ABSTRACT
Background: Pirin, a member of the cupin superfamily, is an iron-binding non-heme protein. It acts as a coregulator of several transcription factors, especially the members of NFκB transcription factor family. Based on the redox state of its iron cofactor, it can assume two different conformations and thereby act as a redox sensor inside the nucleus. Previous studies suggested that pirin may be associated with cancer, inflammatory diseases as well as COVID-19 severities. Hence, it is important to explore the pathogenicity of its missense variants. In this study, we used a number of in silico tools to investigate the effects of missense variants of pirin on its structure, stability, metal cofactor binding affinity and interactions with partner proteins. In addition, we used protein dynamics simulation to elucidate the effects of selected variants on its dynamics. Furthermore, we calculated the frequencies of haplotypes containing pirin missense variants across five major super-populations (African, Admixed American, East Asian, European and South Asian). Results: Among a total of 153 missense variants of pirin, 45 were uniformly predicted to be pathogenic. Of these, seven variants can be considered for further experimental studies. Variants R59P and L116P were predicted to significantly destabilize and damage pirin structure, substantially reduce its affinity to its binding partners and alter pirin residue fluctuation profile via changing the flexibility of several key residues. Additionally, variants R59Q, F78V, G98D, V151D and L220P were found to impact pirin structure and function in multiple ways. As no haplotype was identified to be harboring more than one missense variant, further interrogation of the individual effects of these seven missense variants is highly recommended. Conclusions: Pirin is involved in the transcriptional regulation of several genes and can play an important role in inflammatory responses. The variants predicted to be pathogenic in this study may thus contribute to a better understanding of the underlying molecular mechanisms of various inflammatory diseases. Future studies should be focused on clarifying if any of these variants can be used as disease biomarkers. Supplementary Information: The online version contains supplementary material available at 10.1186/s42269-022-00917-7.
ABSTRACT
BACKGROUND: Association of single nucleotide polymorphisms (SNP) rs7756992 A/G and rs7754840 G/C of cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1) gene with the susceptibility of gestational diabetes mellitus (GDM) has been studied in a group of Bangladeshi women. METHODS: In this case-control study, 212 GDM patients and 256 control subjects were genotyped for rs7756992 and rs7754840 by PCR-RFLP and TaqMan™ allelic discrimination assay method respectively. Genotyping results were confirmed by DNA sequencing and replicated TaqMan™ assay. The odds ratios and their 95% confidence interval were calculated by logistic regression to determine the associations between genotypes and GDM. RESULTS: The genotype frequencies of rs7756992-AA/AG/GG in the GDM group and the control group were 37%/48%, 53%/45%, 10%/7% and those of rs7754840-CC/CG/GG were 51%/55%, 40.1%/39.8%, 9%/5% respectively. Under dominant and log additive models rs7756992 was revealed significantly associated with GDM after being adjusted for family history of diabetes (FHD) and gravidity. Conversely, rs7754840 was significantly associated (P = 0.047) with GDM only under the recessive model after the same adjustment. The risk allele frequency of both SNPs was higher in the GDM group but significantly (P = 0.029) increased prevalence was observed in the rs7756992 G allele. When positive FHD and risk alleles of these SNPs were synergistically present in any pregnant woman, the chance of developing GDM was augmented by many folds. The codominant model revealed 2.5 and 2.1 folds increase in odds by AG (rs7756992) and GC (rs7754840) genotypes and 3.7 and 4.5 folds by GG (rs7756992) and CC (rs7754840) genotypes respectively. A significant 2.7 folds (P = 0.038) increase in odds of GDM resulted from the interaction of rs7756992 and family history of diabetes under the dominant model. The cumulative effect of multigravidity and risk alleles of these SNPs increased the odds of GDM more than 1.5 folds in different genotypes. CONCLUSION: This study not only revealed a significant association between rs7756992 and rs7754840 with GDM but also provided the possibility as potential markers for foretelling about GDM and type 2 diabetes mellitus in Bangladeshi women.
