COLQ and ARHGAP15 are Associated with Diverticular Disease and are Expressed in the Colon.

BACKGROUND: Diverticular disease is a common but poorly understood disease of the gastrointestinal tract. Recent studies have identified several single nucleotide polymorphisms (SNPs) that are associated with diverticular disease. MATERIALS AND METHODS: The genotypes of three SNPs (rs4662344 in ARHGAP15, rs7609897 in COLQ, and rs67153654 in FAM155A) were identified by Taqman assay in 204 patients with diverticular disease. Clinical characteristics were obtained from the medical record to study association with genotype. To evaluate gene expression in colon tissue, qPCR was performed on 24 patients with diverticulitis, and COLQ was localized using immunohistochemistry. RESULTS: The ARHGAP15 and COLQ SNPs were significantly associated with both diverticular disease and specifically diverticulitis, while the FAM155A was not associated with either. No association was found with clinical disease characteristics. Heterozygous genotypes at the ARHGAP15 SNP was associated with lower ARHGAP15 expression in colon tissues. COLQ protein localized to the myenteric plexus in the colon. CONCLUSIONS: This study confirmed association of the ARHGAP15 and COLQ SNPs with diverticular disease in our patients but could not confirm FAM155A SNP association. Neither of these SNPs appeared to associate with more severe disease, but genotype at the ARHGAP15 SNP did impact expression of ARHGAP15 in the colon. Additionally, this study is the first to localize COLQ in the colon. Its presence in the myenteric nervous system suggests COLQ SNP variants may contribute to diverticular disease by altering motility.

Evaluation of molecular and genetic predisposing parameters at diverticular disease of the colon.

BACKGROUND: Diverticular disease (DD) refers to the presence of diverticula throughout the gastrointestinal (GI) tract, mainly along colon. DD might evolve into diverticulitis that is accompanied by severe clinical presentation, which includes abscess formation, perforation, stricture, obstruction and/or fistula. AIM: The aim of the present review is to summarize the role of molecular and genetic factors in DD development, as well as their possible contribution towards new prognostic indicators, diagnostic algorithms and new therapeutic approaches. METHODS AND RESULTS: Except from common predisposing parameters, several genetic mutations, immune factors, neurotransmitters, hormones and protein dysfunctions have been associated to the early onset of DD symptoms, pathogenesis and prognosis of the disease. Specific structural changes in the colonic wall, altered matrix composition and compromised motility have been verified as possible pathogenic factors for the development of DD. Dysregulation in peristaltic activity and reduced ability of the longitudinal muscle to relax following contraction has been also associated with DD evolution. In addition, it has been suspected that genetic defects combined with alterations in intestinal microbiota might play an important role in diverticulitis presentation.

Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms.

OBJECTIVE: Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease. DESIGN: Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry. RESULTS: We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3×10-10 and 0.002 (ORallelic=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33). CONCLUSION: In silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.

Persistent Increased Enteric Glial Expression of S100ß is Associated With Low-grade Inflammation in Patients With Diverticular Disease.

BACKGROUND: Diverticular disease (DD) is a common gastrointestinal inflammatory disorder associated with an enteric neuropathy. Although enteric glial cells (EGCs) are essential regulators of intestinal inflammation and motility functions, their contribution to the pathophysiology of DD remains unclear. Therefore, we analyzed the expression of specific EGC markers in patients with DD. MATERIALS AND METHODS: Expression of the glial markers S100ß, GFAP, Sox10, and Connexin 43 was analyzed by real-time quantitative PCR in colonic specimens of patients with DD and in that of controls. Protein expression levels of S100ß, GFAP, and Connexin 43 were further analyzed using immunohistochemistry in the submucosal and myenteric plexus of patients with DD and in that of controls. Expression of the inflammatory cytokines tumor necrosis factor-α and interleukin-6 was quantified using qPCR, and infiltration of CD3+ lymphocytes was determined using immunohistochemistry. RESULTS: Expression of S100ß was increased in the submucosal and myenteric plexus of patients with DD compared with that in controls, whereas expression of other glial factors remained unchanged. This increased expression of S100ß was correlated to CD3+ lymphocytic infiltrates in patients with DD, whereas no correlation was observed in controls. CONCLUSIONS: DD is associated with limited but significant alterations of the enteric glial network. The increased expression of S100ß is associated with a persistent low-grade inflammation reported in patients with DD, further emphasizing the role of EGCs in intestinal inflammation.

The relationship between diverticular disease of intestine and cirrhosis: a two-sample mendelian randomization study.

