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

Abstract

BACKGROUNDThere is evidence for genetic susceptibility to Crohn’s disease, and a tentative association with tumour necrosis factor (TNF) and HLA class II alleles.AIMSTo examine the potential of genetic linkage between Crohn’s disease and the MHC region on chromosome 6p.METHODSTNF 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.RESULTSIncreased 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 (π=0.60, p=0.002) and unaffected sib pairs (π=0.58, p=0.031) compared with the expected value (π=0.5). In contrast, sharing in discordant sib pairs was significantly decreased (π=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.CONCLUSIONSAll 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.