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. 1999 Apr;44(4):519–526. doi: 10.1136/gut.44.4.519

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

H Yang 1, S Plevy 1, K Taylor 1, D Tyan 1, N Fischel-Ghodsian 1, C McElree 1, S Targan 1, J Rotter 1
PMCID: PMC1727474  PMID: 10075959

Abstract

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 49Crohn'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 (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. 
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. 



Keywords: Crohn's disease; HLA; linkage; inflammatory bowel disease; tumour necrosis factor; genetics

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Figure 1 .

Figure 1

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Location and order of five TNF microsatellite loci within the HLA complex on chromosome 6. Arrows represent location and orientation of PCR primers used for typing. The exact orientation of TNFd and TNFe microsatellites with respect to the TNF locus has not been determined. 


Figure 2 .

Figure 2

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Significant linear relation between phenotypic concordance and proportion of shared TNF-HLA haplotypes identical by descent among sibs. Those who share no haplotypes have the greatest degree of phenotypic discordance and those who share both are the most concordant. Thus, among sibs, similar genotypes (haplotype sharing) are correlated with similar phenotypes (both affected with Crohn's disease or both unaffected). These data are consistent with linkage between the MHC region and Crohn's disease. 


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