title: CYP21A2 polymorphisms in patients with autoimmune Addison's disease, and linkage disequilibrium to HLA risk alleles.
abstract: OBJECTIVE
  Steroid 21-hydroxylase, encoded by CYP21A2, is the major autoantigen in autoimmune Addison's disease (AAD). CYP21A2 is located in the region of the HLA complex on chromosome 6p21.3, which harbours several risk alleles for AAD. The objective was to investigate whether CYP21A2 gene variants confer risk of AAD independently of other risk alleles in the HLA loci.
  
  
  METHODS
  DNA samples from 381 Norwegian patients with AAD and 340 healthy controls (HC) previously genotyped for the HLA-A, -B, -DRB1, and -DQB1 and MICA loci were used for genotyping of CYP21A2.
  
  
  METHODS
  Genotyping of CYP21A2 was carried out by direct sequencing. Linkage of CYP21A2 to the HLA loci was assessed using UNPHASED version 3.0.10 and PHASE version 2.1.
  
  
  RESULTS
  Heterozygotes of the single-nucleotide polymorphisms (SNPs) rs397515394, rs6467, rs6474, rs76565726 and rs6473 were detected significantly more frequently in AAD patients compared with HC (P<0.005), but all SNPs were in a linkage disequilibrium (LD) with high-risk HLA-DRB1 haplotypes. rs6472C protected against AAD (odds ratio=0.15, 95% CI (0.08-0.30), P=3.8×10(-10)). This SNP was not in an LD with HLA loci (P=0.02), but did not increase protection when considering the effect of HLA-DRB1 alleles. Mutations causing congenital adrenal hyperplasia were found in heterozygosity in <1.5% of the cases in both groups.
  
  
  CONCLUSIONS
  Genetic variants of CYP21A2 associated to AAD are in LD with the main AAD risk locus HLA-DRB1, and CYP21A2 does not constitute an independent susceptibility locus.
authors.affiliation: Department of Clinical ScienceUniversity of Bergen, Laboratory building, 8th floor, Bergen 5021, NorwayDepartment of Medical GeneticsOslo University Hospital, Oslo 0407, NorwayDepartment of MedicineHaukeland University Hospital, Bergen 5021, NorwayInstitute of Medical GeneticsUniversity of Oslo, Oslo 0315, Norway Ingeborg.Bronstad@k2.uib.no.
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Brønstad
authors.affiliation: Department of Clinical ScienceUniversity of Bergen, Laboratory building, 8th floor, Bergen 5021, NorwayDepartment of Medical GeneticsOslo University Hospital, Oslo 0407, NorwayDepartment of MedicineHaukeland University Hospital, Bergen 5021, NorwayInstitute of Medical GeneticsUniversity of Oslo, Oslo 0315, Norway.
authors.forename: Beate
authors.initials: B
authors.lastname: Skinningsrud
authors.affiliation: Department of Clinical ScienceUniversity of Bergen, Laboratory building, 8th floor, Bergen 5021, NorwayDepartment of Medical GeneticsOslo University Hospital, Oslo 0407, NorwayDepartment of MedicineHaukeland University Hospital, Bergen 5021, NorwayInstitute of Medical GeneticsUniversity of Oslo, Oslo 0315, Norway.
authors.forename: Eirik
authors.initials: E
authors.lastname: Bratland
authors.affiliation: Department of Clinical ScienceUniversity of Bergen, Laboratory building, 8th floor, Bergen 5021, NorwayDepartment of Medical GeneticsOslo University Hospital, Oslo 0407, NorwayDepartment of MedicineHaukeland University Hospital, Bergen 5021, NorwayInstitute of Medical GeneticsUniversity of Oslo, Oslo 0315, Norway Department of Clinical ScienceUniversity of Bergen, Laboratory building, 8th floor, Bergen 5021, NorwayDepartment of Medical GeneticsOslo University Hospital, Oslo 0407, NorwayDepartment of MedicineHaukeland University Hospital, Bergen 5021, NorwayInstitute of Medical GeneticsUniversity of Oslo, Oslo 0315, Norway.
authors.forename: Kristian
authors.initials: K
authors.lastname: Løvås
authors.affiliation: Department of Clinical ScienceUniversity of Bergen, Laboratory building, 8th floor, Bergen 5021, NorwayDepartment of Medical GeneticsOslo University Hospital, Oslo 0407, NorwayDepartment of MedicineHaukeland University Hospital, Bergen 5021, NorwayInstitute of Medical GeneticsUniversity of Oslo, Oslo 0315, Norway Department of Clinical ScienceUniversity of Bergen, Laboratory building, 8th floor, Bergen 5021, NorwayDepartment of Medical GeneticsOslo University Hospital, Oslo 0407, NorwayDepartment of MedicineHaukeland University Hospital, Bergen 5021, NorwayInstitute of Medical GeneticsUniversity of Oslo, Oslo 0315, Norway.
authors.forename: Dag
authors.initials: D
authors.lastname: Undlien
authors.affiliation: Department of Clinical ScienceUniversity of Bergen, Laboratory building, 8th floor, Bergen 5021, NorwayDepartment of Medical GeneticsOslo University Hospital, Oslo 0407, NorwayDepartment of MedicineHaukeland University Hospital, Bergen 5021, NorwayInstitute of Medical GeneticsUniversity of Oslo, Oslo 0315, Norway Department of Clinical ScienceUniversity of Bergen, Laboratory building, 8th floor, Bergen 5021, NorwayDepartment of Medical GeneticsOslo University Hospital, Oslo 0407, NorwayDepartment of MedicineHaukeland University Hospital, Bergen 5021, NorwayInstitute of Medical GeneticsUniversity of Oslo, Oslo 0315, Norway.
authors.forename: Eystein
authors.initials: E
authors.lastname: Sverre Husebye
authors.affiliation: Department of Clinical ScienceUniversity of Bergen, Laboratory building, 8th floor, Bergen 5021, NorwayDepartment of Medical GeneticsOslo University Hospital, Oslo 0407, NorwayDepartment of MedicineHaukeland University Hospital, Bergen 5021, NorwayInstitute of Medical GeneticsUniversity of Oslo, Oslo 0315, Norway.
authors.forename: Anette Susanne Bøe
authors.initials: AS
authors.lastname: Wolff
mesh_terms: D000224:Addison Disease / Q000235:genetics*; D000483:Alleles; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D013255:Steroid 21-Hydroxylase / Q000235:genetics*
chemical_list: D059811:HLA-DRB1 Chains; C531510:CYP21A2 protein, human; D013255:Steroid 21-Hydroxylase