health information from health visitors and school nurses and linked these data to anthropometric measurements at birth, diagnosis and family history obtained from national registries. Individuals with birth weight and length/height measurements and at least two weight and length/height measurements (at least one at school age) within +/- 4 SD at ages 1-16.5 years were included. Within this population, individuals with IBD diagnosed by two hospital contact at age 5-17 years were identified. Age- and sex-specific Z-scores were computed using generalized additive models for location scale and shape models on the study population and applied to the IBD population. Linear mixed models were used to estimate mean Z-scores in years before and after IBD diagnosis.

Results
In the period 1997-2017, data from 1,305,852 schoolchildren were recorded, and the final sample, after applying the inclusion and exclusion criteria, was 707,918 individuals with a median of 3 pairs of height and weight (IIQ: 2, 5) measurements collected. There were 1,424 cases of IBD [Crohn disease (CD), n= 784; ulcerative colitis (UC), n= 640] with a mean age at diagnosis of 14.16 years old. Preliminary data (results presented in the figure) show that the decline of WAZ, HAZ and BAZ markers in schoolchildren was observed years before IBD diagnosis, remaining for a later period, with a different pattern among individuals diagnosed with CD or UC. Individuals with a later diagnosis of CD, compared to UC, became progressively less healthy, showing a clear decline in anthropometric markers approximately 3 years earlier (UC individuals approximately 1 year earlier) and with a slower recovery after diagnosis.

Conclusion
Preliminary findings show that impaired linear growth and lower weight and body mass index can be observed at least 3 years before diagnosis in schoolchildren with CD and that they are more prominent in this population compared to UC cases. These results emphasize the importance of frequent nutritional screening and monitoring, with the aim of identifying the need for early intervention and providing a healthy transition to adulthood.
P1169 Multimorbidity and Disease Trajectories in Patients with INFLAMMATORY BOWEL DISEASES: Insights from Observational and Genetic Analyses
Authors: Jiang F , Zhao J , Chen J , Wang L , Yuan S , Kalla R , Wellens J , Nowak J , Larrson S , Ludvigsson J , Satsangi J , Theodoratou E , Li X 
Published: January 2024

Abstract

Background
The multi-morbidity pattern of inflammatory bowel disease (IBD) remains under-explored. We integrated both observational and genetic data to elucidate multisystem comorbidities and health consequences of IBD.

Methods
Phenome-wide association study (PheWAS) based on the international classification of disease (ICD)-diagnosed IBD was conducted to explore its associations with 1,053 unique clinical outcomes in the UK Biobank. Disease trajectory analyses were implemented to illustrate sequential patterns of IBD-related comorbidities. The associations of genetic liability to IBD proxied by a polygenic score with identified clinical outcomes were examined to strengthen causality (N=385,917). To investigate potential shared genetic bases and causality, we performed a cross-trait linkage disequilibrium score regression (LDSC) and two-sample Mendelian randomization (TSMR) analysis using the FinnGen biobank (N=377,277). The impact of IBD subtypes and the age at diagnosis were also evaluated in sensitivity analyses.

Results
A total of 5,782 cases with IBD (3,940 cases with UC and 1,800 cases with CD) were diagnosed at baseline in the UK Biobank. Observational PheWAS revealed elevated risks of all-cause mortality with HRs of 1.34 (95%CI=1.24-1.45, P&lt;0.001), 1.61 (95%CI=1.41-1.83, P&lt;0.001) and 1.22 (95%CI=1.10-1.34, P&lt;0.001) for patients with IBD, CD or UC respectively. Increased mortality risk was noted across pediatric, early-onset, and later-onset IBD patients. Sequential patterns of IBD-related comorbidities were primarily found in cardiometabolic, respiratory, digestive and autoimmune diseases. The polygenic PheWAS, LDSC and TSMR analyses supported both strong genetic correlations and causal associations of IBD with immune-mediated (notably psoriatic arthropathies, psoriasis, dermatitis, asthma) as well as non-autoimmune diseases ( pneumonia, anemias, and renal failure).

Conclusion
Our observational and genetic analyses suggest multisystem comorbidities and consequences of IBD, highlighting the need for multidisciplinary clinical management and investigation of shared biologically or genetically regulated mechanisms in the pathogenesis of IBD.
P1174 The disease course of elderly patients with Inflammatory Bowel Disease two years prior to their death
Authors: Majchrzak K , Lo B , Bendtsen F , Burisch J 
Published: January 2024

Abstract

Background
The number of elderly patients with inflammatory bowel disease (IBD) is increasing. Hence, more patients will be dying with their IBD. Limited research has examined the disease course of IBD in the aging body, particularly in the period preceding their death. The purpose of this study was to investigate the disease course of elderly IBD patients leading up to the end of their lives.

