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1.  Improving coeliac disease risk prediction by testing non-HLA variants additional to HLA variants 
Romanos, Jihane | Rosén, Anna | Kumar, Vinod | Trynka, Gosia | Franke, Lude | Szperl, Agata | Gutierrez-Achury, Javier | van Diemen, Cleo C | Kanninga, Roan | Jankipersadsing, Soesma A | Steck, Andrea | Eisenbarth, Georges | van Heel, David A | Cukrowska, Bozena | Bruno, Valentina | Mazzilli, Maria Cristina | Núñez, Concepcion | Bilbao, Jose Ramon | Mearin, M Luisa | Barisani, Donatella | Rewers, Marian | Norris, Jill M | Ivarsson, Anneli | Boezen, H Marieke | Liu, Edwin | Wijmenga, Cisca | Scerri, Cristian | Koltai, Tunde | Kolaček, Sanja | Mišak, Zrinka | Abdović, Slaven | Koletzko, Sibylle | Osiander, Gertraud | Werkstetter, Katharina | Mummert, Eckart | Korponay-Szabo, Ilma R | Gyimesi, Judit | Shamir, Raanan | Hartman, Corina | Bravi, Enzo | Poles, Marco | Auricchio, Renata | Limongelli, G Gianna Giovamma | Greco, Luigi | Troncone, Riccardo | Villanacci, Vincenzo | Bindels, Jacques G | Brand, Ronald | Kupper, Bibi Funke | Esch, Caroline E Hogen | Hopman, Erica G | Koning, Frits | Kooy-Winkelaar, Yvonne | te Marvelde, Chantal | Putter, Hein | Stoopman, Els | Vriezinga, Sabine | Sollid, Ludvig M | Ráki, Melinda | Chmielewska, Ania | Dziechciarz, Piotr | Pieścik-Lech, Małgorzata | Szajewska, Hania | Szaflarska-Szczepanik, Anna | Castillejo, Gemma | Capilla, Amalia | Varea, Vicente | Ribes-Koninckx, Carmen | Lopez, Anna | Crespo, Paula | Martinez, Eva | Polanco, Isabel | Högberg, Lotta | Stenhammar, Lars | Carlsson, Annelie | Webb, Charlotta | Hammarroth, Solveig | Hernell, Olle | Lagerqvist, Carina | Myléus, Anna | Nordyke, Katrina | Norström, Fredrik | Sandström, Olof | Wall, Stig | Karlsson, Eva
Gut  2013;63(3):415-422.
The majority of coeliac disease (CD) patients are not being properly diagnosed and therefore remain untreated, leading to a greater risk of developing CD-associated complications. The major genetic risk heterodimer, HLA-DQ2 and DQ8, is already used clinically to help exclude disease. However, approximately 40% of the population carry these alleles and the majority never develop CD.
We explored whether CD risk prediction can be improved by adding non-HLA-susceptible variants to common HLA testing.
We developed an average weighted genetic risk score with 10, 26 and 57 single nucleotide polymorphisms (SNP) in 2675 cases and 2815 controls and assessed the improvement in risk prediction provided by the non-HLA SNP. Moreover, we assessed the transferability of the genetic risk model with 26 non-HLA variants to a nested case–control population (n=1709) and a prospective cohort (n=1245) and then tested how well this model predicted CD outcome for 985 independent individuals.
Adding 57 non-HLA variants to HLA testing showed a statistically significant improvement compared to scores from models based on HLA only, HLA plus 10 SNP and HLA plus 26 SNP. With 57 non-HLA variants, the area under the receiver operator characteristic curve reached 0.854 compared to 0.823 for HLA only, and 11.1% of individuals were reclassified to a more accurate risk group. We show that the risk model with HLA plus 26 SNP is useful in independent populations.
Predicting risk with 57 additional non-HLA variants improved the identification of potential CD patients. This demonstrates a possible role for combined HLA and non-HLA genetic testing in diagnostic work for CD.
