• Crohn’s disease
• IBD
• IMID
• anti-IL-23 antibodies
• psoriasis
• therapy
• ulcerative colitis
• ustekinumab

• Southeast Asia
• epidemiology
• genetics
• inflammatory bowel disease

• Humans
• Asia, Southeastern/epidemiology
• Genetic Predisposition to Disease
• Incidence
• Inflammatory Bowel Diseases/epidemiology
• Inflammatory Bowel Diseases/genetics
• Risk Factors
• Urbanization

• IBD
• OCTN1
• OCTN2
• SLC22 family
• carnitine
• gene expression and regulation

• Humans
• Solute Carrier Family 22 Member 5/genetics
• Solute Carrier Family 22 Member 5/metabolism
• Gene Expression Regulation
• Organic Cation Transport Proteins/genetics
• Organic Cation Transport Proteins/metabolism
• Organic Cation Transport Proteins/chemistry
• Protein Conformation
• Symporters/genetics
• Symporters/metabolism
• Symporters/chemistry

• 2022JWT5XS PRIN (Progetti di Ricerca di Interesse Nazionale), to L.P. granted by MUR (Ministry of University and Research) - Italy, funded by the European Union - Next Generation EU.
• PNC0000003 The National Plan for NRRP Complementary Investments - AdvaNced Technologies for Human-centrEd Medicine (ANTHEM) to M.G

• crohn’s disease
• inflammatory bowel disease
• interleukin-4
• single nucleotide polymorphism
• ulcerative colitis

Background: TNF-α inhibitors are effective biological agents for treating psoriasis, but the treatment responses differ across patients. This study aimed to identify genetic biomarkers of anti-TNF-α response in Chinese psoriasis patients using a genome-wide association approach.

Methods: We recruited two independent cohorts of Chinese psoriasis patients administered etanercept biosimilar (with or without methotrexate). We identified 61 and 87 good responders (PASI improvement ≥75%), 19 and 10 poor responders (PASI improvement <50%) after 24 weeks treatment in the two cohorts, respectively. Then we performed genome-wide association studies (GWAS) on anti-TNF-α response in each cohort independently, followed by a fixed-effects inverse-variance meta-analysis in the 148 good and 29 poor responders.

Results: We tested genetic associations with >3 million genetic variants in either cohort. Meta-analysis identified significant associations within seven loci at p < 10⁻⁵, which also showed consistent association evidence in the two cohorts. These seven loci include rs2431355 (OR = 6.65, p = 4.46 × 10⁻⁷, IQGAP2-F2RL2 on 5q13.3), rs11801616 (OR = 0.11, p = 1.75 × 10⁻⁶, SDC3 on 1p35.2), rs3754679 (OR = 0.17, p = 7.71 × 10⁻⁶, CNOT11 on 2q11.2), rs13166823 (OR = 0.09, p = 3.71 × 10⁻⁶, IRF1-AS1 on 5q31.1), rs10220768 (OR = 5.49, p = 1.48 × 10⁻⁶, NPAP1 on 15q11.2), rs4796752 (OR = 5.56, p = 1.49 × 10⁻⁶, KRT31 on 17q21.2), and rs13045590 (OR = 0.08, p = 9.67 × 10⁻⁷, CTSZ on 20q13.3). Of the seven SNPs, six SNPs showed significant eQTL effect (p < 1 × 10⁻⁶) for several genes in multiple tissues.

Conclusion: These results suggest novel biological mechanisms and potential biomarkers for the response to anti-TNF therapies. These findings warrant further validation.

