Abstract
Human genome-wide association studies (GWAS) have shown that genetic variation at >130 gene loci is associated with type 2 diabetes (T2D). We asked if the expression of the candidate T2D-associated genes within these loci is regulated by a common locus in pancreatic islets. Using an obese F2 mouse intercross segregating for T2D, we show that the expression of ~40% of the T2D-associated genes is linked to a broad region on mouse chromosome (Chr) 2. As all but 9 of these genes are not physically located on Chr 2, linkage to Chr 2 suggests a genomic factor(s) located on Chr 2 regulates their expression in trans. The transcription factor Nfatc2 is physically located on Chr 2 and its expression demonstrates cis linkage; i.e., its expression maps to itself. When conditioned on the expression of Nfatc2, linkage for the T2D-associated genes was greatly diminished, supporting Nfatc2 as a driver of their expression. Plasma insulin also showed linkage to the same broad region on Chr 2. Overexpression of a constitutively active (ca) form of Nfatc2 induced β-cell proliferation in mouse and human islets, and transcriptionally regulated more than half of the T2D-associated genes. Overexpression of either ca-Nfatc2 or ca-Nfatc1 in mouse islets enhanced insulin secretion, whereas only ca-Nfatc2 was able to promote β-cell proliferation, suggesting distinct molecular pathways mediating insulin secretion vs. β-cell proliferation are regulated by NFAT. Our results suggest that many of the T2D-associated genes are downstream transcriptional targets of NFAT, and may act coordinately in a pathway through which NFAT regulates β-cell proliferation in both mouse and human islets.
Highlights
Human genome-wide association studies (GWAS) have identified genetic variation at >130 loci that is associated with various traits linked to the development of type 2 diabetes (T2D)
We wondered if candidate genes associated with type 2 diabetes in human populations, in addition to being causal for the disease, could be intermediate traits in a pathway leading to disease
We wished to know if there were any regulatory loci that could coordinately drive the expression of these genes in pancreatic islets and complete a pathway; i.e. Driver ! GWAS candidate expression ! type 2 diabetes
Summary
Human genome-wide association studies (GWAS) have identified genetic variation at >130 loci that is associated with various traits linked to the development of T2D. Recent studies have shown that many of the T2D-associated candidate genes primarily affect the health and function of pancreatic islet cells [1]. Understanding the relationship between their functional role in pancreatic islets, and proximity to T2D-associated loci is critically important. Genetic association is defined as a causal relationship between genetic variation at a locus and a disease phenotype. Despite the large number of loci that are associated with T2D, collectively they account for only ~10% of the genetic variability of the disease [2]. This “hidden heritability” has been attributed to the inability to detect rare alleles and/or epistasis [3]. It is possible that dysregulation of pathways leading to T2D occur in many different ways and do not reflect genetic variation at a single locus
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
