Research promoted by the Foundation for the Celiac Disease - FC

From 2010 to 2012 FC was able to grant a total amount of 562,660.00 for funding Italian scientific multicenter programs, two on celiac disease in the pediatric age and one about complicated celiac disease. Abstracts of the projects and main results are here presented.


Pediatric Celiac Disease - 1

Improving the estimation of celiac disease sibling risk.

Principal Investigator: Professor Greco L., Department of Pediatrics, University of Naples Federico II, Naples, Italy.

Celiac Disease (CD) is a polygenic trait, and HLA genes explain less than half of the genetic variation. Through large GWAs more than 40 associated non-HLA genes were identified, but they give a small contribution to the heritability of the disease. The aim of this study is to improve the estimate of the CD risk in siblings, by adding to HLA a small set of non-HLA genes. One-hundred fifty-seven Italian families with a confirmed CD case and at least one other sib and both parents were recruited. Among 249 sibs, 29 developed CD in a 6 year follow-up period. All individuals were typed for HLA and 10 SNPs in non-HLA genes: CCR1/CCR3 (rs6441961), IL12A/SCHIP1 and IL12A (rs17810546 and rs9811792), TAGAP (rs1738074), RGS1 (rs2816316), LPP (rs1464510), OLIG3 (rs2327832), REL (rs842647), IL2/IL21 (rs6822844), SH2B3 (rs3184504). Three associated SNPs (in LPP, REL, and RGS1 genes) were identified through the Transmission Disequilibrium Test and a Bayesian approach was used to assign a score (BS) to each detected HLA+SNPs genotype combination. We then classified CD sibs as at low or at high risk if their BS was respectively < or ≥ median BS value within each HLA risk group. A larger number (72%) of CD sibs showed a BS ≥ the median value and had a more than two fold higher OR than CD sibs with a BS value < the median (O.R?=?2.53, p?=?0.047). Our HLA+SNPs genotype classification, showed both a higher predictive negative value (95% vs 91%) and diagnostic sensitivity (79% vs 45%) than the HLA only. In conclusion, the estimate of the CD risk by HLA+SNPs approach, even if not applicable to prevention, could be a precious tool to improve the prediction of the disease in a cohort of first degree relatives, particularly in the low HLA risk groups.

Publications Related to the FC Grant:

  1. Izzo V, Pinelli M, Tinto N, et al Improving the estimation of celiac disease sibling risk by non-HLA genes. PLoSOne. 2011;6:e26920.
  2. Sperandeo MP, Tosco A, Izzo V, et al Potential celiac patients: a model of celiac disease pathogenesis. PLoS One. 2011;6(7):e21281.
  3. Tosco A, Salvati VM, Auricchio R, et al Natural history of potential celiac disease in children. Clin Gastroenterol Hepatol. 2011 Apr;9(4):320-5; quiz e36.
  4. 4.     Dubois PC, Trynka G, Franke L, et al Multiple common variants for celiac disease influencing immune gene expression. Nat Genet. 2010 Apr;42(4):295-302. Epub 2010 Feb 28. Erratum in: Nat Genet.2010 May;42(5):465.



Pediatric Celiac Disease - 2

Age at Gluten Introduction and Risk of Celiac Disease: a Prospective, Multicentre, Nutritional Intervention Study on Infants at Family Risk (The Italian Baby-Study on Weaning and CD Risk)

Principal Investigator: Professor Catassi C., Department of Pediatrics, Università Politecnica delle Marche, Ancona, Italy.

Objectives: The primary aim of the study was to evaluate in a large cohort of infants at increased risk for celiac disease (CD) the role of age at gluten introduction on the risk of CD-autoimmunity and of CD.

Methods: This is an ongoing not recruiting prospective, multicenter, nationwide intervention trial. 730 infants at increased risk for CD (first-degree relatives of patients with CD) were enrolled. Infants were blindly assigned to introduce gluten at 4th-6th month (group A) or after the 12th month (group B); diet (duration of breastfeeding, adherence to the protocol, amount of gluten administered) was evaluated at 4, 7, 9, and 12 months; CD serology was tested at 15 (plus HLA), 24, 36 and 60 months.

Results: 395 infants were enrolled in group A (F 49.9%) and 335 in group B (F 50%). The current median age of the cohort is 5,1 and the percentage of children older than 3 years is 95%. The type of kinship was: 58.2% one sibling, 39.5% mother, 8% father (two relatives 8.1%). The mean duration of breastfeeding was 4 months. The average gluten consumption was >6 gr/day in 95.1%, 3-6 gr/d in 4.1%, and <3 gr/d in 0.8%. HLA genotyping showed: DR3 or DR3/DR7 in 7.5%, DR5/DR7 in 15.8%, DR3/DR5 or DR3/DR4 or DR3/DRX in 28.7%, DR7/DR7 in 15.8%, DR7/DR4 or DR4/DR4 in 7.5%, others in 24.7%. Overall, at 24 months the incidence of CD-autoimmunity and of CD was higher in group A (CD-autoimmunity: group A 11.1% vs group B 5.7%; p=0.01. CD: group A 8.1% vs group B 4.2%; p=0.03).

