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Micro-RNA Binding Site Polymorphisms in the WFS1 Gene Are Risk Factors of Diabetes Mellitus.

Elek Z, Németh N, Nagy G, Németh H, Somogyi A, Hosszufalusi N, Sasvári-Székely M, Rónai Z - PLoS ONE (2015)

Bottom Line: The two miR-SNPs, rs1046322 and rs9457 showed significant association with T1DM and T2DM, respectively.Haplotype analysis also confirmed the association between the 3' UTR loci and both disease types.Furthermore demonstrating the effect of rs9457 in binding of miR-185, we suggest that the optimal level of wolframin protein, potentially influenced by miR-regulation, is crucial in normal beta cell function.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary.

ABSTRACT
The absolute or relative lack of insulin is the key factor in the pathogenesis of diabetes mellitus. Although the connection between loss of function mutations of the WFS1 gene and DIDMOAD-syndrome including diabetes mellitus underpins the significance of wolframin in the pathogenesis, exact role of WFS1 polymorphic variants in the development of type 1 and type 2 diabetes has not been discovered yet. In this analysis, 787 patients with diabetes and 900 healthy people participated. Genotyping of the 7 WFS1 SNPs was carried out by TaqMan assays. Association study was performed by χ2-test in combination with correction for multiple testing. For functional analysis, the entire 3' UTR of the WFS1 gene was subcloned in a pMIR-Report plasmid and relative luciferase activities were determined. Linkage disequilibrium analysis showed a generally high LD within the investigated region, however the rs1046322 locus was not in LD with the other SNPs. The two miR-SNPs, rs1046322 and rs9457 showed significant association with T1DM and T2DM, respectively. Haplotype analysis also confirmed the association between the 3' UTR loci and both disease types. In vitro experiments showed that miR-185 reduces the amount of the resulting protein, and rs9457 miRSNP significantly influences the rate of reduction in a luciferase reporter assay. Genetic variants of the WFS1 gene might contribute to the genetic risk of T1DM and T2DM. Furthermore demonstrating the effect of rs9457 in binding of miR-185, we suggest that the optimal level of wolframin protein, potentially influenced by miR-regulation, is crucial in normal beta cell function.

No MeSH data available.


Related in: MedlinePlus

Linkage disequilibrium analysis of the investigated WFS1 SNPs.Upper panels indicate the chromosomal positions of the polymorphisms, below the pairwise linkage disequilibrium data of the SNPs are demonstrated. Lewontin’s D’ (Panels A and C) and R2 values (Panels B and D) calculated based on our genotype data (Panels A and B) as well as based on the data obtained from the 1000 Genomes Project (Panels C and D) are shown. Dark background and D’ or R2 = 100 values mean strong linkage disequilibrium between the two appropriate loci. (Colored version of the figure is available online.)
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pone.0139519.g001: Linkage disequilibrium analysis of the investigated WFS1 SNPs.Upper panels indicate the chromosomal positions of the polymorphisms, below the pairwise linkage disequilibrium data of the SNPs are demonstrated. Lewontin’s D’ (Panels A and C) and R2 values (Panels B and D) calculated based on our genotype data (Panels A and B) as well as based on the data obtained from the 1000 Genomes Project (Panels C and D) are shown. Dark background and D’ or R2 = 100 values mean strong linkage disequilibrium between the two appropriate loci. (Colored version of the figure is available online.)

Mentions: Fig 1 Panel A and B show the pairwise linkage disequilibrium (LD) analysis based on our population including healthy control subjects and patients demonstrating Lewontin’s D’ and R2 values, respectively. These results were in good agreement with the LD analysis using the data set of the 1000 Genomes Project (Fig 1 Panel C and D). Generally a high level of LD can be observed in the gene region, although it is notable that the rs1046322 polymorphism was not in linkage disequilibrium with the other sites. Moreover the high D’ values in combination with the low R2 values regarding the rs1801208 polymorphism show a partial linkage disequilibrium of this locus with other SNPs, demonstrating the occurrence of three and the lack of one haplotype out of the four theoretical pairwise allele combinations.


