自身免疫性艾迪生病患者的CYP21A2基因多态性及其与HLA风险等位基因的连锁不平衡

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

作者信息

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

机构信息

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

出版信息

Eur J Endocrinol. 2014 Dec;171(6):743-50. doi: 10.1530/EJE-14-0432. Epub 2014 Sep 23.

DOI:10.1530/EJE-14-0432

PMID:25249698

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.

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.

摘要

目的

由CYP21A2编码的类固醇21-羟化酶是自身免疫性艾迪生病（AAD）的主要自身抗原。CYP21A2位于6号染色体p21.3上的HLA复合体区域，该区域含有多个AAD风险等位基因。目的是研究CYP21A2基因变异是否独立于HLA基因座中的其他风险等位基因赋予AAD风险。

设计

对381名挪威AAD患者和340名健康对照（HC）的DNA样本进行CYP21A2基因分型，这些样本先前已对HLA-A、-B、-DRB1、-DQB1和MICA基因座进行基因分型。

方法

通过直接测序对CYP21A2进行基因分型。使用UNPHASED 3.0.10版本和PHASE 2.1版本评估CYP21A2与HLA基因座的连锁情况。

结果

与HC相比，AAD患者中，单核苷酸多态性（SNP）rs397515394、rs6467、rs6474、rs76565726和rs6473的杂合子检出频率显著更高（P<0.005），但所有SNP均与高危HLA-DRB1单倍型处于连锁不平衡（LD）状态。rs6472C可预防AAD（优势比=0.15，95%可信区间（0.08-0.30），P=3.8×10⁻¹⁰）。该SNP与HLA基因座不处于LD状态（P=0.02），但在考虑HLA-DRB1等位基因的影响时，并未增加保护作用。在两组中，<1.5%的病例中发现杂合状态的导致先天性肾上腺增生的突变。