Methods
This was a nationwide population-based study using the national Danish registries. We used a validated algorithm to identify patients that were diagnosed with Crohn’s disease (CD), ulcerative colitis (UC) and IBD unclassified (IBDU) in a period between 1976-2018 from the Danish National Patient Registry. This information was linked with other national Danish registers which provided data on dates of death, cancer, hospitalisations, and corticosteroid usage. We included 6,183 IBD patients aged 65 and above at death, with no cancer or palliative treatment at the time of death. We analysed IBD-related hospitalisations, corticosteroid usage, and disease relapses (defined as a combined endpoint of corticosteroid prescription and/or hospitalisation, or both), in the two-year period before death.

Results
We analysed CD, UC and IBDU patients separately, and observed a noticeable spike in hospitalisations, prescription rates of corticosteroids and disease relapses in the last two months before the IBD patients’ death. Out of 6,183 IBD patients, 954 (15.43%) were hospitalised in the last two years before their death (see Table 1 for key characteristics). In the last two months, hospitalisation rates were 139 (28.66%) for CD patients, 155 (23.96%) for UC patients and 83 (34.87%) for IBDU patients. Corticosteroids were prescribed to 1,054 (17.05%) out of 6,183 IBD patients, and in the last two months 90 (20.45%) CD patients, 149 (20.13%) UC patients, and 67 (19.36%) IBDU patients received a corticosteroid treatment. Overall, 1,652 (26.72%) IBD patients experienced a disease relapse two years preceding their death, and during the last two months, 553 (22.45%) CD patients, 194 (24.01%) UC patients and 228 (20.25%) IBDU patients experienced relapses.

Conclusion
During the two-year period prior to death, we observed that hospitalisation, prescription, and relapse rates were highest during the final two months of life. For better understanding of the disease course of elderly IBD patients, further research should investigate the cause of death and differences between early- and late disease-onset patients as well as establish a cohort for comparison.
P1191 Genetic determinants for smoking behaviour improve our understanding of sporadic versus familial Inflammatory Bowel Disease
Authors: Jans D , Abakkouy Y , Becelaere S , Verstockt S , Vermeire S , Cleynen I 
Published: January 2024

Abstract

Background
Inflammatory bowel disease (IBD) is influenced by genetic and environmental factors. The latter are often difficult to quantify and may vary over time, unlike genetics. Here, instead of looking at actual smoking behaviour, we explored the impact of genetic determinants of smoking behaviour on IBD risk in sporadic and familial IBD.

Methods
We calculated polygenic scores (PRS) for smoking initiation, smoking cessation, age of smoking initiation, and cigarettes per day in 2784 sporadic cases (1700 CD, 1084 UC), 682 non-IBD controls, and 60 multiplex IBD families with ≥3 affected first-degree relatives (FDR) (142 CD, 31 UC and 100 unaffected FDR). PRS were calculated for different p-value thresholds (5e-8, 1e-5, 0.01, 0.05, 0.1, 0.5 and 1), and based on effect estimates of Saunders et al (Nature 2022, table 1). Groups were compared using logistic regression. P&lt;1.43e-3 was the significance threshold for Bonferroni correction.

Results
Sporadic IBD cases had a higher PRS for smoking initiation than controls (p=4.49e-3), which was driven by the CD cases (p=7.17e-4, fig 1A). CD cases also showed a trend for a higher PRS for cigarettes per day (p=0.026). In familial cases compared to unaffected FDR, we observed some differences in PRS for smoking, but none survived multiple testing (fig 1B). Comparing familial and sporadic cases, we found that the PRS for age at smoking initiation was higher in familial than in sporadic UC (p=9.09e-4, fig 1C). Familial CD showed a trend towards a lower PRS for age at smoking initiation (p=0.023) and smoking cessation (p=0.013) than sporadic CD. Familial CD cases are thus more at risk than sporadic CD cases as they genetically tend to start smoking younger, while the opposite is seen for UC. Also, unaffected FDR of UC families showed a lower PRS for age at smoking initiation (p=5.47e-5, fig 1D) than controls, giving them additional protection. The PRS for smoking cessation (p=3.88e-5) and cigarettes per day (p=4.47e-3) was greater in unaffected FDR of mixed families than in controls, while familial mixed cases had a lower cigarettes per day PRS than sporadic cases (p=1.59e-4).

