1285-P: Differentiating between Diabetic and Idiopathic Gastroparesis: A Genetic Perspective

Abstract

Gastroparesis is a serious medical condition characterized by delayed gastric emptying and symptoms of nausea, vomiting, bloating, fullness after meals, and abdominal pain. An innate immune dysregulation and injury to the interstitial cells of Cajal and other components of the enteric nervous system is likely central to the pathogenesis of gastroparesis. Most common etiologies include diabetes, post-surgical but most cases are idiopathic. Thus far, little is known about the underlying genetic risk factors for gastroparesis. We have done a genome-wide association study comparing idiopathic and diabetic cases with controls as well as contrasting idiopathic versus diabetic cases. We report a novel genetic association of SLC15A4 locus with idiopathic gastroparesis. This signal is driven by multiple variants with top missense variant SLC15A4:NM145648:exon2:c.T716C:p.V239A, rs33990080. Altogether, among EUR cohort we report 69 carriers out of 214 versus controls 165 out of 896 (MAF: cases 0.18; MAF: controls 0.09) and OR: 1.9 (p-value<10^-6) . We furthermore differentiate idiopathic from diabetic gastroparesis with an established diabetes genetic risk score, - result that is statistically significant (p-value<0.0004) . We also delineate a number of significant loci implicated in diabetes risk including (HLA-DQB1,HLA-DQA2, EXOC6B) in the idiopathic versus diabetic gastroparesis analysis. Of particular interest are the Exocyst complex component, 6 (EXOC6/6B) with lead variant rs41420. previously identified to play a role in insulin signaling through its interaction with the glucose transporter GLUT4. Current genetic findings suggest that a mechanism directly connected to macrophage polarization may be implicated in the etiology gastroparesis. The GWAS picture that is emerging implicates novels loci implicated in the pathophysiology of gastroparesis differentiating those of diabetic versus idiopathic etiology. Disclosure S.P.Smieszek: None.