Linkage of inflammatory bowel disease to human chromosome 6p

Abstract

Inflammatory bowel disease (IBD) is characterized by a chronic relapsing intestinal inflammation. IBD is subdivided into Crohn disease and ulcerative colitis phenotypes. Given the immunologic dysregulation in IBD, the human-leukocyte-antigen region on chromosome 6p is of significant interest. Previous association and linkage analysis has provided conflicting evidence as to the existence of an IBD-susceptibility locus in this region. Here we report on a two-stage linkage and association analysis of both a basic population of 353 affected sibling pairs (ASPs) and an extension of this population to 428 white ASPs of northern European extraction. Twenty-eight microsatellite markers on chromosome 6 were genotyped. A peak multipoint LOD score of 4.2 was observed, at D6S461, for the IBD phenotype. A transmission/disequilibrium test (TDT) result of P=.006 was detected for D6S426 in the basic population and was confirmed in the extended cohort (P=.004; 97 vs. 56 transmissions). The subphenotypes of Crohn disease, ulcerative colitis, and mixed IBD contributed equally to this linkage, suggesting a general role for the chromosome 6 locus in IBD. Analysis of five single-nucleotide polymorphisms in the TNFA and LTA genes did not reveal evidence for association of these important candidate genes with IBD. In summary, we provide firm linkage evidence for an IBD-susceptibility locus on chromosome 6p and demonstrate that TNFA and LTA are unlikely to be susceptibility loci for IBD.

Figure 1

Overview of TNF region: relative positions of the TNF microsatellites a–e and of the single-nucleotide polymorphisms of the TNFA and LTA genes and their promoters (top). The physical distances are approximate. Distances in the top panel are derived from GenBank record Y14768. The linkage map of the wider area (bottom) shows genetic map distances, as derived from the analyzed data set.

Figure 2

Multipoint MLS curves for chromosome 6 from the basic family data set. Multipoint analyses were performed with use of the MAPMAKER/SIBS program. Results for CD (dashed line), UC (thin unbroken line), and ALL (thick unbroken line) are shown. Genetic distances between markers were estimated from the data set. Marker positions are denoted by blackened diamonds.

Figure 3

Multipoint MLS curves for markers typed in the peak region of chromosome 6p. Markers were typed in the extended family set of 428 ASPs. Multipoint analyses were performed with use of the MAPMAKER/SIBS program. Results for CD (dashed line), UC (thin unbroken line), and ALL (thick unbroken line) are shown. Genetic distances between markers were estimated from the data set. Marker positions are denoted by blackened diamonds.