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Gut. 2014 Mar;63(3):415-22. doi: 10.1136/gutjnl-2012-304110. Epub 2013 May 23.

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

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  • 1Department of Genetics, University of Groningen, University Medical Centre Groningen, , Groningen, The Netherlands.

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 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.

KEYWORDS:

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

PMID:
23704318
[PubMed - indexed for MEDLINE]
PMCID:
PMC3933173
Free PMC Article
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