Identification of pathogenic cell types and shared genetic loci and genes for Alzheimer’s disease and inflammatory bowel disease

Inflammatory bowel disease (IBD) development is a complex, multifactorial process that involves extrinsic and intrinsic factors such as host genetics, the immune system, the gut microbiome, and environmental risks. To help understand the genetic contribution of clinical, behavioral, psychiatric, and diet-related traits, we aim to provide a deep and comprehensive characterization of the shared genetic architecture between IBD and hundreds of potentially related traits. Utilizing publicly available summary statistics from a previously published IBD genome-wide association study and hundreds of traits from the United Kingdom BioBank (UKBB), we performed linkage disequilibrium score regression (LDSR) analysis to estimate cross-trait genetic correlations between Crohn's disease (CD), ulcerative colitis (UC), and IBD summary statistics with the UKBB traits of interest. Nominally significant (P < .05) genetic correlations were observed for 181 traits in overall IBD, 239 traits in CD, and 94 traits in UC. We replicate the known association between smoking behavior and CD/UC, namely that current tobacco smoking has a positive genetic correlation with CD (rg = 0.12, P = 4.2 × 10-4), while "ever smoking" has a negative genetic correlation with UC (rg = -0.07, P = .042). Globally, all 3 strata (IBD, CD, and UC) demonstrated increased genetic correlations for psychiatric-related traits related to anxiety and depression. The present analysis reveals the shared genetic architecture between multiple traits and IBD, CD, and UC. Understanding the relevance of joint occurrences of IBD with psychiatric diseases may moderate management of these diseases for individuals jointly affected by them.

Inflammatory bowel disease in children and adolescents: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition.

BackgroundEpidemiological and clinical studies have reported an association between leukocyte telomere length (LTL) and Alzheimer’s disease (AD). However, genetic association between the two phenotypes remains largely unknown. We aimed to elucidate the potential shared genetic architecture between LTL and AD.MethodsSummary statistics from genome-wide association studies were obtained from large-scale biobank in European-ancestry populations for LTL (N = 472,174) and AD (71,880 cases, 383,378 controls). We examined the global and local genetic correlation between LTL and AD using linkage-disequilibrium score regression and ρ-HESS. We applied the bivariate causal mixture model (MiXeR) to calculate the number of shared genetic causal variants, and the conditional/conjunctional false discovery rate (condFDR/conjFDR) framework to identify specific shared loci between LTL and AD. Bidirectional two-sample Mendelian randomization (MR) were used to explore the causal associations between LTL and AD.ResultsWe detected a significant genetic correlation between LTL and AD (rg = -0.168). Partitioning the whole genome into 1703 almost independent regions, we observed a significant local genetic correlation for LTL and AD at 19q13.32. MiXeR estimated a total of 360 variants affecting LTL, of which 16 was estimated to influence AD. The condFDR revealed an essential genetic enrichment in LTL conditional on associations with AD, and vice versa. We next identified 8 shared genomic loci between LTL and AD using conjFDR method, of which 4 are novel loci for both the phenotypes. Moreover, 3 shared loci were identified as eQTLs (rs3098168, rs4780338 and rs2680702). All shared loci mapped a subset of 48 credible genes, including USP8, DEXI and APOE. Gene-set analysis identified 18 putative gene sets enriched with the genes mapped to the shared loci. MR analysis suggested that genetically determined AD was causally associated with LTL.ConclusionOur study identified specific shared loci between LTL and AD, providing new insights for polygenic overlap and molecular mechanisms, and highlighting new opportunities for future experimental validation.

