Cost-effective HLA typing with tagging SNPs predicts celiac disease risk haplotypes in the Finnish, Hungarian, and Italian populations
Human leukocyte antigen (HLA) genes, located on chromosome 6p21.3, have a crucial role in susceptibility to various autoimmune and inflammatory diseases, such as celiac disease and type 1 diabetes. Certain HLA heterodimers, namely DQ2 (encoded by the DQA1*05 and DQB1*02 alleles) and DQ8 (DQA1*03 and DQB1*0302), are necessary for the development of celiac disease. Traditional genotyping of HLA genes is laborious, time-consuming, and expensive. A novel HLA-genotyping method, using six HLA-tagging single-nucleotide polymorphisms (SNPs) and suitable for high-throughput approaches, was described recently. Our aim was to validate this method in the Finnish, Hungarian, and Italian populations. The six previously reported HLA-tagging SNPs were genotyped in patients with celiac disease and in healthy individuals from Finland, Hungary, and two distinct regions of Italy. The potential of this method was evaluated in analyzing how well the tag SNP results correlate with the HLA genotypes previously determined using traditional HLA-typing methods. Using the tagging SNP method, it is possible to determine the celiac disease risk haplotypes accurately in Finnish, Hungarian, and Italian populations, with specificity and sensitivity ranging from 95% to 100%. In addition, it predicts homozygosity and heterozygosity for a risk haplotype, allowing studies on genotypic risk effects. The method is transferable between populations and therefore suited for large-scale research studies and screening of celiac disease among high-risk individuals or at the population level.
KeywordsHLA Human leukocyte antigen Celiac disease Tagging SNP
All the study subjects are warmly thanked for their participation in the study. We thank Hanne Ahola for excellent technical assistance and Cleo van Diemen for her statistical expertise. We thank Erzsébet Szathmári, Judit B. Kovács, Margit Lörincz, and Anikó Nagy for their work with the Hungarian families. Anna-Elina Lehesjoki and Albert de la Chapelle are acknowledged for providing us with the Finnish population samples.
This work and the study groups have been funded from the EU Commission by a Marie Curie Excellence Grant (FP6 contract MEXT-CT-2005-025270), the Academy of Finland, the Hungarian Scientific Research Fund (contract OTKA 61868), the University of Helsinki Funds, Biocentrum Helsinki, the Research Fund of Tampere University Hospital, the Competitive Research Funding of the Pirkanmaa Hospital District, the Yrjö Jahnsson Foundation, the Foundation of Pediatric Research, the Sigrid Juselius Foundation, the Finnish Cultural Foundation, the Maud Kuistila Memorial Foundation, the Finnish Society for Gastroenterological Research, the Finnish Celiac Disease Society, the Celiac Disease Consortium (an innovative cluster approved by the Netherlands Genomics Initiative and partly funded by the Dutch Government, grant BSIK03009 to CW), and KP6 EU grant 036383 (PREVENTCD).
The HLA-DQ haplotyping was invented at the University Medical Center Utrecht (UMC Utrecht) and will be developed and marketed by Genome Diagnostics BV. The UMC Utrecht may receive royalties from the worldwide sale of the technology. UMC Utrecht may distribute part of the royalty revenues to the inventors (Wijmenga C and Monsuur A). None of the authors report a financial or other links with Genome Diagnostics BV. Genome Diagnostics had no role in study design, data collection and analysis, decisions to publish, or preparation of the manuscript.
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