Increased burden of rare variants in genes of the endosomal Toll-like receptor pathway in patients with systemic lupus erythematosus

Lupus. 2021 Oct;30(11):1756-1763. doi: 10.1177/09612033211033979. Epub 2021 Jul 16.


Objective: To compare the frequency of rare variants in genes of the pathophysiologically relevant endosomal Toll-like receptor (eTLR) pathway and any quantifiable differences in variant rarity, predicted deleteriousness, or molecular proximity in patients with systemic lupus erythematosus (SLE) and healthy controls.

Patients and methods: 65 genes associated with the eTLR pathway were identified by literature search and pathway analysis. Using next generation sequencing techniques, these were compared in two randomised cohorts of patients with SLE (n = 114 and n = 113) with 197 healthy controls. Genetically determined ethnicity was used to normalise minor allele frequencies (MAF) for the identified genetic variants and these were then compared by their frequency: rare (MAF < 0.005), uncommon (MAF 0.005-0.02), and common (MAF >0.02). This was compared to the results for 65 randomly selected genes.

Results: Patients with SLE are more likely to carry a rare nonsynonymous variant affecting proteins within the eTLR pathway than healthy controls. Furthermore, individuals with SLE are more likely to have multiple rare variants in this pathway. There were no differences in rarity, Combined Annotation Dependent Depletion (CADD) score, or molecular proximity for rare eTLR pathway variants.

Conclusions: Rare non-synonymous variants are enriched in patients with SLE in the eTLR pathway. This supports the hypothesis that SLE arises from several rare variants of relatively large effect rather than many common variants of small effect.

Keywords: Systemic lupus erythematosus; autoimmunity; endosomal Toll-like receptor pathway; genetics; next generation sequencing.

MeSH terms

  • Endosomes / genetics
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Lupus Erythematosus, Systemic* / genetics
  • Mutation
  • Toll-Like Receptors* / genetics


  • Toll-Like Receptors