Table 3.
Summary of Top Genetic Variants Included in Final Population Pharmacodynamic Model of Metformin.
| SNP | Chr | Gene | Minor Allele | Major Allele | Feature | Model-based P-Value | Effect size of minor allele on DP parameter | MAF CEU | MAF YRI | Gene Functions (References cited in this table are in the footnote) |
|---|---|---|---|---|---|---|---|---|---|---|
| rs12907856 | 15 | VPS13C - vacuolar protein sorting-associated 13 gene family | G | A | Proximal | 0.0003 | −0.147 (GA) | 0.30 | 0.30 | This gene encodes a member of a vacuolar protein. SNP in this gene was associated with glucose-stimulated insulin response1–3. |
| rs2815022 | 6 | KCNK16 - Potassium Channel, Two Pore Domain Subfamily K, Member 16 | G | A | Proximal | 0.009 | 0.39 (GA) | 0.48 | 0.26 | This gene encodes the TALK-1 channel, the most abundant potassium channel in human beta-cells and it modulates beta-cells electrical excitability, second-phase insulin secretion and glucose homeostasis4, 5 |
| rs2617102 | 8 | CSMD1 - CUB And Sushi Multiple Domains 1 | C | A | Intron | 0.02 | 0.717 (CA) | 0.19 | 0.20 | This gene encodes an integral membrane protein with unknown molecular function. SNP in this gene was associated with congenital hyperinsulinism of infancy6. |
| rs2954625 | 8 | T | C | Intron | 0.029 | 0.23 (TC) | 0.21 | 0.46 | ||
| rs316009 | 6 | SLC22A2 - Solute Carrier Family 22 (Organic Cation Transporter), Member 2 | T | C | Intron | 0.04 | −0.44 (TC) | 0.10 | 0.08 | This is a transporter in the kidney that secretes metformin into the urine. This SNP is in linkage disequilibrium to a non-synonymous variant, A270S (rs316019), which was associated with metformin disposition7, 8. |
| rs642887 | 18 | EMILIN2 - Elastin Microfibril Interfacer 2 | A | G | Intron | 0.05 | −0.42 (AG) | 0.14 | 0.21 | An extracellular matrix glycoprotein associated with thrombosis. EMILIN2 is involved in regulating platelet activation important for cardiovascular development9, 10, whereas EMILIN1 may be involved in regeneration of islets, which could play a role in blood glucose lowering11. |
| rs6982250 | 8 | SULF1 - Sulfatase 1 | T | C | Intron | 0.0023 | −0.37 (TC) | 0.17 | 0.28 | This gene encodes an enzyme, which is involved in modulating growth factor signaling. Data from sulfatase knockout mice showed that it plays a role in diabetic nephropathy12. |
| rs7159552 | 14 | FOXN3 - Forkhead Box N3 | T | G | Proximal | 0.009 | −0.25 (TG) | 0.27 | 0.35 | This is a transcriptional repressor, which plays an important role in cell cycle arrest. This gene is localized in chromosome 14q24.3-q31, which is a locus associated with insulin-dependent diabetes mellitus susceptibility13. |
| rs7500549 | 16 | WWOX - WW Domain Containing Oxidoreductase | C | T | Intron | 0.029 | −0.16 (CT) | 0.55 | 0.20 | SNP in this locus was associated with reduced insulin secretion14. |
P-value = The significance level that resulted from objective function value changes after SNP addition to the demographic corrected base model. Genetic variant rs3160009 significance threshold was determined through model-based analysis of the SNP effect of carriers of either 1 or 2 alleles; MAF= Minor allele frequency; DP = Disease Progression; CEU= Northern Europeans; YRI=African population.
References for Table 3
Grarup N, Overvad M, Sparso T, Witte DR, Pisinger C, Jorgensen T, Yamauchi T, Hara K, Maeda S, Kadowaki T, Hansen T, Pedersen O. The diabetogenic VPS13C/C2CD4A/C2CD4B rs7172432 variant impairs glucose-stimulated insulin response in 5,722 non-diabetic Danish individuals. Diabetologia. 2011;54(4):789–94. doi: 10.1007/s00125-010-2031-2. PubMed PMID: 21249489.
Holstein JD, Patzer O, Korner A, Stumvoll M, Kovacs P, Holstein A. Genetic variants in GCKR, GIPR, ADCY5 and VPS13C and the risk of severe sulfonylurea-induced hypoglycaemia in patients with type 2 diabetes. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association. 2013;121(1):54–7. doi: 10.1055/s-0032-1321834. PubMed PMID: 22956255.
Windholz J, Kovacs P, Tonjes A, Dittrich K, Bluher S, Kiess W, Stumvoll M, Korner A. Effects of genetic variants in ADCY5, GIPR, GCKR and VPS13C on early impairment of glucose and insulin metabolism in children. PloS one. 2011;6(7):e22101. doi: 10.1371/journal.pone.0022101. PubMed PMID: 21789219; PubMed Central PMCID: PMC3137620.