Inflammatory bowel disease (IBD) is a digestive tract disorder manifesting mainly in two forms, namely Crohn’s disease (inflammation of digestive tract) and ulcerative colitits (inflammation of large intestine lining) .Genetic and environmental factors could potentially predispose towards IBD. From a smoking perspective, ulcerative colitis is frequently observed in ex-smokers of non-smokers whereas Crohn’s disease is frequently observed among smokers. Smoking was reported to have distinct effects in these two types of disorders, nevertheless elicitation of humoral and cellular immunity was observed to be common in both the types of IBDs. Smoking has been implicated in disease amelioration in case of UC. However, smoking has been associated with several adverse effects including cardiovascular disease and carcinogenesis which outweigh the beneficial aspects. The present review collates information on the role of smoking in UC based on latest research outcomes and elucidates the effect of nicotine (an active constituent in smoking) and associated mechanism of action in IBD condition. Genetic and environmental factors are the cause of disorders like inflammatory bowel diseases (IBD). Ulcerative colitis (UC) is a type of IBD which is mostly seen in non-smokers or former smokers. In UC protective effect of smoking is seen due to nicotine presence. While in Crohn’s disease (CD) smoking show opposite effects hence, it is complex to know relationship between IBD’s. Humoral and cellular immunity changes are indulged in the relationship of both the IBD’s. Therapeutically, nicotine is used for many diseases like ulcerative colitis, Alzheimer's disease, Parkinson's disease, Tourette's syndrome, sleep apnea, and attention deficit disorder. In case of active UC nicotine is effective while in most cases this nicotine becomes harmful and causes side effects like nausea, headache, dermatitis etc. Smoking is linked to most hazardous effects like atherosclerosis, pulmonary hypertension, cardiovascular diseases, carcinogenic disorders which make patients to quit smoking. This sudden ceasing of smoking may potentially elevate symptoms. Correlating with the previous data here we will compare effect of smoking based on genetic susceptibility, twins, gender, and smokers and non- smokers. Data is highly contradictory while the involved mechanism in both the cases is still unknown. In this paper we have mainly focused on smoking role in Ulcerative colitis (UC) depending on many studies done in recent years and also the effect and mechanism of nicotine action on our body.

Baseline Disease Activity and Steroid Therapy Stratify Risk of COVID-19 in Patients With Inflammatory Bowel Disease

Background: Individuals with inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are known to have a higher risk of digestive tract cancers as compared to the general population. As the IBD population has gotten older over time, age-related cancers may be more commonly diagnosed. We conducted a population-based study to assess whether incident cancers were being diagnosed more commonly overtime and whether those with IBD were more likely to be diagnosed with cancer. Methods: A population-based surveillance case-control study was conducted in in Alberta, Canada from April 1, 2002 to March 31, 2018. A validated coding algorithm identified all cases of IBD stratified by type of IBD (CD, UC). Each case was age and sex matched to 10 non-IBD cases from the general population, and then linked to the Alberta provincial cancer registry to extract pathology-confirmed incident cancer. Cancer diagnoses were classified: colorectal, small bowel, pancreatic, biliary and liver, breast, cervical, endometrial, thyroid, hematological, lung, neurological, melanoma, non-melanoma skin cancer, prostate, renal, and bladder. Odds ratios (OR), with 95% confidence intervals (CI), compared IBD cases to matched controls using conditional logistic regression. The annual incidence of cancer diagnosis among the at-risk prevalent IBD population was determined with the average annual percentage change (AAPC) calculated using log binomial regression. Results: Overall, 3,695 incident cancers were diagnosed among 35,763 individuals with IBD as compared to 31,365 cancers among 362,248 controls (IBD: OR = 1.22; 95% CI: 1.18, 1.27; CD: OR = 1.42, 95% CI: 1.34, 1.49; UC: OR = 1.13 95% CI: 1.06, 1.20). Annual incident cancers in those with IBD steadily increased by 3.4% per year (AAPC = 3.44%; 95% CI: 2.71%, 4.18%). A higher odds of cancer was observed across digestive tract cancers for those with IBD: biliary and liver (IBD: OR = 7.76; 95% CI: 5.89, 10.22); colorectal cancer (IBD: OR = 1.88; 95% CI: 1.67, 2.15); small bowel (CD: OR = 10.81; 95% CI: 6.89, 16.95; UC: OR = 1.74; 0.73, 4.16); and pancreas (IBD: OR = 8.01; 95% CI: 5.72, 11.20). Outside of the digestive tract the following cancers were more common in those in IBD: hematological (IBD: OR = 1.47, 95% CI: 1.29, 1.67); lung (IBD: OR = 4.16; 95% CI: 3.59, 4.81); neurological (IBD: OR = 4.73; 95% CI: 3.12, 7.18; and renal (IBD: OR = 2.18; 95% CI: 1.77, 2.68). Non-melanoma skin cancers were associated with IBD (OR = 1.11; 95% CI: 1.05, 1.18), but not melanoma (OR = 0.98; 95% CI: 0.82, 1.18). Other solid-organ cancers were not associated or occurred less commonly in those with IBD: prostate (OR = 0.68; 95% CI: 0.60, 0.77); bladder (OR = 0.73; 95% CI: 0.57, 0.92), cervix (OR = 0.83; 95% CI: 0.73, 0.93), endometrium (OR = 0.50; 95% CI: 0.36, 0.70), and thyroid (OR = 0.84; 95% CI: 0.65, 1.10). Conclusion(s): Over time, persons with IBD are being more commonly diagnosed with cancer. Individuals with IBD are more likely to be diagnosed with cancer as compared to the general population with cancers of the digestive tract driving this association. Healthcare providers should be aware of higher occurrence of hematological, neurological, lung and renal cancers in those with IBD.

