Singh, Bhupinder and Maiti, Guru P. and Zhou, Xujie and Fazel-Najafabadi, Mehdi and Bae, Sang-Cheol and Sun, Celi and Terao, Chikashi and Okada, Yukinori and Chua, Kek Heng and Kochi, Yuta and Guthridge, Joel M. and Zhang, Hong and Weirauch, Matthew and James, Judith A. and Harley, John B. and Varshney, Gaurav K. and Looger, Loren L. and Nath, Swapan K. (2021) Lupus susceptibility region containing CDKN1B rs34330 mechanistically influences expression and function of multiple target genes, also linked to proliferation and apoptosis. Arthritis & Rheumatology, 73 (12). pp. 2303-2313. ISSN 2326-5191, DOI https://doi.org/10.1002/art.41799.
Full text not available from this repository.Abstract
In a recent genome-wide association study, a significant genetic association between rs34330 of CDKN1B and risk of systemic lupus erythematosus (SLE) in Han Chinese was identified. This study was undertaken to validate the reported association and elucidate the biochemical mechanisms underlying the effect of the variant. Methods We performed an allelic association analysis in patients with SLE, followed by a meta-analysis assessing genome-wide association data across 11 independent cohorts (n = 28,872). In silico bioinformatics analysis and experimental validation in SLE-relevant cell lines were applied to determine the functional consequences of rs34330. Results We replicated a genetic association between SLE and rs34330 (meta-analysis P = 5.29 x 10(-22), odds ratio 0.84 95% confidence interval 0.81-0.87]). Follow-up bioinformatics and expression quantitative trait locus analysis suggested that rs34330 is located in active chromatin and potentially regulates several target genes. Using luciferase and chromatin immunoprecipitation-real-time quantitative polymerase chain reaction, we demonstrated substantial allele-specific promoter and enhancer activity, and allele-specific binding of 3 histone marks (H3K27ac, H3K4me3, and H3K4me1), RNA polymerase II (Pol II), CCCTC-binding factor, and a critical immune transcription factor (interferon regulatory factor 1 IRF-1]). Chromosome conformation capture revealed long-range chromatin interactions between rs34330 and the promoters of neighboring genes APOLD1 and DDX47, and effects on CDKN1B and the other target genes were directly validated by clustered regularly interspaced short palindromic repeat (CRISPR)-based genome editing. Finally, CRISPR/dead CRISPR-associated protein 9-based epigenetic activation/silencing confirmed these results. Gene-edited cell lines also showed higher levels of proliferation and apoptosis. Conclusion Collectively, these findings suggest a mechanism whereby the rs34330 risk allele (C) influences the presence of histone marks, RNA Pol II, and IRF-1 transcription factor to regulate expression of several target genes linked to proliferation and apoptosis. This process could potentially underlie the association of rs34330 with SLE.
| Item Type: | Article |
|---|---|
| Funders: | United States Department of Health & Human Services National Institutes of Health (NIH) - USA[R01-AR-060366], United States Department of Health & Human Services National Institutes of Health (NIH) - USA[R01-AI-132532], National Research Foundation of Korea[2017M3A9B4050335] |
| Uncontrolled Keywords: | Erythematosus;Association;P27(KIP1);Risk;Loci;Metaanalysis;Reveals;Promote |
| Subjects: | R Medicine R Medicine > RL Dermatology |
| Divisions: | Faculty of Medicine |
| Depositing User: | Ms Zaharah Ramly |
| Date Deposited: | 27 Oct 2022 06:31 |
| Last Modified: | 27 Oct 2022 06:31 |
| URI: | http://eprints.um.edu.my/id/eprint/35327 |
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