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Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk.

Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk.

Authors :
Segrè AV
Wei N
Altshuler D
Florez JC
Source :
Diabetes [Diabetes] 2015 Apr; Vol. 64 (4), pp. 1470-83. Date of Electronic Publication: 2014 Nov 03.
Publication Year :
2015

Abstract

Genome-wide association studies (GWAS) have uncovered >65 common variants associated with type 2 diabetes (T2D); however, their relevance for drug development is not yet clear. Of note, the first two T2D-associated loci (PPARG and KCNJ11/ABCC8) encode known targets of antidiabetes medications. We therefore tested whether other genes/pathways targeted by antidiabetes drugs are associated with T2D. We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis (MAGENTA [Meta-Analysis Gene-set Enrichment of variaNT Associations]) to this gene set, using available GWAS meta-analyses for T2D and seven quantitative glycemic traits. We detected a strong enrichment of drug target genes associated with T2D (P = 2 × 10(-5); 14 potential new associations), primarily driven by insulin and thiazolidinedione (TZD) targets, which was replicated in an independent meta-analysis (Metabochip). The glycemic traits yielded no enrichment. The T2D enrichment signal was largely due to multiple genes of modest effects (P = 4 × 10(-4), after removing known loci), highlighting new associations for follow-up (ACSL1, NFKB1, SLC2A2, incretin targets). Furthermore, we found that TZD targets were enriched for LDL cholesterol associations, illustrating the utility of this approach in identifying potential side effects. These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design.<br /> (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Details

Language :
English
ISSN :
1939-327X
Volume :
64
Issue :
4
Database :
MEDLINE
Journal :
Diabetes
Publication Type :
Academic Journal
Accession number :
25368101
Full Text :
https://doi.org/10.2337/db14-0703