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Genetic variants of RANTES are associated with serum RANTES level and protection for type 1 diabetes

Genes & Immunity volume 7, pages 544–549 (2006)Cite this article

Abstract

RANTES (regulated on activation, normal T-cell expressed and secreted) is a T-helper type 1 (Th1) chemokine that promotes T-cell activation and proliferation. RANTES is genetically associated with asthma, sarcoidosis and multiple sclerosis. The concentration of RANTES is increased at inflammation sites in different autoimmune diseases. Type 1 diabetes (T1D) is a Th1-mediated disease with complex genetic predisposition. We tested RANTES as a candidate gene for association with T1D using three single-nucleotide polymorphism (SNP) variants (rs4251719, rs2306630 and rs2107538) to capture haplotype information. The minor alleles of all SNPs were transmitted less frequently to T1D offspring (transmission rates 37.3% (P=0.002), 38.7% (P=0.007) and 41.0% (P=0.01)) and were less frequently present in patients compared to controls (P=0.009, 0.03 and 0.04, respectively). A similar protective effect was observed for the haplotype carrying three minor alleles (transmission disequilibrium test (TDT): P=0.003; odds ratio (OR)=0.55; confidence interval (CI): 0.37–0.83; case/control: P=0.03; OR=0.74; CI: 0.55–0.98). Both patients and controls carrying the protective haplotype express significantly lower serum levels of RANTES compared to non-carriers. Subsequently, we tested a cohort of 310 celiac disease patients, but failed to detect association. RANTES SNPs are significantly associated with RANTES serum concentration and development of T1D. The rs4251719*A–rs2306630*A–rs2107538*A haplotype associated with low RANTES production confers protection from T1D. Our data imply that RANTES is associated with T1D both genetically and functionally, and contributes to diabetes-prone Th1 cytokine profile.

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Acknowledgements

We are grateful to all the patients and their families and physicians for participating in the study. We thank Jackie Senior for improving the manuscript. The study was supported by grants from the Dutch Diabetes Research Foundation (97.137), The Dutch Digestive Disease Foundation (WS 03-06), The Netherlands Organization for Health Research and Development (ZonMW 912-02-028), The Juvenile Diabetes Research Foundation International (JDRF) (2001.10.004) and the Celiac Disease Consortium, an Innovative Cluster approved by the Netherlands Genomics Initiative and partially funded by the Dutch Government (BSIK03009).

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Authors and Affiliations

  1. Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands

    A Zhernakova, B Z Alizadeh, B Diosdado, C Wijmenga & B P C Koeleman

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

    P Eerligh, P Hanifi-Moghaddam, B O Roep & B P C Koeleman

  3. Diabetes Research Institute, Heinrich-Heine University, Dusseldorf, Germany

    P Hanifi-Moghaddam & N C Schloot

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Correspondence to B P C Koeleman.

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Zhernakova, A., Alizadeh, B., Eerligh, P. et al. Genetic variants of RANTES are associated with serum RANTES level and protection for type 1 diabetes. Genes Immun 7, 544–549 (2006). https://doi.org/10.1038/sj.gene.6364326

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