• National Natural Science Foundation of China
• Basic Public Welfare Research Program of Zhejiang Province

Fibrinogen is a large molecule synthesized in the liver and released in the blood. Circulating levels of fibrinogen are upregulated after bleeding or clotting events and support wound healing. In the context of an injury, thrombin activation drives conversion of fibrinogen to fibrin. Fibrin deposition contains tissue damage, stops blood loss, and prevents microbial infection. In most circumstances, fibrin needs to be removed to allow the resolution of inflammation and tissue repair, whereas failure of this may lead to the development of various disorders. However, the contribution of fibrinogen to tissue inflammation and repair is likely to be context-dependent. In this study, the concept that fibrin needs to be removed to allow tissue repair and to reduce inflammation is challenged by our observations that, in the intestine, fibrinogen is constitutively produced by a subset of intestinal epithelial cells and deposited at the basement membrane as fibrin where it serves as a substrate for wound healing under physiological conditions such as epithelial shedding at the tip of the small intestinal villus and surface epithelium of the colon as well as under pathological conditions that require rapid epithelial repair. The functional integrity of the intestine is ensured by the constant renewal of its simple epithelium. Superficial denuding of the epithelial cell layer occurs regularly and is rapidly corrected by a process called restitution that can be influenced by various soluble and insoluble factors. Epithelial cell interaction with the extracellular matrix greatly influences the healing process by acting on cell morphology, adhesion, and migration. The functional contribution of a fibrin(ogen) matrix in the intestine was studied under physiological and pathological contexts. Our results (immunofluorescence, immunoelectron microscopy, and quantitative PCR) show that fibrin(ogen) is a novel component of the basement membrane associated with the differentiated epithelial cell population in both the small intestine and colon. Fibrin(ogen) alone is a weak ligand for epithelial cells and behaves as an anti-adhesive molecule in the presence of type I collagen. Furthermore, the presence of fibrin(ogen) significantly shortens the time required to achieve closure of wounded epithelial cell monolayers and co-cultures in a PI3K-dependent manner. In human specimens with Crohn’s disease, we observed a major accumulation of fibrin(ogen) throughout the tissue and at denuded sites. In mice in which fibrin formation was inhibited with dabigatran treatment, dextran sulfate sodium administration provoked a significant increase in the disease activity index and pathological features such as mucosal ulceration and crypt abscess formation. Taken together, these results suggest that fibrin(ogen) contributes to epithelial healing under both normal and pathological conditions.

• Animals
• Epithelial Cells/metabolism
• Estrone/analogs & derivatives
• Fibrin/metabolism
• Fibrinogen/metabolism
• Inflammation/metabolism
• Intestines
• Mice
• Phosphatidylinositol 3-Kinases/metabolism
• Wound Healing

• MOP-97836 CIHR
• MOP-123415 CIHR
• Canadian Institutes of Health Research
• Natural Sciences and Engineering Research Council of Canada

The gut microbiome (GM), a complex community of bacteria, viruses, protozoa, and fungi located in the gut of humans and animals, plays significant roles in host health and disease. Animal models are widely used to investigate human diseases in biomedical research and the GM within animal models can change due to the impact of many factors, such as the vendor, husbandry, and environment. Notably, variations in GM can contribute to differences in disease model phenotypes, which can result in poor reproducibility in biomedical research. Variation in the gut microbiome can also impact the translatability of animal models. For example, standard lab mice have different pathogen exposure experiences when compared to wild or pet store mice. As humans have antigen experiences that are more similar to the latter, the use of lab mice with more simplified microbiomes may not yield optimally translatable data. Additionally, the literature describes many methods to manipulate the GM and differences between these methods can also result in differing interpretations of outcomes measures. In this review, we focus on the GM as a potential contributor to the poor reproducibility and translatability of mouse models of disease. First, we summarize the important role of GM in host disease and health through different gut–organ axes and the close association between GM and disease susceptibility through colonization resistance, immune response, and metabolic pathways. Then, we focus on the variation in the microbiome in mouse models of disease and address how this variation can potentially impact disease phenotypes and subsequently influence research reproducibility and translatability. We also discuss the variations between genetic substrains as potential factors that cause poor reproducibility via their effects on the microbiome. In addition, we discuss the utility of complex microbiomes in prospective studies and how manipulation of the GM through differing transfer methods can impact model phenotypes. Lastly, we emphasize the need to explore appropriate methods of GM characterization and manipulation.

