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Clinical and epidemiological research
Extended report
Polymorphisms in the Hsp70 gene locus are genetically associated with systemic lupus erythematosus
  1. Barbara G Fürnrohr1,2,
  2. Sven Wach3,
  3. Jennifer A Kelly4,
  4. Martin Haslbeck5,
  5. Christian K Weber1,
  6. Christian M Stach2,
  7. Axel J Hueber6,
  8. Daniela Graef1,2,
  9. Bernd M Spriewald7,
  10. Karin Manger8,
  11. Martin Herrmann2,
  12. Kenneth M Kaufman4,
  13. Summer G Frank4,
  14. Ellen Goodmon4,
  15. Judith A James4,
  16. Georg Schett2,
  17. Thomas H Winkler3,
  18. John B Harley4,
  19. Reinhard E Voll1,2
  1. 1IZKF Research Group 2, Nikolaus-Fiebiger Centre of Molecular Medicine, University of Erlangen–Nuremberg, Erlangen, Germany
  2. 2Department of Internal Medicine 3, University of Erlangen–Nuremberg, Erlangen, Germany
  3. 3Department of Genetics, Nikolaus-Fiebiger Centre of Molecular Medicine, University of Erlangen–Nuremberg, Erlangen, Germany
  4. 4Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
  5. 5Department of Chemistry, Technical University of Munich, Munich, Germany
  6. 6Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow, UK
  7. 7Department of Internal Medicine 5, University of Erlangen–Nuremberg, Erlangen, Germany
  8. 8Rheumatology Practice, Bamberg, Germany
  1. Correspondence to Reinhard E Voll, IZKF Research Group 2, Nikolaus-Fiebiger Centre of Molecular Medicine and Department of Internal Medicine 3, University of Erlangen–Nuremberg, Glückstr 6, 91054 Erlangen, Germany; rvoll{at}molmed.uni-erlangen.de

Abstract

Background Heat shock proteins (Hsps) play a role in the delivery and presentation of antigenic peptides and are thought to be involved in the pathogenesis of multifactorial diseases.

Objective To investigate genes encoding cytosolic Hsp70 proteins for associations of allelic variants with systemic lupus erythematosus (SLE).

Methods Case–control studies of two independent Caucasian SLE cohorts were performed. In a haplotype-tagging single-nucleotide polymorphism approach, common variants of HspA1L, HspA1A and HspA1B were genotyped and principal component analyses were performed for the cohort from the Oklahoma Medical Research Foundation (OMRF). Relative quantification of mRNA was carried out for each Hsp70 gene in healthy controls. Conditional regression analysis was performed to determine if allelic variants in Hsp70 act independently of HLA-DR3.

Results On analysis of common genetic variants of HspA1L, HspA1A and HspA1B, a haplotype significantly associated with SLE in the Erlangen-SLE cohort was identified, which was confirmed in the OMRF cohort. Depending on the cohorts, OR ranging from 1.43 to 1.88 and 2.64 to 3.16 was observed for individuals heterozygous and homozygous for the associated haplotype, respectively. Patients carrying the risk haplotype or the risk allele more often displayed autoantibodies to Ro and La in both cohorts. In healthy controls bearing this haplotype, the amount of HspA1A mRNA was significantly increased, whereas total Hsp70 protein concentration was not altered.

Conclusions Allelic variants of the Hsp70 genes are significantly associated with SLE in Caucasians, independently of HLA-DR3, and correlate with the presence of autoantibodies to Ro and La. Hence, the Hsp70 gene locus appears to be involved in SLE pathogenesis.

This paper is freely available online under the BMJ Journals unlocked scheme, see http://ard.bmj.com/info/unlocked.dtl

https://doi.org/10.1136/ard.2009.122630

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    Footnotes

    • Funding This study was supported by the Interdisciplinary Center of Clinical Research (IZKF) of the University Hospital Erlangen, project N2. This work has been supported by the National Institutes of Health (grants AI24717, AR62277, AR42460, AR49084, RR20143, AR053483, N01-AI-50026, P20RR015577), the Mary Kirkland Scholarship, the Alliance for Lupus Research and the US Department of Veterans Affairs.

    • Competing interests None.

    • Patient consent Obtained.

    • Ethics approval This study was conducted with the approval of the ethics committee of the Medical Faculty of the University of Erlangen-Nuremberg.

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