The role of M1 to M2 macrophage polarization in the etiology of idiopathic gastroparesis: GWAS perspective

Abstract

Abstract Gastroparesis is a serious medical condition characterized by delayed gastric emptying. 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. We have done a GWAS 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 logistic model 10^−6). The significant effect persists when idiopathic cases are compared with diabetic cases as the MAF of diabetic cases (0.10) is comparable to that of population controls (0.09). Solute carrier family 15 (SLC15) A4 is a lysosome-resident amino acid/oligopeptide transporter that is preferentially expressed in immune cells. It is required for TLR7/9-dependent type I interferon production and plays a critical role in the pathogenesis of lupus and colitis. SLC15A4 was shown to mediate M1-prone metabolic shifts in macrophages and guards immune cells from metabolic stress. Previous reports have shown that when the anti-inflammatory M2 macrophages are switched to pro-inflammatory M1 macrophages, delayed GE was evident in animal models. Current genetic findings suggest that a mechanism directly connected to macrophage polarization may be implicated in a subset of idiopathic gastroparesis patients.