title: Genetic association of PRDM1-ATG5 intergenic region and autophagy with systemic lupus erythematosus in a Chinese population.
abstract: OBJECTIVE
  Recent genome-wide association studies suggested the PRDM1-ATG5 gene region as a systemic lupus erythematosus (SLE)-associated locus both in Caucasian and Chinese populations; however, the candidate gene was still obscure and the possible functional significance needed to be determined.
  
  
  METHODS
  In this study, by a multistage integrative strategy, the authors first performed a case-control association study involving 1745 individuals in the Chinese population by genotyping nine single nucleotide polymorphisms within this region, and a meta-analysis was conducted. Correlation between associated genotypes and expression levels of messenger RNA in B-cell lines from 210 unrelated HapMap data was examined, and was validated in vitro. To determine the biological significance, a genetic association study was also checked in a pathway-based manner and the significant associations were validated in a second 844 Chinese cohort.
  
  
  RESULTS
  A peak of association was found in the intergenic region (p=0.036-3.26×10(-4)). Meta-analysis consolidated the association between rs548234 and SLE (OR 1.254, p=1.28×10(-16)). Significant positive correlations with ATG5 expression were identified, suggesting ATG5 as a candidate gene in the region. Epstein-Barr virus B-cell-based downstream gene expression analysis supported a functional effect of rs548234 and rs6937876, and in-vitro experiments confirmed the regulatory effect of rs6937876 in B-cell populations. Finally, an autophagy pathway-based genetic association study identified ATG7 (p=1.12×10(-4)) and IRGM (p=0.015) as novel candidate genes, and gene-gene interactions were observed between ATG5, ATG7 and IRGM.
  
  
  CONCLUSIONS
  These data may demonstrate that autophagy is involved in the pathogenesis of SLE and imply a common biological pathway in autoimmunity.
authors.affiliation: Renal Division, Institute of Nephrology, Peking University, Beijing, China.
authors.forename: Xu-jie
authors.initials: XJ
authors.lastname: Zhou
authors.forename: Xiao-lan
authors.initials: XL
authors.lastname: Lu
authors.forename: Ji-cheng
authors.initials: JC
authors.lastname: Lv
authors.forename: Hai-zhen
authors.initials: HZ
authors.lastname: Yang
authors.forename: Lian-xiang
authors.initials: LX
authors.lastname: Qin
authors.forename: Ming-hui
authors.initials: MH
authors.lastname: Zhao
authors.forename: Yin
authors.initials: Y
authors.lastname: Su
authors.forename: Zhan-guo
authors.initials: ZG
authors.lastname: Li
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics; D001343:Autophagy / Q000235:genetics*; D000071187:Autophagy-Related Protein 5; D001402:B-Lymphocytes / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012333:RNA, Messenger / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D055815:Young Adult
chemical_list: C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1