PO:06:172 TNC rs2104772 polymorphism and its association with clinical features of systemic lupus erythematosus

higher genetic load is linked to more severe disease.1This study aims to elucidate the role of genetic variation in SLE clinical heterogeneity.Methods Scandinavian patients with SLE meeting the 1997 ACR criteria were genotyped using Illumina's GSA, with clinical data extracted from medical charts.Participants were randomly assigned to a discovery and test cohorts (n=884 and 524).SLE polygenic risk score (SLE-PRS) was calculated using 138 established GWAS non-HLA SLE risk single nucleotide variants (SNVs).Subphenotype-specific PRSs were constructed in the discovery cohort based on 4,088 candidate SNVs associated with immune or inflammatory diseases.Validation in the test cohort was conducted using logistic regression comparing the top quartile to the remainder, adjusting for sex and age.Disease and pathway enrichment analyses were conducted using FUMA2 and Metascape.3Results The SLE-PRS was associated with nephritis (OR=1.4,p=1.110-5) and photosensitivity (OR=1.1,p=3.610-3), but not with other ACR-97 manifestations.Excluding 54 to 75 SNVs not associated with specific SLE subphenotypes enhanced prediction: improved performance for nephritis (OR=1.6,p=4.410-6) and serositis (OR=1.3,p=0.02).Next, we constructed subphenotype-specific PRSs (34 SNVs on average).The nephritis-PRS contained the largest fraction of known SLE loci (23%) (table).Several PRSs demonstrated predictive ability: malar rash-PRS (OR=1.3,p=7.110-5), nephritis-PRS (OR=1.4,p=4.610-12), neurological disorder-PRS (OR=1.1,p=0.02).Enrichment analysis of SNV annotated genes showed association between multiple sclerosis and all PRSs, with the strongest association for neurological disease (p=1.1710-11).Pathway enrichment analysis showed association between photosensitivity and the Nuclear factor of activated T-cells (NFAT) pathway (p=7.810-12) and hematological manifestations with interleukine-27 signaling (p=2.510-6). ConclusionsThe results demonstrate that refined genetic profiles can be associated with specific clinical manifestations of SLE, and that inclusion of non-SLE risk SNVs can enhance predictive power.Functional enrichment analyses further reveal distinct biological pathways underlying different disease features, pointing to potential targets for personalized therapeutic strategies.