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Female-specific association of C-C chemokine receptor 5 gene polymorphisms with Löfgren’s syndrome

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Abstract

C-C chemokine receptors have been suggested to play an important role in sarcoidosis pathogenesis. Previous investigation of the C-C chemokine receptor 5 (CCR5) gene revealed the association of the HHC haplotype with “persistent lung involvement” in two European sarcoidosis populations. Based on this finding, we investigated a possible association of the HHC haplotype and its marker alleles in an extended German sarcoidosis sample that comprised 995 German sarcoidosis families including individuals with the chronic and acute form of the disease, further refined to patients with and without Löfgren’s syndrome. We genotyped this sample and 538 healthy control subjects for 8 single nucleotide polymorphisms (SNPs) that define the HHC haplotype in the CCR5 genomic region. Analysis of 3 sarcoidosis phenotypes (chronic, acute and Löfgren’s syndrome) revealed that the HHC haplotype was not associated with chronic sarcoidosis although a substantial overlap can be assumed between the chronic form examined in our study and “persistent parenchymal lung involvement”, the phenotype for which an association was previously established. However, 2 marker alleles in the putative CCR5 promoter, which are part of the HHC haplotype, are associated with Löfgren’s syndrome. Strikingly, the association is restricted to females. This finding is consistent with recently described sex-specific manifestations of Löfgren’s syndrome and with previous functional studies suggesting an estrogen-dependent CCR5 expression. The female-specific association of SNPs in the putative CCR5 promoter region with Löfgren’s syndrome raises the possibility that the dysregulated, sex-specific modification of CCR5 expression could contribute to the increased risk of women to develop the disease.

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Acknowledgments

The authors wish to thank all patients, families, physicians and technical staff for their cooperation and support. The efforts of the German Sarcoidosis Patients Organisation (Deutsche Sarkoidose-Vereinigung e. V.) are gratefully acknowledged. This study was funded by the German National Genome Research Network (NGFN-2). AF was supported by the Mucosaimmunologie gemeinnützige Forschungsgesellschaft mbH (MFG).

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Authors and Affiliations

  1. Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schittenhelmstrasse 12, 24105, Kiel, Germany

    Annegret Fischer, Ruta Valentonyte, Almut Nebel & Stefan Schreiber

  2. Institute of Medical Informatics and Statistics, Christian-Albrechts-University of Kiel, Kiel, Germany

    Michael Nothnagel

  3. Department of Pneumology, University of Freiburg, Freiburg, Germany

    Joachim Müller-Quernheim

  4. Institute of Human Genetics, University of Lübeck, Lübeck, Germany

    Manfred Schürmann

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  1. Annegret Fischer
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  2. Ruta Valentonyte
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  3. Almut Nebel
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  4. Michael Nothnagel
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  5. Joachim Müller-Quernheim
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  6. Manfred Schürmann
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  7. Stefan Schreiber
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Correspondence to Stefan Schreiber.

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Fischer, A., Valentonyte, R., Nebel, A. et al. Female-specific association of C-C chemokine receptor 5 gene polymorphisms with Löfgren’s syndrome. J Mol Med 86, 553–561 (2008). https://doi.org/10.1007/s00109-008-0315-5

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  • DOI: https://doi.org/10.1007/s00109-008-0315-5

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