scholarly journals Discovery of Coding Genetic Variants Influencing Diabetes-Related Serum Biomarkers and Their Impact on Risk of Type 2 Diabetes

2015 ◽  
Vol 100 (4) ◽  
pp. E664-E671 ◽  
Author(s):  
Tarunveer Singh Ahluwalia ◽  
Kristine Højgaard Allin ◽  
Camilla Helene Sandholt ◽  
Thomas Hempel Sparsø ◽  
Marit Eika Jørgensen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Heat Shock ◽  
Single Nucleotide Polymorphisms ◽  
Genetic Variants ◽  
Binding Protein ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Igf Binding ◽  
Igf Binding Protein

Context: Type 2 diabetes (T2D) prevalence is spiraling globally, and knowledge of its pathophysiological signatures is crucial for a better understanding and treatment of the disease. Objective: We aimed to discover underlying coding genetic variants influencing fasting serum levels of nine biomarkers associated with T2D: adiponectin, C-reactive protein, ferritin, heat shock 70-kDa protein 1B, IGF binding protein 1 and IGF binding protein 2, IL-18, IL-2 receptor-α, and leptin. Design and Participants: A population-based sample of 6215 adult Danes was genotyped for 16 340 coding single-nucleotide polymorphisms and were tested for association with each biomarker. Identified loci were tested for association with T2D through a large-scale meta-analysis involving up to 17 024 T2D cases and up to 64 186 controls. Results: We discovered 11 associations between single-nucleotide polymorphisms and five distinct biomarkers at a study-wide P < 3.4 × 10−7. Nine associations were novel: IL18: BIRC6, RAD17, MARVELD2; ferritin: F5; IGF binding protein 1: SERPING1, KLKB, GCKR, CELSR2, and heat shock 70-kDa protein 1B: CFH. Three of the identified loci (CELSR2, HNF1A, and GCKR) were significantly associated with T2D, of which the association with the CELSR2 locus has not been shown previously. Conclusion: The identified loci influence processes related to insulin signaling, cell communication, immune function, apoptosis, DNA repair, and oxidative stress, all of which could provide a rationale for novel diabetes therapeutic strategies.

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 Polymorphisms in IGF-Binding Protein 1 Are Associated With Impaired Renal Function in Type 2 Diabetes

Diabetes ◽  
2005 ◽  
Vol 54 (12) ◽  
pp. 3547-3553 ◽  
Author(s):  
R. H. Stephens ◽  
P. McElduff ◽  
A. H. Heald ◽  
J. P. New ◽  
J. Worthington ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Renal Function ◽  
Impaired Renal Function ◽  
Binding Protein ◽  
Igf Binding ◽  
Igf Binding Protein

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 < 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 < 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.

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