Abstracts

207 A high genetic risk score is associated with early disease onset, organ damage and decreased survival in systemic lupus erythematosus

Abstract

Background Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease with a complex genetic etiology. Over 100 risk genes for SLE have been identified at genome-wide significance, but their overall effect on disease severity has not previously been studied. We therefore assessed the relationship between a high genetic risk score and the development of organ damage in SLE.

Methods Patients with SLE, who met 4 ACR criteria (n=1001), and healthy controls (n=2802) were genotyped using a 200K Immunochip SNP Array (Illumina). A genetic risk score (GRS) was assigned to each individual based on 57 SLE risk loci which have previously shown association (p<5×10–8) with SLE according to Chen et al (Curr Opin Rheumatol, 2017; 29(5):423–433), weighted by their SLE susceptibility odds ratios (ORs). Clinical data was retrieved from medical charts.

Results SLE prevalence increased with increasing GRS (figure 1A) and was higher in the highest compared to the lowest GRS-quartile (OR 12.32 (9.5315.71) p=7.9×10–86). SLE onset occurred 5 years earlier in the high compared to the low quartile (figure 1B). The OR for organ damage increased with increasing GRS (figure 1C) and was significantly higher in the high compared to the low GRS-quartile (OR 1.47 (1.062.04) p=2.0×10–2). Moreover, patients in the high quartile had an increased prevalence of nephritis (OR 2.22 (1.503.27), p=5.9×10–5), end-stage kidney disease (ESKD) (OR 5.58 (1.5020.79), p=1.0×10–2) anti-dsDNA antibodies (OR 1.83 (1.192.81), p=6.1×10–03), anti-cardiolipin-IgG (OR 2.16 (1.303.59), p=2.8×10–03) and anti-2-glycoprotein-I (OR 1.69 (1.042.74), p=3.3×10–02). Analysis of renal biopsy data showed that the prevalence of proliferative nephritis was significantly higher in the high, compared to the low, quartile (OR 2.42 (1.304.49), p=5.1×10–03). Moreover, the patients in the high GRS-quartile displayed decreased survival until their first organ damage (HR 1.51 (1.042.25), p=3.7×10–02), first cardiovascular event (HR 1.65 (1.032.64), p=2.6×10–02), nephritis onset (HR 2.53 (1.723.71) p=9.6×10–7) and ESKD (6.78 (1.7826.86), p=6.5×10–3). Lastly, OR for mortality increased with increasing GRS (figure 1D), with a 5 year decrease in overall survival in the high compared to the low quartile (HR 1.82 (1.043.19), p=2.4×10–2).

Abstract 207 Figure 1
Abstract 207 Figure 1

Association of the genetic risk score with SLE onset, organ mortality. A) The prevalence of SLE in the patient-control population was plotted for groups with a GRS of <6, 6–6.5, 6.5–7, 7–7.5, 7.5–8, 8–8.5, 8.5–9, 9–9.5, 9.5–10, 10.5–11 and >11. B) The survival until SLE onset was analysed for patients with a GRS in the extreme quartiles. (n=500). C) IN regression analysis, the prevalence of organ damage in patients with a genetic risk score (GRS) above 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0 and 11.5, respectively, was compared to a reference group with a GRS below 7.0. The odds ratio for each each group was plotted against the mean GRSs. Age was used as acovariate in each analysis D) Using the same method and groups as in C, odds ratio for mortality were plotted against mean GRSs.

Conclusions A high genetic risk score is associated with earlier disease onset, increased risk of organ damage and impaired survival. Our results indicate that genetic profiling may be useful for predicting outcomes in patients with SLE.

Funding Source(s): None