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

Ann Rheum Dis. 2020 Mar;79(3):363-369. doi: 10.1136/annrheumdis-2019-216227. Epub 2019 Dec 11.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Antibodies, Anticardiolipin / blood
  • Case-Control Studies
  • Female
  • Genetic Predisposition to Disease / epidemiology*
  • Genotype
  • Humans
  • Kidney Failure, Chronic / genetics
  • Kidney Failure, Chronic / mortality
  • Lupus Coagulation Inhibitor / blood
  • Lupus Erythematosus, Systemic / blood
  • Lupus Erythematosus, Systemic / genetics*
  • Lupus Erythematosus, Systemic / mortality
  • Lupus Nephritis / genetics*
  • Lupus Nephritis / mortality
  • Male
  • Middle Aged
  • Prevalence
  • Risk
  • Risk Assessment / statistics & numerical data*
  • Risk Factors
  • Severity of Illness Index*
  • Survival Rate
  • beta 2-Glycoprotein I / immunology

Substances

  • Antibodies, Anticardiolipin
  • Lupus Coagulation Inhibitor
  • beta 2-Glycoprotein I