Genome-wide analysis of 944 133 individuals provides insights into the etiology of haemorrhoidal disease.

OBJECTIVE: Haemorrhoidal disease (HEM) affects a large and silently suffering fraction of the population but its aetiology, including suspected genetic predisposition, is poorly understood. We report the first genome-wide association study (GWAS) meta-analysis to identify genetic risk factors for HEM to date. DESIGN: We conducted a GWAS meta-analysis of 218 920 patients with HEM and 725 213 controls of European ancestry. Using GWAS summary statistics, we performed multiple genetic correlation analyses between HEM and other traits as well as calculated HEM polygenic risk scores (PRS) and evaluated their translational potential in independent datasets. Using functional annotation of GWAS results, we identified HEM candidate genes, which differential expression and coexpression in HEM tissues were evaluated employing RNA-seq analyses. The localisation of expressed proteins at selected loci was investigated by immunohistochemistry. RESULTS: We demonstrate modest heritability and genetic correlation of HEM with several other diseases from the GI, neuroaffective and cardiovascular domains. HEM PRS validated in 180 435 individuals from independent datasets allowed the identification of those at risk and correlated with younger age of onset and recurrent surgery. We identified 102 independent HEM risk loci harbouring genes whose expression is enriched in blood vessels and GI tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses highlighted HEM gene coexpression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organisation of the extracellular matrix. CONCLUSION: HEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.

Pathophysiology of internal hemorrhoids.

Hemorrhoidal disease is a fairly common and debilitating clinical entity. Despite centuries' of attempts to shed light on its pathophysiology, to cure those affected and to improve sufferers' quality of life, many aspects of the disease remain elusive. Individual beliefs and historical legends, accompanied by undocumented theories, have established and perpetuated the confusion regarding the mechanisms leading to the development of the disease and the rules governing its treatment. Hemorrhoids are classified as internal or external and are viewed as a disease when they become symptomatic. Returning to basic medical sciences, this mini-review focuses on internal hemorrhoids and aims to define the histology and anatomy of the normal and abnormal internal hemorrhoidal plexus and to encourage clinicians to comprehend the pathophysiology of the disease. If doctors can understand the pathophysiology of hemorrhoidal disease, they will be able to clarify the nature of the associated symptoms and complications and to make the correct therapeutic decision.

K-ras Mutations as the Earliest Driving Force in a Subset of Colorectal Carcinomas.

K-ras oncogene is a key factor in colorectal cancer. Based on published and our data we propose that K-ras could be the oncogene responsible for the inactivation of the tumor-suppressor gene APC, currently considered as the initial step in colorectal tumorigenesis. K-ras fulfills the criteria of the oncogene-induced DNA damage model, as it can provoke well-established causes for inactivating tumor-suppressors, i.e. DNA double-strand breaks (causing allele deletion) and ROS production (responsible for point mutation). The model we propose is a variation of the currently existing model and hypothesizes that, in a subgroup of colorectal carcinomas, K-ras mutation may precede APC inactivation, representing the earliest driving force and, probably, an early biomarker of colorectal carcinogenesis. This observation is clinically useful, since it may modify the preventive colorectal cancer strategy, restricting numerically patients undergoing colonoscopies to those bearing K-ras mutation in their colorectum, either in benign polyps or the normal accompanying mucosa.

Elevated intraesophageal pressure in patients with achalasia: a common and important manometric finding.

There is a subgroup of patients with achalasia in which manometry shows elevated intraesophageal pressure, expressed by elevation of esophageal baseline relative to gastric pressure. The aim of this study was to determine the prevalence of elevated intraesophageal pressure in patients with achalasia and its relationship to clinical, radiographic, endoscopic, and other manometric findings. Manometric studies of 62 patients with achalasia were analyzed and elevated intraesophageal pressure was considered any positive elevation of esophageal baseline relative to gastric pressure. Multiple regression analysis was used to determine independent risk factors associated with elevated intraesophageal pressure. Elevated intraesophageal pressure was found in 32 patients (51.6%). Lower esophageal sphincter pressure was the only independent variable associated with elevated intraesophageal pressure (P = 0.0167). Mean lower esophageal sphincter pressure was significantly higher in patients with elevated compared to those with normal intraesophageal pressure (34 +/- 1.96 vs 26.5 +/- 1.73 mm Hg; P = 0.006). In addition, lower esophageal sphincter pressure had a positive correlation with intraesophageal pressure (r = 0.49, P < 0.001). Conversely, no correlation was found between elevated intraesophageal pressure and various symptoms, disease duration, radiologic dilation, a finding of retained fluid during endoscopy, and esophageal length. We conclude that elevated intraesophageal pressure is a common manometric finding in patients with achalasia, with a prevalence of 51.6%, and is associated with significantly higher lower esophageal sphincter pressure.