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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Drosophila Proteins / genetics*
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism
  • Fat Body / metabolism
  • Fat Body / pathology
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study*
  • Glucose / genetics
  • Glucose / metabolism
  • Homeodomain Proteins / genetics*
  • Humans
  • Insulin Resistance / genetics
  • Muscle Proteins / genetics*
  • Organ Specificity
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Transcription Factors / genetics*

Substances

  • Drosophila Proteins
  • HHEX protein, human
  • Homeodomain Proteins
  • Muscle Proteins
  • Transcription Factors
  • ko protein, Drosophila
  • Glucose