• gut microbiome
• modulation
• mouse model of disease
• reproducibility
• translatability
• virome

• U42 OD010918 NIH HHS

Trans-acting expression quantitative trait loci (trans-eQTLs) account for ≥70% expression heritability and could therefore facilitate uncovering mechanisms underlying the origination of complex diseases. Identifying trans-eQTLs is challenging because of small effect sizes, tissue specificity, and a severe multiple-testing burden. Tejaas predicts trans-eQTLs by performing L2-regularized “reverse” multiple regression of each SNP on all genes, aggregating evidence from many small trans-effects while being unaffected by the strong expression correlations. Combined with a novel unsupervised k-nearest neighbor method to remove confounders, Tejaas predicts 18851 unique trans-eQTLs across 49 tissues from GTEx. They are enriched in open chromatin, enhancers, and other regulatory regions. Many overlap with disease-associated SNPs, pointing to tissue-specific transcriptional regulation mechanisms.

• Animals
• Humans
• Organic Cation Transport Proteins/antagonists & inhibitors
• Organic Cation Transport Proteins/metabolism
• Substrate Specificity

• U01 MH109536 NIMH NIH HHS
• R01 MH085548 NIMH NIH HHS
• Wellcome Trust
• G0401207 Medical Research Council
• G0200243 Medical Research Council
• MR/K006584/1 Medical Research Council
• SJN is also supported by the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre, and by awards establishing the Farr Institute of Health Informatics Research at UCLPartners, from the Medical Research Council, Arthritis Research UK, British Heart Foundation, Cancer Research UK, Chief Scientist Office, Economic and Social Research Council, Engineering and Physical Sciences Research Council, National Institute for Health Research, National Institute for Social Care and Health Research, and Wellcome Trust (grant MR/K006584/1).
• This paper represents independent research part-funded by FAPESP (2014/50830-2; 2010/08968-6), the Marie Curie International Research Staff Exchange (FP7-PEOPLE-2011-IRSES/295192), and the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. SDJ is funded by the European Union’s Horizon 2020 research and innovation programme under Marie Skłodowska-Curie grant IF 658195.

• Binding Sites/genetics
• Blood Cells/metabolism
• Blood Cells/pathology
• Blood Chemical Analysis
• Disease/genetics
• Gene Expression Regulation
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Humans
• Linkage Disequilibrium
• Multifactorial Inheritance/genetics
• Phenotype
• Polymorphism, Single Nucleotide
• Protein Binding
• Quantitative Trait Loci
• Risk Factors
• Transcription Factors/metabolism

• S10 RR028832 NCRR NIH HHS
• T32 GM007753 NIGMS NIH HHS
• T32 DK110919 NIDDK NIH HHS
• R00 HG008399 NHGRI NIH HHS
• U01 HG009379 NHGRI NIH HHS
• R01 MH101244 NIMH NIH HHS
• R01 MH109978 NIMH NIH HHS
• F32 HG009987 NHGRI NIH HHS
• R01 MH107649 NIMH NIH HHS

• Crohn’s disease
• IL-10
• IL-4
• Th2 cytokines
• genetics
• inflammatory bowel disease
• polymorphisms
• ulcerative colitis

To investigate genetic factors that might help define which Crohn’s disease (CD) patients are likely to benefit from anti-tumor necrosis factor (TNF) therapy.

This was a prospective cohort study. Patients were recruited from a university digestive disease practice database. We included CD patients who received anti-TNF therapy, had available medical records (with information on treatment duration and efficacy) and who consented to participation. Patients with allergic reactions were excluded. Patients were grouped as ever-responders or non-responders. Genomic DNA was extracted from peripheral blood, and 7 single nucleotide polymorphisms (SNPs) were assessed. The main outcome measure (following exposure to the drug) was response to therapy. The patient genotypes were assessed as the predictors of outcome. Possible confounders and effect modifiers included age, gender, race, and socioeconomic status disease, as well as disease characteristics (such as Montreal criteria).

