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Noncoding Polymorphism rs6832151 Is an Attractive Candidate for Genome Editing Aimed at Finding New Molecular Mechanisms of Autoimmune Diseases

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Abstract—Currently only a small fraction of the proteins encoded in the human genome serve as pharmaceutical targets. Genome-wide association studies are a powerful tool to uncover new genetic loci responsible for predisposition to complex diseases, such as autoimmune disorders. However, further work is still required to identify causative single-nucleotide polymorphisms (SNPs) which directly mediate the disease risk at these loci, and to determine their target genes. These genes can be located millions base pairs away from the regulatory SNPs. Here, by using bioinformatic tools and databases, we identified five intergenic autoimmunity-associated polymorphisms with high probability of being causative, for which the target genes are still unknown. We tested their ability to influence gene expression using luciferase reporter system. The polymorphism rs6832151 affected the reporter expression in the CEM human T-cell line upon the highest enhancer activity. Target genes of this SNP could be further identified by introducing point mutations to the genome and comparison of transcriptomes of the derivative cell sublines carrying alternative alleles of rs6832151.

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ACKNOWLEDGMENTS

The authors are especially grateful to I.E. Vorontsov for help in editing and designing this acticle.

Funding

The study was carried out with the financial support of the Russian Science Foundation (project no. 18-75-00072).

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  1. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991, Moscow, Russia

    A. S. Ustiugova & M. A. Afanasyeva

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  1. A. S. Ustiugova
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Correspondence to A. S. Ustiugova.

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This study does not contain any research involving humans or animals as research objects.

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Supplementary materials are available for this article at https://doi.org/10.1134/S0026893320040160 and are accessible for authorized users.

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Abbreviations: TF, transcription factor; eQTL, expression quantitative trait loci; GWAS, Genome-wide association studies; GFI1, Growth Factor Independent 1 Transcriptional Repressor; PICS, Probabilistic Identification of Causal SNPs; SNP, single nucleotide polymorphism; H3K27Ac, acetylation of lysine 27 on histone H3 protein subunit; ENCODE, Encyclopedia of DNA Elements.

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Ustiugova, A.S., Afanasyeva, M.A. Noncoding Polymorphism rs6832151 Is an Attractive Candidate for Genome Editing Aimed at Finding New Molecular Mechanisms of Autoimmune Diseases. Mol Biol 54, 730–738 (2020). https://doi.org/10.1134/S0026893320040160

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