Genetic Association of Peptidoglycan Recognition Protein Variants with Inflammatory Bowel Disease

Abstract

Inflammatory bowel disease (IBD) is a common disease, includes Crohn's disease (CD) and ulcerative colitis (UC), and is determined by altered gut bacterial populations and aberrant host immune response. Peptidoglycan recognition proteins (PGLYRP) are innate immunity bactericidal proteins expressed in the intestine. In mice, PGLYRPs modulate bacterial populations in the gut and sensitivity to experimentally induced UC. The role of PGLYRPs in humans with CD and/or UC has not been previously investigated. Here we tested the hypothesis that genetic variants in PGLYRP1, PGLYRP2, PGLYRP3 and PGLYRP4 genes associate with CD and/or UC and with gender and/or age of onset of disease in the patient population. We sequenced all PGLYRP exons in 372 CD patients, 77 UC patients, 265 population controls, 210 familial CD controls, and 24 familial UC controls, identified all polymorphisms in these populations, and analyzed the variants for significant association with CD and UC. We identified 16 polymorphisms in the four PGLYRP genes that significantly associated with CD, UC, and/or subgroups of patient populations. Of the 16, 5 significantly associated with both CD and UC, 6 with CD, and 5 with UC. 12 significant variants result in amino acid substitutions and based on structural modeling several of these missense variants may have structural and/or functional consequences for PGLYRP proteins. Our data demonstrate that genetic variants in PGLYRP genes associate with CD and UC and may provide a novel insight into the mechanism of pathogenesis of IBD.