RT Journal Article
SR Electronic
T1 Pathways targeted by anti-diabetes drugs are enriched for multiple genes associated with type 2 diabetes risk
JF Diabetes
JO Diabetes
FD American Diabetes Association
SP DB_140703
DO 10.2337/db14-0703
A1 Segrè, Ayellet V.
A1 Wei, Nancy
A1 ,
A1 ,
A1 Altshuler, David
A1 Florez, Jose C.
YR 2014
UL http://diabetes.diabetesjournals.org/content/early/2014/10/28/db14-0703.abstract
AB 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. Notably, the first two T2D-associated loci (PPARG and KCNJ11/ABCC8) encode known targets of anti-diabetes medications. We therefore tested whether other genes/pathways targeted by anti-diabetes drugs are associated with T2D. We compiled a list of 102 genes in pathways targeted by marketed anti-diabetic medications and applied gene-set enrichment analysis (MAGENTA) 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 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.