Table 1.
Most clinically relevant and GWAS replicated CD genes
| GENE | SNP or mutational variant | Function | Phenotype/comments |
|---|---|---|---|
| NOD2/CARD 15 | 1007fs, G908R, R702W86,87 | Innate immune responses | Ileal disease. Stricturing phenotype. |
| TLR4 | Asp299Gly88 | Lymphocyte lineage | |
| IL23R | RS10048196,89 | Variants lead to increased risk or protection for CD | |
| OCTN1 | rs10501523 | Fistulizing disease in NOD2/CARD15- patients | |
| ATG16L1 | T300A3,4,90 | Mucosal homeostasis and cellular component degradation | Autophagy pathway |
| IRGM | RS117418618,91 | Regulation of autophagy formation in response to intracellular pathogens | |
| DLG5 | R30Q22 | ||
| LRRk2 | RS1117559365 | Common in pediatric CD; Inversely related in female children | |
| IBD5 | 503F92–94 | The 503F variant (rs1050152) of OCTN1, is near the center of the IBD5 haplotype | |
| PTPN22 | Rs247660195,96 | Responsiveness of T and B cell receptors | 620W gain-of-function variant is associated with reduced risk of CD |
| IL 10R | 1082A/G97 | T regulatory cell responses and anti-inflammation | Increased risk of CD |
| TNF alpha | 308A98 | Extra-intestinal associations | Uveitis risk |
Notes: Bolded genes are highly significant genes in multiple GWAS. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) also known as caspase recruitment domain-containing protein 15 (CARD15) or inflammatory bowel disease protein 1 (IBD1) is a protein that in humans is encoded by the NOD2 gene, which plays an important role in recognizing bacterial molecules and stimulating an immune reaction.99 NOD2 is an intracellular pattern recognition receptor, which recognizes molecules containing the specific structure called muramyl dipeptide found in bacteria.100 TLR 4 is a toll-like receptor. It detects lipopolysaccharide from gram-negative bacteria and is thus important in the activation of the innate immune system.101 Interleukin 23 receptor (IL23R), is a type I cytokine receptor.102 OCTN1 encoded protein is an integral protein of the plasma membrane responsible for the cotransport of sodium ions and ergothioneine, which is an antioxidant, into cells.103 Autophagy-related protein 16–1 (ATG16L1), is a protein that is essential for autophagy.104 Immunity-related GTPase family M protein (IRGM), which plays a role in the innate immune response by regulating autophagy formation in response to intracellular pathogens.105 Disks large homolog 5 (DLG5), which functions as a scaffolding molecule at sites of cell-cell contact.106 The protein encoded by this gene localizes to the plasma membrane and cytoplasm and interacts with components of adherens junctions and the cytoskeleton. It is proposed to function in the transmission of extracellular signals to the cytoskeleton and in the maintenance of epithelial cell structure. Leucine-rich repeat kinase 2 (LRRk2), encodes a protein which is a substrate for chaperone-mediated autophagy.107 The RS11175593 SNP for LRRK2 just downstream MUC 19 encodes for protective mucus on epithelium. IBD5 is a 250 kb cytokine gene cluster on chromosome 5q31 and associated with risk of developing Crohn’s disease.92 Protein tyrosine phosphatase, non-receptor type 22 (PTPN22) affects the responsiveness of T and B cell receptors, and mutations are associated with autoimmune diseases.108 Interleukin 10 receptor (IL10R), the protein encoded by this gene is a receptor for interleukin 10, which has been shown to mediate the immunosuppressive signal of interleukin 10, and thus inhibits the synthesis of proinflammatory cytokines.109 Tumor necrosis factor-alpha (TNF-alpha) is a cytokine involved in systemic inflammation.110
Abbreviations: CD, Crohn’s disease; GWAS, genome-wide association studies; SNP, single nucleotide polymorphism; TLR, toll-like receptor; OCTNI, organic cation transporter novel type 1; GTP,guanosine triphosphate; MUC, mucin gene; IBD5, inflammatory bowel disease 5.