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Improving coeliac disease risk prediction by testing non-HLA variants additional to HLA variants
Jihane Romanos1, Anna Rosén, Vinod Kumar
1Department of Genetics, University of Groningen, University Medical Centre Groningen, , Groningen, The Netherlands.
Insights
Improved coeliac disease (CD) risk prediction is possible by adding non-HLA variants to human leukocyte antigen (HLA) testing. This combined genetic approach enhances the identification of individuals at risk for CD.
Area of Science:
- Genetics
- Immunology
- Gastroenterology
Background:
- Coeliac disease (CD) diagnosis is often delayed, increasing risks of complications.
- Human Leukocyte Antigen (HLA)-DQ2/DQ8 alleles are key genetic risk factors but are present in many healthy individuals.
- Current diagnostic methods need improvement for accurate risk stratification.
Purpose of the Study:
- To enhance coeliac disease risk prediction by integrating non-HLA genetic variants with standard HLA testing.
- To evaluate the diagnostic utility of genetic risk scores incorporating single nucleotide polymorphisms (SNPs).
Main Methods:
- Developed genetic risk scores using 10, 26, and 57 non-HLA SNPs in a large case-control cohort (2675 cases, 2815 controls).
- Assessed the predictive performance and transferability of these models in independent populations.
- Validated the model's ability to predict CD outcomes in 985 individuals.
Main Results:
- Incorporating 57 non-HLA variants significantly improved CD risk prediction compared to HLA testing alone or with fewer SNPs (AUC 0.854 vs. 0.823).
- The model with 57 non-HLA variants reclassified 11.1% of individuals into more accurate risk categories.
- A model with 26 non-HLA variants demonstrated utility in independent populations.
Conclusions:
- Adding 57 non-HLA variants substantially improves the identification of potential coeliac disease patients.
- Combined HLA and non-HLA genetic testing shows promise for enhancing CD diagnostic strategies.
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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