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BMC Genomics. 2013 Feb 27;14:136. doi: 10.1186/1471-2164-14-136.

A Drosophila functional evaluation of candidates from human genome-wide association studies of type 2 diabetes and related metabolic traits identifies tissue-specific roles for dHHEX.

Author information

1
Department of Developmental and Regenerative Biology, Mount SinaiSchool of Medicine, New York, NY, USA.

Abstract

BACKGROUND:

Genome-wide association studies (GWAS) identify regions of the genome that are associated with particular traits, but do not typically identify specific causative genetic elements. For example, while a large number of single nucleotide polymorphisms associated with type 2 diabetes (T2D) and related traits have been identified by human GWAS, only a few genes have functional evidence to support or to rule out a role in cellular metabolism or dietary interactions. Here, we use a recently developed Drosophila model in which high-sucrose feeding induces phenotypes similar to T2D to assess orthologs of human GWAS-identified candidate genes for risk of T2D and related traits.

RESULTS:

Disrupting orthologs of certain T2D candidate genes (HHEX, THADA, PPARG, KCNJ11) led to sucrose-dependent toxicity. Tissue-specific knockdown of the HHEX ortholog dHHEX (CG7056) directed metabolic defects and enhanced lethality; for example, fat-body-specific loss of dHHEX led to increased hemolymph glucose and reduced insulin sensitivity.

CONCLUSION:

Candidate genes identified in human genetic studies of metabolic traits can be prioritized and functionally characterized using a simple Drosophila approach. To our knowledge, this is the first large-scale effort to study the functional interaction between GWAS-identified candidate genes and an environmental risk factor such as diet in a model organism system.

PMID:
23445342
PMCID:
PMC3608171
DOI:
10.1186/1471-2164-14-136
[Indexed for MEDLINE]
Free PMC Article

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