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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 and Jankipersadsing, Soesma A., et al. (2014) In Gut 63(3). p.415-422
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. 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... (More)

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.

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@article{e3e8ee8d-cd52-4fee-9dc4-3dd977c78408,
  abstract     = {<p>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.</p>},
  author       = {Romanos, Jihane and Rosén, Anna and Kumar, Vinod and Trynka, Gosia and Franke, Lude and Szperl, Agata and Gutierrez-Achury, Javier and Van Diemen, Cleo C. and Kanninga, Roan and Jankipersadsing, Soesma A. and Steck, Andrea K and Eisenbarth, Georges and Van Heel, David A. and Cukrowska, Bozena and Bruno, Valentina and Mazzilli, Maria Cristina and Núñez, Concepcion and Bilbao, Jose Ramon and Mearin, M. Luisa and Barisani, Donatella and Rewers, Marian and Norris, Jill M and Ivarsson, Anneli and Boezen, H. Marieke and Liu, Edwin and Wijmenga, Cisca and ,  and Carlsson, Annelie},
  issn         = {0017-5749},
  language     = {eng},
  number       = {3},
  pages        = {415--422},
  publisher    = {BMJ Publishing Group},
  series       = {Gut},
  title        = {Improving coeliac disease risk prediction by testing non-HLA variants additional to HLA variants},
  url          = {http://dx.doi.org/10.1136/gutjnl-2012-304110},
  volume       = {63},
  year         = {2014},
}