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Improving coeliac disease risk prediction by testing non-HLA variants additional to HLA variants.

ABSTRACT: 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.

SUBMITTER: Romanos J

PROVIDER: S-EPMC3933173 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Improving coeliac disease risk prediction by testing non-HLA variants additional to HLA variants.

Romanos Jihane J Rosén Anna A Kumar Vinod V Trynka Gosia G Franke Lude L Szperl Agata A Gutierrez-Achury Javier J van Diemen Cleo C CC Kanninga Roan R Jankipersadsing Soesma A SA Steck Andrea A Eisenbarth Georges G van Heel David A DA Cukrowska Bozena B Bruno Valentina V Mazzilli Maria Cristina MC Núñez Concepcion C Bilbao Jose Ramon JR Mearin M Luisa ML Barisani Donatella D Rewers Marian M Norris Jill M JM Ivarsson Anneli A Boezen H Marieke HM Liu Edwin E Wijmenga Cisca C

Gut 20130523 3

<h4>Background</h4>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.<h4>Objective</h4>We explored whether CD risk prediction can be improved by adding non-HLA-suscep ...[more]

PMID: 23704318

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Project description:Non-coeliac gluten sensitivity (NCGS) refers to patients with primarily gastrointestinal symptoms without enteropathy that symptomatically benefit from gluten-free diet (GFD). Little is known about its pathophysiology, propensity to neurological manifestations, and if these differ from patients with coeliac disease (CD). We investigated the clinical and immunological characteristics of patients presenting with neurological manifestations with CD and those with NCGS.We compared clinical, neurophysiological, and imaging data of patients with CD and NCGS presenting with neurological dysfunction assessed and followed up regularly over a period of 20 years.Out of 700 patients, 562 were included. Exclusion criteria included no bowel biopsy to confirm CD, no HLA type available, and failure to adhere to GFD. All patients presented with neurological dysfunction and had circulating anti-gliadin antibodies. Out of 562 patients, 228 (41%) had evidence of enteropathy (Group 1, CD) and 334 (59%) did not (Group 2, NCGS). The most common neurological manifestations were cerebellar ataxia, peripheral neuropathy, and encephalopathy. There was a greater proportion of patients with encephalopathy in Group 1 and with a greater proportion of neuropathy in Group 2. The severity of ataxia did not differ between the two groups. Patients in Group 1 had more severe neuropathy. All patients from both groups responded to gluten-free diet. Anti-tissue transglutaminase (TG2) antibodies were found in 91% of patients in Group 1 and in 29% of patients in Group 2. Comparison between those patients in Group 2 with HLA-DQ2/DQ8 and those without as well as those with positive TG2 compared with those with negative TG2 antibodies identified no differences within these subgroups. Serological positivity for TG6 antibodies was similar in the two groups (67 and 60%).The neurological manifestations of CD and NCGS are similar and equally responsive to a GFD suggestive of common pathophysiological mechanisms.

Dataset Information

Improving coeliac disease risk prediction by testing non-HLA variants additional to HLA variants.

Publications

Improving coeliac disease risk prediction by testing non-HLA variants additional to HLA variants.

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