A terrific update on the genetics of inflammatory bowel diseases (DPB McGovern, S Kugathasan, JH Cho. Gastroenterol 2015; 149: 1163-76) explains why and how this information matters right now. The article is a little difficult to read due to its review of highly technical material.
Here’s what I think were the key points:
- Big advances in understanding the genetics started with the first genome-wide association studies (GWAS) using genome-wide single nucleotide polymorphisms (SNP) chips in 2005. “The conceptual basis of GWAS is that most complex (ie, not single-gene Mendelian) genetic disorders are polygenic, being driven by multiple common genetic polymorphisms.”
- “Early GWAS identified the most significant loci.” Now, more than 200 loci associated with IBD have been identified with GWAS and Immunochip data. Table 1 lists these loci over 4 pages. About 2/3rds of these are associated with Crohn’s disease (CD) and ulcerative colitis (UC) whereas the remaining 1/3rd are unique to either CD or UC.
- These loci provide insight into disease mechanisms. NOD2 mutations result in “impaired activation of NF-κB” This supported “the general concept that deficiencies of innate immune cell function represent a central factor in Crohn’s disease, distinguishing it from ulcerative colitis.”
- ATG16L1 gene mutation “establish the fact that the CD risk allele is correlated with impaired autophagy.” This is leading directly into treatment efforts.
- IL23R. “The most significant association is Arg381Gln…confers a 2- to 3-fold protection against development of IBD.” The protective effect is thought to be due to “decreased numbers of interleukin (IL)-23 dependent CD4+ Th17 and CD8+ Tc17 cells…decreasing IL-23 signaling, such as through monoclonal antibody blockade of anti-p40 or anit-p19 may be beneficial.”
- FUT2 mutations. These mutations affect the mucus layer in Crohn’s disease.
- Studies in non-Caucasians highlight other susceptibility regions.
- “Currently, sequencing of the whole exome has become not only a practical method but also a cost-effective option to identify functionally relevant variants in the protein encoding regions of the genome.”
Very Early Onset IBD:
- Whole exome sequencing (WES) identified XIAP (X-linked inhibitor of apoptosis) in a case of boy with very early onset (VEO) IBD. XIAP is a positive regulator of NOD2 function. WES has also identified FOXP3, and IL10RB genes.
- “The VEO group experiences a more severe disease course and more frequently shows a positive family history for IBD in support of higher genetic load.” Table 2 lists ~40 genes associated with VEO. These genes are involved in epithelial barrier function, neutropenia/defects in phagocyte function, hype-and autoinflammation, and regulatory T cells and immune regulation.
Genetic Testing Will Impact Current Therapies and Help Explain Extraintestinal Manifestations:
- Currently testing for TPMT variations is recommended prior to use of thiopurines due to concerns of toxicity in individuals with decreased metabolism of these medications. However, genetic testing can identify other individuals with propensity to leukopenia (eg. NUDT15 polymorphism) and those with increase risk for pancreatitis (eg. HAL-DQA1-HLA-DRB1)
- Primary Sclerosing Cholangitis (PSC) is associated with numerous genetic loci as well. PSC “genetically is more similar to UC than to CD.” Most other extraintestinal manifestation studies have been underpowered.
- IBD share more genetic similarity to spondyloarthropathy (SpA) than any other immune-mediated diseases. “The vast majority of shared susceptibility loci are concordant between IBD and SpA.”
- With regard to psoriasis, the genetic relationship to IBD is complex. Anti-TNF agents can cause psoriaform lesions in IBD patients. In addition, anti-IL17a therapy, “so successful in psoriasis, appears to worsen Crohn’s disease” but not in those with a TNFSF15 variant. Specific genotyping may help identify which patients with CD are susceptible to psoriaform lesions and those who may improve with therapy typically given for psoriasis.
My take: This article shows how understanding genetics of IBD is providing insight into pathophysiology and more personalized treatment approaches.
Briefly noted: EM Stoffel, CR Boland. Gastroenterol 2015; 149: 1191-1203. Excellent review of the genetics and genetic testing for Hereditary Colorectal Cancer. The review includes polyposis syndromes and Lynch syndrome.