Sakai K, Imamura M, Tanaka Y, Iwata M, Hirose H, Kaku K, Maegawa H, Watada H, Tobe K, Kashiwagi A, Kawamori R, Maeda S. Replication study for the association of 9 East Asian GWAS-derived loci with susceptibility to type 2 diabetes in a Japanese population. PloS one. 2013;8(9):e76317. doi: 10.1371/journal.pone.0076317. PubMed PMID: 24086726; PubMed Central PMCID: PMC3783369.
Vierra NC, Dadi PK, Jeong I, Dickerson M, Powell DR, Jacobson DA. Type 2 Diabetes-Associated K+ Channel TALK-1 Modulates beta-Cell Electrical Excitability, Second-Phase Insulin Secretion, and Glucose Homeostasis. Diabetes. 2015;64(11):3818–28. doi: 10.2337/db15-0280. PubMed PMID: 26239056; PubMed Central PMCID: PMC4613978.
Proverbio MC, Mangano E, Gessi A, Bordoni R, Spinelli R, Asselta R, Valin PS, Di Candia S, Zamproni I, Diceglie C, Mora S, Caruso-Nicoletti M, Salvatoni A, De Bellis G, Battaglia C. Whole genome SNP genotyping and exome sequencing reveal novel genetic variants and putative causative genes in congenital hyperinsulinism. PloS one. 2013;8(7):e68740. doi: 10.1371/journal.pone.0068740. PubMed PMID: 23869231; PubMed Central PMCID: PMC3711910.
Wang ZJ, Yin OQ, Tomlinson B, Chow MS. OCT2 polymorphisms and in-vivo renal functional consequence: studies with metformin and cimetidine. Pharmacogenetics and genomics. 2008;18(7):637–45. doi: 10.1097/FPC.0b013e328302cd41. PubMed PMID: 18551044.
Chen Y, Li S, Brown C, Cheatham S, Castro RA, Leabman MK, Urban TJ, Chen L, Yee SW, Choi JH, Huang Y, Brett CM, Burchard EG, Giacomini KM. Effect of genetic variation in the organic cation transporter 2 on the renal elimination of metformin. Pharmacogenetics and genomics. 2009;19(7):497–504. doi: 10.1097/FPC.0b013e32832cc7e9. PubMed PMID: 19483665; PubMed Central PMCID: PMC3104496.
Huang M, Sannaningaiah D, Zhao N, Gong Y, Grondolsky J, Hoover-Plow J. EMILIN2 regulates platelet activation, thrombus formation, and clot retraction. PloS one. 2015;10(2):e0115284. doi: 10.1371/journal.pone.0115284. PubMed PMID: 25658937; PubMed Central PMCID: PMC4319747.
Bot S, Andreuzzi E, Capuano A, Schiavinato A, Colombatti A, Doliana R. Multiple-interactions among EMILIN1 and EMILIN2 N- and C-terminal domains. Matrix biology : journal of the International Society for Matrix Biology. 2015;41:44–55. doi: 10.1016/j.matbio.2014.10.001. PubMed PMID: 25445627.
Lavoie JR, Creskey MC, Muradia G, Bell GI, Sherman SE, Gao J, Stewart DJ, Cyr TD, Hess DA, Rosu-Myles M. EMILIN-1 and ILK are Novel Markers of Islet Regenerative Function in Human Multipotent Mesenchymal Stromal Cells. Stem cells. 2016. doi: 10.1002/stem.2385. PubMed PMID: 27090767.
Takashima Y, Keino-Masu K, Yashiro H, Hara S, Suzuki T, van Kuppevelt TH, Masu M, Nagata M. Heparan sulfate 6-O-endosulfatases, Sulf1 and Sulf2, regulate glomerular integrity by modulating growth factor signaling. American journal of physiology Renal physiology. 2016;310(5):F395–408. doi: 10.1152/ajprenal.00445.2015. PubMed PMID: 26764203.
Field LL, Tobias R, Thomson G, Plon S. Susceptibility to insulin-dependent diabetes mellitus maps to a locus (IDDM11) on human chromosome 14q24.3-q31. Genomics. 1996;33(1):1–8. doi: 10.1006/geno.1996.0153. PubMed PMID: 8617492.
Chang YC, Chiu YF, Liu PH, Shih KC, Lin MW, Sheu WH, Quertermous T, Curb JD, Hsiung CA, Lee WJ, Lee PC, Chen YT, Chuang LM. Replication of genome-wide association signals of type 2 diabetes in Han Chinese in a prospective cohort. Clinical endocrinology. 2012;76(3):365–72. doi: 10.1111/j.1365-2265.2011.04175.x. PubMed PMID: 21767287.