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.