High Genetic Risk Score Associated With Organ Damage, Renal Dysfunction, and All-Cause Mortality in SLE

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The study evaluated the association between high genetic disease risk and disease severity in patients with systemic lupus erythematosus.

High genetic risk score (GRS) may predict organ damage, end-stage renal disease, and all-cause mortality in patients with systemic lupus erythematosus (SLE), according to study results published in Annals of Rheumatic Disease.1

Investigators genotyped data of a discovery cohort and a replication cohort that included patients with SLE and healthy controls. Patients with SLE (n=1001) were enrolled in the discovery cohort from various clinics in Sweden; healthy controls (n=2802) were enrolled from blood donor centers in the same areas. The replication cohort included 5524 patients with SLE and 9859 healthy controls of European descent, initially enrolled for a study published in 2017.2 Genotyping data were collected from both cohorts using a 200K Immunochip single nucleotide polymorphism array. Cumulative GRSs were assigned to each study participant based on 57 SNPs with known associations to SLE. Risk allele counts of the 57 SNPs were calculated for each participant by summing the total number of risk alleles. Ordinal and logistic regression were used to assess GRS differences between patients and healthy controls.

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Results indicated that SLE was more prevalent in the high GRS quartile compared with the low GRS quartile in both the discovery (odds ratio [OR], 12.32; 95% CI, 9.53-15.71; P =7.9×10-86) and replication (OR, 7.48; 95% CI, 6.73-8.32; P =2.2×10-304) cohorts. In the discovery cohort, compared with patients in the low GRS quartile, those in the high GRS quartile had a 6-year earlier mean disease onset (33 vs 39 years; P =4.3×10-5), higher prevalence of damage accrual (OR, 1.47; 95% CI, 1.06-2.04; P =2.0×10-2), and higher prevalence of any renal disorder (OR, 2.22; 95% CI, 1.50-3.27; P =5.9×10-5), end-stage renal disease (OR, 5.58; 95% CI, 1.50-20.79; P =1.0×10-2), and proliferative nephritis (OR, 2.42; 95% CI, 1.30-4.49; P =5.1×10-3).

Patients in the high GRS quartile vs the low GRS quartile of the discovery cohort were also more likely to have a positive antiphospholipid antibodies test (OR, 1.84; 95% CI, 1.16-2.9; P =9.4×10-3), with more than doubled odds of being triple positive (OR, 2.27; 95% CI, 1.02-5.09; P =4.6×10-2). In survival analyses conducted in the discovery cohort, compared with the low GRS quartile, the high GRS quartile displayed earlier onset of first organ damage (43 vs 51 years), first cardiovascular event (45 vs 51 years), nephritis (31 vs 39 years), and end-stage renal disease (43 vs 64 years). Decreased overall survival was also observed in the high-to-low quartile comparisons (hazard ratio, 1.83; 95% CI, 1.02-3.30; P =4.3×10-2).

These data support the prognostic capacity of GRS for SLE outcomes. The highest GRS quartile was strongly associated with poorer outcomes, including organ damage, cardiovascular events, renal dysfunction, and all-cause mortality. “Our results indicate that genetic profiling may be useful for predicting outcomes in patients with SLE,” the investigators wrote.


1. Reid S, Alexsson A, Frodlund M, et al. High genetic risk score is associated with early disease onset, damage accrual and decreased survival in systemic lupus erythematosus [published online December 11, 2019]. Ann Rheum Dis. doi:10.1136/annrheumdis-2019-216227

2. Langefeld CD, Ainsworth HC, Vyse TJ. Transancestral mapping and genetic load in systemic lupus erythematosus. Nat Commun. 2017;8:16021.