Testing for potential nonglycemic effects of TZDs or other antidiabetes drug classes on global lipid plasma levels through GSEA of genetic associations
| LDL-C GWAS meta-analysis | Triglyceride GWAS meta-analysis | HDL-C GWAS meta-analysis | ||||||
|---|---|---|---|---|---|---|---|---|
| Antidiabetes drug target gene set | Number of genes analyzed* | Nominal MAGENTA enrichment P value | Excess number of genes above enrichment cutoff | Nominal MAGENTA enrichment P value | Excess number of genes above enrichment cutoff | Nominal MAGENTA enrichmentP value | Excess number of genes above enrichment cutoff | Antidiabetes drug target genes in LD to validated lipid SNPs‡ |
| TZDs | 38 | 0.0007† | 9 | 0.06 | 4 | 0.35 | 1 | APOA1 (TG, HDL-C, LDL-C), IRS1 (HDL-C, TG), SCARB1 (HDL-C) |
| All nine classes of drugs | 94–95 | 0.01 | 10 | 0.03 | 8 | 0.22 | 3 | APOA1 (TG, HDL-C, LDL-C), IRS1 (HDL-C, TG), SCARB1 (HDL-C) |
| Insulin | 16 | 0.19 | 2 | 0.35 | 1 | 0.35 | 1 | IRS1 (HDL-C, TG) |
| GLP-1 receptor agonists | 17 | 0.65 | 0 | 0.10 | 3 | 0.24 | 0 | — |
| DPP4 inhibitors | 18–20 | 0.91 | 0 | 0.67 | 0 | 0.88 | 0 | — |
TG, triglyceride.
*Number of genes analyzed after excluding genes in HLA region and genes on sex chromosomes and correcting for physical clustering along the genome of genes within a given gene set. The number varies a bit between GWAS meta-analyses due to slight differences in SNP coverage between traits. Because of the physical proximity of APOC3 and APOA1, these genes were collapsed into one effective gene in the enrichment analysis (choosing the more significant gene P value) to prevent inflation of the gene set enrichment P value.
†Passes Bonferroni correction, P < 0.003.
‡Based on 95 loci associated with global lipid traits in (33).