scholarly journals In Vivo Reporter Assays Uncover Changes in Enhancer Activity Caused by Type 2 Diabetes–Associated Single Nucleotide Polymorphisms

Diabetes ◽  
2020 ◽  
Vol 69 (12) ◽  
pp. 2794-2805
Author(s):  
Ana Eufrásio ◽  
Chiara Perrod ◽  
Fábio J. Ferreira ◽  
Marta Duque ◽  
Mafalda Galhardo ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Single Nucleotide Polymorphisms ◽  
Nucleotide Polymorphisms ◽  
Enhancer Activity ◽  
Single Nucleotide ◽  
Reporter Assays

scholarly journals In vivo reporter assays uncover changes in enhancer activity caused by type 2 diabetes associated SNPs

2020 ◽  
Author(s):  
Ada Admin ◽  
Ana Eufrásio ◽  
Chiara Perrod ◽  
Marta Duque ◽  
Fábio J.Ferreira ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Nucleotide Polymorphisms ◽  
Enhancer Activity ◽  
Single Nucleotide ◽  
Increased Risk ◽  
Nucleotide Mutation ◽  
Reporter Assays ◽  
Coding Snp

Many single nucleotide polymorphisms (SNPs) associated to type 2 diabetes overlap with putative endocrine pancreatic enhancers, suggesting that these SNPs modulate enhancer activity and consequently, gene expression. We performed <i>in vivo</i> mosaic transgenesis assays in zebrafish to quantitatively test the enhancer activity of type 2 diabetes-associated <i>loci</i>. Six out of ten tested sequences are endocrine pancreatic enhancers. The risk variant of two sequences decreased enhancer activity, while in another two incremented it. One of the latter (rs13266634) locates in a <i>SLC30A8 </i>exon, encoding a tryptophan-to-arginine substitution that decreases <i>SLC30A8 </i>function, being the canonical explanation for type 2 diabetes risk association. However, other type 2 diabetes associated SNPs that truncate SLC30A8, confer protection to this disease, contradicting this explanation. Here, we clarify this incongruence showing that rs13266634 boosts the activity of an overlapping enhancer, suggesting a SLC30A8 gain-of-function as the cause for the increased risk for the disease. We further dissected the functionality of this enhancer finding a single nucleotide mutation sufficient to impair its activity. Overall, this work assesses <i>in vivo</i> the importance of disease-associated SNPs in the activity of endocrine pancreatic enhancers, including a poorly explored case where a coding SNP modulates the activity of an enhancer.

scholarly journals In vivo reporter assays uncover changes in enhancer activity caused by type 2 diabetes associated SNPs

2020 ◽  
Author(s):  
Ada Admin ◽  
Ana Eufrásio ◽  
Chiara Perrod ◽  
Marta Duque ◽  
Fábio J.Ferreira ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Nucleotide Polymorphisms ◽  
Enhancer Activity ◽  
Single Nucleotide ◽  
Increased Risk ◽  
Nucleotide Mutation ◽  
Reporter Assays ◽  
Coding Snp

Many single nucleotide polymorphisms (SNPs) associated to type 2 diabetes overlap with putative endocrine pancreatic enhancers, suggesting that these SNPs modulate enhancer activity and consequently, gene expression. We performed <i>in vivo</i> mosaic transgenesis assays in zebrafish to quantitatively test the enhancer activity of type 2 diabetes-associated <i>loci</i>. Six out of ten tested sequences are endocrine pancreatic enhancers. The risk variant of two sequences decreased enhancer activity, while in another two incremented it. One of the latter (rs13266634) locates in a <i>SLC30A8 </i>exon, encoding a tryptophan-to-arginine substitution that decreases <i>SLC30A8 </i>function, being the canonical explanation for type 2 diabetes risk association. However, other type 2 diabetes associated SNPs that truncate SLC30A8, confer protection to this disease, contradicting this explanation. Here, we clarify this incongruence showing that rs13266634 boosts the activity of an overlapping enhancer, suggesting a SLC30A8 gain-of-function as the cause for the increased risk for the disease. We further dissected the functionality of this enhancer finding a single nucleotide mutation sufficient to impair its activity. Overall, this work assesses <i>in vivo</i> the importance of disease-associated SNPs in the activity of endocrine pancreatic enhancers, including a poorly explored case where a coding SNP modulates the activity of an enhancer.

scholarly journals AHSG Tag Single Nucleotide Polymorphisms Associate With Type 2 Diabetes and Dyslipidemia: Studies of Metabolic Traits in 7,683 White Danish Subjects

Diabetes ◽  
2008 ◽  
Vol 57 (5) ◽  
pp. 1427-1432 ◽  
Author(s):  
G. Andersen ◽  
K. S. Burgdorf ◽  
T. Sparso ◽  
K. Borch-Johnsen ◽  
T. Jorgensen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Single Nucleotide Polymorphisms ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Metabolic Traits

scholarly journals Molecular Screening and Association Analyses of the Interleukin 6 Receptor Gene Variants with Type 2 Diabetes, Diabetic Nephropathy, and Insulin Sensitivity

2005 ◽  
Vol 90 (2) ◽  
pp. 1123-1129 ◽  
Author(s):  
Hua Wang ◽  
Zhengxian Zhang ◽  
Winston Chu ◽  
Terri Hale ◽  
Judith J. Cooper ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Nephropathy ◽  
Insulin Sensitivity ◽  
Single Nucleotide Polymorphisms ◽  
Untranslated Region ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Northern European ◽  
A Minor

IL-6 levels and polymorphisms have been implicated in type 2 diabetes mellitus (T2DM) and insulin resistance. The IL-6 receptor (IL-6R) comprises two subunits, IL-6R and gp130, of which IL-6R confers specificity to IL-6 action and is located in a region of replicated linkage to T2DM on chromosome 1q21. We screened this gene for variation in Northern European Caucasian and African-American ethnic groups. We identified 11 variants with a minor allele frequency over 5%, including two amino acid changes (D358A and V385I) and four variants in the 3′ untranslated region. No variant was associated with obesity or measures of insulin sensitivity, but two single nucleotide polymorphisms in the 3′ untranslated region showed a trend to an association with T2DM in all Caucasians, and three single nucleotide polymorphisms, including D358A, showed a trend (P &lt; 0.06) to an association with T2DM among the subset of Northern European Caucasians. Variant V385I was unique to African-Americans and was significantly associated with diabetes and diabetic nephropathy (P &lt; 0.05). Among individuals heterozygous for the four variants in the transcribed sequence, one allele was significantly overrepresented, thus suggesting the existence of a regulatory variant controlling mRNA stability or expression. IL-6R is not likely to explain the linkage to diabetes in this region, but our work supports a minor role of variants in T2DM risk and suggests that sequence variants may alter IL-6R mRNA levels and possibly levels of soluble IL-6R.

scholarly journals ABCG2 regulatory single-nucleotide polymorphisms alter in vivo enhancer activity and expression

2017 ◽  
Vol 27 (12) ◽  
pp. 454-463 ◽  
Author(s):  
Rachel J. Eclov ◽  
Mee J. Kim ◽  
Aparna Chhibber ◽  
Robin P. Smith ◽  
Nadav Ahituv ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Nucleotide Polymorphisms ◽  
Enhancer Activity ◽  
Single Nucleotide
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