The correlation between diverticular disease of the intestine and cirrhosis is well-established, however, the presence of a genetic causal link between the two conditions remains uncertain. The study employed a two-sample Mendelian randomization approach utilizing the most recent genome-wide association study (GWAS) data to investigate the correlation between diverticulosis and liver cirrhosis. The primary analysis was conducted using the Inverse Variance Weighted (IVW) method, and was further corroborated by an array of statistical techniques including MR-Egger, Weighted Median, Weighted Mode, cML-MA, ConMix, MR-RAPS, and DIVW to ensure robustness and reliability of the findings.Heterogeneity was evaluated using Cochran's Q test, horizontal pleiotropy was assessed through MR-Egger regression, and leave-one-out analyses were performed to validate the causal relationships. The IVW method found that diverticular disease significantly reduces the risk of cirrhosis (OR = 0.849, 95% CI: 0.743-0.971, P = 0.016). All models had P-values < 0.05 and negative ß values. MR-Egger regression showed no horizontal pleiotropy (P = 0.215), confirming SNP reliability. Cochran's Q values for IVW and MR-Egger were 57.23 (P = 0.39) and 55.62 (P = 0.41), indicating no heterogeneity. Sensitivity analysis with the leave-one-out method validated the robustness of the results. This research utilizes Mendelian randomization to illustrate the potential protective role of diverticulosis against liver cirrhosis. The results are analyzed through the lenses of gut microbiota and cytokine levels, providing new perspectives that may inform clinical approaches to diagnosis and treatment.

Genetic, epigenetic and environmental factors in diverticular disease: systematic review.

BACKGROUND: Diverticulosis is a normal anatomical variant of the colon present in more than 70% of the westernized population over the age of 80. Approximately 3% will develop diverticulitis in their lifetime. Many patients present emergently, suffer high morbidity rates and require substantial healthcare resources. Diverticulosis is the most common finding at colonoscopy and has the potential for causing a significant morbidity rate and burden on healthcare. There is a need to better understand the aetiology and pathogenesis of diverticular disease. Research suggests a genetic susceptibility of 40-50% in the formation of diverticular disease. The aim of this review is to present the hypothesized functional effects of the identified gene loci and environmental factors. METHODS: A systematic literature review was performed using PubMed, MEDLINE and Embase. Medical subject headings terms used were: 'diverticular disease, diverticulosis, diverticulitis, genomics, genetics and epigenetics'. A review of grey literature identified environmental factors. RESULTS: Of 995 articles identified, 59 articles met the inclusion criteria. Age, obesity and smoking are strongly associated environmental risk factors. Intrinsic factors of the colonic wall are associated with the presence of diverticula. Genetic pathways of interest and environmental risk factors were identified. The COLQ, FAM155A, PHGR1, ARHGAP15, S100A10, and TNFSF15 genes are the strongest candidates for further research. CONCLUSION: There is increasing evidence to support the role of genomics in the spectrum of diverticular disease. Genomic, epigenetic and omic research with demographic context will help improve the understanding and management of this complex disease.

Genetic Risk Factors for Diverticular Disease-Emerging Evidence.

Diverticular disease is traditionally understood as an environmental disease caused by diet and constipation. However, genes are increasing understood to play a role in pathogenesis. Twin studies suggest a substantial component of individual risk is due to heritable factors. Association of diverticular disease with other traits suggests an underlying biological mechanism and recently genome-wide association studies have described the genetic architecture underlying this complex phenotype. These studies suggest a new paradigm for understanding this common surgical disease.

Genetic Risk of Diverticular Disease Predicts Early Stoppage of Nicorandil.

Gastrointestinal fistulation has been widely reported as an adverse effect of nicorandil therapy in Europe. People who have underlying diverticular disease are most at risk of this side effect. In Western countries, diverticular disease is highly prevalent and can be clinically silent. This study aimed to identify diverticular disease genetic risk scores (GRSs) associated with early nicorandil stoppage, a surrogate marker for drug intolerance. A case-control study was carried out on 1,077 patients from the Genetics of Diabetes Audit and Research Tayside Scotland (GoDARTS) database. Cases were defined as having < 9 nicorandil prescriptions with no identifiable reason for stopping (n = 230). Controls had either ≥ 9 prescriptions, treatment continuation to death/study end or stoppage post-myocardial infarction. Two diverticular GRSs were created and used in logistic regression models. Isosorbide mononitrate was used as a control analysis. Patients with a raised diverticular GRS, based on 23 replicable loci, had increased risk of stopping nicorandil therapy early (univariate (odds ratio (OR) 2.26; P = 0.04], multivariate (OR 3.96; P = 0.01)). Similar trends were noted when using the full 42 variant diverticular score but statistical significance was not reached. The isosorbide control analysis did not reach statistical significance. Our analysis demonstrates a novel positive association between a raised diverticular GRS and early stoppage of nicorandil therapy.

