CYP21A2 polymorphisms in patients with autoimmune Addison's disease, and linkage disequilibrium to HLA risk alleles

ObjectiveSteroid 21-hydroxylase, encoded byCYP21A2, is the major autoantigen in autoimmune Addison's disease (AAD).CYP21A2is located in the region of the HLA complex on chromosome 6p21.3, which harbours several risk alleles for AAD. The objective was to investigate whetherCYP21A2gene variants confer risk of AAD independently of other risk alleles in theHLAloci.DesignDNA samples from 381 Norwegian patients with AAD and 340 healthy controls (HC) previously genotyped for theHLA-A, -B, -DRB1, and -DQB1andMICAloci were used for genotyping ofCYP21A2.MethodsGenotyping ofCYP21A2was carried out by direct sequencing. Linkage ofCYP21A2to theHLAloci was assessed using UNPHASED version 3.0.10 and PHASE version 2.1.ResultsHeterozygotes 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-riskHLA–DRB1haplotypes. 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 withHLAloci (P=0.02), but did not increase protection when considering the effect ofHLA–DRB1alleles. Mutations causing congenital adrenal hyperplasia were found in heterozygosity in <1.5% of the cases in both groups.ConclusionGenetic variants ofCYP21A2associated to AAD are in LD with the main AAD risk locus HLA-DRB1, andCYP21A2does not constitute an independent susceptibility locus.