121 patients were included. Twenty-one were non-responders, and 100 were ever-responders. Fas ligand SNP (rs763110) genotype frequencies, TNF gene -308 SNP (rs1800629) genotype frequencies, and their combination, were significantly different between groups on multivariable analysis controlling for Montreal disease behavior and perianal disease. The odds of a patient with a Fas ligand CC genotype being a non-responder were four-fold higher as compared to a TC or TT genotype (P = 0.009, OR = 4.30, 95%CI: 1.45-12.80). The presence of the A (minor) TNF gene -308 allele correlated with three-fold higher odds of being a non-responder (P = 0.049, OR = 2.88, 95%CI: 1.01-8.22). Patients with the combination of the Fas ligand CC genotype and the TNF -308 A allele had nearly five-fold higher odds of being a non-responder (P = 0.015, OR = 4.76, 95%CI: 1.35-16.77). No difference was seen for the remaining SNPs.

The Fas-ligand SNP and TNF gene -308 SNP are associated with anti-TNF treatment response in CD and may help select patients likely to benefit from therapy.

• Anti-tumor necrosis factor
• Fas ligand
• Antibody
• Response
• Crohn’s disease
• Single nucleotide polymorphisms
• Genotype
• Tumor necrosis factor gene

• Adalimumab/therapeutic use
• Adult
• Alleles
• Certolizumab Pegol/therapeutic use
• Colonoscopy
• Crohn Disease/diagnostic imaging
• Crohn Disease/drug therapy
• Crohn Disease/genetics
• Fas Ligand Protein/genetics
• Female
• Gastrointestinal Agents/therapeutic use
• Genotype
• Humans
• Infliximab/therapeutic use
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Prospective Studies
• Tumor Necrosis Factor-alpha/antagonists & inhibitors
• Tumor Necrosis Factor-alpha/genetics

• Complex diseases
• Inflammatory bowel diseases
• NGS
• Next-generation sequencing
• Variant priorization
• Variants of unknown significance (VUS)
• WES
• WGS
• Whole-exome sequencing
• Whole-genome sequencing

Psoriasis and the spectrum of inflammatory bowel diseases (IBD) are chronic, inflammatory, organotropic conditions. The epidemiologic coexistence of these diseases is corroborated by findings at the level of disease, biogeography, and intrafamilial and intrapatient coincidence. The identification of shared susceptibility loci and DNA polymorphisms has confirmed this correlation at a genetic level. The pathogenesis of both diseases implicates the innate and adaptive segments of the immune system. Increased permeability of the epidermal barrier in skin and intestine underlies the augmented interaction of allergens and pathogens with inflammatory receptors of immune cells. The immune response between psoriasis and IBD is similar and comprises phagocytic, dendritic, and natural killer cell, along with a milieu of cytokines and antimicrobial peptides that stimulate T-cells. The interplay between dendritic cells and Th17 cells appears to be the core dysregulated immune pathway in all these conditions. The distinct similarities in the pathogenesis are also reflected in the wide overlapping of their therapeutic approaches. Small-molecule pharmacologic immunomodulators have been applied, and more recently, biologic treatments that target proinflammatory interleukins have been introduced or are currently being evaluated. However, the fact that some treatments are quite selective for either skin or gut conditions also highlights their crucial pathophysiologic differences. In the present review, a comprehensive comparison of risk factors, pathogenesis links, and therapeutic strategies for psoriasis and IBD is presented. Specific emphasis is placed on the role of the immune cell species and inflammatory mediators participating in the pathogenesis of these diseases.