Micro-RNA Binding Site Polymorphisms in the WFS1 Gene Are Risk Factors of Diabetes Mellitus.

Elek Z, Németh N, Nagy G, Németh H, Somogyi A, Hosszufalusi N, Sasvári-Székely M, Rónai Z - PLoS ONE (2015)

Linkage disequilibrium analysis of the investigated WFS1 SNPs.Upper panels indicate the chromosomal positions of the polymorphisms, below the pairwise linkage disequilibrium data of the SNPs are demonstrated. Lewontin’s D’ (Panels A and C) and R2 values (Panels B and D) calculated based on our genotype data (Panels A and B) as well as based on the data obtained from the 1000 Genomes Project (Panels C and D) are shown. Dark background and D’ or R2 = 100 values mean strong linkage disequilibrium between the two appropriate loci. (Colored version of the figure is available online.)
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4591293&req=5

pone.0139519.g001: Linkage disequilibrium analysis of the investigated WFS1 SNPs.Upper panels indicate the chromosomal positions of the polymorphisms, below the pairwise linkage disequilibrium data of the SNPs are demonstrated. Lewontin’s D’ (Panels A and C) and R2 values (Panels B and D) calculated based on our genotype data (Panels A and B) as well as based on the data obtained from the 1000 Genomes Project (Panels C and D) are shown. Dark background and D’ or R2 = 100 values mean strong linkage disequilibrium between the two appropriate loci. (Colored version of the figure is available online.)
Mentions: Fig 1 Panel A and B show the pairwise linkage disequilibrium (LD) analysis based on our population including healthy control subjects and patients demonstrating Lewontin’s D’ and R2 values, respectively. These results were in good agreement with the LD analysis using the data set of the 1000 Genomes Project (Fig 1 Panel C and D). Generally a high level of LD can be observed in the gene region, although it is notable that the rs1046322 polymorphism was not in linkage disequilibrium with the other sites. Moreover the high D’ values in combination with the low R2 values regarding the rs1801208 polymorphism show a partial linkage disequilibrium of this locus with other SNPs, demonstrating the occurrence of three and the lack of one haplotype out of the four theoretical pairwise allele combinations.

Bottom Line: The two miR-SNPs, rs1046322 and rs9457 showed significant association with T1DM and T2DM, respectively.Haplotype analysis also confirmed the association between the 3' UTR loci and both disease types.Furthermore demonstrating the effect of rs9457 in binding of miR-185, we suggest that the optimal level of wolframin protein, potentially influenced by miR-regulation, is crucial in normal beta cell function.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary.

ABSTRACT
The absolute or relative lack of insulin is the key factor in the pathogenesis of diabetes mellitus. Although the connection between loss of function mutations of the WFS1 gene and DIDMOAD-syndrome including diabetes mellitus underpins the significance of wolframin in the pathogenesis, exact role of WFS1 polymorphic variants in the development of type 1 and type 2 diabetes has not been discovered yet. In this analysis, 787 patients with diabetes and 900 healthy people participated. Genotyping of the 7 WFS1 SNPs was carried out by TaqMan assays. Association study was performed by χ2-test in combination with correction for multiple testing. For functional analysis, the entire 3' UTR of the WFS1 gene was subcloned in a pMIR-Report plasmid and relative luciferase activities were determined. Linkage disequilibrium analysis showed a generally high LD within the investigated region, however the rs1046322 locus was not in LD with the other SNPs. The two miR-SNPs, rs1046322 and rs9457 showed significant association with T1DM and T2DM, respectively. Haplotype analysis also confirmed the association between the 3' UTR loci and both disease types. In vitro experiments showed that miR-185 reduces the amount of the resulting protein, and rs9457 miRSNP significantly influences the rate of reduction in a luciferase reporter assay. Genetic variants of the WFS1 gene might contribute to the genetic risk of T1DM and T2DM. Furthermore demonstrating the effect of rs9457 in binding of miR-185, we suggest that the optimal level of wolframin protein, potentially influenced by miR-regulation, is crucial in normal beta cell function.

No MeSH data available.


Related in: MedlinePlus