Immunogenetics

, Volume 61, Issue 4, pp 247–256 | Cite as

Cost-effective HLA typing with tagging SNPs predicts celiac disease risk haplotypes in the Finnish, Hungarian, and Italian populations

  • Lotta Koskinen
  • Jihane Romanos
  • Katri Kaukinen
  • Kirsi Mustalahti
  • Ilma Korponay-Szabo
  • Donatella Barisani
  • Maria Teresa Bardella
  • Fabiana Ziberna
  • Serena Vatta
  • György Széles
  • Zsuzsa Pocsai
  • Kati Karell
  • Katri Haimila
  • Róza Ádány
  • Tarcisio Not
  • Alessandro Ventura
  • Markku Mäki
  • Jukka Partanen
  • Cisca Wijmenga
  • Päivi Saavalainen
Original Paper

Abstract

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.

Keywords

HLA Human leukocyte antigen Celiac disease Tagging SNP 

Notes

Acknowledgements

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.

Supplementary material

251_2009_361_MOESM1_ESM.doc (88 kb)
Supplementary Table 1 Results of the quality check in the Hungarian (HUN), Finnish (FIN), and Italian (ITA), case control sample sets (DOC 88 kb)
251_2009_361_MOESM2_ESM.doc (114 kb)
Supplementary Table 2 Detailed sensitivities, specificities, positive predictive values, correlations (r 2), and false results in the Finnish, Hungarian, and Italian materials (DOC 114 kb)
251_2009_361_MOESM3_ESM.xls (22 kb)
Supplementary Table 3 Results of the logistics regression analysis to assess the celiac disease risk conferred by different HLA genotypes

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Lotta Koskinen
    • 1
  • Jihane Romanos
    • 2
  • Katri Kaukinen
    • 3
  • Kirsi Mustalahti
    • 4
  • Ilma Korponay-Szabo
    • 5
    • 6
  • Donatella Barisani
    • 7
  • Maria Teresa Bardella
    • 8
    • 9
  • Fabiana Ziberna
    • 10
  • Serena Vatta
    • 10
  • György Széles
    • 11
  • Zsuzsa Pocsai
    • 12
  • Kati Karell
    • 13
  • Katri Haimila
    • 13
  • Róza Ádány
    • 12
  • Tarcisio Not
    • 10
  • Alessandro Ventura
    • 10
  • Markku Mäki
    • 4
  • Jukka Partanen
    • 13
  • Cisca Wijmenga
    • 2
  • Päivi Saavalainen
    • 1
    • 14
  1. 1.Department of Medical Genetics and Research Program for Molecular Medicine, Biomedicum HelsinkiUniversity of HelsinkiHelsinkiFinland
  2. 2.Genetics Department, University Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
  3. 3.Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital and Medical SchoolUniversity of TampereTampereFinland
  4. 4.Pediatric Research Center, University of Tampere Medical School and Tampere University HospitalUniversity of TampereTampereFinland
  5. 5.Coeliac Disease CenterHeim Pal Children’s HospitalBudapestHungary
  6. 6.Department of PediatricsUniversity of DebrecenDebrecenHungary
  7. 7.Department of Experimental Medicine, Faculty of MedicineUniversity of Milano-BicoccaMonzaItaly
  8. 8.Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina ElenaMilanItaly
  9. 9.Department of Medical SciencesUniversity of MilanMilanItaly
  10. 10.Department of Reproductive and Development SciencesUniversity of Trieste and IRCCS “Burlo Garofolo” Children HospitalTriesteItaly
  11. 11.Faculty of Public Health, Department of Epidemiology and BiostatisticsUniversity of DebrecenDebrecenHungary
  12. 12.Faculty of Public Health, Department of Preventive MedicineUniversity of DebrecenDebrecenHungary
  13. 13.Research and DevelopmentFinnish Red Cross Blood ServiceHelsinkiFinland
  14. 14.Department of Medical Genetics, Haartman Institute, Biomedicum HelsinkiUniversity of HelsinkiHelsinkiFinland

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