Article Text

Download PDFPDF
Extended report
Polymorphisms of the IgH enhancer HS1.2 and risk of systemic lupus erythematosus
  1. Domenico Frezza1,
  2. Barbara Tolusso2,
  3. Vincenzo Giambra3,
  4. Elisa Gremese2,
  5. Maurizio Marchini4,
  6. Marcin Nowik2,
  7. Eliseo Serone1,
  8. Pietro D'Addabbo5,
  9. Claudia Mattioli1,
  10. Silvia Canestri2,
  11. Luca Petricca2,
  12. Graziella D'Antona2,
  13. Barbara K Birshtein6,
  14. Raffaella Scorza4,
  15. Gianfranco Ferraccioli2
  1. 1Department of Biology “Enrico Calef”, University of Roma Tor Vergata, Roma, Italy
  2. 2Division of Rheumatology, Catholic University of the Sacred Heart, Rome, Italy
  3. 3Terry Fox Laboratory, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada
  4. 4Referral Center for Systemic Autoimmune Diseases, University of Milan, Milan, Italy
  5. 5Department of Biology University of Bari, Bari, Italy
  6. 6Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA
  1. Correspondence to Prof. Gianfranco Ferraccioli Institute of Rheumatology and Affine Sciences-Catholic University of the Sacred Heart-CIC-Viale Moscati 31-00168 Rome, Itatly; gf.ferraccioli{at} or Prof Domenico Frezza, Laboratory of Genetics, Department of Biology “Enrico Calef”, University of Roma “Tor Vergata”, Viale della Ricerca Scientifica, 00133 Rome, Italy; frezza{at}


Objective To determine whether the allelic frequency variation of the HS1.2 enhancer of the immunoglobulin heavy chain (IgH) 3′ regulatory region (3′RR-1) locus represents a risk factor for systemic lupus erythematosus (SLE) and to identify a possible functional difference in the two most frequent alleles (*1 and *2) in binding nuclear factor- κB (NF-κB) and Sp1.

Methods The frequency of the enhancer HS1.2 alleles was determined in two cohorts of patients with SLE (n=293) and in 1185 controls. Electrophoretic mobility shift assays (EMSA) were carried out with B cell nuclear extracts with different probes of HS1.2 alleles *1 and *2 to map the consensus binding sites of the nuclear factors. A confirmatory cohort of 121 patients with SLE was also included.

Results The frequency of allele *2 of the HS1.2 enhancer was significantly increased in patients with SLE compared with controls (OR 1.60, 95% CI 1.33 to 1.92, p<0.001). EMSA experiments showed the presence of the Sp1 binding site in both alleles whereas only allele *2 carried the consensus for the NF-κB factor. The presence versus absence of allele *2 in patients with SLE correlated with a higher concentration of IgM levels and with the expression of B cell activating factor receptor (BAFF-R).

Conclusions The increased frequency of allele *2 in patients with SLE identifies a new genetic risk factor for SLE. A possible biological effect of the polymorphism could be the difference observed in the localisation of an NF-κB binding site which is specific for allele *2 and absent in allele *1. These observations suggest a functional effect of the HS1.2 enhancer in this disease.

View Full Text

Statistics from


  • Funding This research was partially supported by grant MIUR PRIN, University of Tor Vergata annual fund to DF, by ASRALES Foundation to GF and by NIH R01AI13509 to BKB.

  • Competing interests None.

  • Ethics approval The study was approved by the Institutional Review Board of the Catholic University of the Sacred Heart and all subjects gave their informed consent.

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

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.