Effective detection of human leukocyte antigen risk alleles in celiac disease using tag single nucleotide polymorphisms.
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.


METHODS
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.


CONCLUSIONS
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.
Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.
Alienke J
AJ
Monsuur
Paul I W
PI
de Bakker
Alexandra
A
Zhernakova
Dalila
D
Pinto
Willem
W
Verduijn
Jihane
J
Romanos
Renata
R
Auricchio
Ana
A
Lopez
David A
DA
van Heel
J Bart A
JB
Crusius
Cisca
C
Wijmenga
D000483:Alleles; D016022:Case-Control Studies; D002446:Celiac Disease / Q000235:genetics*; D015331:Cohort Studies; D020022:Genetic Predisposition to Disease; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
D006680:HLA Antigens