Pathways Targeted by Antidiabetes Drugs Are Enriched for Multiple Genes Associated With Type 2 Diabetes Risk
Article Figures & Tables
Figures
- Figure 1
An overview of the study design, analytical steps, and questions addressed. The strategy addressed a number of key questions about the relationship between human genetic associations with T2D or related glycemic traits and antidiabetes drug targets. A similar strategy can be applied to other diseases and traits. 2-h glucose and 2-h insulin, glucose or insulin plasma levels measured 2 h after an oral glucose tolerance test; HbA1c, a measure for long-term glycemia; HOMA-B, a measure for β-cell function; HOMA-IR, a measure for insulin resistance.
- Figure 2
Distribution of T2D gene association P values of antidiabetes drug targets. To visualize the enrichment of multiple modest associations with T2D among antidiabetes drug target genes, we plotted the noncumulative distribution of adjusted gene association P values (calculated with MAGENTA) for all the antidiabetes drug targets (99 autosomal genes), as shown in the first track (red line). The following two tracks display from top to bottom the individual gene P values (represented by vertical lines) for the insulin targets subset and the TZD targets subset. Common insulin and TZD targets are shown in blue. The dashed line marks the 75th percentile enrichment cutoff.
Tables
- Table 1
Target genes and pathways of nine classes of FDA-approved antidiabetes medications
Medication class Mechanism of action Physiological effect Tissue Number of target genes* Target genes of antidiabetes medication class* Target genes in LD to known T2D or glycemic trait–associated SNPs† References Insulin Downstream signaling from insulin/IGF-I receptor Signals glucose uptake Liver, muscle, fat 17 ACACA, AKT1, FOXO1, GAB1, INSR, IRS1, IRS2, IRS4, PIK3CA, PIK3R1, SLC2A1, SLC2A2, SLC2A3, SLC2A4, SLC2A5, SHC1, TRIB3 IRS1: T2D, fasting insulin, insulin resistance; SLC2A2 (GLUT2): fasting glucose 11,19,42 Metformin (biguanide) AMP-activated protein kinase pathway; complex I inhibition Improves insulin sensitivity; reduces gluconeogenesis Liver, muscle 6 PRKAA2, SLC22A1, SLC22A2, SLC2A1, SLC2A4, STK11 — 20,30 TZDs PPARG receptor pathway Fat, muscle, liver 42 ABCA1, ACSL1, ADIPOQ, ADIPOR1, ADIPOR2, APOA1, APOC3, CCL2, CD36, CPT1A, CPT1B, CPT2, CRP, EDN1, F3, FACL2, FGB, GK, HSD11B1, ICAM1, IL6, IRS1, IRS2, MMP9, NFKB1, NFKB2, NOS2A, PDK4, PIK3CA, PIK3R1, PPARA, PPARD, PPARG, PTGS1, RETN, RXRA, SCARB1, SLC2A4, SLC27A1, SORBS1, TNF, VCAM1 PPARG: T2D; IRS1: T2D, fasting insulin 11,21,22,42 Sulfonylureas ATP-sensitive K channel inhibition Increases insulin production and secretion from β-cells in pancreas and/or decreases glucagon secretion from α-cells in pancreas Pancreas, liver, fat 5 ABCC8, ABCC9, KCNJ11, SLC2A4, TNF KCNJ11: T2D ABCC8: T2D 23–25 GLP-1 receptor agonists GLP-1 receptor pathway Pancreas, GI tract 18 ATF4, BCL2, CASP12, CPA1, DDIT3, EIF2S1, GCG, GLP1R, HSPA5, JUNB, NGFB, NGFR, PDX1, PPP1R15A, PPYR1, PRKACA, XBP1, XIAP PDX1: fasting glucose‡ 16–18 DPP4 inhibitors Inhibits DPP4 degradation (i.e., GLP-1, GIP) Diffuse 20 ADCYAP1, CCL11, CCL5, CCL22, CXCL9, CXCL10, CXCL11, CXCL12, DPP4, DPP8, DPP9, FAP, GHRH, GIP, GIPR, GRP, GLP2R, NPY, PYY, TAC1 GIPR: T2D‡, fasting glucose‡, 2-h glucose, 2-h insulin 18,26 Amylin mimetics Amylin receptor pathway Pancreas, GI tract 2 IAPP, IDE IDE: T2D 27 Meglitinides ATP-sensitive K channel inhibition Pancreas, liver, fat 2 ABCC8, KCNJ11 KCNJ11/ABCC8: T2D 28 α-Glucosidase inhibitors Inhibits α-glucosidase enzymes, α-amylase inhibition Affects sugar absorption in gut by preventing digestion of carbohydrates Small intestine, pancreas 2 AMY2A, GAA — 29 GI, gastrointestinal.
