title: Improving the estimation of celiac disease sibling risk by non-HLA genes.
abstract: 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.
authors.affiliation: Department of Pediatrics, University of Naples Federico II, Naples, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Izzo
authors.forename: Michele
authors.initials: M
authors.lastname: Pinelli
authors.forename: Nadia
authors.initials: N
authors.lastname: Tinto
authors.forename: Maria Valeria
authors.initials: MV
authors.lastname: Esposito
authors.forename: Arturo
authors.initials: A
authors.lastname: Cola
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Sperandeo
authors.forename: Francesca
authors.initials: F
authors.lastname: Tucci
authors.forename: Sergio
authors.initials: S
authors.lastname: Cocozza
authors.forename: Luigi
authors.initials: L
authors.lastname: Greco
authors.forename: Lucia
authors.initials: L
authors.lastname: Sacchetti
mesh_terms: D001499:Bayes Theorem; D002446:Celiac Disease / Q000175:diagnosis* / Q000235:genetics*; D015331:Cohort Studies; D005190:Family; D020022:Genetic Predisposition to Disease; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D007558:Italy; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D012306:Risk; D035781:Siblings
chemical_list: D006680:HLA Antigens
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