Haplotypes of PADI4 susceptible to rheumatoid arthritis are also associated with ulcerative colitis in the Japanese population

Abstract

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a chronic inflammatory disorder characterized by intractable inflammation specific to the gastrointestinal tract. The precise etiology of IBD remains unknown. Recently, haplotypes of peptidylarginine deiminase type 4 (PADI4) have been identified as the rheumatoid arthritis (RA)-susceptible gene. PADI4 is located at 1p36, which is one of chromosomal loci susceptible for IBD. Then, we examined whether haplotypes and diplotypes of PADI4 are associated with IBD in the Japanese population. We studied haplotypes of PADI4 in 114 patients with UC, 83 patients with CD, and 200 gender-matched healthy controls by PCR-restriction fragment length polymorphism. Frequencies and distributions of haplotypes and diplotypes were compared statistically between patients and controls by logistic regression analysis. The frequency of haplotype 1 was significantly decreased in patients with UC, compared to that in controls (P = 0.037; odds ratio (OR) = 0.702). In contrast, the frequency of haplotype 2 in patients with UC was significantly higher than that in controls (P = 0.003; OR = 1.722). Moreover, of a total of 114 patients with UC, 15 (13.2%) had a diplotype homozygous for haplotype 2, the frequency being significantly higher than in controls (9/200, 4.5%; P = 0.008, OR = 3.215). Our results indicate that haplotype 1 of PADI4 is associated with non-susceptibility to UC, whereas haplotype 2 is susceptible to UC. Thus, it is likely that PADI4 is one of genetic determinants of UC 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.