*Genes involved in pathways targeted by antidiabetes medications were compiled from the literature.
†Validated SNP associations are based on GWAS of European descent individuals; details of associations are in Supplementary Table 1.
‡These genes were added to our drug target gene list before their association with T2D or a related glycemic trait was reported (3). Genes in boldface refer to drug targets in LD to SNPs associated with T2D or glycemic traits.
- Table 2
GSEA of T2D and glycemic trait associations in the antidiabetes drug target gene set
GWAS meta-analysis Nominal MAGENTA enrichment P value* Number of OBS genes/loci above enrichment cutoff Number of EXP genes/loci above enrichment cutoff Excess number of genes/loci above enrichment cutoff (OBS − EXP)† Enrichment fold (OBS/EXP) Number of genes near validated GWAS SNPs‡ Genes near validated GWAS SNPs‡ T2D 1.7 × 10−5 41** 23 18 1.78 6*** PPARG, IRS1§, KCNJ11/ABCC8‖, IDE, GIPR¶ Fasting glucose 0.078 31 24 7 1.29 1 SLC2A2 HOMA-IR 0.11 29 24 5 1.21 0 — 2-h insulin 0.24 27 24 3 1.13 1 IRS1 HOMA-B 0.27 26 23 3 1.13 0 — Fasting insulin 0.29 26 24 2 1.08 0 — 2-h glucose 0.74 20 23 0 0.87 0 — HbA1c 0.75 20 23 0 0.87 0 — The 2-h glucose and 2-h insulin concentrations were measured after an oral glucose tolerance test. EXP, expected; OBS, observed.
*The gene set enrichment P value was calculated by MAGENTA using a 75th percentile enrichment cutoff.
**44 genes had scores above the enrichment cutoff, but 3 genes were removed from GSEA to correct for physical clustering along the genome (see Table 4).
***Only 4 loci contributed to enrichment signal. See next two footnotes for explanation.
†Estimated number of antidiabetes drug targets that may be true associations with T2D, 14 of which have not yet reached genome-wide significance.
‡Genes were mapped onto 55 established T2D SNPs using the larger of the two boundaries around each SNP: ±100 kb or LD r2 > 0.5 (see research design and methods and Supplementary Table 3).
§The gene association P value of IR1S did not surpass the enrichment cutoff because the established T2D GWAS SNP near IRS1 lies farther away than the gene boundaries used in MAGENTA (+110 kb/−40 kb).
‖KCNJ11/ABCC8 were collapsed to one effective gene in the GSEA due to their physical proximity.
¶GIPR was added to our drug target gene list before its association with T2D reached genome-wide significance in a joint meta-analysis of DIAGRAMv3 and Metabochip (3).
- Table 3
GSEA of T2D associations in individual drug class target sets before and after removing genes in established T2D loci
All genes analyzed Excluding genes in LD to validated T2D SNPs Antidiabetes drug target gene set Number of genes analyzed* Nominal MAGENTA enrichment P value Enrichment fold (OBS/EXP) Excess number of genes above enrichment cutoff (OBS − EXP) Number of genes analyzed* Nominal MAGENTA enrichment P value Enrichment fold (OBS/EXP) Excess number of genes above enrichment cutoff (OBS − EXP) Genes in LD to validated T2D SNPs† All nine classes of drugs 92 1.7 × 10−5 1.8 18 87 4 × 10−4 1.7 15 PPARG, IRS1‡, KCNJ11/ABCC8, IDE, GIPR Insulin 16 0.001 2.5 6 15 8 × 10−4 2.5 6 IRS1 TZDs 38 0.02 1.6 6 36 0.01 1.7 6 PPARG, IRS1 DPP4 inhibitors 18 0.15 1.4 2 17 0.22 1.5 2 — GLP-1 receptor agonists 17 0.38 1.3 1 17 0.49 1.3 1 — EXP, expected; OBS, observed.
*Number of genes analyzed after excluding genes in HLA region (one gene) and genes on sex chromosomes (three genes) and correcting for physical clustering of subsets of genes within a given gene set along the genome (six genes).
†Genes were mapped onto 55 established T2D SNPs using the larger of two boundaries around each SNP: ±100 kb or LD r2 > 0.5 (see research design and methods and Supplementary Table 3).
‡The gene P value of IRS1 did not pass the enrichment cutoff because the validated T2D GWAS SNP near IRS1 lies farther away than the gene boundaries used in the MAGENTA analysis.
