Linkage of Crohn's disease to the major histocompatibility complex region is detected by multiple non-parametric analyses

Background-There is evidence for genetic susceptibility to Crohn's disease, and a tentative association with tumour necrosis factor (TNF) and HLA class II alleles. Aims-To examine the potential of genetic Linkage between Crohn's disease and the MHC region on chromosome 6p. Methods-TNF microsatellite markers and, for some families, additional HLA antigens were typed for 323 individuals from 49 Crohn's disease multiplex families to generate informative haplotypes. Non-parametric linkage analysis methods, including sib pair and affected relative pair methods, were used. Results-Increased sharing of haplotypes was observed in affected sib pairs: 92% (48/52) shared one or two haplotypes versus an expected 75% if linkage did not exist (p=0.004). After other affected relative pairs were included, the significance level reached 0.001. The mean proportion of haplotype sharing was increased for both concordant affected (pi=0.60, p=0.002) and unaffected sib pairs ( pi=0.58, p=0.031) compared with the expected value (pi=0.5). In contrast, sharing in discordant sib pairs was significantly decreased (pi=0.42, p=0.007). Linear regression analysis using all three types of sib pairs yielded a slope of -0.38 at p=0.00003. It seemed that the HLA effect was stronger in non-Jewish families than in Jewish families. Conclusions-All available analytical methods support linkage of Crohn's disease to the MHC region in these Crohn's disease families. This region is estimated to contribute approximately 10-33% of the total genetic risk to Crohn's disease.