Relation between HLA and copy number variation of steroid 21-hydroxylase in a Swedish cohort of patients with autoimmune Addison's disease.
Addison's disease
autoantibodies
autoimmune disease
genetics
Journal
European journal of endocrinology
ISSN: 1479-683X
Titre abrégé: Eur J Endocrinol
Pays: England
ID NLM: 9423848
Informations de publication
Date de publication:
02 Aug 2023
02 Aug 2023
Historique:
received:
03
11
2022
revised:
27
03
2023
accepted:
26
06
2023
medline:
22
8
2023
pubmed:
9
8
2023
entrez:
8
8
2023
Statut:
ppublish
Résumé
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. Case-control study on patients with AAD and healthy controls. 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. 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. 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.
Identifiants
pubmed: 37553728
pii: 7239340
doi: 10.1093/ejendo/lvad102
doi:
Substances chimiques
Steroid 21-Hydroxylase
EC 1.14.14.16
Autoantibodies
0
CYP21A2 protein, human
EC 1.14.14.16
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
235-241Subventions
Organisme : Swedish Research Council for Medicine and Health
Organisme : Knut and Wallenberg Foundation
Organisme : Novo Nordisk Foundation
Organisme : Stockholm County Council
Organisme : Karolinska Institutet
Investigateurs
Lars Rönnblom
(L)
Kerstin Lindblad-Toh
(K)
Marie Wahren-Herlenius
(M)
Gunnel Nordmark
(G)
Ingrid E Lundberg
(IE)
Ann-Christine Syvänen
(AC)
Johanna K Sandling
(JK)
Sergey V Kozyrev
(SV)
Maija-Leena Eloranta
(ML)
Matteo Bianchi
(M)
Solbritt Rantapää-Dahlqvist
(S)
Jennifer R S Meadows
(JRS)
Jessika Nordin
(J)
Johanna Dahlqvist
(J)
Argyri Mathioudaki
(A)
Fabiana H G Farias
(FHG)
Karolina Tandre
(K)
Kerstin Lindblad-Toh
(K)
Gerli Rosengren Pielberg
(GR)
Anna Lobell
(A)
Åsa Karlsson
(Å)
Eva Murén
(E)
Göran Andersson
(G)
Kerstin M Ahlgren
(KM)
Lars Rönnblom
(L)
Nils Landegren
(N)
Olle Kämpe
(O)
Peter Söderkvist
(P)
Anna-Karin Åkerman
(AK)
Anna-Lena Hulting
(AL)
Bengt Lindberg
(B)
Elena Lundberg
(E)
Gudmundur Johannsson
(G)
Jakob Skov
(J)
Jeanette Wahlberg
(J)
Karel Duchen
(K)
Magnus Isaksson
(M)
Maria Elfving
(M)
Maria Halldin Stenlid
(MH)
Mona Landin-Olsson
(M)
Ola Nilsson
(O)
Olle Kämpe
(O)
Olov Ekwall
(O)
Per Dahlqvist
(P)
Ragnhildur Bergthorsdottir
(R)
Ricard Nergårdh
(R)
Sigridur Björnsdottir
(S)
Sophie Bensing
(S)
Tommy Olsson
(T)
Informations de copyright
© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology.
Déclaration de conflit d'intérêts
Conflict of interest: L.R. has received honorarium for lectures from AstraZeneca and participated in advisory board for UCB. O.K. is a board member of Navinci Diagnostics AB and member of the Scientific Advisory Board for the Leo Foundation Skin Immunology Research Center, University of Copenhagen.