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

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=7.9x10(-86) and OR 7.48 (6.73 to 8.32), p=2.2x10(-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=4.3x10(-5)), displayed higher prevalence of damage accrual (OR 1.47 (1.06 to 2.04), p=2.0x10(-2)), renal disorder (OR 2.22 (1.50 to 3.27), p=5.9x10(-5)), anti-dsDNA (OR 1.83 (1.19 to 2.81), p=6.1x10(-3)), end-stage renal disease (ESRD) (OR 5.58 (1.50 to 20.79), p=1.0x10(-2)), proliferative nephritis (OR 2.42 (1.30 to 4.49), p=5.1x10(-3)), anti-cardiolipin-IgG (OR 1.89 (1.13 to 3.18), p=1.6x10(-2)), anti-beta 2-glycoprotein-I-IgG (OR 2.29 (1.29 to 4.06), p=4.8x10(-3)) and positive lupus anticoagulant test (OR 2.12 (1.16 to 3.89), p=1.5x10(-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=3.7x10(-2)), first cardiovascular event (HR 1.65 (1.03 to 2.64), p=2.6x10(-2)), nephritis (HR 2.53 (1.72 to 3.71), p=9.6x10(-7)), ESRD (HR 6.78 (1.78 to 26.86), p=6.5x10(-3)) and decreased overall survival (HR 1.83 (1.02 to 3.30), p=4.3x10(-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.