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Effective detection of human leukocyte antigen risk alleles in celiac disease using tag single nucleotide
Alienke J Monsuur1, Paul I W de Bakker, Alexandra Zhernakova
1Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.
Insights
A new method using six single nucleotide polymorphisms (SNPs) accurately predicts celiac disease (CD) associated HLA risk factors. This simplifies and reduces the cost of diagnosing CD, aiding disease susceptibility studies.
Area of Science:
- Immunogenetics
- Human genetics
- Molecular biology
Background:
- Human Leukocyte Antigen (HLA) genes in the MHC region are crucial in autoimmune disorders like celiac disease (CD).
- Specific HLA variants, such as DQ2.5 and DQ8, are strongly associated with CD risk.
- Current HLA risk factor typing methods are complex and costly.
Purpose of the Study:
- To develop a simplified experimental approach for identifying CD-associated HLA risk factors.
- To utilize tagging single nucleotide polymorphisms (SNPs) for predicting high-risk HLA variants.
Main Methods:
- Exploited linkage disequilibrium between six tag SNPs and CD-associated HLA risk factors (DQ2.5, DQ8, DQ2.2, DQ7).
- Empirically compared predicted DQ types (based on tag SNPs) with validated laboratory typing methods.
- Validated the approach in three large European celiac populations.
Main Results:
- Six tag SNPs accurately predicted HLA risk factors in over 95% of CD patients.
- Achieved high sensitivity (>0.991), specificity (>0.996), and predictive value (>0.948) for the tag SNP method.
- Demonstrated broad applicability across European populations.
Conclusions:
- The tag SNP method offers a highly accurate and cost-effective approach for predicting CD-associated HLA risk factors.
- This method provides an excellent basis for population-wide screening of celiac disease.
- The approach is broadly applicable and simplifies genetic risk assessment for CD.
Background:
The HLA genes, located in the MHC region on chromosome 6p21.3, play an important role in many autoimmune disorders, such as celiac disease (CD), type 1 diabetes (T1D), rheumatoid arthritis, multiple sclerosis, psoriasis and others. Known HLA variants that confer risk to CD, for example, include DQA1*05/DQB1*02 (DQ2.5) and DQA1*03/DQB1*0302 (DQ8). To diagnose the majority of CD patients and to study disease susceptibility and progression, typing these strongly associated HLA risk factors is of utmost importance. However, current genotyping methods for HLA risk factors involve many reactions, and are complicated and expensive. We sought a simple experimental approach using tagging SNPs that predict the CD-associated HLA risk factors.
Methodology:
Our tagging approach exploits linkage disequilibrium between single nucleotide polymorphism (SNPs) and the CD-associated HLA risk factors DQ2.5 and DQ8 that indicate direct risk, and DQA1*0201/DQB1*0202 (DQ2.2) and DQA1*0505/DQB1*0301 (DQ7) that attribute to the risk of DQ2.5 to CD. To evaluate the predictive power of this approach, we performed an empirical comparison of the predicted DQ types, based on these six tag SNPs, with those executed with current validated laboratory typing methods of the HLA-DQA1 and -DQB1 genes in three large cohorts. The results were validated in three European celiac populations.
Conclusion:
Using this method, only six SNPs were needed to predict the risk types carried by >95% of CD patients. We determined that for this tagging approach the sensitivity was >0.991, specificity >0.996 and the predictive value >0.948. Our results show that this tag SNP method is very accurate and provides an excellent basis for population screening for CD. This method is broadly applicable in European populations.
