Genetic Association of Peptidoglycan Recognition Protein Variants with Inflammatory Bowel Disease

<div><p>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 <i>PGLYRP1</i>, <i>PGLYRP2</i>, <i>PGLYRP3</i> and <i>PGLYRP4</i> genes associate with CD and/or UC and with gender and/or age of onset of disease in the patient population. We sequenced all <i>PGLYRP</i> 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 <i>PGLYRP</i> 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 <i>PGLYRP</i> genes associate with CD and UC and may provide a novel insight into the mechanism of pathogenesis of IBD.</p></div

Chromosomal locations of <i>PGLYRPs</i> and schematic gene, cDNA, and protein structures, with positions of polymorphisms significantly associated with CD and/or UC.

<p>Genes show exons and introns, cDNAs show exons and start and stop codons, and proteins show domains and locations of significant polymorphisms.</p

<i>PGLYRP3</i> exon 1, SNP rs3006473, c.-38T>C, UTR associates with gender in CD and with gender and age of onset in UC patients.

<p>Complete data are shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067393#pone.0067393.s002" target="_blank">Tables S2</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067393#pone.0067393.s003" target="_blank">S3</a>, and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067393#pone.0067393.s009" target="_blank">S9</a>.</p><p>* or **CA, Cochran Armitage Trend test data for the *recessive mode or **dominant model.</p

<i>PGLYRP1</i> and <i>PGLYRP3 variants</i> associate with UC patients.

<p>Complete data are shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067393#pone.0067393.s002" target="_blank">Tables S2</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067393#pone.0067393.s003" target="_blank">S3</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067393#pone.0067393.s004" target="_blank">S4</a>, and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067393#pone.0067393.s010" target="_blank">S10</a>.</p><p>*CA, Cochran Armitage Trend test data for the recessive model.</p

<i>PGLYRP3</i> exon 2, SNP rs79540951, c.201G>A, p.Leu67 associates with gender in UC.

<p>Complete data are shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067393#pone.0067393.s003" target="_blank">Tables S3</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067393#pone.0067393.s010" target="_blank">S10</a>.</p><p>*CA, Cochran Armitage Trend test data for the recessive model.</p

<i>PGLYRP-4</i> variant associates with CD patients.

<p>Complete data are shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067393#pone.0067393.s002" target="_blank">Tables S2</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067393#pone.0067393.s014" target="_blank">S14</a>.</p><p>*CA, Cochran Armitage Trend test data for the recessive model.</p

<i>PGLYRP1</i> exon 1, SNP rs2072562, c.-19A>C, UTR, associates with gender and age of onset in CD and with gender in UC patients.

<p>Complete data are shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067393#pone.0067393.s002" target="_blank">Tables S2</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067393#pone.0067393.s003" target="_blank">S3</a>, and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067393#pone.0067393.s004" target="_blank">S4</a>.</p><p>*CA, Cochran Armitage Trend test data for the recessive model.</p

Summary of PGLYRP variants that significantly associate with Crohn's disease and ulcerative colitis.

<p>Complete data are shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067393#pone-0067393-t003" target="_blank">Tables 3</a> to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067393#pone-0067393-t014" target="_blank">14</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067393#pone.0067393.s002" target="_blank">S2</a> to S</p><p><i>P</i> values showing trend towards significance are shown in italics; nc, not calculated.</p

<i>PGLYRP4</i> exon 2, SNP rs12096209, c.8C>T, p.Pro3Leu associates with gender in CD patients.

<p>Complete data are shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067393#pone.0067393.s002" target="_blank">Tables S2</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067393#pone.0067393.s012" target="_blank">S12</a>.</p><p>*CA, Cochran Armitage Trend test data for the recessive model.</p

<i>PGLYRP2</i> exon 3, SNP rs4440547, c.1181G>A, p.Arg394Gln associates with gender in CD patients.

<p>Complete data are shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067393#pone.0067393.s002" target="_blank">Tables S2</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067393#pone.0067393.s008" target="_blank">S8</a>.</p><p>*CA, Cochran Armitage Trend test data for the recessive model.</p