PMCID: PMC3933173  PMID: 23704318
Coeliac Disease; Genetic Testing; Hla; Molecular Genetics; Celiac Disease
2.  Fine mapping of the celiac disease-associated LPP locus reveals a potential functional variant 
Human Molecular Genetics  2013;23(9):2481-2489.
Using the Immunochip for genotyping, we identified 39 non-human leukocyte antigen (non-HLA) loci associated to celiac disease (CeD), an immune-mediated disease with a worldwide frequency of ∼1%. The most significant non-HLA signal mapped to the intronic region of 70 kb in the LPP gene. Our aim was to fine map and identify possible functional variants in the LPP locus. We performed a meta-analysis in a cohort of 25 169 individuals from six different populations previously genotyped using Immunochip. Imputation using data from the Genome of the Netherlands and 1000 Genomes projects, followed by meta-analysis, confirmed the strong association signal on the LPP locus (rs2030519, P = 1.79 × 10−49), without any novel associations. The conditional analysis on this top SNP-indicated association to a single common haplotype. By performing haplotype analyses in each population separately, as well as in a combined group of the four populations that reach the significant threshold after correction (P < 0.008), we narrowed down the CeD-associated region from 70 to 2.8 kb (P = 1.35 × 10−44). By intersecting regulatory data from the ENCODE project, we found a functional SNP, rs4686484 (P = 3.12 × 10−49), that maps to several B-cell enhancer elements and a highly conserved region. This SNP was also predicted to change the binding motif of the transcription factors IRF4, IRF11, Nkx2.7 and Nkx2.9, suggesting its role in transcriptional regulation. We later found significantly low levels of LPP mRNA in CeD biopsies compared with controls, thus our results suggest that rs4686484 is the functional variant in this locus, while LPP expression is decreased in CeD.
PMCID: PMC3976328  PMID: 24334606
3.  Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4 
The Journal of Experimental Medicine  2012;209(13):2395-2408.
Pest resistance molecules, α-amylase/trypsin inhibitors from wheat, activate innate immune cells through engagement of TLR4 to elicit inflammatory responses in the intestine.
Ingestion of wheat, barley, or rye triggers small intestinal inflammation in patients with celiac disease. Specifically, the storage proteins of these cereals (gluten) elicit an adaptive Th1-mediated immune response in individuals carrying HLA-DQ2 or HLA-DQ8 as major genetic predisposition. This well-defined role of adaptive immunity contrasts with an ill-defined component of innate immunity in celiac disease. We identify the α-amylase/trypsin inhibitors (ATIs) CM3 and 0.19, pest resistance molecules in wheat, as strong activators of innate immune responses in monocytes, macrophages, and dendritic cells. ATIs engage the TLR4–MD2–CD14 complex and lead to up-regulation of maturation markers and elicit release of proinflammatory cytokines in cells from celiac and nonceliac patients and in celiac patients’ biopsies. Mice deficient in TLR4 or TLR4 signaling are protected from intestinal and systemic immune responses upon oral challenge with ATIs. These findings define cereal ATIs as novel contributors to celiac disease. Moreover, ATIs may fuel inflammation and immune reactions in other intestinal and nonintestinal immune disorders.
PMCID: PMC3526354  PMID: 23209313
4.  Hepcidin Expression in Iron Overload Diseases Is Variably Modulated by Circulating Factors 
PLoS ONE  2012;7(5):e36425.
