Editors' ChoiceGenetics

“It’s ARAP” for Type II Diabetes

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Science Translational Medicine  29 Jan 2014:
Vol. 6, Issue 221, pp. 221ec22
DOI: 10.1126/scitranslmed.3008474

Genome-wide association studies (GWASs) have been able to identify associations between genetic differences in human disease. However, the reasons why a particular genetic mutation leads to disease are often not readily apparent. In a study by Kulzer and colleagues, not only is a specific genetic variant nominated as causal for type II diabetes discovered, but the underlying mechanism is investigated, implicating the gene ARAP1.

The authors homed in on the 11q13.4 region of association, which was previously identified in a large case control meta-analysis of human type II diabetes. This region encompasses five genes: PDE2A, ARAP1, STARD10, ATG16L2, and FCHSD2. Such gene-rich regions are common in GWAS-significant loci, complicating interpretation. In addition to the association to type II diabetes, the genetic variation is also robustly associated with other traits, such as fasting proinsulin and 32,33 proinsulin, suggesting that pancreatic cells might be involved in the mechanism of risk for type II diabetes. To assess the biological consequences driving the association with type II diabetes, the authors performed allelic expression imbalance—a method used to identify genetic variation that changes expression level of a given transcript. Of the genes evaluated, only ARAP1 showed substantial allelic expression imbalance, which is consistent with the model that the risk of developing type II diabetes is associated with changing ARAP1 expression in the population. No meaningful evidence was observed for STARD10, PDE2A, or FCHSD2, but this does not conclusively rule out the possibility of further biological consequences of those genes in the risk of developing type II diabetes. The authors went one step further by evaluating the transcription factor–binding sites in the region that might regulate the expression of ARAP1. They showed that PAX6 binds to the allele with lower expression (in the allelic expression imbalance assay), suggesting that PAX6 suppresses the transcription of ARAP1, potentially when in complex with PAX4. This study is an example of how careful experimentation following up significant loci revealed in GWASs can point to biological mechanisms of action and eventually wrap up our understanding of human disease.

J. R. Kulzer et al., A common functional regulatory variant at a type 2 diabetes locus upregulates ARAP1 expression in the pancreatic beta cell. Am. J. Hum. Genet., published online 16 January 2014 (10.1016/j.ajhg.2013.12.011). [Abstract]

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