Editors' ChoiceDiabetes

Bioinformatics Is “HIP” in the Islets

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Science Translational Medicine  27 Jul 2011:
Vol. 3, Issue 93, pp. 93ec116
DOI: 10.1126/scitranslmed.3002931

Advances in technology have generated an overwhelming amount of data in almost every sector, nowhere more so than in the field of human genetics. With resources such as whole-genome sequencing, exome sequencing, and single-nucleotide polymorphism (SNP) arrays, it is possible to interrogate the genome in countless ways. Despite the abundance of genetic data generated by such techniques, identification of causative genes can still remain challenging, especially in genome-wide association studies (GWASs). As an answer to this, Berchtold et al. have applied a newer bioinformatics approach to GWAS data, with surprising results for genes in diabetes.

The authors had previously described a unique in silico “phenome-interactome network analysis” that combines annotated gene and disease phenotype data with high-confidence human protein interaction data in order to predict proteins likely to be involved in a disease. Applying this technique now to a GWAS data set of type 1 diabetes, Berchtold et al. identified an unexpected candidate gene, Huntingtin-interacting protein 14 (HIP14). Discovered in 2002, HIP14, which is a widely expressed protein with palmitoyl transferase activity, is best known for its physical interaction with the causative Huntingtin protein in Huntington’s disease. Berchtold and colleagues go on to demonstrate that HIP14 is expressed within mouse, rat, and human pancreatic islets and is linked to increased glucose-stimulated insulin secretion and protection from apoptosis in cultured β-cells. Going back to genetic data sets, the authors were unable to detect direct association of SNPs in HIP14 with disease in a large cohort of type 1 diabetes families but did find potential SNPs that could affect transcription of HIP14, suggesting that either rare variants or variations at a distance could still affect HIP14 expression.

Although the studies of HIP14 in islet cells are still preliminary, the current results highlight the successful application of a novel method to augment gene-finding approaches and have revealed a surprising new area of research at the interface of Huntington’s disease and diabetes. Indeed, given the observation of increased diabetes risk in Huntington’s patients, the discovery of HIP14 provides a potential mechanistic link for this association, possibly through posttranslational modification of amyloid-like proteins in both settings. Further research on this previously unidentified protein and its multiple roles will be of great interest in defining its potential as a causative gene and a therapeutic target.

L. A. Berchtold et al., Huntingtin-interacting protein 14 is a type 1 diabetes candidate protein regulating insulin secretion and β-cell apoptosis. Proc. Natl. Acad. Sci. U.S.A. 24 June 2011 (10.1073pnas.1104384108). [Abstract]

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