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Human Molecular Genetics Pages 307-311  

Association of ulcerative colitis with rare VNTR alleles of the human intestinal mucin gene, MUC3
Introduction
Results
Discussion
Materials And Methods
   Patients and controls
   Reverse transcription and PCR amplification (RT-PCR)
   Southern blotting analysis
   Statistical analysis
References

Association of ulcerative colitis with rare VNTR alleles of the human intestinal mucin gene, MUC3

Association of ulcerative colitis with rare VNTR alleles of the human intestinal mucin gene, MUC3

Kennoki Kyo1,4, Miles Parkes2,5, Yoshiki Takei1, Hiroyuki Nishimori1, Paulomi Vyas2, Jack Satsangi2,5, Jon Simmons5, Hirokazu Nagawa4, Shozo Baba3, Derek Jewell5, Tetsuichiro Muto4, G. Mark Lathrop2 and Yusuke Nakamura1,*

1Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan, 2The Wellcome Trust Centre for Human Genetics, Windmill Road, Headington, Oxford OX3 7BN, UK, 3Second Department of Surgery, Hamamatsu University, School of Medicine, 3600, Handa-cho, Hamamatsu-shi, Shizuoka 431-3192, Japan, 4First Department of Surgery, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan and 5Department of Gastroenterology, Radcliffe Infirmary, Oxford OX2 6HE, UK

Received September 17, 1998; Revised and Accepted November 12, 1998

Ulcerative colitis (UC), a common form of inflammatory bowel disease, is a multifactorial disorder with significant genetic influence. Recently, evidence of linkage on chromosome 7q near the intestinal mucin gene MUC3 was reported by an affected sib-pair analysis. Previous reports indicate a possible mucin abnormality in UC patients, but whether genetic differences in a specific mucin gene are associated with UC is unknown. Here we analysed polymorphisms of variable number of tandem repeats (VNTRs) within this gene using DNAs obtained from 243 Japanese (75 patients with UC and 168 controls), and to confirm the result we undertook a two-stage examination using 328 Caucasian samples (72 and 85 with UC in the first and second stages, respectively, and 171 controls). When the frequency of patients carrying one or two rare VNTR alleles was compared with that of controls, a significant increase was found first in Japanese patients (odds ratio 2.72, 95% CI 1.17-6.32, P = 0.0308). In Caucasians, the odds ratio was 2.80 (95% CI 1.36-5.75, P = 0.0079) in the first stage, 2.43 (95% CI 1.20-4.92, P = 0.0196) in the second stage and 2.60 (95% CI 1.41-4.80, P = 0.0024) in total. The overall odds ratio was 2.64 (95% CI 1.60-4.33, P = 0.0001). This result suggests that rare alleles of the MUC3 gene may confer genetic predisposition to UC.

INTRODUCTION

Ulcerative colitis (UC) is one of the most common forms of inflammatory bowel diseases (IBDs), a condition with a prevalence of 50-150 per 100 000 population in the Western world (1). Although the aetiology is unknown, epidemiological studies showing familial aggregation of IBD patients (2,3) and increased concordance rates in monozygotic twins compared with dizygotic twins (4,5) have suggested that genetic components are significant. In fact, linkage analysis for susceptibility genes in IBDs involving 186 affected sibling pairs showed evidence for linkage to markers D12S83, D7S669 and D3S1573 with lod scores of 5.47, 3.08 and 2.69, respectively (6). Our investigation was motivated by the fact that marker D7S669 is located near the human intestinal mucin gene MUC3 and by previous reports indicating a possible abnormality in mucin composition in UC patients (7-10).

MUC3 is expressed mainly in the small and large intestines (11,12). This gene contains two separate regions of 51 bp tandem repeats which cover several kilobases and encode portions of the protein backbone, and these regions contain 18 bp interrupting sequences in some of the repeat units (11). Though sequences of the C-terminus and other variable number of tandem repeats (VNTRs) of this gene were elucidated recently (13,14), the entire structure of this gene is still unknown because it is difficult to clone.

Because several diseases are known to be related to VNTR polymorphisms, we looked for an association between the risk of UC and variations in the size of the alleles determined by the 51 bp repetitive element, using both Japanese and Caucasian DNA samples. Here we report the possible involvement of rare MUC3 variants in the development of UC.