- Table 4
Top-ranked antidiabetes target genes above enrichment cutoff based on their DIAGRAMv3 T2D gene association P values
Gene Description T2D medication class MAGENTA T2D gene association P value Best local SNP rs number Best local SNP DIAGRAMv3 P value Gene in LD to established T2D SNPs IDE Insulin-degrading enzyme Amylin mimetics 1.55 × 10−15 rs7911264 4.50 × 10−13 + PPARG Peroxisome proliferator–activated receptor γ TZDs 6.32 × 10−9 rs11709077 1.12 × 10−9 + KCNJ11* Potassium inwardly rectifying channel, subfamily J, member 11 Sulfonylureas, meglitinides 6.88 × 10−4 rs5215 4.36 × 10−6 + ABCC8* ATP-binding cassette, subfamily C (CFTR/MRP), member 8 Sulfonylureas 1.22 × 10−3 rs5215 4.36 × 10−6 + GIP Gastric inhibitory polypeptide DPP inhibitors 7.62 × 10−3 rs3809770 1.03 × 10−4 − ACSL1 Acyl-CoA synthetase long-chain family member 1 TZDs 1.83 × 10−2 rs735949 7.76 × 10−5 − IRS2 Insulin receptor substrate 2 Insulin, TZDs 1.89 × 10−2 rs1330545 1.02 × 10−4 − GLP1R Glucagon-like peptide 1 receptor GLP-1 receptor agonists 2.39 × 10−2 rs1929902 5.35 × 10−5 − GLP2R Glucagon-like peptide 2 receptor DPP inhibitors 2.87 × 10−2 rs17743194 4.28 × 10−5 − NFKB1 Nuclear factor of κ light polypeptide gene enhancer in B-cells 1 TZDs 3.01 × 10−2 rs4648055 2.04 × 10−4 − ADIPOQ Adiponectin, C1Q, and collagen domain containing TZDs 3.22 × 10−2 rs7649121 2.12 × 10−4 − CXCL9† Chemokine (C-X-C motif) ligand 9 DPP inhibitors 3.83 × 10−2 rs13131187 3.13 × 10−4 − CXCL11† Chemokine (C-X-C motif) ligand 11 DPP inhibitors 3.86 × 10−2 rs13131187 3.13 × 10−4 − CXCL10† Chemokine (C-X-C motif) ligand 10 DPP inhibitors 3.89 × 10−2 rs13131187 3.13 × 10−4 − SLC2A2 Solute carrier family 2 (facilitated glucose transporter), member 2 Insulin 5.33 × 10−2 rs8192675 6.99 × 10−4 − TRIB3 Tribbles pseudokinase 3 Insulin 5.85 × 10−2 rs1555318 4.42 × 10−4 − GAA Glucosidase, α; acid α-Glucosidase inhibitors 6.14 × 10−2 rs2361710 9.28 × 10−4 − GAB1 GRB2-associated binding protein 1 Insulin 7.07 × 10−2 rs300938 6.97 × 10−4 − VCAM1 Vascular cell adhesion molecule 1 TZDs 8.35 × 10−2 rs1932351 5.58 × 10−4 − NGF Nerve growth factor (β-polypeptide) GLP-1 receptor agonists 8.94 × 10−2 rs11466094 5.63 × 10−4 − CPT2 Carnitine palmitoyltransferase 2 TZDs 9.48 × 10−2 rs1288351 7.58 × 10−4 − NFKB2 Nuclear factor of κ light polypeptide gene enhancer in B-cells 2 (pT9/p100) TZDs 9.64 × 10−2 rs7897947 2.44 × 10−3 − DDIT3 DNA damage–inducible transcript 3 GLP-1 receptor agonists 1.13 × 10−1 rs813516 3.20 × 10−3 − GRP Gastrin-releasing peptide DPP inhibitors 1.16 × 10−1 rs9951619 5.96 × 10−4 − SLC2A4 Solute carrier family 2 (facilitated glucose transporter), member T Insulin, sulfonylureas, metformin, TZDs 1.21 × 10−1 rs4562 2.23 × 10−3 − TAC1 Tachykinin, precursor 1 DPP inhibitors 1.28 × 10−1 rs17168923 1.72 × 10−3 − SLC22A1 Solute carrier family 22 (organic cation transporter), member 1 Metformin 1.34 × 10−1 rs8191811 1.15 × 10−3 − ADIPOR1 Adiponectin receptor 1 TZDs 1.45 × 10−1 rs782810 1.62 × 10−3 − SLC2A3 Solute carrier family 2 (facilitated glucose transporter), member 3 Insulin 1.45 × 10−1 rs3782681 2.13 × 10−3 − GIPR Gastric inhibitory polypeptide receptor DPP inhibitors 1.68 × 10−1 rs8108269 3.12 × 10−3 + AMY2A Amylase, α2A (pancreatic) α-Glucosidase inhibitors 1.70 × 10−1 rs1058607 6.75 × 10−3 − CPT1A Carnitine palmitoyltransferase 1A (liver) TZDs 1.82 × 10−1 rs2507833 2.77 × 10−3 − FOXO1 Forkhead box O1 Insulin 2.02 × 10−1 rs12874490 