Analysis of candidate genes in celiac disease. A tool to identify life threatening associated genes?





D. Nuzzo, F. Cataldo, L. Scola, G.I. Forte, A. Crivello, A. Giacalone, S. Accomando, G. Candore, C. Caruso, D. Lio

Gruppo di Studio sull'Immunosenescenza, Dipartimento di Biopatologia e Metodologie Biomediche, Università di Palermo, Corso Tukory 211, 90134 Palermo



Given the clear role of gluten in causing autoimmunity, celiac disease (CD) represents a unique example of an immune mediated disease for which early diagnosis and dietary treatment can prevent its severe, sometimes life threatening, complications. Patients with undiagnosed and untreated CD, as well as those diagnosed later in life, have an increased morbidity and mortality due to associated conditions. Since CD is a multisystem disorder, these patients are at risk of chronic ill health, permanent stunted growth, infertility, skeletal disorders, and malignancy. Moreover, the mortality rate at every age is twofold greater in untreated coeliacs. As well known, CD has a strong genetic component, with a sibling relative risk of about 10-15%. The major susceptibility locus is in Major Histocompatibility Complex (MHC) encompassing the human leukocyte antigen ( HLA ), and the HLA alleles DQA1*0501 and DQB1*0201 are strongly associated with CD. However, haplotype sharing studies suggest that genes within the MHC complex contribute no more than 40% to the risk for gluten intolerance. This means that a CD genetic risk is also conferred by some other non-HLA genes, and it has been suggested that some genes, encoding for the pro-inflammatory cytokines and involved in the immunological mediated lesions of CD, are associated with the risk for gluten intolerance. In this paper are reported data on the evaluation, by a PCR-ARMS technique, of a Transforming growth factor-beta2 (TGF-β2) polymorphism association to celiac disease studying the 1249-1250InsACAA/Non-Ins genotype distribution in 88 CD patient 99 age and sex matched control and 28 >95 years old healthy subjects living in west-Sicily. TGF-β2, actually is involved both in the control of inflammatory response, activating tissue remodelling, and in the induction of IgA isotope switching in B cells. Considering these functions, an increased TGF-2 production might be involved in mucosal damage and IgA autoantibody production in CD subjects. Our data demonstrate that, in spite of functional role of the cytokine, genotype frequencies of CD patients are not different from that of age matched and >95 years old healthy control groups. On the other hand, we have recently reported that celiac patients show a pro-inflammatory cytokine genetic profile characterized by the simultaneous presence of both the tumour necrosis factor-alpha -308A and of the interferon-gamma +874T allele positive genotypes. Both the two alleles are associated to an increased production of the two major pro-inflammatory cytokines and it is well known that an high pro-inflammatory profile is considered detrimental for life span expectation facilitating rising of the major aging associated disease (Cardiovascular diseases, Dementia, Osteoporosis, Malignancy) that are considered among the major CD late complications. Moreover a decrease of interferon-gamma +874T allele was found associated to longevity in a group of centenarian woman. All together these findings seem to suggest that the genotype profile associated to CD susceptibility might be detrimental for long life expectancy and studies on genetic asset of CD patients might enlighten candidate gene for anti-ageing strategies.




Key words: Celiac disease, longevity, TGF-beta2, centenarians







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