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.
Conclusion These data may demonstrate that autophagy is involved in the pathogenesis of SLE and imply a common biological pathway in autoimmunity.
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Funding This work was supported by grants from the National Natural Science Foundation of China (no 30801022, No 30825021) and the Foundation of Ministry of Health of China (no 200802052).
Competing interests None.
Patient consent Obtained.
Ethics approval This study was conducted with the approval of the medical ethics committee of Peking University.
Provenance and peer review Not commissioned; externally peer reviewed.