Relation between HLA and copy number variation of steroid 21-hydroxylase in a Swedish cohort of patients with autoimmune Addison's disease
Author:
Lundtoft Christian1ORCID, Eriksson Daniel234, Bianchi Matteo5, Aranda-Guillén Maribel2, Landegren Nils26, Rantapää-Dahlqvist Solbritt7ORCID, Söderkvist Peter8, Meadows Jennifer R S5, Rönnblom Lars, Lindblad-Toh Kerstin, Wahren-Herlenius Marie, Nordmark Gunnel, Lundberg Ingrid E, Syvänen Ann-Christine, Sandling Johanna K, Kozyrev Sergey V, Eloranta Maija-Leena, Bianchi Matteo, Rantapää-Dahlqvist Solbritt, Meadows Jennifer R S, Nordin Jessika, Dahlqvist Johanna, Mathioudaki Argyri, Farias Fabiana H G, Tandre Karolina, Lindblad-Toh Kerstin, Pielberg Gerli Rosengren, Lobell Anna, Karlsson Åsa, Murén Eva, Andersson Göran, Ahlgren Kerstin M, Rönnblom Lars, Landegren Nils, Kämpe Olle, Söderkvist Peter, Åkerman Anna-Karin, Hulting Anna-Lena, Lindberg Bengt, Lundberg Elena, Johannsson Gudmundur, Skov Jakob, Wahlberg Jeanette, Duchen Karel, Isaksson Magnus, Elfving Maria, Stenlid Maria Halldin, Landin-Olsson Mona, Nilsson Ola, Kämpe Olle, Ekwall Olov, Dahlqvist Per, Bergthorsdottir Ragnhildur, Nergårdh Ricard, Björnsdottir Sigridur, Bensing Sophie, Olsson Tommy, Bensing Sophie910ORCID, Pielberg Gerli Rosengren5, Lindblad-Toh Kerstin511, Rönnblom Lars1, Kämpe Olle291213ORCID, , ,
Affiliation:
1. Department of Medical Sciences, Uppsala University , Uppsala , Sweden 2. Department of Medicine (Solna), Center for Molecular Medicine, Karolinska Instituttet , Stockholm , Sweden 3. Department of Clinical Genetics, Uppsala University Hospital , Uppsala , Sweden 4. Department of Immunology, Genetics and Pathology, Uppsala University , Uppsala , Sweden 5. Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University , Uppsala , Sweden 6. Department of Medical Biochemistry and Microbiology, Uppsala University , Uppsala , Sweden 7. Department of Public Health and Clinical Medicine/Rheumatology, Umeå University , Umeå , Sweden 8. Department of Biomedical and Clinical Sciences, Linköping University , Linköping , Sweden 9. Department of Endocrinology, Karolinska University Hospital , Stockholm , Sweden 10. Department of Molecular Medicine and Surgery, Karolinska Institutet , Stockholm , Sweden 11. Broad Institute, MIT and Harvard , Cambridge, MA , United States 12. Department of Clinical Science, University of Bergen , Bergen , Norway 13. K.G. Jebsen Center for Autoimmune Diseases, University of Bergen , Bergen , Norway
Abstract
Abstract
Objective
Autoantibodies against the adrenal enzyme 21-hydroxylase is a hallmark manifestation in autoimmune Addison's disease (AAD). Steroid 21-hydroxylase is encoded by CYP21A2, which is located in the human leucocyte antigen (HLA) region together with the highly similar pseudogene CYP21A1P. A high level of copy number variation is seen for the 2 genes, and therefore, we asked whether genetic variation of the CYP21 genes is associated with AAD.
Design
Case-control study on patients with AAD and healthy controls.
Methods
Using next-generation DNA sequencing, we estimated the copy number of CYP21A2 and CYP21A1P, together with HLA alleles, in 479 Swedish patients with AAD and autoantibodies against 21-hydroxylase and in 1393 healthy controls.
Results
With 95% of individuals carrying 2 functional 21-hydroxylase genes, no difference in CYP21A2 copy number was found when comparing patients and controls. In contrast, we discovered a lower copy number of the pseudogene CYP21A1P among AAD patients (P = 5 × 10−44), together with associations of additional nucleotide variants, in the CYP21 region. However, the strongest association was found for HLA-DQB1*02:01 (P = 9 × 10−63), which, in combination with the DRB1*04:04-DQB1*03:02 haplotype, imposed the greatest risk of AAD.
Conclusions
We identified strong associations between copy number variants in the CYP21 region and risk of AAD, although these associations most likely are due to linkage disequilibrium with disease-associated HLA class II alleles.
Funder
Swedish Research Council for Medicine and Health Knut and Wallenberg Foundation Novo Nordisk Foundation Stockholm County Council Karolinska Institutet
Publisher
Oxford University Press (OUP)
Subject
Endocrinology,General Medicine,Endocrinology, Diabetes and Metabolism
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