Common variation in FAM155A is associated with diverticulitis but not diverticulosis

Abstract

colonic diverticulosis is a very common condition. Many patients develop diverticulitis or other complications of diverticular disease. Recent genome-wide association studies (GWAS) consistently identified three major genetic susceptibility factors for both conditions, but did not discriminate diverticulititis and diverticulosis in particular due the limitations of registry-based approaches. Here, we aimed to confirm the role of the identified variants for diverticulosis and diverticulitis, respectively, within a well-phenotyped cohort of patients who underwent colonoscopy. Risk variants rs4662344 in Rho GTPase-activating protein 15 (ARHGAP15), rs7609897 in collagen-like tail subunit of asymmetric acetylcholinesterase (COLQ) and rs67153654 in family with sequence similarity 155 A (FAM155A) were genotyped in 1,332 patients. Diverticulosis was assessed by colonoscopy, and diverticulitis by imaging, clinical symptoms and inflammatory markers. Risk of diverticulosis and diverticulitis was analyzed in regression models adjusted for cofactors. Overall, the variant in FAM155A was associated with diverticulitis, but not diverticulosis, when controlling for age, BMI, alcohol consumption, and smoking status (oR adjusted 0.49 [95% CI 0.27-0.89], p = 0.002). Our results contribute to the assessment specific genetic variants identified in GWAS in the predisposition to the development of diverticulitis in patients with diverticulosis. Colonic diverticulosis is a widespread gastrointestinal condition described as formation of diverticula, which are sac-like protrusions of mucosa and submucosa through muscularis externa 1,2. Although diverticulosis is predominantly asymptomatic, many patients develop symptoms 3,4. These manifestations are classified as uncomplicated and complicated diverticular disease (DD), an inflammation of the tissue (diverticulitis) or diverticular bleeding. The prevalence of the disease and its complications is constantly increasing due to the aging populations 5,6. Therefore, the identification of underlying pathobiological mechanisms of the disease is relevant for improving everyday clinical practice. It is hypothesized that environmental factors together with structural alteration of the colonic wall and remodeling of the enteric nervous system are all predisposing components in the development of colonic diverticula 5. In recent years, epidemiological twin data have suggested that genetic factors are another major cofactor in the pathogenesis of DD 7,8. Up to date, there has been relatively little research effort to determine these genes and their sequence variants that are associated with the development of DD 9. Recently an Icelandic study group published a genome-wide association study (GWAS) searching for sequence variants that affect the

S3-Leitlinie Divertikelkrankheit/Divertikulitis – Gemeinsame Leitlinie der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) und der Deutschen Gesellschaft für Allgemein- und Viszeralchirurgie (DGAV)

“…Zwischen 2017 und 2019 konnte durch drei genomweite Assoziationsstudien ein Überblick über das genetische Risikoprofil der nicht-syndromatischen Divertikulose erhoben werden [64,65,86]. Insgesamt ergibt sich ein zwischen den genomweiten Assoziationsstudien und den Replikationsstudien [87] konsistentes Bild. Es konnten bis zu 48 Risikogene mit genomweiter Signifikanz identifiziert werden [65], von denen mindestens 35 auch in mindestens einer unabhängigen Kohorte repliziert werden konnten.…”

“…Die Ergebnisse dieser Studien vertiefen die bisherigen pathophysiologischen Konzepte und identifizieren spezifische molekulare Signalwege. Die identifizierten Gene lassen überraschend weitgehend in molekulare Mechanismen einordnen und zeigen eine interessante Überlappung mit den monogenen und syndromatischen Divertikuloseformen [65,87]: Eine Reihe von Loci wie COLQ, COL6A1, GDNF und GPR158 deuten auf neuromuskuläre Dysfunktion. Drei Loci zeigen pathophysiologische Verbindungen zum Kalzium-Signalweg in den glatten Muskelzellen des Dünndarms (CPI-17, CECNB2, ANO1).…”

Pathophysiology of Diverticular Disease: From Diverticula Formation to Symptom Generation

“…The first GWAS in the Icelandic and Danish populations identified different loci linked to the disease and located in the intronic region of ARHGAP15 , COLQ , and FAM155 genes [ 25 ]. Specifically, the ARHGAP15 and COLQ variants associate with uncomplicated DD, whereas FAM155 mutation is linked to diverticulitis, but not with diverticulosis [ 25 , 29 ]. The ARHGAP15 gene encodes the Rho GTPase activating protein 15, linked with phagocyte function and inflammation [ 30 ].…”

The prevalence of symptomatic uncomplicated diverticular disease could be lower than expected: a single-center colonoscopy-based cohort study

“…This clinical syndrome is the main form of diverticular disease, and is characterized by long-lasting, moderate-to-severe left-lower quadrant pain, in absence of macroscopic sign of acute diverticulitis and not fulfilling the criteria for irritable bowel syndrome (IBS) diagnosis [2,3]. This clinical syndrome is still under active debate because, although it seems to be associated with specific genetic and molecular alterations [4][5][6], mucosal overexpression of pro-inflammatory cytokines [7,8], with raised levels of fecal calprotectin [3] and fecal microbiota imbalance [9], some studies failed to find significant relationship between abdominal pain, diverticulosis, SUDD and occurrence of inflammation [10,11].…”