High genetic risk score is associated with early disease onset, damage accrual and decreased survival in systemic lupus erythematosus

Abstract

Objectives: To investigate associations between a high genetic disease risk and disease severity in patients with systemic lupus erythematosus (SLE).

Methods: Patients with SLE (n=1001, discovery cohort and n=5524, replication cohort) and healthy controls (n=2802 and n=9859) were genotyped using a 200K Immunochip single nucleotide polymorphism array. A genetic risk score (GRS) was assigned to each individual based on 57 SLE risk loci.

Results: SLE was more prevalent in the high, compared with the low, GRS-quartile (OR 12.32 (9.53 to 15.71), p=7.9×10^-86 and OR 7.48 (6.73 to 8.32), p=2.2×10^-304 for the discovery and the replication cohorts, respectively). In the discovery cohort, patients in the high GRS-quartile had a 6-year earlier mean disease onset (HR 1.47 (1.22 to 1.75), p=4.3×10^-5), displayed higher prevalence of damage accrual (OR 1.47 (1.06 to 2.04), p=2.0×10^-2), renal disorder (OR 2.22 (1.50 to 3.27), p=5.9×10^-5), anti-dsDNA (OR 1.83 (1.19 to 2.81), p=6.1×10^-3), end-stage renal disease (ESRD) (OR 5.58 (1.50 to 20.79), p=1.0×10^-2), proliferative nephritis (OR 2.42 (1.30 to 4.49), p=5.1×10^-3), anti-cardiolipin-IgG (OR 1.89 (1.13 to 3.18), p=1.6×10^-2), anti-β₂-glycoprotein-I-IgG (OR 2.29 (1.29 to 4.06), p=4.8×10^-3) and positive lupus anticoagulant test (OR 2.12 (1.16 to 3.89), p=1.5×10^-2) compared with patients in the low GRS-quartile. Survival analysis showed earlier onset of the first organ damage (HR 1.51 (1.04 to 2.25), p=3.7×10^-2), first cardiovascular event (HR 1.65 (1.03 to 2.64), p=2.6×10^-2), nephritis (HR 2.53 (1.72 to 3.71), p=9.6×10^-7), ESRD (HR 6.78 (1.78 to 26.86), p=6.5×10^-3) and decreased overall survival (HR 1.83 (1.02 to 3.30), p=4.3×10^-2) in high to low quartile comparison.

Conclusions: A high GRS is associated with increased risk of organ damage, renal dysfunction and all-cause mortality. Our results indicate that genetic profiling may be useful for predicting outcomes in patients with SLE.

Keywords: antiphospholipid syndrome; cardiovascular disease; gene polymorphism; lupus nephritis; systemic lupus erythematosus.

Figure 1

Cumulative genetic risk and SLE development. (A) The distribution of the RAC in the patients (n=1001) and healthy controls (n=2802). (B) The distribution of the weighted GRS in the same individuals. (C) The patients and healthy controls were ordered according to their GRSs and divided into 38 groups, each including 100 individuals (with exception of the first group, which consisted of 103 individuals). The SLE prevalence of each group was plotted against its mean GRS. (D) The survival until SLE onset was analysed for patients with a GRS in the extreme quartiles (n=500). GRS, genetic risk score; RAC, risk allele count; SLE, systemic lupus erythematosus.

Figure 2

Prediction accuracy of the weighted GRS depending on age at SLE onset. ROC curve analysis was used to assess the prediction ability of the GRS in patients aged below 20 (n=158), 20–40 (n=475) and >40 (n=368) years at SLE diagnosis. The prediction accuracy of the unweighted RAC is shown in the same figure. AUC, area under the ROC curve; GRS, genetic risk score; RAC, risk allele count; ROC, receiver operating characteristic; SLE, systemic lupus erythematosus.

Figure 3

Association of high GRS with organ damage and overall mortality. (A) In five separate logistic regression models, the probability of having 0 vs >0, or 1/2/3/≥4 vs 0, points on the SLICC SDI was calculated for patients with a GRS in the high, compared with the low, quartile. Age was included as a covariate in the analyses. (B) Using the same statistical model and covariate as in A, the OR for mortality compared with patients with a GRS<7 was plotted for patients with a GRS of 7–8, 8–9, 9–10, 10–11 and >11. Patients with a GRS<7 were compared with patients with a GRS>7. GRS, genetic risk score, SDI, SLICC Damage Index; SLICC, Systemic Lupus Collaborating Clinics.

Figure 4

Survival comparison until nephritis onset in patients with a high or low GRS. Patients with a GRS in the extreme quartiles meeting the ACR-82 nephritis criterion, with a known date of nephritis diagnosis (n=109), were included as cases in the analysis, with their age at the time of nephritis diagnosis as the time variable. Patients in the extreme quartiles not meeting the nephritis criterion (n=245) were included as censored individuals, with their age at last-follow up as the time variable. The high and low quartiles were compared using the generalised Wilcoxon test. GRS, genetic risk score.