RESULTS

We investigated the distribution of sizes of MUC3 alleles by Southern blotting analysis involving hybridization of PvuII-digested genomic fragments with a clone composed of the 51 nucleotide repeat sequence present in this gene, and detected two polymorphic systems in each individual. The distributions of allele sizes were the same in Japanese and Caucasians; the distribution within the first system ranged from 20 to 40 kb, and the other system showed variants 10-15 kb long (Fig. 1, Table 1). As the size differences represented by bands resulting from the first of these polymorphic systems were too subtle to analyse precisely by standard agarose gel electrophoresis, we chose to analyse the system that produced smaller fragments. We defined restriction fragments that were observed in [ge]5% of the alleles in the control population as ‘common’ alleles, and those occurring in <5% as ‘rare’ alleles. This definition was based on the allele classification in HRAS1 VNTR (15,16). In Japanese samples, three common and 14 rare alleles were observed (Table 1). The common alleles occurred at frequencies of 47.9, 14.6 and 33.6%, respectively, and represented 96.1% of the 336 alleles in the control population. The frequencies of rare alleles were all <1%. When the frequency of patients carrying one or two rare VNTR alleles was compared with that of controls, a significant increase was found in UC patients, and the odds ratio (with 95% confidence intervals) for rare VNTR alleles of the MUC3 gene was 2.72 (1.17-6.32, P = 0.0308). In Caucasian samples, four common alleles were observed (Table 1), and these occurred at frequencies of 9.1, 36.0, 38.6 and 11.4%, respectively, and represented 95.0% of the 342 alleles in the control population. The frequencies of rare alleles were all <2%. Here also the frequency of rare alleles increased significantly in UC patients, and in the first-stage examination the odds ratio was 2.80 (1.36-5.75, P = 0.0079), which was not significantly different from that of the Japanese population. However, since the allele distribution, i.e. the number of common alleles and the frequency of rare alleles, was quite different between the two populations, we decided to carry out second-stage examination to investigate whether the coincidence of the odds ratios between the two populations was fortuitous or not. Again we found a significantly increased frequency of rare alleles in UC patients, with the odds ratio of 2.43 (1.20-4.92, P = 0.0196), and did not find any significant difference in the allele distributions between the first- and the second-stage examinations of Caucasian UC patients. The odds ratio in the Caucasian population in total was 2.60 (1.41-4.80, P = 0.0024) and, since we found no evidence for heterogeneity of the odds ratios between the two populations([chi]2 = 0.006), an overall estimate was made by the Mantel-Haenszel method to reveal association with an odds ratio of 2.64 (1.60-4.33, P = 0.0001; Table 2).


Figure 1. Autoradiograph of Southern blots showing variations of MUC3 alleles in Japanese (a) and in Caucasians (b). Molecular weight markers are indicated immediately to the left of each figure.

DISCUSSION

This is the first study to show an association between UC and a specific intestinal mucin gene, and there are two important features to our study. One is that the MUC3 gene lies in a chromosomal region of potential linkage with IBDs (6); two major intestinal mucins are known, MUC2 and MUC3, but no markers around the MUC2 gene have ever shown linkage to UC (6,17). The other feature is that we observed the association in different populations; ethnic difference is one of the characteristics of IBDs which makes it difficult to obtain consistent results in linkage analyses. Our findings suggest that the association between rare alleles of the MUC3 gene and UC may be common among races.

A large portion of each mucin gene consists of tandem repeats which encode its protein backbone, and tandemly repeated sequences are prone to undergo deletions or insertions via unequal sister chromatid exchange or unequal crossover, becoming in the course of generations highly polymorphic VNTR loci containing more, or fewer, repeat units in a given allele than the ancestral sequence. For example, the human MUC1 gene contains from as few as 20 to as many as 125 tandem repeats in the population (18), and the MUC2 gene from 51 to 115 repeats (19).

