Dataset Information

A Rare Variant (rs933717) at FBXO31-MAP1LC3B in Chinese Is Associated With Systemic Lupus Erythematosus.

ABSTRACT: 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 MAP1LC3B expression; increased MAP1LC3B 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.

SUBMITTER: Qi YY

PROVIDER: S-EPMC5788706 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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A Rare Variant (rs933717) at FBXO31-MAP1LC3B in Chinese Is Associated With Systemic Lupus Erythematosus.

Qi Yuan-Yuan YY Zhou Xu-Jie XJ Nath Swapan K SK Sun Celi C Wang Yan-Na YN Hou Ping P Mu Rong R Li Chun C Guo Jian-Ping JP Li Zhan-Guo ZG Wang Geng G Xu Hu-Ji HJ Hao Yan-Jie YJ Zhang Zhuo-Li ZL Yue Wei-Hua WH Zhang Huoru H Zhao Ming-Hui MH Zhang Hong H

Arthritis & rheumatology (Hoboken, N.J.) 20180109 2

<h4>Objective</h4>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.<h4>Methods</h4>First, we performed a gene family-based genetic association analysis in SLE patien ...[more]

PMID: 29044928

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Project description:Recently, common variants within or near ATG5, which is a key autophagy gene required for the formation of autophagosomes, have been identified as a candidate gene of systemic lupus erythematosus (SLE) by several genome-wide association studies. Moreover, elevated ATG5 expression was observed in SLE as well as other autoimmune diseases. However, no significant associations between variants within ATG5 and SLE were identified in several Chinese populations. The present study was conducted to further check the genetic role of ATG5 by associating both common and rare variants of ATG5 in Chinese patients with lupus nephritis (LN), a major phenotype with poor prognosis in SLE.To detect the association of common variants of ATG5 with LN, 7 tagging single nucleotide polymorphisms (SNPs) designed in immunochip and 4 SNPs reported to be associated with SLE were genotyped in 500 LN patients and 500 healthy controls. Furthermore, direct sequencing of exons and their flanking regions in 90 LN patients, 30 SLE patients, and 60 healthy controls were performed. Functional genomic annotation was performed by using public databases.None of the 11 tagging SNPs was observed to be associated with LN. By sequencing, 13 variants were identified, including 5 common SNPs, 7 not previously described, and 1 reported as rare variants (<1%) in the Single Nucleotide Polymorphism Database or the 1000 Genome project. None of the 5 common SNPs showed significant association between patients and controls, whereas increased frequencies of rare or novel variants were observed in patients compared with healthy controls, with 6/90 in LN patients, 2/30 in SLE patients, and 1/163 in healthy controls. Although these rare variants were observed to be located in the flanking regions of exons instead of missense mutations, patients carrying them tended to have severe clinical phenotype, and in silicon analysis suggested their regulatory effects.Increased frequencies of rare variants of ATG5 were identified in patients with LN and SLE compared with healthy controls, highlighting a likely important role of rare ATG5 variants in Chinese SLE patients.

Dataset Information

A Rare Variant (rs933717) at FBXO31-MAP1LC3B in Chinese Is Associated With Systemic Lupus Erythematosus.

Publications

A Rare Variant (rs933717) at FBXO31-MAP1LC3B in Chinese Is Associated With Systemic Lupus Erythematosus.

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