Abstract
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= 3.7x10-146), and strengthened in SjD positive for both SSA/SSB antibodies (OR 13.67, 95% CI 10.88-17.32, p= 4.6x10-108). 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= 6.4x10-13). 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= 2.2x10-6, and presented higher frequencies of ANA, SSA and SSA/SSB antibodies, p < 1x10-5. 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.
Published Version
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