Detecting Genetic Associations betweenATG5and Lupus Nephritis bytrans-eQTL

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.

Autophagy and immunological aberrations in systemic lupus erythematosus

“…These data strongly supported the notion that autophagy plays an important role in the genetic etiology of SLE . Combining with further follow‐up studies, several variants locating in other autophagy‐related genes were observed to be associated with susceptibility to SLE, including ATG7 , IRGM , LRRK2 , MAP1LC3B, MTMR3 , and APOL1 (Table ) .…”

IFNα Impairs Autophagic Degradation of mtDNA Promoting Autoreactivity of SLE Monocytes in a STING-Dependent Fashion

“…GWAS in SLE peripheral blood mononuclear cells (PBMCs) have identified ATG16L1, ATG5, ATG7, and IRGM autophagy genes as susceptibility loci ( Zhang et al., 2015 , Zhou et al., 2011 ). To understand the regulation of the autophagic flux in freshly isolated CD14 + monocytes of active, untreated SLE patients ( Table S1 ), we monitored the expression and subcellular localization of indispensable autophagy components ( Klionsky et al., 2016 ), namely the first ubiquitin-like conjugation system that is necessary for elongation of phagophore membrane (Atg5-Atg12), the second conjugation system that is required for autophagosome formation (PE-LC3B), the sequestrator of substrates to be cleared (SQSTM1/P62), and the acidic compartment for the digestion of autophagy substrates, the lysosome (LAMP1).…”

Podocytes and autophagy: a potential therapeutic target in lupus nephritis

“…However, all the above reported associated variants are not located in coding regions. Some of the functional consequences of these polymorphisms are confirmed to be expression regulatory by cis-eQTL or trans-eQTL effects, causing a cytokine imbalance [14,17,20,21,[27][28][29][30]. Our previous data also showed that PRDM1-ATG5 risk allelic variant is associated with increased ATG5 expression and IFNA signature genes in B cells [14].…”

“…Several GWASs confirm the genetic associations between variants in/near ATG5 and SLE, in both Caucasians and Asians [14][15][16]. Further candidate gene/pathway analysis revealed that variants locating in additional autophagy related genes, including ATG7, IRGM, DRAM1, CDKN1B, APOL1, MTMR3, CLEC16A, LRRK2, ATG16L2, and MAP1LC3B are associated with susceptibility to SLE [14,[17][18][19][20][21][22][23][24][25]. A small subphenotype analysis suggests risk alleles of ATG5 associated with anemia, the presence of anti-DNA autoantibodies and renal involvement [26].…”