Genetics of Spondyloarthropathies and Inflammatory Bowel Disease: Searching for Common Susceptibility Factors

Abstract

Ileocolonoscopic evidence for subclinical gut inflammation is found in a subpopulation of spondyloarthropathy (SpA) patients. The prevalence of microscopic intestinal lesions is even higher and can be classified as either an acute or a chronic type of inflammation. The latter condition is associated with an increased risk of developing overt inflammatory bowel disease (IBD), especially Crohn's disease (CD), over time. Evidence for genetic predisposition in both SpA and IBD is strong, and has resulted in the identification of several linked chromosomal loci and putative candidate genes. The regular co-existence of SpA and IBD within the same family suggests a common genetic component. Interestingly, comparison of genome-wide linkage and association data reveals thirteen disease-associated chromosomal regions that are shared between SpA and IBD. This should convince geneticists to examine genes within these regions as potential susceptibility genes for the development of both SpA and IBD. Significant association of such shared genetic determinants was established for NOD2 (16q), the major histocompatibility complex I allele HLA-B27 (6p) and recently also the interleukin 23 receptor (1p). Transgenic animals in which tumor necrosis factor alpha or HLA-B27 is overexpressed suffer both joint and gut abnormalities resembling human SpA/CD pathology, providing additional evidence for a common genetic predisposition for the onset of joint and gut inflammation. In view of a hypothetical pathway leading to intestinal and articular inflammation in SpA and IBD, we review and compare genome-wide linkage and genetic association data obtained for SpA and IBD.Keywords: Spondyloarthropathy, Crohn's disease, genetic susceptibility, NOD2, HLA-B27, IL23R.Spondyloarthropathy (SpA) and inflammatory bowel disease (IBD) are chronic inflammatory conditions in which the initiating events are complex. In SpA, the axial skeleton, the sacroiliac joints and, to a lesser degree, peripheral joints become inflamed, whereas in IBD involving Crohn's disease (CD) and ulcerative colitis (UC), the intestine is the primary site of inflammation. The estimated prevalence in Western countries is 0.3-2% for SpA and 0.1-0.3% for IBD. The unity between SpA and IBD is illustrated by a strong clinical as well as molecular overlap. The first symptoms present themselves in early adulthood, usually before the age of 30, but early childhood and late onset disease occur sporadically. Medical treatment is mainly based on diminishing the inflammation and maintaining the remission states. Spondyloarthropathy is a heterogeneous group generally divided into 5 disease categories: ankylosing spondylitis (AS), reactive arthritis (ReA), psoriatic arthritis (PsA), SpA associated with IBD (SpA-IBD) and undifferentiated SpA. In the SpA-IBD group, patients suffer from clinically overt CD or UC. However, the gut is also an important site of inflammation in patients belonging to the other SpA disease categories. In ileocolonoscopic studies of SpA patients, histological ...