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. 2025 Jul 1;64(7):4341-4346.
doi: 10.1093/rheumatology/keae693.

A high polygenic risk score is associated with SSA/SSB antibody positivity and early onset in primary Sjögren's disease

Cecilia Fugmann  1 , Sarah Reid  1 , Pascal Pucholt  1 , Marika Kvarnström  2   3 , Albin Björk  2   3 , Johannes Mofors  2 , Christopher Sjöwall  4 , Per Eriksson  4 , Peter Olsson  5 , Thomas Mandl  5 , Helena Forsblad-d'Elia  6 , Sara Magnusson Bucher  7 , Svein Joar Johnsen  8   9 , Katrine Brække Norheim  8   9 , Silke Appel  10 , Daniel Hammenfors  11 , Janicke Liaaen Jensen  12 , Øyvind Palm  13 , Roald Omdal  9   10 , Roland Jonsson  10 , Eva Baecklund  1 , Marie Wahren-Herlenius  2   10 , Dag Leonard  1 , Juliana Imgenberg-Kreuz  1 , Gunnel Nordmark  1
Affiliations

A high polygenic risk score is associated with SSA/SSB antibody positivity and early onset in primary Sjögren's disease

Cecilia Fugmann et al. Rheumatology (Oxford). .

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.

Keywords: HLA; SSA; SSB; Sjögren’s disease; antinuclear antibodies; genome-wide association studies (GWAS); polygenic risk score (PRS); single nucleotide variant (SNV).

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Figures

None
Graphical abstract
Figure 1.
Figure 1.
Density plots and ROC curves for PRS in Sjögren’s disease antibody groups. (A) Density plots representing the distribution of PRS with HLA scores in controls and patients with SjD stratified by antibody status. An individual SjD patient can be part of more than one group. Ridges are sorted by increasing group mean and ridges gradient indicates low (dark purple) to high (light yellow) PRS scores. (B) As in panel A but for PRS without HLA score. (C) ROC curve analysis for SjD prediction accuracy of PRS with HLA. (D) As in panel C but for PRS without HLA. ANA: antinuclear antibodies; AUC: area under the curve; HLA: human leukocyte antigen; PRS: polygenic risk score; Q: quartile; ROC: receiver operating characteristics; SjD: Sjögren’s disease; SSA: anti-SSA antibodies; SSB: anti-SSB antibodies; SSA+ SSB+/−: SSA antibodies with or without SSB antibodies; SSA+ SSB+: positive for both SSA and SSB antibodies
See this image and copyright information in PMC

References

    1. Retamozo S, Acar-Denizli N, Horvath IF et al. ; Sjögren Big Data Consortium. Influence of the age at diagnosis in the disease expression of primary Sjogren syndrome. Analysis of 12,753 patients from the Sjogren Big Data Consortium. Clin Exp Rheumatol 2021;39(Suppl 133):166–74. - PubMed
    1. Thorlacius GE, Hultin-Rosenberg L, Sandling JK et al. Genetic and clinical basis for two distinct subtypes of primary Sjogren’s syndrome. Rheumatology (Oxford) 2021;60:837–48. - PMC - PubMed
    1. Theander E, Jonsson R, Sjostrom B et al. Prediction of Sjogren’s syndrome years before diagnosis and identification of patients with early onset and severe disease course by autoantibody profiling. Arthritis Rheumatol 2015;67:2427–36. - PubMed
    1. Thorlacius GE, Bjork A, Wahren-Herlenius M. Genetics and epigenetics of primary Sjogren syndrome: implications for future therapies. Nat Rev Rheumatol 2023;19:288–306. - PMC - PubMed
    1. Khatri B, Tessneer KL, Rasmussen A et al. ; UK Primary Sjögren’s Syndrome Registry. Genome-wide association study identifies Sjogren’s risk loci with functional implications in immune and glandular cells. Nat Commun 2022;13:4287. - PMC - PubMed