Gastroenterology

Gastroenterology

Volume 120, Issue 4, March 2001, Pages 834-840
Gastroenterology

Alimentary Tract
Evidence for inflammatory bowel disease of a susceptibility locus on the X chromosome,☆☆

https://doi.org/10.1053/gast.2001.22453Get rights and content

Abstract

Background & Aims: The technique of genomewide scanning has been applied successfully in inflammatory bowel disease (IBD). A number of putative susceptibility loci have been identified through genomewide searches including replicated regions of linkage on chromosomes 12, 16, 6 (the HLA region), and 14. We have investigated the contribution of the X chromosome in 145 Belgian affected relative pairs. Methods: In the first stage of the study, 79 (68 CD, 11 mixed) sibling pairs were genotyped at 12 microsatellite markers covering the X chromosome. In the second stage, 10 additional markers in the X-pericentromeric region were studied in the families involved in stage 1 together with 62 additional families (52 sibling pairs, 14 second-degree relative pairs). Results: In the first stage, evidence for linkage was found over a 30-cM pericentromeric region spanning dXs991, dXs990, and dXs8096 (multipoint maximum LOD score in the CD subgroup, 2.5; P = 0.0003). The remainder of the X chromosome was excluded (exclusion under LOD-2) for a locus with λs = 2. Fine mapping in the second stage confirmed linkage, and narrowed and shifted the linked region to Xq21.3 around dXs1203 (nonparametric linkage [NPL], 2.90; P = 0.0017). The NPL-1 interval around the linkage peak comprises 19.7 cM. Conclusions: These data provide suggestive evidence for the presence and chromosomal location of an X-linked susceptibility gene in IBD.

GASTROENTEROLOGY 2001;120:834-840

Section snippets

Patients

All patients were seen at the Gastroenterology Unit of the University Hospital Gasthuisberg Leuven. Diagnosis was established using conventional clinical, radiologic, endoscopic, and histologic criteria, as described previously.27 In the first stage, 56 families including 79 white sibling pairs (68 CD, 11 mixed) were studied (Table 2).

A family was called mixed if both CD and UC occurred within 1 family. Both parents were genotyped in 25 of 56 families (44.6%); in another 10 families (17.9%), 1

Stage 1

Twelve markers were analyzed in the first stage, covering 140 cM (96%) of the X chromosome. Results of the single-point analysis are shown in Table 3.

. Single-point analysis of first data set (SIBPAIR)

MarkercMLOD (P value), overallLOD (P value), CD only
DXS996140.00 (0.50)0.00 (0.50)
DXS999100.00 (0.50)0.00 (0.50)
DXS451120.21 (0.16)0.03 (0.36)
DMD10.17 (0.19)0.13 (0.22)
DXS53841.52 (0.0041)1.40 (0.006)
DXS1068101.00 (0.016)1.14 (0.011)
MAOB120.13 (0.22)0.10 (0.25)
DXS991160.32 (0.11)0.90 (0.02)
DXS99010

Discussion

This is the most detailed molecular study on the contribution of the X chromosome in IBD yet reported. Previous studies have mainly concentrated on the autosomal regions where statistical methods are much more straightforward. Recent modifications of existing programs of NPL have allowed ourselves and other investigators10 to dissect the contribution of the X chromosome.

The present data provide suggestive evidence for the presence of an X-linked susceptibility locus in IBD. Exclusion mapping

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    Supported by the Funds for Scientific Research (FWO), Belgium (to S.V.), the Medical Research Council, U.K. (To M.P. and J.S.), and a grant from A. Lazzari.

    ☆☆

    Address requests for reprints to: P. Rutgeerts, M.D., Ph.D., Gastroenterology Unit, UZ Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. e-mail: [email protected]; fax: (32) 16-344399.

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