title: Improving coeliac disease risk prediction by testing non-HLA variants additional to HLA variants.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  We explored whether CD risk prediction can be improved by adding non-HLA-susceptible variants to common HLA testing.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Genetics, University of Groningen, University Medical Centre Groningen, , Groningen, The Netherlands.
authors.forename: Jihane
authors.initials: J
authors.lastname: Romanos
authors.forename: Anna
authors.initials: A
authors.lastname: Rosén
authors.forename: Vinod
authors.initials: V
authors.lastname: Kumar
authors.forename: Gosia
authors.initials: G
authors.lastname: Trynka
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.forename: Agata
authors.initials: A
authors.lastname: Szperl
authors.forename: Javier
authors.initials: J
authors.lastname: Gutierrez-Achury
authors.forename: Cleo C
authors.initials: CC
authors.lastname: van Diemen
authors.forename: Roan
authors.initials: R
authors.lastname: Kanninga
authors.forename: Soesma A
authors.initials: SA
authors.lastname: Jankipersadsing
authors.forename: Andrea
authors.initials: A
authors.lastname: Steck
authors.forename: Georges
authors.initials: G
authors.lastname: Eisenbarth
authors.forename: David A
authors.initials: DA
authors.lastname: van Heel
authors.forename: Bozena
authors.initials: B
authors.lastname: Cukrowska
authors.forename: Valentina
authors.initials: V
authors.lastname: Bruno
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Mazzilli
authors.forename: Concepcion
authors.initials: C
authors.lastname: Núñez
authors.forename: Jose Ramon
authors.initials: JR
authors.lastname: Bilbao
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Mearin
authors.forename: Donatella
authors.initials: D
authors.lastname: Barisani
authors.forename: Marian
authors.initials: M
authors.lastname: Rewers
authors.forename: Jill M
authors.initials: JM
authors.lastname: Norris
authors.forename: Anneli
authors.initials: A
authors.lastname: Ivarsson
authors.forename: H Marieke
authors.initials: HM
authors.lastname: Boezen
authors.forename: Edwin
authors.initials: E
authors.lastname: Liu
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
mesh_terms: D016022:Case-Control Studies; D002446:Celiac Disease / Q000175:diagnosis* / Q000235:genetics; D003661:Decision Support Techniques; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006683:HLA-DQ Antigens / Q000235:genetics*; D006801:Humans; D016015:Logistic Models; D008297:Male; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012372:ROC Curve; D018570:Risk Assessment
chemical_list: D005819:Genetic Markers; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; C109756:HLA-DQ8 antigen
keywords: Celiac Disease; Coeliac Disease; Genetic Testing; Hla; Molecular Genetics