Grant Struan F A, Baldassano Robert N, Hakonarson Hakon
The Center for Applied Genomics and Division of Human Genetics, The Abramson Research Center of the Joseph Stokes Jr Research Institute, Department of Pediatrics, The Children's Hospital of Philadelphia, PA 19104-4318, USA.
Expert Rev Mol Diagn. 2008 Mar;8(2):199-207. doi: 10.1586/14737159.8.2.199.
Inflammatory bowel disease constitutes two related clinical entities, Crohn's disease (CD) and ulcerative colitis (UC), both of which have increased in prevalence over the last decade. Family and twin studies have strongly indicated that genetic factors play a large role in an individual's risk of developing inflammatory bowel disease. Despite this, it has proven difficult to isolate disease genes that confer susceptibility to this disease using classical candidate gene and linkage approaches, with the notable exception of the isolation of the caspase recruitment domain family, member 15 (CARD15) gene. However, over the last 2 years, genome-wide association (GWA) studies have become feasible, where modern high-throughput single nucleotide polymorphism (SNP) genotyping technologies can be applied to large and comprehensively phenotyped patient cohorts. Such approaches have enabled scientists to robustly associate specific variants with many complex diseases, including age-related macular degeneration, Type 2 diabetes, breast cancer and asthma. In the inflammatory bowel disease field, positive associations with CD and UC coming from GWA studies have been reported for an ever increasing number of genes. The most consistently and strongly associated variants have been in the CARD15, the interleukin 23 receptor (IL23R) and autophagy-related 16-like 1 (ATG16L1) genes. With respect to ATG16L1, the G allele of SNP rs2241880 has been shown in multiple association studies to confer strong risk for CD, although its association with UC remains more debatable. This SNP is in fact a common coding variant, specifically a threonine-to-alanine substitution at amino acid position 300 of the ATG16L1 protein (T300A), and appears to account for all of the disease risk conferred by this locus. This review addresses recent advances in GWA studies of inflammatory bowel disease, with specific focus on the growing evidence of the ATG16L1 gene's role in CD and how its protein product operating within the autophagic pathway makes autophagy an attractive therapeutic target for this debilitating disorder.
炎症性肠病由两种相关的临床实体组成，即克罗恩病（CD）和溃疡性结肠炎（UC），在过去十年中，这两种疾病的患病率均有所上升。家族研究和双胞胎研究有力地表明，遗传因素在个体患炎症性肠病的风险中起很大作用。尽管如此，事实证明，使用经典的候选基因和连锁分析方法来分离赋予这种疾病易感性的疾病基因是困难的，半胱天冬酶募集结构域家族成员15（CARD15）基因的分离是一个显著的例外。然而，在过去两年中，全基因组关联（GWA）研究变得可行，现代高通量单核苷酸多态性（SNP）基因分型技术可应用于大规模且全面表型化的患者队列。此类方法使科学家能够有力地将特定变异与许多复杂疾病联系起来，包括年龄相关性黄斑变性、2型糖尿病、乳腺癌和哮喘。在炎症性肠病领域，越来越多的基因被报道与GWA研究中的CD和UC呈正相关。最一致且强烈相关的变异存在于CARD15、白细胞介素23受体（IL23R）和自噬相关16样蛋白1（ATG16L1）基因中。关于ATG16L1，SNP rs2241880的G等位基因在多项关联研究中显示会赋予CD较强的患病风险，尽管其与UC的关联仍更具争议性。实际上，该SNP是一种常见的编码变异，具体为ATG16L1蛋白第300位氨基酸由苏氨酸替换为丙氨酸（T300A），并且似乎解释了该基因座所赋予的所有疾病风险。本综述阐述了炎症性肠病GWA研究的最新进展，特别关注ATG16L1基因在CD中的作用的证据不断增加，以及其蛋白产物在自噬途径中的运作如何使自噬成为这种使人衰弱疾病的一个有吸引力的治疗靶点。