Hepcidin is a regulatory hormone that plays a major role in controlling body iron homeostasis. Circulating factors (holotransferrin, cytokines, erythroid regulators) might variably contribute to hepcidin modulation in different pathological conditions. There are few studies analysing the relationship between hepcidin transcript and related protein expression profiles in humans. Our aims were: a. to measure hepcidin expression at either hepatic, serum and urinary level in three paradigmatic iron overload conditions (hemochromatosis, thalassemia and dysmetabolic iron overload syndrome) and in controls; b. to measure mRNA hepcidin expression in two different hepatic cell lines (HepG2 and Huh-7) exposed to patients and controls sera to assess whether circulating factors could influence hepcidin transcription in different pathological conditions. Our findings suggest that hepcidin assays reflect hepatic hepcidin production, but also indicate that correlation is not ideal, likely due to methodological limits and to several post-trascriptional events. In vitro study showed that THAL sera down-regulated, HFE-HH and C-NAFLD sera up-regulated hepcidin synthesis. HAMP mRNA expression in Huh-7 cells exposed to sera form C-Donors, HFE-HH and THAL reproduced, at lower level, the results observed in HepG2, suggesting the important but not critical role of HFE in hepcidin regulation.
PMCID: PMC3346721  PMID: 22586470
5.  A Meta-Analysis of Genome-Wide Association Scans Identifies IL18RAP, PTPN2, TAGAP, and PUS10 As Shared Risk Loci for Crohn's Disease and Celiac Disease 
PLoS Genetics  2011;7(1):e1001283.
Crohn's disease (CD) and celiac disease (CelD) are chronic intestinal inflammatory diseases, involving genetic and environmental factors in their pathogenesis. The two diseases can co-occur within families, and studies suggest that CelD patients have a higher risk to develop CD than the general population. These observations suggest that CD and CelD may share common genetic risk loci. Two such shared loci, IL18RAP and PTPN2, have already been identified independently in these two diseases. The aim of our study was to explicitly identify shared risk loci for these diseases by combining results from genome-wide association study (GWAS) datasets of CD and CelD. Specifically, GWAS results from CelD (768 cases, 1,422 controls) and CD (3,230 cases, 4,829 controls) were combined in a meta-analysis. Nine independent regions had nominal association p-value <1.0×10−5 in this meta-analysis and showed evidence of association to the individual diseases in the original scans (p-value <1×10−2 in CelD and <1×10−3 in CD). These include the two previously reported shared loci, IL18RAP and PTPN2, with p-values of 3.37×10−8 and 6.39×10−9, respectively, in the meta-analysis. The other seven had not been reported as shared loci and thus were tested in additional CelD (3,149 cases and 4,714 controls) and CD (1,835 cases and 1,669 controls) cohorts. Two of these loci, TAGAP and PUS10, showed significant evidence of replication (Bonferroni corrected p-values <0.0071) in the combined CelD and CD replication cohorts and were firmly established as shared risk loci of genome-wide significance, with overall combined p-values of 1.55×10−10 and 1.38×10−11 respectively. Through a meta-analysis of GWAS data from CD and CelD, we have identified four shared risk loci: PTPN2, IL18RAP, TAGAP, and PUS10. The combined analysis of the two datasets provided the power, lacking in the individual GWAS for single diseases, to detect shared loci with a relatively small effect.
Author Summary
Celiac disease and Crohn's disease are both chronic inflammatory diseases of the digestive tract. Both of these diseases are complex genetic traits with multiple genetic and non-genetic risk factors. Recent genome-wide association (GWA) studies have identified some of the genetic risk factors for these diseases. Interestingly, in addition to some similarities in phenotype, these studies have shown that CelD and CD share some genetic risk factors. Specifically, by comparing the results of independent GWA studies of CD and CelD, two genetic risk loci were found in common: the PTPN2 locus and the IL18RAP locus. Therefore, in order to directly test for additional shared genetic risk factors, we combined the GWA results from two large studies of CelD and CD, essentially creating a combined phenotype with anyone with CD or CelD being coded as affected. Association results were then replicated in additional cohorts of CelD and CD. It is expected that shared risk loci should show association in this analysis, whereas the signal of risk loci specific to either of the two diseases should be diluted. With this method of meta-analysis, we identified next to PTPN2 and IL18 RAP two loci harbouring TAGAP and PUS10 as shared risk loci for Crohn's disease and celiac disease at genome-wide significance.
PMCID: PMC3029251  PMID: 21298027

Results 1-5 (5)