Conclusion
We found that genetic determinants of smoking behaviour are associated with disease risk in familial and sporadic IBD. While CD risk overall is associated with a greater genetic propensity for smoking initiation, the higher risk in families is linked to genetic age at start of smoking. Meanwhile, unaffected FDR of these families are protected through a higher genetic propensity to stop smoking in mixed families, or to start smoking sooner in UC families, compared to population controls. This study improves our understanding of familial vs sporadic IBD, and could help stratify individuals at risk of IBD.
P1193 NOD2 and Beyond: Unmasking Tobacco-Induced Epigenetic Changes in Crohn's Disease
Authors: Vañó I , Monfort Ferré D , Boronat Toscano A , Menacho M , Valldosera G , Caro A , Clua Ferré L , Suau R , Manyé J , Serena C 
Published: January 2024

Abstract

Background
Smoking has been shown to have a very negative impact on Crohn's disease (CD). Indeed, this harmful habit induces the early onset of the disease and doubles the risk of postoperative recurrence. This research project involves a thorough analysis of omics data, with a primary focus on DNA methylation, one of the most prevalent epigenetic modifications. Our hypothesis is that tobacco-induced alterations in gene methylation pattern of subcutaneous adipose tissue (SAT), particularly within key pathways, contribute to a more adverse disease profile in smokers.

Methods
A comprehensive epigenome-wide analysis was conducted using the Illumina EPIC/450k array to investigate subcutaneous adipose tissue in patients with CD, encompassing both smokers and non-smokers. Utilizing tools such as dmpfinder and Bumphunter (minfi), differentially methylated positions (DMPs) and regions (DMRs) were identified. Additionally, gene expression analysis for key genes was performed to establish correlations between methylation and subsequent gene expression, not only in SAT but also in other fat depots such as visceral adipose tissue (VAT) or peripheral blood mononuclear cells (PBMCs).

Results
A distinctive DNA methylation pattern in the SAT of smokers compared to non-smoker CD patients was identified (Fig. 1A). Over 27,270 DMPs associated with significant biological processes related to DNA damage, inflammation, or immunity were uncovered (Fig. 1B-C). Additionally, more than 13,000 DMRs located in the promoter region were identified (Fig. 1C). The relationship between methylation levels in the promoter regions and subsequent gene expression on SAT was validated for selected genes. Specifically, NOD2 exhibited higher DNA methylation in the promoter region among smokers compared to non-smokers CD patients (p value=0.04), resulting in reduced NOD2 gene expression on SAT (p value=0.04) (Fig.1D). Consistent results were observed in other tissues such as VAT and PBMCs (Fig. 1E). Finally, we observe the implication of NOD2 in pathways related to immune response, inflammation or apoptosis and a trend indicating that lower NOD2 expression is associated with higher levels of C-reactive protein (CRP)(Fig. 1F).

Conclusion
Our study reveals that smoking produces DNA methylation changes on SAT of CD patients and affects the expression of several key genes involved in the pathogeny of CD. Particularly, our results unveil a new link between tobacco-smoking and lower NOD2 expression and associate this to an elevated levels of PCR, paving the way for a fresh perspective in exploring disease prognosis.
P1196 Genomic structural variation and polygenic risk score for Inflammatory Bowel Disease
Authors: Jun Y K , Jeong J , Kim B M , Kim J , Choi Y , Shin C M , Park Y S , Kim N , Lee D H , Lee S , Yoon H 
Published: January 2024

Abstract

Background
Genome-wide association studies (GWAS) of patients with inflammatory bowel disease (IBD) have identified multiple single-nucleotide polymorphisms (SNPs) and genetic variants involving structural changes in the DNA sequence. SNPs and structural variants (SVs) can play a crucial role in IBD pathogenesis. In this study, we evaluated large deletions induced by SVs in patients with IBD. Additionally, we evaluated the ethnic contribution to a polygenic risk score (PRS) for IBD.

Methods
Seventy-five Patients with IBD of Korean ancestry from Seoul National University Bundang Hospital (SNUBH) were subjected to whole-genome sequencing (49 patients with UC and 26 patients with CD). SVs involving large deletions were detected and analyzed by using the Genome Aggregation Database (gnomAD) and AnnotSV. The SVs were prioritized based on a list of 241 IBD-associated SNPs identified in the previous GWAS. The prediction performance of European- and Korean-derived PRSs for IBD was also evaluated. For calculating PRS, we applied previously published models derived from the European and Korean populations, respectively, and used Korean Genome and Epidemiology Study (KoGES) database as the Korean controls.