3.00 × 10−3 − HSD11B1 Hydroxysteroid (11-β) dehydrogenase 1 TZDs 2.03 × 10−1 rs3737913 1.78 × 10−3 − ACACA Acetyl-CoA carboxylase α Insulin 2.04 × 10−1 rs3744589 2.17 × 10−3 − CCL22 Chemokine (C-C motif) ligand 22 DPP inhibitors 2.05 × 10−1 rs8102 3.70 × 10−3 − PTGS1 Prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxygenase) TZDs 2.06 × 10−1 rs12005866 2.54 × 10−3 − PIK3CA Phosphatidylinositol-T,5-bisphosphate 3-kinase, catalytic subunit α Insulin, TZDs 2.07 × 10−1 rs6443629 3.79 × 10−3 − SLC2A5 Solute carrier family 2 (facilitated glucose/fructose transporter), member 5 Insulin 2.13 × 10−1 rs4908803 2.44 × 10−3 − PDX1 Pancreatic and duodenal homeobox 1 GLP-1 receptor agonists 2.19 × 10−1 rs9581940 2.37 × 10−3 − SCARB1 Scavenger receptor class B, member 1 TZDs 2.46 × 10−1 rs1031605 1.95 × 10−3 − PPARD Peroxisome proliferator–activated receptor δ TZDs 2.55 × 10−1 rs10484578 3.55 × 10−3 − CPA1 Carboxypeptidase A1 (pancreatic) GLP-1 receptor agonists 2.61 × 10−1 rs10263705 4.01 × 10−3 − IAPP Islet amyloid polypeptide Amylin mimetics 2.82 × 10−1 rs11045995 2.65 × 10−3 − The listed genes are the top-ranked antidiabetes drug targets with an adjusted T2D gene association P value (based on DIAGRAMv3) above the 75th percentile enrichment cutoff. One-half of these genes are predicted by MAGENTA to be true associations with T2D that have not yet reached genome-wide significance.
*,†These are each a cluster of two or three genes physically adjacent to each other along the chromosome that share the same most significant local T2D SNP and hence were collapsed to one effective gene in the GSEA. TNF was excluded from the GSEA because it lies in the HLA region. IRS1 did not pass the enrichment cutoff because it lies >110 kb from the T2D GWAS SNP (beyond the SNP-to-gene mapping boundaries used), and hence its gene association score was weak.
- Table 5
Replication of T2D association enrichment signal in antidiabetes drug target set in an independent T2D meta-analysis (Metabochip)
Genes mapped to established and high-confidence set of T2D SNPs* Number of Metabochip replication SNPs (null set) near one or more drug target genes† Number of top-ranked T2D SNPs near one or more drug target genes Gene set enrichment P value Genes near established or high-confidence T2D SNPs Nearest gene 48 5 0.003 PPARG1, KCNJ111, IRS11, GIPR2, ACSL13 Genes in LD‡ 83 7 0.04 PPARG1, KCNJ111, ABCC81, IDE1 IRS1 GIPR2, NFKB13, ACSL13 *T2D SNP set tested includes 137 loci: 59 established or highly probable SNPs and 78 high-confidence T2D SNPs based on Metabochip analysis (described in research design and methods).
†This set includes a null set of 16,408 LD-pruned Metabochip replication SNPs that does not contain SNPs in LD to previously established T2D SNPs, ∼5,000 T2D replication SNPs, monogenic diabetes genes, or QT-interval replication SNPs (see research design and methods ).
‡LD boundaries are defined in research design and methods.
1Genes near previously established T2D SNPs.
2Gene near T2D SNP found in the joint T2D meta-analysis of DIAGRAMv3 and Metabochip, which did not reach genome-wide significance in DIAGRAMv3 alone.
3Genes near T2D SNPs that have not yet reached genome-wide significance but have a high posterior probability of being associated with T2D based on Metabochip analysis (3).
- Table 6
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).
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