Conclusion: Introducing gluten after 12 months of age may prevent the developing of CD in the first two years of life. A prolonged follow-up is required.

Publications Related to the FC Grant:

  1. Lionetti E, Castellaneta S, Pulvirenti A, Tonutti E, Francavilla R, Fasano A, Catassi C, and “the Italian Working Group of Weaning and CD risk. Prevalence and natural history of potential celiac disease in at-family-risk infants prospectively investigated from birth. J Ped 2012; 161:908-14.
  2.  Sellitto M, Bai G, Serena G, et al Proof of concept of microbiome-metabolome analysis and delayed gluten exposure on celiac disease autoimmunity in genetically at-risk infants. PLoS One. 2012;7(3):e33387.
  3. Fasano A, Catassi C. Early feeding practices and their impact on development of celiac disease. Nestle Nutr Workshop Ser Pediatr Program. 2011;68:201-9; discussion 210-3. Epub 2011 Oct 3. Review.
  4. Lionetti E, Catassi C. New clues in celiac disease epidemiology, pathogenesis, clinical manifestations, and treatment. Int Rev Immunol. 2011 Aug;30(4):219-31. Review.



Complicated Celiac Disease

Complicated adult Celiac Disease

Principal Investigator: Professor Corazza G.R., First Department of Medicine, Fondazione IRCCS Policlinico S. Matteo, University of Pavia, Pavia, Italy

The natural history of complicated celiac disease is not well known. In some cases that are diagnosed late in adult age, the disease presents right from the start with complications (refractory celiac disease, ulcerative jejunoileitis, collagenous sprue and enteropathy-associated T-cell lymphoma). According to the data collected while carrying out this project, the prevalence of complicated celiac disease in Italy is around 0.75%. Complication predictors include diagnosis after the age of 50, a delay between onset of symptoms and diagnosis of more than 10 years, typical symptoms (frank malabsorption syndrome) and the presence of HLA-DQ2 homozygosis. On the basis of the diagnostic delay and the clinical presentation, the Pavia research group has constructed a mathematical model which makes it possible to estimate the risk and possible progression towards the complicated for of celiac disease. The study has also made it possible to define a number of aspects, about which little was formerly known, of the immunological pathogenetic mechanisms that underlie the complications of celiac disease, such as the role of the CD40/CD40L system which at mucosal level amplifies the inflammatory response by triggering an interaction between lymphocytes and antigen-presenting cells. Another important objective of the project is verification of the involvement of certain viruses, generally associated with the development of some tumors, in the natural history of complicated celiac disease. The presence of these viruses was therefore evaluated in the intestinal biopsies taken from 18 patients with complicated celiac disease and 26 patients with non-complicated celiac disease, by means of a highly sensitive method, named PCR, which can be used to detect the specific genomic sequences of the viruses. The study showed that 72% of the patients with complicated celiac disease tested positive for the presence of the Epstein-Barr virus, a significantly higher fraction compared to patients with non-complicated celiac disease (15.3%). In conclusion, the Epstein-Barr virus seems to have a role in the progression of celiac disease towards complicated forms, representing a basis for designing new studies into the mechanisms of the onset of complications in some subjects with celiac disease. The project also obtained encouraging preliminary results on the use of mesenchymal stem cells in regulating gliadin-specific T lymphocytes, i.e. the immune system cells involved in the intestinal inflammatory process induced by gluten. This result therefore provides a basis for the development of potential treatments of refractory celiac disease by means of the use of stem cells.

Publications Related to the FC Grant:

  1. Vittorio Perfetti, Laura Brunetti, Federico Biagi, et al TCRb clonality improves diagnostic yield of TCRg clonality in refractory coeliac disease. J Clin Gastroenterol 2012; in press.
  2. Di Sabatino A, Rovedatti L, Vetrano S, et al Involvement of CD40-CD40 ligand in uncomplicated and refractory celiac disease. Am J Gastroenterol 2011;106:519-27.
  3. Biagi F, Bianchi PI, Vattiato C, et al. The influence of HLA-DQ2 and DQ8 on severity in celiac disease. J Clin Gastroenterol 2012;46:46-50
  4. Ciccocioppo R, Russo ML, Bernardo ME, et al. Mesenchymal stromal cell infusions as rescue therapy in an adult with autoimmune enteropathy. Mayo Clinic Proceedings, in press.
  5. Ciccocioppo R, Bernardo ME, Russo ML, et al Hematopoietic stem cell transplantation restores gluten tolerance in celiac disease. Submitted for publication