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World J Gastroenterol. Nov 7, 2014; 20(41): 15037-15048
Published online Nov 7, 2014. doi: 10.3748/wjg.v20.i41.15037
Immunogenetic biomarkers in inflammatory bowel diseases: Role of the IBD3 region
Manuel Muro, Ruth López-Hernández, Anna Mrowiec
Manuel Muro, Ruth López-Hernández, Anna Mrowiec, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Immunology Service, University Hospital Virgen de la Arrixaca, 30120 Murcia, Spain
Author contributions: Muro M, López-Hernández R and Mrowiec A made substantial contributions to conception and design of the article; Muro M wrote the first draft of the article; López-Hernández R and Mrowiec A revised it critically for important intellectual content; all the authors have approved for publication the final version of the article.
Supported by The Projects from Foundation Seneca, No. 05748/PI/07 and No. 04487/GERM/06; the Fondo de Investigación Sanitaria (FIS) projects CIBERehd, No. PI11/02644 and No. PI11/02686 (in part); the ISCII and Fundación para la Formación e Investigación Sanitarias de la Región de Murcia (FFIS), No. CA11/00034 (to López-Hernández R)
Correspondence to: Manuel Muro, PhD, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Immunology Service, University Hospital Virgen de la Arrixaca, Madrid-Cartagena s/n, El Palmar, 30120 Murcia, Spain.
Telephone: +34-968-369599 Fax: +34-968-349678
Received: September 20, 2013
Revised: March 1, 2014
Accepted: April 15, 2014
Published online: November 7, 2014

Many studies have demonstrated the linkage between the IBD3 region (6p21.1-23), an area which encompasses the famous human leukocyte antigen (HLA) complex, and Crohn’s disease (CD) or ulcerative colitis (UC). IBD3 is the only region that meets genome-wide significance, and provides stronger evidence of the linkage than 16p13.1-16q12.2 (IBD1), the locus that contains the susceptibility gene CARD15. However, despite these findings, IBD3 susceptibility genes remain elusive and unclear due to the strong linkage disequilibrium, extensive polymorphism, and high gene density that characterize this area and also due to varying allele frequencies in populations around the world. This area presents an extremely high abundance of genes, including the classical and non-classical major histocompatibility complex (MHC) class I and II genes, and other genes, namely MHC class III genes tumor necrosis factor (TNF)-α and -β, and Hsp, whose proteins play key functions in immunological processes. To date, it is not clear which genes within the MHC family contribute to the IBD pathogenesis, although certain HLA alleles have been associated with IBD. Recent insights into the biological function of other genes encoded within the IBD3 region, such as the MHC class I chain-related (MIC) genes, have led investigators to a more comprehensive exploration of this region. MHC class I chain-related molecule A (MICA) is highly polymorphic and interacts with NKG2D, its receptor on the surface of NK, Tγδ and T CD8+ cells. Increased expression of MICA in intestinal epithelial cells and increased expression of NKG2D in CD4+ T cells (lamina propria) in patients with CD have also been reported. MICA alleles have also been associated with IBD, and a variation at amino acid position 129 of the α2-heavy chain domain seems to categorize MICA alleles into strong and weak binders of NKG2D receptor, thereby influencing the effector cells’ function. In this regard, a relevant role of MICA-129-Val/Met single nucleotide polymorphism has recently been implicated in the pathogenesis of IBD. TNF-α and -β also play an important role in inflammatory response. In fact, IBD is commonly treated with TNF-α inhibitors. Additionally, polymorphisms of TNF-α gene are known to affect the gene expression level and particular TNF-α genotypes may influence the response of IBD patients treated with TNF-α inhibitors.

Keywords: IBD3, Tumor necrosis factor, MICA, HLA, Inflammatory bowel disease

Core tip: This review gathers information about the importance of IBD3 genomic region in susceptibility to inflammatory bowel disease (IBD). The new and old immunogenetic biomarkers of the IBD3 region (human leukocyte antigen, MHC class I chain-related molecule A, MHC class I chain-related molecule B, and tumor necrosis factor-α and -β) and their role on IBD susceptibility are discussed in the light of recent publications. IBD3 gene polymorphisms and their clinical relevance for the treatment of the IBD patients are also discussed. Insights into the natural history of these complex diseases may allow in the future appropriate patient selection for early aggressive therapy aimed at modifying the course of the disease.