• Crohn’s disease
• immune cells
• inflammation
• inflammatory bowel disease
• psoriasis
• ulcerative colitis

• CROHN'S DISEASE
• GENETIC POLYMORPHISMS

Major advances in genotyping technology have generated high-density maps of single nucleotide polymorphism (SNP) markers that provide an unprecedented opportunity to identify genes underlying complex traits. Several family-based statistical methods showing robust population stratification have been developed to test the association between multiple markers and disease-susceptibility genes. Only a few methods focus on testing for maternally mediated genetic effects, which is a critical risk for birth defects. The present study focuses on testing for association and maternally mediated genetic effects with family-based methods.

In the present study, we proposed a new method, max_PC integrating principal component analysis, to test association or maternally mediated genetic effects with case-parent data. The proposed method only uses the genotypes of case-parents triads and accommodates missing SNP data. Our results demonstrated that this method is powerful to test association or maternally mediated genetic effects and attractive because it provides a tool for testing the null hypothesis of no association and no maternally mediated genetic effects. Simulations with the permutation procedure as well as an application in the Crohn’s disease study showed that the type I error rates of the proposed statistic were nominal with slightly higher power as compared to those of the max_Z² test.

We conclude that the max_PC is a good approach to test association or maternally mediated genetic effects.

• Goblet cells
• Inflammatory bowel disease
• Intestinal stem cells
• Organoids
• Paneth cells
• Stem cell transplantation

• Cancer
• Hallmarks
• Inflammation
• Phytochemicals
• Tumor

• Antineoplastic Agents/therapeutic use
• Cell Transformation, Neoplastic/drug effects
• Genetic Heterogeneity/drug effects
• Humans
• Inflammation/drug therapy
• Inflammation/genetics
• Inflammation/pathology
• Molecular Targeted Therapy
• Neoplasm Proteins/antagonists & inhibitors
• Neoplasms/drug therapy
• Neoplasms/genetics
• Neoplasms/pathology
• Signal Transduction/drug effects

• R01CA 156776-01 NCI NIH HHS
• K01 AT007324 NCCIH NIH HHS
• 5P01CA073992 NCI NIH HHS
• R01 CA156776 NCI NIH HHS
• P01 AT003961 NCCIH NIH HHS
• P01 CA073992 NCI NIH HHS
• R21 CA188818 NCI NIH HHS
• I01 BX001517 BLRD VA
• K01AT007324 NCCIH NIH HHS
• 1R01CA151304 NCI NIH HHS
• R21 CA18881801A1 NCI NIH HHS
• 1P01AT003961 NCCIH NIH HHS
• C301/A14762 Cancer Research UK
• 1R03CA1711326 NCI NIH HHS
• R01 CA151304 NCI NIH HHS

• Case-Control Studies
• Crohn Disease/genetics
• Gene Expression
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Humans
• Interferon-gamma/metabolism
• Intestines
• Linkage Disequilibrium
• Logistic Models
• Macrophages
• Microarray Analysis
• Polymorphism, Single Nucleotide
• Quantitative Trait Loci
• Sequence Analysis, RNA

• T32 GM007223 NIGMS NIH HHS
• T32 HD007149 NICHD NIH HHS
• R01 DK092235 NIDDK NIH HHS
• U01 DK62429 NIDDK NIH HHS
• U01 DK062422 NIDDK NIH HHS

• pediatric inflammatory bowel disease
• comorbidity
• exome sequencing
• autoimmune disorders
• asthma
• genetics

• Animals
• Asian People/genetics
• Asian People/statistics & numerical data
• Calcium Channels/genetics
• Case-Control Studies
• Chromosome Mapping
• Exfoliation Syndrome/epidemiology
• Exfoliation Syndrome/genetics
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Glaucoma, Open-Angle/epidemiology
• Glaucoma, Open-Angle/genetics
• HEK293 Cells
• HeLa Cells
• Humans
• Japan/epidemiology
• MCF-7 Cells
• Mice
• Mice, Inbred C57BL
• Polymorphism, Single Nucleotide
• Tumor Cells, Cultured

