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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.
Highlights
Celiac disease (CD) is a chronic small-intestinal enteropathy, triggered by gluten proteins contained in wheat, barley and rye [1]
All individuals were typed for 10 CD previously associated Single Nucleotide Polymorphisms (SNP) [13] and the Transmission Disequilibrium Test (TDT) test was performed on results obtained from 157 trios of the training set (Fig. 1)
We considered in CD families the risk to develop the disease according to a specific Histocompatibility Leucocyte Antigens (HLA) haplotypes, obtaining a risk range from 0.01 to $0.20 [1]
Summary
Celiac disease (CD) is a chronic small-intestinal enteropathy, triggered by gluten proteins contained in wheat, barley and rye [1]. The evidence of a strong genetic component is suggested by a remarkable familiar aggregation: the prevalence of CD is, 10 times higher in first degree relatives (,10%) than in the whole population (1%) [1,2,3] a and very high concordance (.80%) is found in monozygotic twins [4]. At present Histocompatibility Leucocyte Antigens (HLA) explains ,35% [5] of the genetic variance associated to CD. In particular the higher risk groups (.10%) were those belonging to G1 and G2 groups [1]. Since HLA alone can explain about 1/3rd of the genetic susceptibility to the disease, other variants should be implicated
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