Abstract
Objectives. Numerous loci were identified to perturb gene expression in trans. As elevated ATG5 expression was observed in systemic lupus erythematosus (SLE), the study was conducted to analyze the genome-wide genetic regulatory mechanisms associated with ATG5 expression in a Chinese population with lupus nephritis (LN). Methods. The online expression quantitative trait loci database was searched for trans-expression single nucleotide polymorphisms (trans-eSNPs) of ATG5. Tagging trans-eSNPs were genotyped by a custom-made genotyping chip in 280 patients and 199 controls. For positive findings, clinical information and bioinformation analyses were performed. Results. Four trans-eSNPs were observed to be associated with susceptibility to LN (P < 0.05), including ANKRD50 rs17008504, AGA rs2271100, PAK7 rs6056923, and TET2 rs1391441, while seven other trans-eSNPs showed marginal significant associations (0.05 < P < 0.1). Correlations between the trans-eSNPs and ATG5 expression and different expression levels of ATG5 in SLE patients and controls were validated, and their regulatory effects were annotated. However, no significant associations were observed between different genotypes of trans-eSNPs and severity or outcome of the patients. Conclusion. Using the new systemic genetics approach, we identified 10 loci associated with susceptibility to LN potentially, which may be complementary to future pathway based genetic studies.
Highlights
A strong body of evidence has suggested the complex genetic basis of systemic lupus erythematosus (SLE), and to date more than 50 loci have been identified, largely improving our insights into the pathogenesis of SLE [1, 2]
Marginal significance was observed between 7/68 trans-eSNPs and susceptibility to lupus nephritis (LN) (0.05 < P < 0.1), including rs712377 on SLC25A21 (OR = 1.283, 95% CI = 0.984 to 1.671, P = 0.065), rs1391438 on TET2 (OR = 1.266, 95% CI = 0.978 to 1.638, P = 0.073), rs10878953 on CPSF6 (OR = 1.268, 95% CI = 0.977 to 1.647, P = 0.075), rs7529592 on AKNAD1 trans-eSNPs of ATG5 selection: the online expression quantitative trait loci (eQTL) database
Hypothesis-free genome-wide association studies (GWASs) have significantly broadened our views about genetic pathogenesis of SLE [1]
Summary
A strong body of evidence has suggested the complex genetic basis of systemic lupus erythematosus (SLE), and to date more than 50 loci have been identified, largely improving our insights into the pathogenesis of SLE [1, 2]. A number of eQTL were observed to influence gene expression through cis-acting regulatory effects (with the variants located within or near the target gene) [5], significantly broadening our understanding of genetic pathogenesis of diseases [6, 7]. In our Journal of Immunology Research previous study [11], only variants in the PRDM1-ATG5 intergenic region not within ATG5 were detected to be associated with susceptibility to SLE, and they were detected to affect ATG5 expression level through a cis-eQTL effect. As a strong body of evidence supported that numerous loci perturb gene expression in trans [12,13,14], we hypothesized that genetic polymorphisms of autophagy genes may function at the upstream of ATG5 by transeQTL effects to further modulate SLE susceptibility
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