A Rare Variant (rs933717) at FBXO 31‐ MAP 1 LC 3B FBXO FBXO 31‐ MAP MAP 1 LC LC 3B in Chinese Is Associated With Systemic Lupus Erythematosus

摘要

Objective Recent evidence from genetic, cell biology, and animal model studies has suggested a pivotal role of autophagy in mediating systemic lupus erythematosus ( SLE ). However, the genetic basis has not yet been thoroughly examined. Therefore, the aim of the present study was to identify additional susceptibility variants in autophagy‐related genes along with their functional significance. Methods First, we performed a gene family–based genetic association analysis in SLE patients with the use of ImmunoChip arrays, and then we selected the most strongly associated polymorphisms for replication in additional cohorts. To identify regulatory clues, we analyzed publicly available blood expression quantitative trait locus data and Encyclopedia of DNA Elements data?on transcription factor binding sites and cell type‐specific differential expression. Functional effects were tested by luciferase reporter assays, electrophoretic mobility shift assays, and differential gene expression assays. Results In 14,474 samples, we observed that the rare Chinese variant rs933717T was associated with susceptibility to SLE (0.11% in cases versus 0.87% in controls; P = 2.36 × 10 – 10 , odds ratio 0.13). The rs933717 risk allele C correlated with increased MAP 1 LC 3B expression; increased MAP 1 LC 3B messenger RNA was observed in SLE patients and in lupus‐prone mice. In reporter gene constructs, the risk allele increased luciferase activity up to 2.7‐3.8‐fold in both HEK 293T and Jurkat cell lines, and the binding of HEK 293T and Jurkat cell nuclear extracts to the risk allele was also increased. Conclusion We observed a likely genetic association between light chain 3B, a widely used marker for autophagy, and susceptibility to SLE .