Enrichment of Motilin Receptor Loss-of-Function Variants in Gastroparesis

Abstract

Introduction: Gastroparesis is a serious medical condition characterized by delayed gastric emptying and symptoms of nausea, vomiting, bloating, fullness after meals, and abdominal pain. Methods: To ascertain the genetic risk factors for gastroparesis, we conducted the largest thus far whole-genome sequencing study of gastroparesis. We investigated the frequency and effect of rare loss-of-function variants in patients with both idiopathic and diabetic gastroparesis enrolled in a clinical study of gastroparesis. Results: Among rare loss-of-function variants, we reported an increased frequency of a frameshift mutation p.Leu202ArgfsTer105, within the motilin receptor gene, variant rs562138828 (odds ratio 4.9). We currently replicated this finding in an independent large cohort of gastroparesis samples obtained from patients participating in the ongoing phase III gastroparesis clinical study. Discussion: Motilin receptor is an important therapeutic target for the treatment of hypomotility disorders. The identified genetic variants may be important risk factors for disease as well as may inform treatments, especially those targeting motilin receptor.

Common Pathophysiological Mechanisms and Treatment of Diabetic Gastroparesis

“…The frequency of the code-shifting mutation p.l u202argfster105 within the motilin receptor gene variant rs562138828 was found to be increased in patients with DGP. 49 Motilin is a 22-amino acid peptide hormone that is largely generated by enteroendocrine cells in the small intestine duodenum and is expressed in the gastrointestinal tracts of humans and other species. 50 Motilin’s principal organ of action is the stomach, which induces contraction of the gastric body and sinus and relaxation of the pylorus and plays an important role in encouraging gastric emptying during the interdigestive phase.…”

“…Motilin receptors are expressed in the muscles and myenteric plexus of the human colon and are important therapeutic targets for the treatment of gastrointestinal motility disorders. 49 Motilin receptor agonists promote enteric cholinergic activity in a short- or long-lasting way, which promotes stomach emptying. Low doses of a motilin receptor agonist that specifically activates nerve receptors in the stomach rather than smooth muscle receptors to stimulate gastric emptying and the vagus nerve to increase appetite and lessen nauseous symptoms are available.…”

A pilot genome‐wide association study meta‐analysis of gastroparesis

“…As observed in other GI motility disorders, underlying genetic factors may play a predisposing role in GP through mechanisms that lead to immune dysregulation, dysmotility, and abnormal gut‐brain crosstalk 12,13 . Despite this, genetic studies of GP have been scarce, mostly limited to candidate genes, and the heritability of GP remains unknown 14,15 . To gain initial insights into the genetic predisposition and pathophysiology of GP, we conducted a pilot genome‐wide association study (GWAS) meta‐analysis in a total of 880 well‐characterized GP cases and 58,271 controls of European ancestry from two independent GP case‐control cohorts.…”

“… 12 , 13 Despite this, genetic studies of GP have been scarce, mostly limited to candidate genes, and the heritability of GP remains unknown. 14 , 15 To gain initial insights into the genetic predisposition and pathophysiology of GP, we conducted a pilot genome‐wide association study (GWAS) meta‐analysis in a total of 880 well‐characterized GP cases and 58,271 controls of European ancestry from two independent GP case‐control cohorts.…”