|Genetic association of PRDM1-ATG5 intergenic region and autophagy with systemic lupus erythematosus in a Chinese population|
|Zhou, Xu-jie1,2; Lu, Xiao-lan3; Lv, Ji-cheng1,2; Yang, Hai-zhen4; Qin, Lian-xiang1,2; Zhao, Ming-hui1,2; Su, Yin3; Li, Zhan-guo3; Zhang, Hong1,2|
|刊名||ANNALS OF THE RHEUMATIC DISEASES|
|WOS标题词||Science & Technology|
|关键词[WOS]||GENOME-WIDE ASSOCIATION ; NF-KAPPA-B ; CROHNS-DISEASE ; SUSCEPTIBILITY LOCI ; RHEUMATOID-ARTHRITIS ; REVISED CRITERIA ; DENDRITIC CELLS ; VARIANTS ; PATHOGENESIS ; ACTIVATION|
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=0.036-3.26x10(-4)). Meta-analysis consolidated the association between rs548234 and SLE (OR 1.254, p=1.28x10(-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=1.12x10(-4)) and IRGM (p=0.015) as novel candidate genes, and gene-gene interactions were observed between ATG5, ATG7 and IRGM.
Conclusion These data may demonstrate that autophagy is involved in the pathogenesis of SLE and imply a common biological pathway in autoimmunity.
|项目编号||30801022 ; 30825021 ; 200802052|
|资助机构||National Natural Science Foundation of China ; Foundation of Ministry of Health of China|
|作者单位||1.Peking Univ, Inst Nephrol, Div Renal, Beijing 100034, Peoples R China|
2.Minist Hlth China, Key Lab Renal Dis, Beijing, Peoples R China
3.Peking Univ Peoples Hosp, Dept Rheumatol & Immunol, Beijing, Peoples R China
4.Peking Univ First Hosp, Dept Dermatol, Beijing, Peoples R China
|Zhou, Xu-jie,Lu, Xiao-lan,Lv, Ji-cheng,et al. Genetic association of PRDM1-ATG5 intergenic region and autophagy with systemic lupus erythematosus in a Chinese population[J]. ANNALS OF THE RHEUMATIC DISEASES,2011,70(7):1330-1337.|
|APA||Zhou, Xu-jie.,Lu, Xiao-lan.,Lv, Ji-cheng.,Yang, Hai-zhen.,Qin, Lian-xiang.,...&Zhang, Hong.(2011).Genetic association of PRDM1-ATG5 intergenic region and autophagy with systemic lupus erythematosus in a Chinese population.ANNALS OF THE RHEUMATIC DISEASES,70(7),1330-1337.|
|MLA||Zhou, Xu-jie,et al."Genetic association of PRDM1-ATG5 intergenic region and autophagy with systemic lupus erythematosus in a Chinese population".ANNALS OF THE RHEUMATIC DISEASES 70.7(2011):1330-1337.|