Classification of genetic profiles of Crohn’s disease: a focus on the ATG16L1 gene

摘要

Inflammatory bowel disease constitutes two related clinical entities, Crohn’s disease (CD) andnulcerative colitis (UC), both of which have increased in prevalence over the last decade. Familynand twin studies have strongly indicated that genetic factors play a large role in an individual’snrisk of developing inflammatory bowel disease. Despite this, it has proven difficult to isolatendisease genes that confer susceptibility to this disease using classical candidate gene and linkagenapproaches, with the notable exception of the isolation of the caspase recruitment domainnfamily, member 15 (CARD15) gene. However, over the last 2 years, genome-wide associationn(GWA) studies have become feasible, where modern high-throughput single nucleotidenpolymorphism (SNP) genotyping technologies can be applied to large and comprehensivelynphenotyped patient cohorts. Such approaches have enabled scientists to robustly associatenspecific variants with many complex diseases, including age-related macular degeneration,nType 2 diabetes, breast cancer and asthma. In the inflammatory bowel disease field, positivenassociations with CD and UC coming from GWA studies have been reported for an evernincreasing number of genes. The most consistently and strongly associated variants have been innthe CARD15, the interleukin 23 receptor (IL23R) and autophagy-related 16-like 1 (ATG16L1)ngenes. With respect to ATG16L1, the G allele of SNP rs2241880 has been shown in multiplenassociation studies to confer strong risk for CD, although its association with UC remains morendebatable. This SNP is in fact a common coding variant, specifically a threonine-to-alaninensubstitution at amino acid position 300 of the ATG16L1 protein (T300A), and appears tonaccount for all of the disease risk conferred by this locus. This review addresses recent advancesnin GWA studies of inflammatory bowel disease, with specific focus on the growing evidence ofnthe ATG16L1 gene’s role in CD and how its protein product operating within the autophagicnpathway makes autophagy an attractive therapeutic target for this debilitating disorder.