A high polygenic risk score is associated with SSA/SSB antibody positivity and early onset in primary Sjögren’s disease
Year: 2024
Type: article
Study design: Observational Study
Abstract: OBJECTIVES: To calculate a polygenic risk score (PRS) based on single nucleotide variants (SNVs) previously associated with primary Sjögren's disease (SjD) with genome-wide significance and determine the genetic risk for SjD stratified by antibodies, sex and age at diagnosis. METHODS: Patients with SjD (n = 1065) were genotyped using Illumina OmniExpressExome chip. Control genotype data were available (n = 7742). Two PRSs were constructed, one including HLA gene variants (n = 21 SNVs), and one without HLA (n = 18 SNVs). High PRS quartile (Q4) individuals were compared with low PRS (Q1-3). RESULTS: A high PRS was associated with SSA antibody-positive SjD (OR 9.16, 95% CI 7.75-10.85, P = 3.7 × 10-146), and strengthened in SjD positive for both SSA/SSB antibodies (OR 13.67, 95% CI 10.88-17.32, P = 4.6 × 10-108). High PRS classified SSA/SSB antibody-positive SjD with very good accuracy (AUC 0.86). PRS without HLA showed a weaker association with SSA/SSB positive SjD (OR 2.09, 95% CI 1.71-2.55, P = 6.4 × 10-13). Antibody negative SjD displayed a PRS similar to controls. Patients in the high PRS quartile were significantly younger at diagnosis, 48.9 ± 14.9 vs 53.4 ± 13.4 years in the low PRS quartiles (Q1-3), P = 2.2 × 10-6, and presented higher frequencies of ANA, SSA and SSA/SSB antibodies, P < 1 × 10-5. CONCLUSION: A high PRS is associated with SSA/SSB antibody positivity and early disease onset, both largely attributed to the weight of the HLA alleles. Integration of PRS with other biomarkers applied to clinical phenotypes could be a useful tool for disease risk stratification and treatment decisions.
Source: Lara D. Veeken
Authors: Cecilia Fugmann, Sarah Reid, Pascal Pucholt, Marika Kvarnström, Albin Björk, Johannes Mofors, Christopher Sjöwall, Per Eriksson, Peter Olsson, Thomas Mandl, Helena Forsblad-d’Elia, Sara Magnusson Bucher, Svein Joar Johnsen, Katrine Brække Norheim, Silke Appel, Daniel Hammenfors, Janicke Liaaen Jensen, Øyvind Palm, Roald Omdal, Roland Jonsson, Eva Baecklund, Marie Wahren-Herlenius, Dag Leonard, Juliana Imgenberg-Kreuz, Gunnel Nordmark
Institutions: Uppsala University, Science for Life Laboratory, Karolinska Institutet, Linköping University, Lund University, Skåne University Hospital, University of Gothenburg, Örebro University, Stavanger University Hospital, University of Bergen, Haukeland University Hospital, University of Oslo, Oslo University Hospital
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,679
Funders: Wellcome Trust, Hjärt-Lungfonden, Karolinska Institutet, Knut och Alice Wallenbergs Stiftelse, Stockholms Läns Landsting, Vetenskapsrådet, Norges Forskningsråd, Akademiska Sjukhuset, Uppsala Universitet, Agnes och Mac Rudbergs Stiftelse, Stiftelsen Konung Gustaf V:s 80-årsfond, Reumatikerförbundet, Science for Life Laboratory, Uppsala Multidisciplinary Center for Advanced Computational Science
Awards: G1441096865, G2388255308, G3321450376, G3761937116, G4572525476, Dissecting the pathogenic mechanism in congenital heart block, G5381885355, Developing the basis for precision medicine in primary Sjögren’s syndrome, G5824843607, G582688034, Swedish twin registry, G6565658171, G712881263, G796431723, G7991887228, G8929258666, G893917011, G8967904610
OpenAlex ID: W4405527919