Allelic association and recombination hotspots in the mucin gene (MUC) complex on chromosome 11p15.5

A family of four highly polymorphic genes encoding secreted gel forming mucins is located in the middle of a recombination rich region of the short arm of chromosome 11 (11p15.5; tel MUC6-MUC2-MUC5AC-MUC5B cen; approx. 400 kb). These genes are of interest as risk factors for inflammatory diseases of the epithelia, and we have for example reported association of a VNTR polymorphism of the major mucin domain of MUC2 with asthma, despite the fact that MUC2 is not a major respiratory mucin. To understand the significance of this and other mucin gene associations it is important to describe the patterns of linkage disequilibrium (LD) across this chromosomal region, which is still incomplete on HapMap and the UCSC Golden Path sequence. Our previous studies on the 40 core CEPH families provided direct evidence for several recombination events within the immediate region of the gene complex. This study examines these recombination events in more detail, and also the patterns of LD across the gene complex. We refine the location of the breakpoints, and the combined data suggest two probable recombination hotspots. Three breakpoints are located between MUC6 and MUC2: there is no association between MUC6 and MUC2, and the data collected here, combined with that publicly available, maps a hotspot to a region of 4 kb. The other recombinants map between MUC2 and intron 8 of MUC5B. Relatively strong LD is detected between MUC2 and MUC5AC, and although 10/70 of the chromosomes tested shared a common haplotype, which extends from MUC2 to MUC5B, statistically significant association was not detected between MUC2 and the markers tested in MUC5B. We discuss the possibility that the previously reported association between MUC2 and asthma is most likely attributable to association with functional variation in MUC5AC, which encodes one of the two major mucins expressed in both healthy and diseased airways.