Table 1.
Genetic Associations with Crohn’s Disease and Ulcerative Colitis.*
| Gene | Genomic Region |
No. of Genes in Region† |
Associated with Crohn’s Disease |
Associated with Ulcerative Colitis |
Function |
|---|---|---|---|---|---|
| Innate immune responses | |||||
|
NOD2 (nucleotide-binding oligomerization domain 2) |
16q12 | 1 | Yes | No | Senses bacterial peptidoglycan to activate cell signaling |
| ATG16L1 (autophagy-related, 16-like) | 2q37 | 1 | Yes | No | Component of autophagy complex |
| IRGM (immunity-related GTPase M) | 5q33 | 3 | Yes | Equivocal | Role in autophagy; required for interferon-γ– mediated clearance of intracellular pathogens |
| Interleukin-23–Th17 pathway | |||||
| IL23R (interleukin-23 receptor) | 1p31 | 1 | Yes | Yes‡ | Unique component of heterodimeric interleukin-23 receptor |
| IL12B (interleukin-12B, p40 subunit) | 5q33 | 1 | Yes | Yes‡ | Component of interleukin-23 cytokine; common to interleukin-12 |
|
STAT3 (signal transducer and activator of tran- scription 3) |
17q21 | 4 | Yes | Yes‡ | Major STAT downstream of various cytokines, in- cluding interleukin-6, 10, 17, 21, 22, and 23 |
| CCR6 (chemokine [C-C motif ] receptor 6) | 6q27 | 3 | Yes | No | Cell-membrane protein mediating migration and recruitment of inflammatory cells |
| Other genes in association regions | |||||
| PTGER4 (prostaglandin E receptor 4) | 5p13 | 0 | Yes | No | One of the receptors for the inflammatory mediator PGE2 |
| ZNF365 (zinc finger protein 365) | 10q21 | 1 | Yes | No | Reported role in mitosis |
|
SLC22A4 (solute-carrier family 22, organic-cation transporter) |
5q31 | 7 | Yes | Equivocal | Plasma membrane polyspecific organic cation transporter |
| PTPN2 (T-cell protein tyrosine phosphatase) | 18p11 | 1 | Yes | No | Multiple interactions with STAT proteins; also as- sociated with type 1 diabetes |
| Major histocompatibility complex (MHC) | 6p21 | — | Yes‡ | Yes | Distinct MHC class II associations between ulcer- ative colitis and Crohn’s disease |
| NKX2-3 (NK2–transcription-factor–related, locus 3) | 10q24 | 1 | Yes | Yes‡ | Homeodomain-containing transcription factor af- fecting lymphoid and spleen development |
| MST1 (macrophage stimulating 1) | 3p21 | 35 | Yes | Yes‡ | Involved in macrophage chemotaxis and activation following proinflammatory signals |
| PLA2G2E (secretory phospholipase A2) | 1p36 | 0§ | No | Yes | Releases arachidonic acid from membrane phos- pholipids |
| IL10 (interleukin-10) | 1q32 | 1§ | Equivocal | Yes | Immunosuppressive cytokine with a central role in regulating intestinal inflammation |
| IFNG (interferon-γ) | 12q15 | 2§ | No | Yes | Critical cytokine in innate and adaptive immunity against intracellular pathogens |
Each genomic region listed in the table has been reported to be highly associated with either Crohn’s disease or ulcerative colitis (P<10−11). Because epidemiologic studies predict that some genetic loci will demonstrate similar association trends in Crohn’s disease and ulcerative colitis, loci strongly associated in one disease have been tested for association in the converse phenotype. Because in this situation the multiple testing burden is reduced, less stringent thresholds for association in the converse phenotype provide evidence for disease association.
The number of genes in the associated region was obtained from Barrett et al.2 unless otherwise specified. In some cases, the association signal identified in genomewide association studies is confined to a genomic region containing only one gene, strongly implicating that gene in the pathogenesis (e.g., chromosomes 16q12, 2q37, 1p31, and 5p33). In other cases, the association signal encompasses multiple genes and the causal gene or genes are unknown, most notably the chromosome 3p21 association signal encompassing 35 expressed transcripts. At the other extreme, the association can be confined to a region containing no genes (e.g., chromosome 5p13). However, in the case of the chromosome 5p13 association signal, PTGER4 is the closest gene to the association signal and is a compelling functional candidate gene; polymorphisms in this region that are associated with Crohn’s disease regulate PTGER4 messenger RNA levels.6
There is less significant evidence for an association in the converse phenotype.
The number of genes in the associated region was obtained from Silverberg et al.40
The number of genes in the associated region was obtained from Franke et al.11