: The objective of the present study was to quantify the national pediatric inpatient inflammatory bowel disease (IBD) burden in terms of the number of IBD-related hospitalizations, the number of days spent in the hospital, and hospitalization costs. : Hospitalizations for children and adolescents 20 years and younger with a primary diagnosis of either Crohn disease (CD) or ulcerative colitis (UC) were selected from the 2006 Kids' Inpatient Database (KID). Length of the hospital stay in days (LOS) and charges for the hospitalization were found directly in the Kids' Inpatient Database, and cost was calculated using the hospital's cost-to-charge ratio. Predictor variables included patient characteristics, such as age and severity of illness, and hospital characteristics. Ordinary-least-squares regressions were developed and estimated to explain hospitalization costs. : In 2006, there were 10,777 IBD-related hospitalizations. The total and mean costs for CD were $66.3 million and $10,176 (95% confidence interval [CI] $9647-$10,705), and for UC were $48.6 million and $11,836 (95% CI $10,760-$12,912). For CD, 0- to 5-year-old patients had the highest mean LOS (8.10, 95% CI 5.53-10.67, days) and mean cost ($13,894, 95% CI $9053-$18,735), whereas, for UC, 11- to 15-year-old patients had the highest mean LOS (7.49, 95% CI 6.88-8.10, 95% CI 5.53-10.67, days) and mean cost ($13,407, 95% CI $11,704-$15,110). : For a pediatric disease with a rather low prevalence rate, the estimated annual inpatient pediatric burden of IBD is a sizeable $152.4 million (2010 US$) and 64,985 days spent in the hospital. As medications and outpatient treatments improve for the treatment of IBD, there is an opportunity for significant reduction in inpatient burden.

Does Consuming the Recommend Daily Level of Fiber Prevent Crohn's Disease?

The occurrence of ischemic heart disease (IHD), atrial fibrillation, and flutter demonstrates certain associations with inflammatory bowel disease (IBD), warranting further exploration at the genetic architecture level. This study focused on genome-wide association study (GWAS) data of IHD, atrial fibrillation and flutter, and IBD, analyzing from two dimensions: genetic correlation and shared locus identification. Initially, linkage disequilibrium score regression and genetic covariance analyzer were utilized to assess the overall genetic correlations. Subsequently, the association patterns of local genomic regions were determined using Local Ancestry Variance Association (LAVA) analysis. Mendelian randomization (MR) was employed to assess causal effects. The genetic overlap among different traits was analyzed based on the statistical framework of conditional/conjunctional false discovery rate (cond/conjFDR). Finally, shared loci across these traits were identified by integrating conjFDR analysis with GWAS multi-trait analysis (MTAG). At the genomic level, significant overall correlations were observed among IHD, atrial fibrillation and flutter, and IBD and Crohn's disease (CD), while associations with ulcerative colitis appeared less pronounced. At the local level, IHD and IBD (including subtypes) showed significant associations in multiple regions. However, atrial fibrillation and flutter exhibited local associations only in the context of CD. Through conjFDR analysis, the genetic overlap across these diseases was validated. Additionally, several shared genetic loci were identified by integrating conjFDR and MTAG analyses, with genes confirmed in both IHD and IBD (including subtypes), such as SMAD3, PLCG2, ZNF831, PTPN22, RP11-136O12.2, and RP11-449I17.5. Moreover, six common genes were identified in the analysis between atrial fibrillation and flutter and IBD (including subtypes), such as ZMIZ1, MTHFS, ERAP2, GNA12, and RP1-15D23.2. This study offers empirical evidence of the genetic association between IHD, atrial fibrillation and flutter, and IBD comorbidity, providing new insights for cases where IBD co-occurs with IHD or atrial fibrillation and flutter.