Results
We found a total of 146 SVs involving large deletions in the IBD cohort. Among them, 10 SVs were annotated as likely pathogenic, according to AnnotSV and American College of Medical Genetics and Genomics guidelines; 24 SVs had the probability of being loss-of-function intolerant (pLI ≥ 0.9). We found that the frequency of large deletions that overlapped with the regions coding NOTCH1, HGF, PTPN2, and SENP7 were rare in the IBD cohort compared to the gnomAD population (Table). The large deletions that overlapped with the regions coding IL2RA, ITGA4, BANK1, and STAT3 were identified in the IBD cohort but not in the gnomAD population. The PRS for IBD in the IBD cohort was significantly higher than that in the Korean controls under the Korean- or European-derived model (Figure A). However, the PRSs for CD or UC were not able to distinguish patients with CD and UC in the IBD cohort (Figure B and C).

Conclusion
Our finding suggests that SVs involving large deletion may be an important genomic variability in predicting the development of IBD. The PRS for IBD can predict IBD development without ethnic specificity.
P1198 Pediatric inflammatory bowel diseases in patients with genetic syndromes: a case-control multicentre SIGENP study
Authors: Di Sario F , Olivetti L , Felici E , Garassino C , Labriola F , Branislava C , Pensabene L , Murone P , Arrigo S , Ancona S , Zuin G , Colella G , Penagini F , Martinelli M , Miele E , Fioretti M T , Graziano F , D'Arcangelo G , Bramuzzo M , Lega S , Catassi C , Gatti S 
Published: January 2024

Abstract

Background
Genetic syndromes are associated with a strong susceptibility to autoimmune disorders with an increased risk of developing inflammatory bowel diseases (IBD). However, data regarding the impact of genetics in the development of IBD are limited (Gatti S. et al, Frontiers in Pediatrics 2021). Furthermore, patients with genetic syndromes are affected by multiple comorbidities which increase diagnostic and therapeutic complexity as well as the risk of developing adverse reactions to drugs.

Methods
In this retrospective, multicenter case-control study, we recruited IBD children with a genetic syndrome (cases: group 1) and 2 matched IBD patients for each case (controls: group 2) comparable for gender, age at diagnosis, type of IBD and follow-up period. IBD subjects were diagnosed at 11 Italian pediatric IBD units between 2010 and 2022. Monogenic VEO-IBD were excluded. Genetic data were collected. Clinical and disease characteristics, presence of comorbidities, use of drugs and side effects, surgical outcomes and mortality were compared at diagnosis and at the last follow-up between the 2 groups.

Results
A total of 23 IBD children with a genetic condition/syndrome (Table 1) and 46 matched controls were identified.
In all cases, except 5 the diagnosis of IBD followed the genetic diagnosis. Thirty patients had Crohn’s disease (CD) and 39 had Ulcerative Colitis (UC). The 2 groups were comparable in terms of gender, age at diagnosis (8,9±4.6 vs 9.4±4.4 years), duration of follow up (5.6±3.4 vs 4.1±2.9 years) and severity of disease at diagnosis evaluated by w-PCDAI (34,7±23,5 vs 43,1±20,4) and PUCAI (45,3±16 vs 46,2±15,5) scores. Diagnostic delay was longer in patients with genetic conditions compared to controls, without reaching statistical significance (11,1 vs 4,6 months; p= 0,06). Prevalence of comorbidities was significantly higher in group 1 compared to controls both at diagnosis (43,4 vs 11,5%; p &lt;0,005) and at last follow-up (39,1 vs 11,6%; p &lt;0,02). Use of immunosuppressors, steroids and biologic drugs was similar at diagnosis and at last follow-up in the 2 groups. More IBD patients in group 1 developed side effects related to immunosuppressors (26 vs 4%; p &lt; 0,02), while no difference was observed in biologics-related side effects. The need of surgery was comparable in the 2 groups (13 vs 13,9 %), whereas mortality was slightly higher in patients with IBD and genetic syndrome (13 vs 7%).

Conclusion
In pediatric IBD patients the presence of genetic syndromes does not significantly modify the course of the disease itself, but increases complexity due to the multiple comorbidities and immunosoppressive drug toxicity.