• R01 EY011721 NEI NIH HHS
• R29 EY011721 NEI NIH HHS
• EY018825 NEI NIH HHS
• Howard Hughes Medical Institute
• 085475/B/08/Z Wellcome Trust
• R01 EY018825 NEI NIH HHS
• EY023512 NEI NIH HHS
• R01 EY020928 NEI NIH HHS
• Wellcome Trust
• 085475/08/Z Wellcome Trust
• P30 EY014104 NEI NIH HHS
• EY11721 NEI NIH HHS
• R01 EY023512 NEI NIH HHS
• R01 EY013882 NEI NIH HHS

• Genetic epidemiology
• genome-wide association studies
• leishmaniasis
• lymphatic filariasis
• malaria
• onchocerciasis
• schistosomiasis
• soil-transmitted helminth diseases
• trypanosomiasis

• Genetic overlap
• Genome-wide association study
• Human leukocyte antigen system
• Immune dysregulation
• Major histocompatibility complex
• Polygenic risk score

Mycobacterium leprae infects macrophages and Schwann cells inducing a gene expression program to facilitate its replication and progression to disease. MicroRNAs (miRNAs) are key regulators of gene expression and could be involved during the infection. To address the genetic influence of miRNAs in leprosy, we enrolled 1,098 individuals and conducted a case-control analysis in order to study four miRNAs genes containing single nucleotide polymorphism (miRSNP). We tested miRSNP-125a (rs12975333 G>T), miRSNP-223 (rs34952329 *>T), miRSNP-196a-2 (rs11614913 C>T) and miRSNP-146a (rs2910164 G>C). Amongst them, miRSNP-146a was the unique gene associated with risk to leprosy per se (GC OR = 1.44, p = 0.04; CC OR = 2.18, p = 0.0091). We replicated this finding showing that the C-allele was over-transmitted (p = 0.003) using a transmission-disequilibrium test. A functional analysis revealed that live M. leprae (MOI 100∶1) was able to induce miR-146a expression in THP-1 (p<0.05). Furthermore, pure neural leprosy biopsies expressed augmented levels of that miRNA as compared to biopsy samples from neuropathies not related with leprosy (p = 0.001). Interestingly, carriers of the risk variant (C-allele) produce higher levels of mature miR-146a in nerves (p = 0.04). From skin biopsies, although we observed augmented levels of miR-146a, we were not able to correlate it with a particular clinical form or neither host genotype. MiR-146a is known to modulate TNF levels, thus we assessed TNF expression (nerve biopsies) and released by peripheral blood mononuclear cells infected with BCG Moreau. In both cases lower TNF levels correlates with subjects carrying the risk C-allele, (p = 0.0453 and p = 0.0352; respectively), which is consistent with an immunomodulatory role of this miRNA in leprosy.

In spite of the successful drug therapy, leprosy is still affecting people worldwide. It is well known that host genetic background influences leprosy development and that genetic variants have been associated with the disease. Therefore we conducted a study to evaluate the role of microRNAs (miRNAs) polymorphisms in leprosy. We observed that a polymorphism in miR-146a is associated with the risk to develop leprosy in Brazilians. Based on the analysis of clinical specimens, we found that the genetic variant was correlated with elevated levels of miR-146a and it is also a negative regulator of tumor necrosis factor (TNF), an important inflammatory mediator in the leprosy context. These findings provide tenable evidences that miR-146a is important in the control of gene expression during M. leprae infection and also may contribute with leprosy development by controlling TNF levels.

• Alleles
• Case-Control Studies
• Genetic Predisposition to Disease
• Genotype
• Heterozygote
• Humans
• Leprosy/genetics
• Leukocytes, Mononuclear/metabolism
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Polymorphism, Single Nucleotide