BackgroundIron deficiency anemia (IDA) is common in persons with inflammatory bowel disease (IBD). Current evidence-based guidelines suggest iron replacement therapy in IBD patients with IDA. Intravenous (IV) iron has been demonstrated to be more effective than oral iron replacement in the IBD population, and this is thought to be related to oral iron being poorly tolerated, absorbed, and possibly having an adverse impact on the gut microbiome. Studies have not directly compared the response of IV iron between persons with ulcerative colitis (UC) and Crohn’s disease (CD).Aims(1) To compare the increase in serum hemoglobin and ferritin following IV iron therapy between persons with UC and CD. (2) To determine factors associated with response to IV iron (other than disease type), including age, sex, IBD therapies, abdominal surgeries, and IBD phenotype.MethodsIn a retrospective chart review, we evaluated 536 IV iron infusions (iron sucrose) prescribed to 117 IBD patients by a single gastroenterologist between 2012–2020, and collected data on IBD type, age, sex, medications (IBD therapies, NSAIDs, ASA, oral iron), abdominal surgeries, and IBD phenotype. Statistical analysis was performed using SPSS version 26.ResultsMost IV iron infusions were given to patients with CD (77% of infusions, 68% of persons). The majority of infusions were given as a series of multiple iron infusions (84%) over a mean of 27 weeks, rather than a single infusion. Persons with UC had a greater increase in serum ferritin than those with CD (mean difference ± SE of 13.2 ± 5.6 µg/L, p = 0.02). There was no significant difference in the increase in serum hemoglobin between UC and CD (UC= 6.5 ± 1.0 g/L; CD 4.9 ± 2.1 g/L; p = 0.62).ConclusionsPersons with UC had a better ferritin response to IV iron therapy than persons with CD. Patients with UC were prescribed less IV iron than those with CD. In summary, persons with CD may require greater dosing of IV iron therapy than patients with UC. Further studies are needed to discern if this difference is secondary to CD being associated with a greater extent of mucosal disease burden, impaired iron absorption, or a greater intolerance to oral iron.Funding AgenciesFellowship Funding from Pfizer Canada

Background/Objectives: Elderly populations are under-represented in inflammatory bowel disease (IBD) clinical trials, with limited data on phenotype, treatment patterns, outcomes, and comorbidities. The main objective of this study was to evaluate, in an elderly cohort with IBD, demographic and disease characteristics, comorbidity, polypharmacy, and treatment patterns according to the development of IBD at or before old age. Secondarily, the same analysis was performed based on the type of IBD: ulcerative colitis (UC) or Crohn's disease (CD). Materials and Methods: Observational, single-center, retrospective study including patients diagnosed with IBD and aged 65 years or older seen at the IBD office of the Regional University Hospital of Malaga between September and November 2022. Data were recorded on demographic, disease-related, and IBD treatment-related variables, comorbidities, and polypharmacy. A descriptive and analytical study was undertaken according to the age of IBD onset and type of IBD. Results: Of the patients included, 50.8% were male, 55.1% had CD, and 44.9% UC. IBD onset was before age 65 years in 69.5% and ≥65 years in 30.5%. Elderly with IBD who debuted <65 presented longer disease duration (19.67 ± 9.82 years) and required more IBD-related surgeries (37.8%); elderly with IBD who debuted ≥65 were older (77.69 ± 6.26 years), with no differences in the other variables. According to the type of IBD, elderly UC patients were older (74.55 ± 6.9 years), used more aminosalicylates (77.4%), and had higher rates of polypharmacy (90.6%). Elderly patients with CD had higher IBD activity (moderate/severe in 72.3%), used more biologic drugs (58.5%), and required more IBD-related surgeries (44.6%). Conclusions: Elderly patients who develop IBD before or after the age of 65 years are overall very similar in baseline and disease-related characteristics. Elderly with CD have higher IBD activity and require more biologic drugs and IBD-related surgeries. Elderly with UC are older and have higher rates of polypharmacy and aminosalicylate use.

This Month in Gastroenterology

AGA Medical Position Statement on the Diagnosis and Management of Colorectal Neoplasia in Inflammatory Bowel Disease

BackgroundObservational studies have reported associations between inflammatory bowel diseases (IBDs) and prostate cancer. However, the causality remains controversial. We aimed to identify causal associations between IBD and prostate cancer.MethodsA two-sample...

Characterization of Myeloid Neoplasms in Inflammatory Bowel Disease