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Improving coeliac disease risk prediction by testing non-HLA variants additional to HLA variants
  1. Jihane Romanos1,2,
  2. Anna Rosén3,4,
  3. Vinod Kumar1,
  4. Gosia Trynka1,5,
  5. Lude Franke1,
  6. Agata Szperl1,
  7. Javier Gutierrez-Achury1,
  8. Cleo C van Diemen1,
  9. Roan Kanninga1,
  10. Soesma A Jankipersadsing1,
  11. Andrea Steck6,
  12. Georges Eisenbarth6,
  13. David A van Heel7,
  14. Bozena Cukrowska8,
  15. Valentina Bruno9,
  16. Maria Cristina Mazzilli10,
  17. Concepcion Núñez11,
  18. Jose Ramon Bilbao12,
  19. M Luisa Mearin13,
  20. Donatella Barisani14,
  21. Marian Rewers6,
  22. Jill M Norris15,
  23. Anneli Ivarsson3,
  24. H Marieke Boezen16,
  25. Edwin Liu6,
  26. Cisca Wijmenga1,
  27. PreventCD Group
  1. 1Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
  2. 2School of Medicine, Lebanese American University, Beirut, Lebanon
  3. 3Department of Public Health and Clinical Medicine, Epidemiology and Global Health, Umeå University, Umeå, Sweden
  4. 4Department of Medical Biosciences, Medical and Clinical Genetics, Umeå University, Umeå, Sweden
  5. 5Division of Genetics and Division of Rheumatology, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, USA
  6. 6Barbara Davis Centre for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado, USA
  7. 7Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, London, UK
  8. 8Department of Pathology, Children's Memorial Health Institute, Warsaw, Poland
  9. 9European Laboratory for Food-Induced Disease, University of Naples Federico II, Naples, Italy
  10. 10Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
  11. 11Clinical Immunology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos IdISSC, Madrid, Spain
  12. 12Immunogenetics Research Laboratory, Hospital de Cruces, Bizkaia, Spain
  13. 13Department of Paediatrics, Leiden University Medical Centre, Leiden, The Netherlands
  14. 14Department of Experimental Medicine, Faculty of Medicine, University of Milano-Bicocca, Monza, Italy
  15. 15Epidemiology Department, Colorado School of Public Health, Aurora, USA
  16. 16Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
  1. Correspondence to Professor Cisca Wijmenga, Department of Genetics, University Medical Centre Groningen, PO Box 30001, Groningen 9700 RB, The Netherlands; c.wijmenga{at}


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.

Design 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.

  • Coeliac Disease
  • Genetic Testing
  • Hla
  • Molecular Genetics
  • Celiac Disease

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