title: The pharmacogenetics of type 2 diabetes: a systematic review.
abstract: OBJECTIVE
  We performed a systematic review to identify which genetic variants predict response to diabetes medications.
  
  
  METHODS
  We performed a search of electronic databases (PubMed, EMBASE, and Cochrane Database) and a manual search to identify original, longitudinal studies of the effect of diabetes medications on incident diabetes, HbA1c, fasting glucose, and postprandial glucose in prediabetes or type 2 diabetes by genetic variation. Two investigators reviewed titles, abstracts, and articles independently. Two investigators abstracted data sequentially and evaluated study quality independently. Quality evaluations were based on the Strengthening the Reporting of Genetic Association Studies guidelines and Human Genome Epidemiology Network guidance.
  
  
  RESULTS
  Of 7,279 citations, we included 34 articles (N = 10,407) evaluating metformin (n = 14), sulfonylureas (n = 4), repaglinide (n = 8), pioglitazone (n = 3), rosiglitazone (n = 4), and acarbose (n = 4). Studies were not standalone randomized controlled trials, and most evaluated patients with diabetes. Significant medication-gene interactions for glycemic outcomes included 1) metformin and the SLC22A1, SLC22A2, SLC47A1, PRKAB2, PRKAA2, PRKAA1, and STK11 loci; 2) sulfonylureas and the CYP2C9 and TCF7L2 loci; 3) repaglinide and the KCNJ11, SLC30A8, NEUROD1/BETA2, UCP2, and PAX4 loci; 4) pioglitazone and the PPARG2 and PTPRD loci; 5) rosiglitazone and the KCNQ1 and RBP4 loci; and 5) acarbose and the PPARA, HNF4A, LIPC, and PPARGC1A loci. Data were insufficient for meta-analysis.
  
  
  CONCLUSIONS
  We found evidence of pharmacogenetic interactions for metformin, sulfonylureas, repaglinide, thiazolidinediones, and acarbose consistent with their pharmacokinetics and pharmacodynamics. While high-quality controlled studies with prespecified analyses are still lacking, our results bring the promise of personalized medicine in diabetes one step closer to fruition.
authors.affiliation: Corresponding author: Nisa M. Maruthur, maruthur@jhmi.edu.
authors.forename: Nisa M
authors.initials: NM
authors.lastname: Maruthur
authors.forename: Matthew O
authors.initials: MO
authors.lastname: Gribble
authors.forename: Wendy L
authors.initials: WL
authors.lastname: Bennett
authors.forename: Shari
authors.initials: S
authors.lastname: Bolen
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Wilson
authors.forename: Poojitha
authors.initials: P
authors.lastname: Balakrishnan
authors.forename: Anita
authors.initials: A
authors.lastname: Sahu
authors.forename: Eric
authors.initials: E
authors.lastname: Bass
authors.forename: W H Linda
authors.initials: WH
authors.lastname: Kao
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Clark
mesh_terms: D020909:Acarbose / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D001786:Blood Glucose / Q000235:genetics* / Q000378:metabolism; D002219:Carbamates / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008687:Metformin / Q000627:therapeutic use; D010597:Pharmacogenetics; D000077205:Pioglitazone; D010880:Piperidines / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D011236:Prediabetic State / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000077154:Rosiglitazone; D013453:Sulfonylurea Compounds / Q000627:therapeutic use; D045162:Thiazolidinediones / Q000627:therapeutic use
chemical_list: D054316:Biomarkers, Pharmacological; D001786:Blood Glucose; D002219:Carbamates; D007004:Hypoglycemic Agents; D010880:Piperidines; D013453:Sulfonylurea Compounds; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C072379:repaglinide; D008687:Metformin; D020909:Acarbose; D000077205:Pioglitazone