Genetic load in incomplete lupus erythematosus

Abstract

Objective: Patients with incomplete lupus erythematosus (ILE) have lupus features but insufficient criteria for SLE classification. Some patients with ILE transition to SLE, but most avoid major organ involvement. This study tested whether the milder disease course in ILE is influenced by reduced SLE risk allele genetic load.

Methods: We calculated the genetic load based on 99 SLE-associated risk alleles in European American patients with SLE (≥4 American College of Rheumatology (ACR) 1997 criteria, n=170), patients with ILE (3 ACR 1997 criteria, n=169), a subset of patients with ILE not meeting Systemic Lupus International Collaborating Clinics (SLICC) classification (ILE^SLICC, n=119) and healthy controls (n=133). Unweighted genetic loads were calculated as the total sum of risk alleles for each individual, while weighted genetic loads were defined as the sum of risk alleles multiplied by the natural logarithm of the previously published OR of each risk allele for SLE susceptibility.

Results: The median unweighted and weighted SLE risk allele genetic load was significantly greater in patients with ILE (unweighted: 81, p value=0.01; weighted: 16.3, p value=0.001) and patients with SLE (80, p value=0.02; 16.29, p value=0.0006) compared with healthy controls (78, 15.76). Patients with ILE^SLICC trended towards an increased genetic load, although not statistically significant (unweighted: 80, p value=0.14; weighted: 16.05, p value=0.07). However, the median genetic load did not significantly differ between ILE and SLE, and genetic load did not differentiate patients with ILE and SLE (area under the curve=0.51, p=0.78) by receiver operator characteristic analysis.

Conclusions: Patients with ILE and SLE have comparable genetic loads of SLE risk loci, suggesting similar genetic predispositions between these conditions. Phenotypical differences between SLE and ILE may instead be influenced by ILE-specific variants and gene-environment interactions.

Keywords: Autoimmune Diseases; Polymorphism, Genetic; Systemic Lupus Erythematosus.

Figure 1

Patients with ILE exhibit increased genetic load of SLE risk alleles, similar to patients with SLE. (A) Unweighted and (B) weighted SLE risk allele genetic loads in European American patients with SLE (n=170), patients with ILE (n=169) and healthy controls (n=133). Graphs show the median and IQR. Statistical significance was determined using Kruskal-Wallis with Dunn’s post hoc test. *P<0.05, **P<0.01, ***P<0.001. ILE, incomplete lupus erythematosus.

Figure 2

The genetic load of SLE risk alleles does not distinguish patients with ILE from patients with SLE. (A–D) ORs comparing individuals with a given weighted genetic load (±2.0) with those within the lowest 10% for (A) patients with SLE (n=170) and healthy controls (n=133), (B) patients with ILE (n=169) and healthy controls, (C) patients with ILE who also do not meet SLICC criteria (ILE^SLICC, n=117) and healthy controls, or (D) patients with SLE and ILE. (E) Receiver operating characteristic analysis to assess the prediction ability of weighted genetic load in patients with SLE, patients with ILE and healthy controls. AUC, area under the curve; ILE, incomplete lupus erythematosus; SLICC, Systemic Lupus International Collaborating Clinics.