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

作者：Pendse Jay; Ramachandran Prasanna V; Na Jianbo; Narisu Narisu; Fink Jill L; Cagan Ross L; Collins Francis S; Baranski Thomas J^*

来源：BMC Genomics, 2013, 14(1): 136.

DOI：10.1186/1471-2164-14-136

• Genome-wide association study
• Drosophila melanogaster
• Diabetes mellitus
• type 2
• Hyperglycemia
• Dyslipidemias
• Phylogeny
• Reverse genetics
• High-throughput screening assays
• HHEX protein
• human

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.

• 出版日期2013-2-27