A pedigree-based linkage study of coeliac disease: failure to replicate previous positive findings

Coeliac Disease (CD) is a gluten sensitive enteropathy characterised by villous atrophy and crypt cell hyperplasia. There is a tight HLA association between CD and the HLA DQ alleles DQA1*0501, DQB1*0201 (DQ2), arranged in either cis- or trans- configuration, are found in 98.9% of cases in Northern European populations and 80% in Greeks and Ashkenazi Jews resident in Israel. We have previously shown that the HLA alleles and CD do not co-segregate in families multiply affected with CD, suggesting that the HLA association is entirely due to the necessity to have these normal DQ alleles for CD to manifest, and that the main genetic predisposition lies at a locus other than the MHC. It is therefore possible to conduct genetic linkage studies in order to isolate the non HLA genes which predispose to CD. Recently a group conducted a genome screen for the non HLA genes in an affected sib-pair analysis and identified four non HLA loci with positive lod scores. We examined these loci using a pedigree based linkage study. Our pedigree sample consisted of a cohort of 21 families with 60 affected individuals and 125 unaffected family members. We used 11 microsatellite markers at the loci implicated and analysed the genotype data using both MLINK and MFLINK to detect linkage. The MLINK and MFLINK analyses did not provide any evidence to support the earlier findings, although the difficulties involved in analysing complex diseases mean that one cannot be certain that these regions do not harbour susceptibility loci, at least in some families.