Haplotypes of PADI4 susceptible to rheumatoid arthritis are also associated with ulcerative colitis in the Japanese population
Introduction
Chronic inflammatory bowel disease (IBD) is a multifactorial disorder that is characterized by inflammation specific to the gastrointestinal tract, which results in intestinal malabsorption, immune defense abnormalities, and an exaggerated inflammatory response [1], [2]. Various immune and inflammatory cells, such as lymphocytes, macrophages, and dendritic cells, play important roles in the development and progression of IBD [3], [4], [5]. In addition, bacterial antigens have been implied in the pathological inflammation and may mediate both innate and adaptive responses underlying chronic inflammation [6], [7], [8]. IBD consists of two main subtypes: ulcerative colitis (UC) and Crohn's disease (CD) [1], [2]. Although the precise etiology of IBD remains unknown, both several environmental factors such as dietary components and microorganisms and genetic factors may contribute to the occurrence of IBD [6], [7], [8]. In order to identify the genes underlying the etiology of IBD, genome-wide linkage analyses and candidate gene-based association studies have launched and shown possible IBD-susceptibility loci at 16q12 (IBD1), 12q13 (IBD2), 6p13 (IBD3), 14q11 (IBD4), 5q31–q33 (IBD5), 19p13 (IBD6), 1p36 (IBD7), 16q11 (IBD8), 3p21 (IBD9), and other loci [8], [9].
Recently, peptidylarginine deiminase type 4 (PADI4) located at 1p36 is identified as the rheumatoid arthritis (RA)-susceptible gene [10]. RA is involved in autoimmune diseases, of which pathoetiology is probably similar to UC in a number of respects with not only mechanisms of immune defense abnormalities, such as the elevated production of autoantibody [1], [2], but also arthritic manifestations, e.g. ankylosing spondylitis and sacroiliitis [11]. Although RA complicated by UC is uncommon, recent report has described the development of UC in patients with RA [12]. More importantly, PADI4 also lies within the IBD-susceptibility locus (IBD7) [8], [9], [10].
Based on the above findings, we hypothesized that PADI4 could play a role in the pathogenesis of IBD as well as RA. Thus, in this study, we have examined whether haplotypes and diplotypes of PADI4 are associated with IBD in the Japanese population.
Section snippets
Subjects
The study subjects comprised unrelated 114 patients with UC, unrelated 83 patients with CD, and 200 gender-matched, unrelated, healthy volunteers as control. The characteristics of subjects are shown in Table 1. Age at onset is indicated as the mean ± standard deviation (SD). All participants were Japanese who were randomly recruited from 8 general health clinics in the Nagasaki district of Japan. The study protocol was approved by the Committee for Ethical Issues dealing with the Human Genome
Results and discussion
The distributions of genotypes of each SNP on PADI4 in each group corresponded to the Hardy–Weinberg equilibrium (Data not shown). We identified 7 haplotypes composed of 3 SNPs among the subjects in this study (Table 2, Table 3). However, the rare frequent haplotypes, Hap 5, Hap 6, and Hap 7, were excluded in Table 2, Table 3. The frequencies and distributions of haplotypes in our study population corresponded to that in previous studies on association with RA in other Japanese populations [10]
Acknowledgments
We are grateful to physicians, patients, and volunteers for participating in this study.
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