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Although HLA-DQ genes are the major celiac disease (CD) susceptibility genes, results from Finnish families suggest that not all DQ2-encoding haplotypes confer equal susceptibility to CD, implying the effect of other gene(s) in the HLA region. The aim of the present work was to extend and confirm the aforementioned results in a southern European population ( Italian) and to better localize the additional risk factor/s. The association of nine loci spanning the HLA region from DR to HFE, 4.5-Mb telomeric of HLA-A, was tested. The analysis was performed by comparing marker frequencies in DR3-DQ2 haplotypes transmitted and non-transmitted to the affected offspring in 156 Italian CD families selected for having at least one DR3-positive parent. The same analysis was performed independently in 101 Finnish CD families selected with the same criteria. Three alleles, MICA-A5.1, MICB-CA24 and MIB-350, all characteristic of the B8-DR3 extended haplotype, showed a significantly increased frequency in DR3 transmitted haplotypes in the Italian families. DR3 haplotypes carrying the combination of these alleles conferred an approximate fourfold increased CD risk. B8-DR3 transmitted haplotypes were significantly more conserved telomerically down to the MIC-Class I region. Similar results were seen in the Finnish families. The major conclusion that holds true in both populations is that, while DQ2 is an absolute requirement for the development of CD, the presence of an additional genetic factor within the MIC-Class I region confers an approximate 4-fold increased risk of the disease.

Coeliac disease (CD) is a multifactorial disease for which there is an intensive search for genetic risk factors. Some authors found an association between the CTLA-4 region and CD. In the present work, we investigate the possible implication of the CTLA-4 region as a genetic risk factor for CD, through two statistical approaches: the maximum likelihood score (MLS) test in a large Italian sample of affected sib-pairs using polymorphic genetic markers on chromosome 2, and the transmission disequilibrium test (TDT) in continental Italian and Tunisian families using the CTLA-4 exon 1 49 A/G polymorphism. None of these approaches provides evidence for linkage or association between the CTLA-4 region and CD. This might result from a difference in the CTLA-4 region from population to population, either in its involvement as a risk factor or in the strength of linkage disequilibrium.

Gluten has recently been introduced into the diet of the Mediterranean and European population, but a considerable proportion has not adapted to this change and has developed intolerance to gluten. At least one million EEC citizens are gluten intolerant. In Italy each year 12 million ECU is spent in the diagnosis of uncomplicated gluten intolerance, 10 million ECU for complex diagnosis and 32 million ECU for long-term complications and malignancies. The total financial load of gluten intolerance, in its present state, is about 150 million ECU/year in Italy. Four million ECU is actually needed to develop a genetic probe, which may make the population screening feasible. A National Task Force "Free from Gluten" has been set up by the Italian Coeliac Society to stimulate fund-raising activities supporting genetic and basic research on gluten intolerance.

Coeliac disease (CD) is a chronic inflammatory disorder where dietary gluten is not tolerated. In the lesion there are gluten reactive T cells predominantly secreting gamma-interferon. Both HLA and non-HLA genes contribute to CD susceptibility. Interleukin-12 (IL-12) regulates gamma-interferon production. The IL12B gene is located in a region (5q31.1-33.1) where there is evidence for linkage with CD. Allele 1 of an IL12B 3'UTR single-nucleotide polymorphism leads to increased expression of IL-12, and was recently implicated in susceptibility for type 1 diabetes (T1D). We found no evidence for association of allele 1 to CD by the transmission/disequilibrium test or case-control approach. No increased frequency was observed in patients belonging to families where the disease was linked to markers on chromosome 5q. Unlike T1D, allele 1 does not appear to confer susceptibility to CD.