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. 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.