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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We wish to thank Dr. Hamed Taheri for the samples provided.
This study was financially supported by a grant from Zahedan University of Medical Sciences, Zahedan, Iran (Grant No. 9457).
The authors declare that they have no competing interests.
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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Schematic diagram of chromosome 5 and the locations of studied variants (TIF 47 kb)
LD analysis of rs41291957, rs12659504, rs353292, rs4705342, and rs4705343. Poor linkage disequilibrium was observed between rs41291957 and rs12659504 (TIF 92 kb)
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)
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)
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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
- Bioinformatics analysis
- Chronic kidney disease