A polygenic risk score to help discriminate primary adrenal insufficiency of different etiologies.

Autor: Aranda-Guillén M; Center, for Molecular Medicine, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden., Røyrvik EC; Department of Clinical Science, University of Bergen, Bergen, Norway.; K.G. Jebsen Center for Autoimmune Disorders, Bergen, Norway.; Department of Genetics and Bioinformatics, Norwegian Institute of Public Health, Oslo, Norway., Fletcher-Sandersjöö S; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden., Artaza H; Department of Clinical Science, University of Bergen, Bergen, Norway.; K.G. Jebsen Center for Autoimmune Disorders, Bergen, Norway., Botusan IR; Center, for Molecular Medicine, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden.; Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden., Grytaas MA; Department of Medicine, Haukeland University Hospital, Bergen, Norway., Hallgren Å; Center, for Molecular Medicine, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden., Breivik L; Department of Clinical Science, University of Bergen, Bergen, Norway., Pettersson M; Center for Molecular Medicine, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.; Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden., Jørgensen AP; Section for specialized Endocrinology, Oslo University Hospital, Oslo, Norway., Lindstrand A; Center for Molecular Medicine, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.; Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden., Vogt E; Department of Clinical Science, University of Bergen, Bergen, Norway.; Department of Medicine, Haukeland University Hospital, Bergen, Norway., Husebye ES; Center, for Molecular Medicine, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden.; Department of Clinical Science, University of Bergen, Bergen, Norway.; K.G. Jebsen Center for Autoimmune Disorders, Bergen, Norway.; Department of Medicine, Haukeland University Hospital, Bergen, Norway., Kämpe O; Center, for Molecular Medicine, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden.; K.G. Jebsen Center for Autoimmune Disorders, Bergen, Norway.; Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden., Wolff ASB; Department of Clinical Science, University of Bergen, Bergen, Norway.; K.G. Jebsen Center for Autoimmune Disorders, Bergen, Norway.; Department of Medicine, Haukeland University Hospital, Bergen, Norway., Bensing S; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.; Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden., Johansson S; Department of Clinical Science, University of Bergen, Bergen, Norway.; Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway., Eriksson D; Center, for Molecular Medicine, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden.; Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
Jazyk: angličtina
Zdroj: Journal of internal medicine [J Intern Med] 2023 Jul; Vol. 294 (1), pp. 96-109. Date of Electronic Publication: 2023 May 21.
DOI: 10.1111/joim.13649
Abstrakt: Background: Autoimmune Addison's disease (AAD) is the most common cause of primary adrenal insufficiency (PAI). Despite its exceptionally high heritability, tools to estimate disease susceptibility in individual patients are lacking. We hypothesized that polygenic risk score (PRS) for AAD could help investigate PAI pathogenesis in pediatric patients.
Methods: We here constructed and evaluated a PRS for AAD in 1223 seropositive cases and 4097 controls. To test its clinical utility, we reevaluated 18 pediatric patients, whose whole genome we also sequenced. We next explored the individual PRS in more than 120 seronegative patients with idiopathic PAI.
Results: The genetic susceptibility to AAD-quantified using PRS-was on average 1.5 standard deviations (SD) higher in patients compared with healthy controls (p < 2e - 16), and 1.2 SD higher in the young patients compared with the old (p = 3e - 4). Using the novel PRS, we searched for pediatric patients with strikingly low AAD susceptibility and identified cases of monogenic PAI, previously misdiagnosed as AAD. By stratifying seronegative adult patients by autoimmune comorbidities and disease duration we could delineate subgroups of PRS suggesting various disease etiologies.
Conclusions: The PRS performed well for case-control differentiation and susceptibility estimation in individual patients. Remarkably, a PRS for AAD holds promise as a means to detect disease etiologies other than autoimmunity.
(© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)
Databáze: MEDLINE
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