Table 1. Frequency and size of each allele in control and in patients with UC
Japanese Caucasian
Allele
(size in kb)		 Control (%)
n = 168		 UC (%)
n = 75		 Allele
(size in kb)		 Control (%)
n = 171		 UC (%)
1st n = 72 2nd n = 85 Total n = 157
      a1 (18.00) 0 (0) 0 (0) 1 (0.6) 1 (0.3)
      a2 (15.64) 0 (0) 1 (0.7) 0 (0) 1 (0.3)
A1 (14.94) 1 (0.3) 0 (0)
A2 (14.89) 1 (0.3) 0 (0)
A3 (14.73) 1 (0.3) 0 (0)
A4 (14.04) 1 (0.3) 2 (1.3)
A5 (13.69) 1 (0.3) 0 (0)
A6 (13.39) 0 (0) 1 (0.7)
A7 (13.33) 161 (47.9) 61 (40.7) a3 (13.33) 31 (9.1) 7 (4.9) 11 (6.5) 18 (5.7)
A8 (13.28) 0 (0) 2 (1.3)
A9 (13.06) 2 (0.6) 1 (0.7)
A10 (12.96) 1 (0.3) 0 (0)
      a4 (12.50) 0 (0) 1 (0.7) 0 (0) 1 (0.3)
      a5 (12.04) 123 (36.0) 54 (37.5) 60 (35.3) 114 (36.3)
A11 (11.99) 3 (0.9) 2 (1.3)
A12 (11.71) 49 (14.6) 23 (15.3) a6 (11.71) 132 (38.6) 51 (35.4) 71 (41.8) 122 (38.9)
A13 (11.46) 1 (0.3) 2 (1.3)
      a7 (11.42) 6 (1.8) 4 (2.8) 6 (3.5) 10 (3.2)
      a8 (11.18) 3 (0.9) 3 (2.1) 2 (1.2) 5 (1.6)
A14 (11.06) 113 (33.6) 53 (35.3) a9 (11.06) 39 (11.4) 15 (10.4) 10 (5.9) 25 (8.0)
      a10 (10.94) 5 (1.5) 5 (3.5) 8 (4.7) 13 (4.1)
A15 (10.70) 0 (0) 1 (0.7)
A16 (10.30) 1 (0.3) 1 (0.7)
A17 (10.11) 0 (0) 1 (0.7)
      a11 (9.82) 0 (0) 2 (1.4) 0 (0) 2 (0.6)
      a12 (9.48) 1 (0.3) 1 (0.7) 0 (0) 1 (0.3)
      a13 (9.38) 2 (0.6) 0 (0) 1 (0.6) 1 (0.3)
Total 336 150   342 144 170 314

Table 2. Frequency of individuals carrying rare alleles
Population Control (%) UC (%) Odds ratio (95% CI) P-value
Japanese 11/168 (6.5) 12/75 (16.0) 2.72 (1.17-6.32) 0.0308
Caucasian        
1st stage   17/72 (23.6) 2.80 (1.36-5.75) 0.0079
2nd stage   18/85 (21.2) 2.43 (1.20-4.92) 0.0196
Subtotal 17/171 (9.9) 35/157 (22.3) 2.60 (1.41-4.80) 0.0024
Combined (Mantel-Haenszel statistics)     2.64 (1.60-4.33) 0.0001
Homogeneity test for odds ratios in Japanese and in Caucasian: [chi]2 = 0.006.

Human colonic mucin glycoproteins can be fractionated by ion-exchange chromatography into six species (I-VI). A selective reduction in species IV, one of the major mucin components, has been observed specifically in UC patients (7-9). That this abnormality is seen in monozygotic twins with UC as well as in their apparently healthy twin siblings clearly suggests a genetic basis for the observation (10). Furthermore, a comparable abnormality occurs in one of the best animal models of colitis, the cotton-top tamarin (Saguinus oedipus). When kept in captivity, this monkey develops a spontaneous chronic colitis that is histologically and clinically similar to human ulcerative colitis (20,21).

The mechanism by which variation in the MUC3 VNTR might lead to a deficiency of mucin species IV is open to discussion. It is possible that variation in the length of the 51 bp repetitive region may itself influence mucin production or stability of the protein; in that scenario, substitutions or deletions caused by unequal sister chromatid exchange or unequal crossover might influence the quantity of functional mucin generated. However, a more plausible explanation is that rare alleles of the MUC3 gene may lead to qualitative abnormalities. Polymorphisms due to VNTRs in coding regions appear to alter protein configurations. For example, certain VNTR alleles of the dopamine D4 receptor affect the personality trait of novelty-seeking (22), and expansion of a VNTR within the androgen receptor results in spinal and bulbar atrophy (23). It is reasonable to suppose that the relative positions of the 18 bp interrupting sequences in the 51 bp repetitive region may affect the configuration of the mucin protein. A high-mannose oligosaccharide side chain of mucin is processed to a complex form in the Golgi apparatus, and whether a given oligosaccharide is processed or not is determined by the configuration of the protein, i.e. its accessibility to the processing enzymes (24). Thus, some variants of MUC3 glycoprotein might have difficulty in this process because of the alteration in the protein backbone structure, and that could explain not only the selective reduction in one mucin component but also the significant increase in mannose-rich glycoproteins of low molecular weight reported in UC patients (25).

