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Functional miR143/145 Cluster Variants and Haplotypes Are Associated with Chronic Kidney Disease: a Preliminary Case-Control Study and Computational Analyses

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Abstract

MiR-143/145 cluster is a novel transcriptional target of many signaling pathways, with variations within this cluster contributed to the risk of multiple diseases. To date, no data regarding the link between miR143/145 cluster polymorphisms and the risk of developing chronic kidney disease (CKD) has been reported. Hence, we aimed to examine such association in a population of Iranian ancestry. In this preliminary study, 276 CKD patients and 300 unrelated age and sex-matched healthy controls were recruited. Genotyping was performed by PCR-RFLP and allele-specific-PCR methods. Computational analyses were performed to predict the potential effects of the variants. Our findings indicated that rs41291957, rs12659504, and rs353292 polymorphisms were positively associated with CKD, while rs4705342 and rs4705343 polymorphisms demonstrated a significant negative association with the disease. Moreover, a significant association was observed between CC + TC and TT genotypes and CKD stages. We found that AACTT, AATTC, AATTT, GATTC, GATTT, and GGCTT haplotypes significantly enhanced the risk of CKD compared with the Grs41291957AArs12659504Crs353292Trs4705342Trs4705343 haplotype. Computational analysis showed that rs353292, rs4705342, and rs4705343 might alter the binding of the transcription factors in this gene cluster. We found that miR-143/145 cluster polymorphisms were associated with CKD risk in a sample of the Iranian population. Replicated studies on different ethnicities are necessary to investigate the association between these promoter variants and clinical outcomes.

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Acknowledgments

We wish to thank Dr. Hamed Taheri for the samples provided.

Funding

This study was financially supported by a grant from Zahedan University of Medical Sciences, Zahedan, Iran (Grant No. 9457).

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Authors and Affiliations

  1. Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran

    Saman Sargazi, Milad Heidari Nia, Fariba Mirani Sargazi, Roghayeh Sheervalilou, Ramin Saravani, Sara Bahrami & Shekoufeh Mirinejad

  2. Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran

    Ramin Saravani

  3. Nephrology Department, Faculty of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran

    Ali Alidadi

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  1. Saman Sargazi
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Contributions

SS and RS conceived and designed the experiments. MHN and RS analyzed the data. SB and FMS performed the genotyping. SS and SM wrote the first draft of the manuscript. SS, AA, and RS contributed to the writing of the manuscript. SS and RS made critical revisions and approved the final version. All authors reviewed and approved the final manuscript.

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Correspondence to Saman Sargazi or Ramin Saravani.

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Ethical approval was obtained from the local Ethics committee of Zahedan University of Medical Sciences (Ethical code: IR.ZAUMS.REC.1398.172), in accordance with the Declaration of Helsinki.

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Supplementary Information

Supplementary Fig. 1

Schematic diagram of chromosome 5 and the locations of studied variants (TIF 47 kb)

High Resolution Image (PNG 181 kb)

Supplementary Fig. 2

LD analysis of rs41291957, rs12659504, rs353292, rs4705342, and rs4705343. Poor linkage disequilibrium was observed between rs41291957 and rs12659504 (TIF 92 kb)

High Resolution Image (PNG 1179 kb)

Supplementary Fig. 3

The impact of rs353292 C/T (A) and rs4705342 C/T (B) on transcription factor binding sites through promoter of miR-143. A new C/EBPbeta binding site is created due to the presence of the T allele in the rs353292 position. T allele of rs4705342 creates a new XBP-1 binding site in the miR-143 promoter region. Other studied variants did not alter transcription factor binding sites (TIF 69 kb)

High Resolution Image (PNG 491 kb)

Supplementary Fig. 4

The results of core promoter motifs analysis performed by the elemeNT server for T allele of rs4705343 (A) and C allele of rs4705343 (B) allele. An alternate TATA box was expanded by the T allele (TIF 60 kb)

High Resolution Image (PNG 464 kb)

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Sargazi, S., Heidari Nia, M., Mirani Sargazi, F. et al. Functional miR143/145 Cluster Variants and Haplotypes Are Associated with Chronic Kidney Disease: a Preliminary Case-Control Study and Computational Analyses. Appl Biochem Biotechnol 193, 1532–1544 (2021). https://doi.org/10.1007/s12010-021-03489-w

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