ESPEYB20 6. Adrenals Important for Clinical Practice (3 abstracts)
6.4. A polygenic risk score to help discriminate primary adrenal insufficiency of different etiologies
Aranda-Guillén M , Røyrvik EC , Fletcher-Sandersjöö S , Artaza H , Botusan IR , Grytaas MA , Hallgren Æ , Breivik L , Pettersson M , Jørgensen AP , Lindstrand A , Vogt E , Norwegian Addison Registry Study Group , The Swedish Addison Registry Study Group , Husebye ES , Kämpe O , Wolff ASB , Bensing S , Johansson S & Eriksson D
J Intern Med. 2023; 294(1): 96–109.PMID: 37151110. https://pubmed.ncbi.nlm.nih.gov/37151110/
Brief summary: The authors designed a polygenic risk score (PRS) to aid in estimating disease susceptibility in patients with autoimmune Addison’s disease (AAD).
Autoimmune Addison’s disease (AAD) is the most common cause of primary adrenal insufficiency (PAI) in adults. Despite its exceptionally high heritability, tools to estimate disease susceptibility in individual patients are lacking (1–3). The aim of this study was to investigate whether the polygenic risk score (PRS) for AAD could help investigate the pathogenesis of PAI in pediatric patients.
Herein, the authors designed a PRS to aid in estimating disease susceptibility in individual patients with AAD. The PRS was evaluated in 1223 seropositive cases with AAD and 4097 controls. In addition, the score was reevaluated in 18 children with presumed AAD along with whole genome sequencing, and in 120 seronegative patients with idiopathic PAI. The final PRS14AAD consisted of 5 SNPs and 9 HLA alleles.
The odds ratio for AAD per 1 S.D. of PRS was 6.4 and the average PRS in cases was about 1.5 S.D. above the average PRS in controls, meaning that 96% of cases were above the 50th centile of the controls. In addition, 79% of cases and 80% of controls were correctly classified.
In a subset of the cohort cases with childhood onset of AAD (n=18), the genetic susceptibility at the individual level was calculated using PRS14AAD along with whole genome sequencing of the cases and their family members. Most patients with early onset AAD had PRS at or above the median for cases with confirmed AAD. In the two cases with a low PRS, WGS identified pathogenic variants explaining the cause of PAI (CYP11A1 and NROB1). For every S.D. increase of PRS, the average age of disease onset decreased 3 years and the collective burden of known risk alleles explained up to 20 years of difference of average age of onset.
The PRS in seronegative (21OH-Ab) patients with AAD was lower than in seropositive cases. Cases without comorbidity centered between seropositive cases and controls, while those that had type 1 diabetes had a PRS at the level of the seropositive AAD cases. In addition, the authors show that patients that were seronegative already within 5 years after diagnosis had a lower genetic predisposition to AAD compared to those that screened negative for 21OH autoantibodies after 20 years of diagnosis. Seronegative cases are thus not merely a subset of individuals that over time lost their autoantibodies, but whether they have a different disease etiology still remains to be investigated.
In conclusion, estimation of the PRS14AAD at the individual level has a good negative predictive value for AAD. For patients with a negative or borderline titer of 21OH-Ab, a low PRS should lead the clinician to investigate the etiology further, such as whether the PAI has a monogenic cause. The PRS at the individual level remains constant during the life-span.
References: 1. Skov J, Höijer J, Magnusson PKE, Ludvigsson JF, Kämpe O, Bensing S. Heritability of Addison’s disease and prevalence of associated autoimmunity in a cohort of 112,100 Swedish twins. Endocrine. 2017; 58(3): 521–527. 2. Eriksson D, Røyrvik EC, Aranda-Guillen M, Berger AH, Landegren N, Artaza H, et al. GWAS for autoimmune Addison’s disease identifies multiple risk loci and highlights AIRE in disease susceptibility. Nature Commun. 2021; 12:959. 3. Røyrvik EC, Husebye ES. The genetics of autoimmune Addison disease: past, present and future. Nat Rev Endocrinol. 2022; 18: 399–412.
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ESPE Yearbook of Paediatric Endocrinology
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