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Revisiting genome wide association studies (GWAS) in coeliac disease: replication study in Spanish population and expression analysis of candidate genes
  1. Leticia Plaza-Izurieta1,2,
  2. Ainara Castellanos-Rubio1,
  3. Iñaki Irastorza1,
  4. Nora Fernández-Jimenez1,2,
  5. Galder Gutierrez1,
  6. CEGEC3,*,
  7. Jose Ramon Bilbao1,2
  1. 1Endocrinology Diabetes and Nutrition Research Group, Hospital de Cruces, Barakaldo, Spain
  2. 2Department of Genetics, University of the Basque Country, Physical Anthropology and Animal Physiology, Leioa, Basque Country, Spain
  3. 3Spanish Consortium for Genetics of Celiac Disease – Spanish Celiac Disease Society (SEEC), Spain
  1. Correspondence to Jose Ramon Bilbao, Immunogenetics Research Laboratory, Endocrinology, Diabetes and Nutrition Research Group, Hospital de Cruces, Barakaldo E48903 Bizkaia, Basque Country, Spain; joseramon.bilbaocatala{at}


Introduction Recent genome wide association studies (GWAS) on coeliac disease (CD) have identified risk loci harbouring genes that fit the accepted pathogenic model and are considered aetiological candidates.

Methods Using Taqman single nucleotide polymorphism (SNP) and expression assays, the study genotyped 11 SNPs tagging eight GWAS regions (1q31, 2q11–2q12, 3p21, 3q25–3q26, 3q28, 4q27, 6q25 and 12q24) in a Spanish cohort of 1094 CD patients and 540 controls, and performed expression analyses of candidate genes (RGS1, IL18R1/IL18RAP, CCR3, IL12A/SCHIP1, LPP, IL2/IL21-KIAA1109, TAGAP, and SH2B3) in intestinal mucosa from 29 CD children and eight controls.

Results Polymorphisms in 1q31, 2q11–2q12, and 3q25 showed association in our cohort, and also 3q28 and 4q27 when combined with a previous study. Expression levels of IL12A, IL18RAP, IL21, KIAA1109, LPP, SCHIP1, and SH2B3 were affected by disease status, but the correlation between genotype and mRNA levels was observed only in IL12A, LPP, SCHIP1, and SH2B3.

Conclusions Expression differences between treated CD patients and controls along with SNP expression associations suggest a possible primary role for these four genes and their variants in pathogenesis. The lack of SNP effect in the remaining genes is probably a consequence of arbitrary candidate gene selection within association signals that are not based on functional studies.

  • Coeliac disease

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  • * CEGEC participants: Montserrat Alsina, María Esteve and Laura Pardo (CATLAB-Hospital Universitari Mutua de Terrassa-Barcelona); Luis Castaño, Pablo Oliver and Juan Carlos Vitoria (Hospital Universitario de Cruces, Barakaldo-Bizkaia); Luis Rodrigo, Carlos López-Larrea and Antonio López-Vázquez (Hospital General de Asturias, Oviedo-Asturias); Idoia Hualde and Zuriñe García (Hospital de Txagorritxu, Vitoria-Gasteiz); Blanca Hernández, María Antonia Ramos-Arroyo and Félix Sánchez-Valverde (Hospital Virgen del Camino, Pamplona-Iruña); Carme Farré, Teresa Marqués and Pere Vilar (Hospital Sant Joan de Deu, Esplugues de Llobregat-Barcelona), Eduardo Arranz and José Antonio Garrote (Universidad de Valladolid, Valladolid, Spain).

  • Funding This work was partially funded by Research Project grants from the Spanish Ministry of Science and Innovation (07/0796) and Basque Departments of Health (2006/111030) and Industry (SAIO-2008/00231) to JRB. LP-I and NF-J are predoctoral fellows supported by grants from the Basque Department of Education (BIF-2009-099 and BIF-2010-189, respectively). JRB is co-funded by the I3SNS Program of the Spanish Ministry of Health (CES05/036). CEGEC in Valladolid wants also to acknowledge the financial support of Instituto de Salud Carlos III (PI070244), Spanish Ministry of Science and Innovation (CES08/016 and CA08/300), Fundación IECSCYL, Phadia Spain and also thanks to Ms Alicia Ortega for her technical help in handling and classification of samples.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Institutional Board of CEGEC participating centres.

  • Provenance and peer review Not commissioned; externally peer reviewed.