Polymorphisms of the IgH enhancer HS1.2 and risk of systemic lupus erythematosus

Domenico Frezza, Barbara Tolusso, Vincenzo Giambra, Elisa Gremese, Maurizio Marchini, Marcin Nowik, Eliseo Serone, Pietro D'Addabbo, Claudia Mattioli, Silvia Canestri, Luca Petricca, Graziella D'Antona, Barbara K. Birshtein, Raffaella Scorza, Gianfranco Ferraccioli

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1309-1315
Number of pages7
JournalAnnals of the Rheumatic Diseases
Volume71
Issue number8
DOIs
StatePublished - Aug 2012

Fingerprint

Immunoglobulin Heavy Chains
Polymorphism
Systemic Lupus Erythematosus
Electrophoretic mobility
Alleles
Binding Sites
Assays
Interleukin-4 Receptors
Nucleic Acid Regulatory Sequences
Immunoglobulin M
Electrophoretic Mobility Shift Assay
Cells
Gene Frequency
Cell Extracts
Experiments
B-Lymphocytes

ASJC Scopus subject areas

  • Rheumatology
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Allergy

Cite this

Frezza, D., Tolusso, B., Giambra, V., Gremese, E., Marchini, M., Nowik, M., ... Ferraccioli, G. (2012). Polymorphisms of the IgH enhancer HS1.2 and risk of systemic lupus erythematosus. Annals of the Rheumatic Diseases, 71(8), 1309-1315. https://doi.org/10.1136/ard.2010.147025

Polymorphisms of the IgH enhancer HS1.2 and risk of systemic lupus erythematosus. / Frezza, Domenico; Tolusso, Barbara; Giambra, Vincenzo; Gremese, Elisa; Marchini, Maurizio; Nowik, Marcin; Serone, Eliseo; D'Addabbo, Pietro; Mattioli, Claudia; Canestri, Silvia; Petricca, Luca; D'Antona, Graziella; Birshtein, Barbara K.; Scorza, Raffaella; Ferraccioli, Gianfranco.

In: Annals of the Rheumatic Diseases, Vol. 71, No. 8, 08.2012, p. 1309-1315.

Research output: Contribution to journalArticle

Frezza, D, Tolusso, B, Giambra, V, Gremese, E, Marchini, M, Nowik, M, Serone, E, D'Addabbo, P, Mattioli, C, Canestri, S, Petricca, L, D'Antona, G, Birshtein, BK, Scorza, R & Ferraccioli, G 2012, 'Polymorphisms of the IgH enhancer HS1.2 and risk of systemic lupus erythematosus', Annals of the Rheumatic Diseases, vol. 71, no. 8, pp. 1309-1315. https://doi.org/10.1136/ard.2010.147025
Frezza, Domenico ; Tolusso, Barbara ; Giambra, Vincenzo ; Gremese, Elisa ; Marchini, Maurizio ; Nowik, Marcin ; Serone, Eliseo ; D'Addabbo, Pietro ; Mattioli, Claudia ; Canestri, Silvia ; Petricca, Luca ; D'Antona, Graziella ; Birshtein, Barbara K. ; Scorza, Raffaella ; Ferraccioli, Gianfranco. / Polymorphisms of the IgH enhancer HS1.2 and risk of systemic lupus erythematosus. In: Annals of the Rheumatic Diseases. 2012 ; Vol. 71, No. 8. pp. 1309-1315.
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abstract = "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.",
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AU - Frezza, Domenico

AU - Tolusso, Barbara

AU - Giambra, Vincenzo

AU - Gremese, Elisa

AU - Marchini, Maurizio

AU - Nowik, Marcin

AU - Serone, Eliseo

AU - D'Addabbo, Pietro

AU - Mattioli, Claudia

AU - Canestri, Silvia

AU - Petricca, Luca

AU - D'Antona, Graziella

AU - Birshtein, Barbara K.

AU - Scorza, Raffaella

AU - Ferraccioli, Gianfranco

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N2 - 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.

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