title: Polymorphisms in the Hsp70 gene locus are genetically associated with systemic lupus erythematosus.
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.
authors.affiliation: Nikolaus-Fiebiger Centre of Molecular Medicine, University of Erlangen-Nuremberg, Germany.
authors.forename: Barbara G
authors.initials: BG
authors.lastname: Fürnrohr
authors.forename: Sven
authors.initials: S
authors.lastname: Wach
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kelly
authors.forename: Martin
authors.initials: M
authors.lastname: Haslbeck
authors.forename: Christian K
authors.initials: CK
authors.lastname: Weber
authors.forename: Christian M
authors.initials: CM
authors.lastname: Stach
authors.forename: Axel J
authors.initials: AJ
authors.lastname: Hueber
authors.forename: Daniela
authors.initials: D
authors.lastname: Graef
authors.forename: Bernd M
authors.initials: BM
authors.lastname: Spriewald
authors.forename: Karin
authors.initials: K
authors.lastname: Manger
authors.forename: Martin
authors.initials: M
authors.lastname: Herrmann
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Kaufman
authors.forename: Summer G
authors.initials: SG
authors.lastname: Frank
authors.forename: Ellen
authors.initials: E
authors.lastname: Goodmon
authors.forename: Judith A
authors.initials: JA
authors.lastname: James
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Winkler
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
authors.forename: Reinhard E
authors.initials: RE
authors.lastname: Voll
mesh_terms: D016022:Case-Control Studies; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D018840:HSP70 Heat-Shock Proteins; C490786:HSPA1A protein, human; D012333:RNA, Messenger