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

Fugmann C, Reid S, Pucholt P, Kvarnström M, Björk A, Mofors J, Sjöwall C, Eriksson P, Olsson P, Mandl T, Forsblad-d'Elia H, Magnusson Bucher S, Johnsen SJ, Norheim KB, Appel S, Hammenfors D, Jensen JL, Palm Ø, Omdal R, Jonsson R, Baecklund E, Wahren-Herlenius M, Leonard D, Imgenberg-Kreuz J, Nordmark G

Rheumatology (Oxford) 64 (7) 4341-4346 [2025-07-01; online 2024-12-18]

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. 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). 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. 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.

NGI SNP genotyping [Service]

NGI Uppsala (SNP&SEQ Technology Platform) [Service]

PubMed 39693120

DOI 10.1093/rheumatology/keae693

Crossref 10.1093/rheumatology/keae693

pii: 7927842
pmc: PMC12212914