A Common Type 2 Diabetes Risk Variant Potentiates Activity of an Evolutionarily Conserved Islet Stretch Enhancer and Increases C2CD4A and C2CD4B Expression
| Autor: | Shubham Khetan, Asli Uyar, Ryan P. Welch, Markku Laakso, Anubhuti Mathur, Michael L. Stitzel, Brooke N. Wolford, Stephen C. J. Parker, Ricardo D’Oliveira Albanus, Jeroen R. Huyghe, Michael Boehnke, Duygu Ucar, Swarooparani Vadlamudi, Francis S. Collins, Romy Kursawe, Nathan Lawlor, Mohan Bolisetty, Karen L. Mohlke, Ina Kycia, Johanna Kuusisto, Christian Fuchsberger |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
endocrine system endocrine system diseases Genome-wide association study Locus (genetics) Biology Polymorphism Single Nucleotide Article Cell Line Evolution Molecular 03 medical and health sciences Islets of Langerhans Mice Risk Factors Genetics Animals Humans Allele Enhancer Gene Genetics (clinical) Alleles Conserved Sequence Genetic association Aged geography Chromosomes Human Pair 15 geography.geographical_feature_category Base Sequence NFATC Transcription Factors Calcium-Binding Proteins Nuclear Proteins Middle Aged Islet Physical Chromosome Mapping Chromatin Rats 030104 developmental biology Enhancer Elements Genetic Mutation Cytokines DNA Intergenic Inflammation Mediators Functional genomics Proinsulin Transcription Factors |
| Popis: | Genome-wide association studies (GWASs) and functional genomics approaches implicate enhancer disruption in islet dysfunction and type 2 diabetes (T2D) risk. We applied genetic fine-mapping and functional (epi)genomic approaches to a T2D- and proinsulin-associated 15q22.2 locus to identify a most likely causal variant, determine its direction of effect, and elucidate plausible target genes. Fine-mapping and conditional analyses of proinsulin levels of 8,635 non-diabetic individuals from the METSIM study support a single association signal represented by a cluster of 16 strongly associated (p < 10−17) variants in high linkage disequilibrium (r2 > 0.8) with the GWAS index SNP rs7172432. These variants reside in an evolutionarily and functionally conserved islet and β cell stretch or super enhancer; the most strongly associated variant (rs7163757, p = 3 × 10−19) overlaps a conserved islet open chromatin site. DNA sequence containing the rs7163757 risk allele displayed 2-fold higher enhancer activity than the non-risk allele in reporter assays (p < 0.01) and was differentially bound by β cell nuclear extract proteins. Transcription factor NFAT specifically potentiated risk-allele enhancer activity and altered patterns of nuclear protein binding to the risk allele in vitro, suggesting that it could be a factor mediating risk-allele effects. Finally, the rs7163757 proinsulin-raising and T2D risk allele (C) was associated with increased expression of C2CD4B, and possibly C2CD4A, both of which were induced by inflammatory cytokines, in human islets. Together, these data suggest that rs7163757 contributes to genetic risk of islet dysfunction and T2D by increasing NFAT-mediated islet enhancer activity and modulating C2CD4B, and possibly C2CD4A, expression in (patho)physiologic states. |
| Databáze: | OpenAIRE |
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