title: Polymorphisms of the IgH enhancer HS1.2 and risk of systemic lupus erythematosus.
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.
authors.affiliation: Laboratory of Genetics, Department of Biology Enrico Calef, University of Roma Tor Vergata, Rome, Italy. frezza@uniroma2.it
authors.forename: Domenico
authors.initials: D
authors.lastname: Frezza
authors.forename: Barbara
authors.initials: B
authors.lastname: Tolusso
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Giambra
authors.forename: Elisa
authors.initials: E
authors.lastname: Gremese
authors.forename: Maurizio
authors.initials: M
authors.lastname: Marchini
authors.forename: Marcin
authors.initials: M
authors.lastname: Nowik
authors.forename: Eliseo
authors.initials: E
authors.lastname: Serone
authors.forename: Pietro
authors.initials: P
authors.lastname: D'Addabbo
authors.forename: Claudia
authors.initials: C
authors.lastname: Mattioli
authors.forename: Silvia
authors.initials: S
authors.lastname: Canestri
authors.forename: Luca
authors.initials: L
authors.lastname: Petricca
authors.forename: Graziella
authors.initials: G
authors.lastname: D'Antona
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Birshtein
authors.forename: Raffaella
authors.initials: R
authors.lastname: Scorza
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Ferraccioli
mesh_terms: D000328:Adult; D001483:Base Sequence; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007136:Immunoglobulins / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000235:genetics; D011110:Polymorphism, Genetic; D012307:Risk Factors
chemical_list: C530726:HS1,2-A enhancer protein, human; D007143:Immunoglobulin Heavy Chains; D007136:Immunoglobulins; D016328:NF-kappa B; C090698:SP1 antigen