primary prevention of coeliac disease - Associazione Italiana ...

32 COELIAC DISEASE IN THE SAHARAWI
A long series of association studies from different Caucasian populations provided a
convincing case that within the HLA region, the combined presence of the DQA1*0501
and DQB1*0201 alleles, encoded by genes located in the class II sub-region, is the
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primary predisposing factor for CD . These alleles are found either in phase within the
DR3-DQA1*0501-DQB1*0201 haplotype or in trans in individuals carrying the DR7-
HLA-DQA1*0201-DQB1*0201/DR5-HLA-DQA1*0501-DQB1*0301 genotype.
Additionally, although to a much lesser extent, another molecule, HLA-DQA1*0301-
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DQB1*0302, found on DR4 haplotypes, is associated with CD . More recently, linkage
analysis in families with multiple cases, in particular tests of allele sharing by affected
sibpairs (ASPs), proved that the HLA region encodes the main disease locus
predisposing to CD. From these linkage data it was possible to compute that this region
contributes about 40 % of the observed familial clustering of the disease assuming a
2-3.
multiplicative model of inheritance
The role of these DQ molecules is further substantiated by the observation that
antigen-presenting-cells positive for the DQA1*0501-DQB1*0201 (DQ2) and
DQA1*0301-DQB1*0302 (DQ8) molecules are able to recognize and present gluten
derived peptides to T cells obtained from biopsy specimens from the small intestine of
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CD patients . The gluten-reactive T cell clones isolated from biopsies were CD4+,
CD8- and inhibition studies with anti-HLA antibodies demonstrated predominant
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antigen presentation by the dimers encoded by the HLA-DQ loci .
Non-HLA genes and CD
The linkage data from affected sib pair (ASP) families from different populations
indicates that the locus specific ls for the whole HLA region is equal to ~3. This value,
assuming a multiplicative model of epistasis (which fits with the rapid fall off in
recurrence risk from first to second to third degree relatives) is equal to 40% of the
familial clustering of the disease (log3/log15). These results imply that 60% of the
familial clustering of the disease must be accounted for by non-HLA genes. To detect
these non-HLA loci , some whole genome scans have been performed but, with the
exception of the major disease locus in the HLA region on 6p21, they have given weak
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and conflicting results . These results illustrate the difficulties of detecting (or
replicating the detection of) genes of low to moderate effects using ASP-based
methods. Low penetrance, compounded by small individual genetic effects of most of
the non-HLA disease loci create major limitations on the power of a study (and all the
linkage scans so far performed were severely under-powered). Additionally, locus and
allelic heterogeneity further complicate the search. Nevertheless, the generation of
primary hypotheses deriving from linkage analysis remains an invaluable step when
embarking on an effort to define the genetic risk factors involved in an inherited disease
especially since whole genome scans of association are still technically and
economically impractical and the presence of a disease model with strong epistasis
between the disease loci could severely impair association studies but not linkage
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analysis . Prior evidence of linkage dramatically lowers the threshold (P value to 10 )
required in an association/LD study of the linked region to be confident that the result is
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not a false positive . Some of the aforementioned factors, in particular those related to
the statistical power of the study, could be alleviated by further increasing the number of