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Ingeborg Brønstad, Beate Skinningsrud, Eirik Bratland, Kristian Løvås, Dag Undlien, Eystein Sverre Husebye, and Anette Susanne Bøe Wolff

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.

Design

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.

Conclusion

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.

Open access

Anette Boe Wolff, Lars Breivik, Karl Ove Hufthammer, Marianne Aardal Grytaas, Eirik Bratland, Eystein Sverre Husebye, and Bergithe Eikeland Oftedal

Background

The most common cause of primary adrenal failure (Addison’s disease) in the Western world is autoimmunity characterized by autoantibodies against the steroidogenic enzyme 21-hydroxylase (CYP21A2, 21OH). Detection of 21OH-autoantibodies is currently used for aetiological diagnosis, but how levels of 21OH-autoantibodies vary over time is not known.

Setting

Samples from the national Norwegian Addison’s Registry and Biobank established in 1996 (n = 711). Multi-parameter modelling of the course of 21OH-autoantibody indices over time.

Results

21OH-autoantibody positivity is remarkably stable, and >90% of the patients are still positive 30 years after diagnosis. Even though the antibody levels decline with disease duration, it is only rarely that this downturn reaches negativity. 21OH-autoantibody indices are affected by age at diagnosis, sex, type of Addison’s disease (isolated vs autoimmune polyendocrine syndrome type I or II) and HLA genotype.

Conclusion

21OH-autoantibodies are reliable and robust markers for autoimmune Addison’s disease, linked to HLA risk genotype. However, a negative test in patients with long disease duration does not exclude autoimmune aetiology.