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CTLA4 is differentially associated with autoimmune diseases in the Dutch population

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An Erratum to this article was published on 08 December 2005

Abstract

Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) is an important negative regulator of T-cell response and its genetic association with type 1 diabetes (T1D) has recently been demonstrated. The frequent co-association of autoimmune diseases (AID) and the implication from multiple genome scans that the CTLA4 gene region is a general autoimmune region, led us to study the role of CTLA4 in independent cohorts of T1D, coeliac disease (CD) and rheumatoid arthritis (RA) patients. We present independent data that confirm the association of CTLA4 in Dutch patients with juvenile onset T1D and show differential association of CTLA4 with CD and RA. The CTLA4 gene polymorphisms were tested for association in 350 T1D, 310 CD, 520 RA patients and 900 controls. In addition, 218 families were tested by the transmission disequilibrium test (TDT). T1D patients showed the highest association with the MH30*G: −1147*C: +49*G: CT60*G: JO37_3*G (haplotype 2) in both a case/control cohort (P=0.002, OR=1.42) and by TDT (P=0.02, OR=1.43). In contrast, this haplotype showed no association in the RA and CD cohorts. However, we observed an increased frequency of the MH30*G: −1147*T: +49*A: CT60*G: JO37_3*A (haplotype 3) in the CD patients diagnosed at a young age (OR=1.6, P=0.026, P c=0.052). Furthermore, when T1D and CD patients were stratified based on the HLA risk, the T1D susceptible CTLA4 haplotype 2 was over-represented in the high HLA-risk T1D and CD groups. In conclusion, we confirmed association between CTLA4 haplotype 2 and T1D in the Dutch population. Association with another CTLA4 haplotype (haplotype 3) was confirmed for CD, but only in those patients who had an early age of expression. No effect was found between RA and CTLA4. The association of the CTLA4 haplotype 2 with the high-risk HLA genotype in T1D and CD, which share DQ2 as the one of high-risk alleles, might provide a clue to understanding the common genetic background of AID.

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Acknowledgements

We wish to thank all the patients and their families who participated in the study. We thank Alfons Bardoel for help with genotyping, Harry van Someren for his work on the patient database, Alienke Monsuur and Peter Eerligh for useful discussions and Jackie Senior for editing the manuscript. This study was supported by grants from the Dutch Diabetes Research Foundation (97.137), the Dutch Digestive Diseases Foundation (WS 03–06), the Netherlands Organisation for Health Research and Development (ZonMW 912-02-028), the Juvenile Diabetes Research Foundation International (JDRF) (2001.10.004) and the Coeliac Disease Consortium, an Innovative Cluster approved by the Netherlands Genomics Initiative and partly funded by the Dutch Government (BSIK03009).

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  1. Department of Medical Genetics, University Medical Centre, Wilhelmina Children’s Hospital, PO Box 85090, 3508, AB, Utrecht, The Netherlands

    Alexandra Zhernakova, Cisca Wijmenga & Bobby P. C. Koeleman

  2. Department of Immunohaematology and Blood Transfusion, Leiden University Medical Centre, Leiden, The Netherlands

    Peter Eerligh, Bart O. Roep & Bobby P. C. Koeleman

  3. Rheumatology Department, University Hospital St Radboud, Nijmegen, The Netherlands

    Pilar Barrera

  4. Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands

    Joanna Z. Weseloy & Tom W. J. Huizinga

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  1. Alexandra Zhernakova
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Correspondence to Bobby P. C. Koeleman.

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An erratum to this article can be found at http://dx.doi.org/10.1007/s00439-005-0087-8

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Zhernakova, A., Eerligh, P., Barrera, P. et al. CTLA4 is differentially associated with autoimmune diseases in the Dutch population. Hum Genet 118, 58–66 (2005). https://doi.org/10.1007/s00439-005-0006-z

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