The immune system is thought to play a crucial role in the pathogenesis of IBDs as shown by the significantly high prevalence of antibodies to intestinal epithelial antigens both in patients with IBDs and in their relatives (26), and there are two possibilities with regard to our study. Carbohydrate side chains of mucin serve as specific binding sites for microorganisms, and competitively inhibit binding of bacteria to epithelial cells (27,28). Selective reduction of some mucin components may therefore impair mucosal defence against luminal bacteria which in turn may stimulate the auto-immune response to epithelial antigens (29,30). In spite of MUC3 expression throughout the gut, restriction of the inflammation to the large intestine in UC patients may be attributable to the 107-fold higher concentration of bacteria in the large intestine compared with the small intestine (31). The other possibility is that the immune response may be caused by the protein backbone of MUC3. The mannose-rich underglycosylated glycoprotein exposes the protein backbone, and this peptide can affect T cell function (32), or antibodies against the peptide may cross-react with intestinal epithelial antigen (33). Antibodies against the Gala(1,3)Gal epitope are reported to react with MUC1 peptide (34).

In conclusion, our findings lend support to the hypothesis that mucin abnormality may be a significant factor in the pathogenesis of UC, and further suggest that altered MUC3 alleles may genetically predispose individuals to UC.

MATERIALS AND METHODS

Patients and controls

In the Japanese population we studied 75 unrelated patients with UC and 168 unrelated controls, and to confirm the result we undertook two-stage examinations using Caucasian DNA samples obtained from 72 unrelated UC patients for the first examination, 85 for the second, and 171 healthy unrelated individuals. Japanese UC patients were ascertained through the First Department of Surgery, the University of Tokyo, or through the Second Department of Surgery, School of Medicine, Hamamatsu University, and for Japanese controls, patients who were operated on for breast cancer were used because of sample availability and no evidence of an altered risk of UC in patients with breast cancer. Caucasian patients were ascertained through the Gastroenterology Unit, Nuffield Department of Medicine, Radcliffe Infirmary. They were all British or North European Caucasian; Jewish patients were excluded because Jews have a greater prevalence of UC. Only British Caucasians were used for Caucasian controls, and they had neither a personal nor a family history of IBDs.

Reverse transcription and PCR amplification (RT-PCR)

One microgram of poly(A)+ RNA isolated from colon cancer cell line SW480 was reverse-transcribed using an oligo-dT15 primer and reverse transcriptase (Boehringer Mannheim, Mannheim, Germany). The cDNA product was amplified in a 25 µl reaction volume, using 25 pmol of each of the following primers that were synthesized by means of an Oligo 1000M DNA Synthesizer (Beckman, Fullerton, CA) on the basis of the 51 nucleotide tandem repeats reported previously (11): 5[prime]-TTTGATAACCACCTCTGAGAC-3[prime] (GSP1) and 5[prime]-GGAACATAGAAGAAGTGAAGC-3[prime] (GSP2). The PCR regime included one cycle of 94°C for 2 min, then 35 cycles of 94°C for 30 s, 55°C for 30 s, and 1 min at 72°C. This protocol was followed by an extension cycle of 5 min at 72°C. The PCR products were cloned into the vector pCR2.1 using the TA Cloning kit (Invitrogen, Carlsbad, CA) according to the manufacturer’s instructions. Clones containing MUC3 tandem repeats were detected by hybridization with the GSP3 primer (5[prime]-CACAGTACTCCCAGCTTCACTTCTTC-3[prime]) and sequenced with an ABI 377 Autosequencer (Perkin-Elmer, Foster City, CA). These plasmid clones served as probes for Southern blotting.

Southern blotting analysis

Five micrograms of each genomic DNA was digested to completion with restriction enzyme PvuII (Toyobo, Tokyo, Japan) and the fragments were separated by electrophoresis in 0.5% agarose gels (20 × 25 cm) run at 40 V for 72 h, then denatured in 0.4 M NaOH for 20 min. DNAs were transferred to nylon membranes as described previously (35). Plasmid clones containing 51 bp tandem repeats were labelled by the random priming method with DNA polymerase I (Klenow; Toyobo) and [[alpha]-32P]dCTP (Amersham, Buckinghamshire, UK) for 3 h at 37°C, then hybridized to the membranes at 65°C overnight in a solution containing 7% polyethylene glycol 8000, 10% SDS and 200 µg/ml of salmon sperm DNA. The membranes were washed first in 2× SSC and then in a solution of 0.1% SSC and 0.1% SDS at 65°C, before exposure to Kodak X-OMAT AR film (Kodak, Rochester, NY).

Statistical analysis

The frequencies of individuals carrying one or two rare VNTR alleles were compared in patients and controls using Fisher’s exact test. We examined both Japanese and Caucasian samples, and analysed the overall estimation by the Mantel-Haenszel statistical method after obtaining a non-significant homogeneity test. The association was considered statistically significant when the P-value was <0.05.

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*To whom correspondence should be addressed. Tel: +81 3 5449 5372; Fax: +81 3 5449 5433; Email: yusuke@ims.u-tokyo.ac.jp

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