Abstract
The CDKN1A gene encoding a cell cycle inhibitor, p21(WAF1/CIP1), is located in the systemic lupus erythematosus (SLE) susceptibility locus on chromosome 6p21.2. Decreased cellular levels of p21 are associated with SLE. Here, we examine four single-nucleotide polymorphisms (SNPs) within the promoter and two in the first intron of CDKN1A for association with SLE susceptibility. A comparison of 742 Korean SLE patients with 1017 controls disclosed that one SNP (rs762624 C>A at position −899), located at a putative Myb-binding site in the promoter, was associated with SLE susceptibility (P=0.00047). This association was independent of the SLE-association signal of HLA-DRB1 on 6p21.3, as it was significant after adjustment for SLE-risk DRB1 alleles (P=0.0012). The same SNP was associated with lupus nephritis (P=0.000014). The risk allele-carrying promoter sequence displayed ∼15% lower activity than the non-risk sequence upon fusion to the luciferase gene (P=0.025). Endogenous CDKN1A mRNA levels measured in Epstein–Barr virus-transformed B cells established from 16 control subjects were linearly correlated with a decreasing copy number of the risk allele (P=0.024). Accordingly, we conclude that the minor allele A at −899 of CDKN1A is associated with increased susceptibility to SLE and lupus nephritis, and decreased cellular levels of p21.
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Acknowledgements
We are grateful to the participants who donated blood samples for this study, Jung-Ah Kim, Young-Hi Lee and Eun-Kyoung Ju for their assistance in clinical data collection and genomic DNA purification and Yikyeong Kim for technical and administrative assistance. The study was approved by the Institutional Review Board of Hanyang University Medical Center, Seoul, Korea. This project was funded by grants from the Research Program for New Drug Target Discovery (M10748000231-08N4800-23110 to C Kang) and from Korea Healthcare Technology R&D Project (A010252 and A080588 to SC Bae). K Kim and C Kang are participants to the Brain Korea 21 Program.
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Kim, K., Sung, YK., Kang, C. et al. A regulatory SNP at position −899 in CDKN1A is associated with systemic lupus erythematosus and lupus nephritis. Genes Immun 10, 482–486 (2009). https://doi.org/10.1038/gene.2009.5
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DOI: https://doi.org/10.1038/gene.2009.5
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