Current and Evolving Concepts on the Pathogenesis of Diverticular Disease.

BACKGROUND AND AIMS: Diverticulosis of the colon is the most common anatomic alteration of the human colon, and it is characterized by the out-pouching of the colonic mucosa and submucosa through the muscular layer. Recurrent abdominal pain is experienced by about 20% of patients with diverticulosis, and inflammation of diverticula may lead to acute diverticulitis. In the past few years, several studies have investigated the factors predisposing or triggering diverticular disease (DD) occurrence. Moreover, new physiopathological knowledge has been acquired. The aim of this study was to review current knowledge regarding the pathogenesis of DD. METHODS: A search of PubMed and EMBASE database was performed to identify articles relevant to the pathogenesis of DD. RESULTS: Several papers have shown that genetic predisposition, environmental factors, and colonic dysmotility are implicated in the pathogenesis of DD. More recent studies have associated specific host immune responses, gut microbiota imbalance and therefore low-grade inflammation as contributors to symptom occurrence in DD and diverticulitis. CONCLUSIONS: Current and evolving evidence highlighted the role of genetic susceptibility, environment, colonic motility, visceral sensitivity, immune response, and microbiota in the pathogenesis of this disease. Further studies are required to identify potential targets for medical or surgical decision-making.

Pathogenesis of Diverticulosis and Diverticular Disease.

In this session different problems regarding the pathogenesis of diverticular disease were considered, including "Genetics", "Neuromuscular function abnormalities", "Patterns of mucosa inflammation", and "Impact of lifestyle". The patients affected by diverticular disease have clear genetic pattern, that might predispose to the occurrence of the disease as well as to its complications. Neuromuscular abnormalities may be recognized already at the stage of diverticulosis, and inflammation may explain symptoms occurrence in symptomatic uncomplicated diverticular disease (SUDD) or symptoms persistence after an episode of acute diverticulitis. Finally, lifestyle might also have an impact on symptoms' occurrence. Specifically smoking, but also obesity seem to play an important role, while the role of low-fiber diet and constipation is now under debate.

Genome-wide association analyses identify 39 new susceptibility loci for diverticular disease.

Diverticular disease is common and has a high morbidity. Treatments are limited owing to the poor understanding of its pathophysiology. Here, to elucidate its etiology, we performed a genome-wide association study of diverticular disease (27,444 cases; 382,284 controls) from the UK Biobank and tested for replication in the Michigan Genomics Initiative (2,572 cases; 28,649 controls). We identified 42 loci associated with diverticular disease; 39 of these loci are novel. Using data-driven expression-prioritized integration for complex traits (DEPICT), we show that genes in these associated regions are significantly enriched for expression in mesenchymal stem cells and multiple connective tissue cell types and are co-expressed with genes that have a role in vascular and mesenchymal biology. Genes in these associated loci have roles in immunity, extracellular matrix biology, cell adhesion, membrane transport and intestinal motility. Phenome-wide association analysis of the 42 variants shows a common etiology of diverticular disease with obesity and hernia. These analyses shed light on the genomic landscape of diverticular disease.

Sequence variants in ARHGAP15, COLQ and FAM155A associate with diverticular disease and diverticulitis.

Diverticular disease is characterized by pouches (that is, diverticulae) due to weakness in the bowel wall, which can become infected and inflamed causing diverticulitis, with potentially severe complications. Here, we test 32.4 million sequence variants identified through whole-genome sequencing (WGS) of 15,220 Icelanders for association with diverticular disease (5,426 cases) and its more severe form diverticulitis (2,764 cases). Subsequently, 16 sequence variants are followed up in a diverticular disease sample from Denmark (5,970 cases, 3,020 controls). In the combined Icelandic and Danish data sets we observe significant association of intronic variants in ARHGAP15 (Rho GTPase-activating protein 15; rs4662344-T: P=1.9 × 10-18, odds ratio (OR)=1.23) and COLQ (collagen-like tail subunit of asymmetric acetylcholinesterase; rs7609897-T: P=1.5 × 10-10, OR=0.87) with diverticular disease and in FAM155A (family with sequence similarity 155A; rs67153654-A: P=3.0 × 10-11, OR=0.82) with diverticulitis. These are the first loci shown to associate with diverticular disease in a genome-wide study.