title: A pharmacogenetic association between a variation in calpain 10 (CAPN10) gene and the response to metformin treatment in patients with type 2 diabetes.
abstract: OBJECTIVE
  The aim of the present study was to investigate possible associations of the single-nucleotide variants in six genes encoding the key molecules mediating the metformin pharmacodynamic effect with the response to treatment with metformin in patients with type 2 diabetes.
  
  
  METHODS
  One hundred forty-eight drug-naïve patients with type 2 diabetes were included in the study. PRKAA1 rs249429, STK11 rs741765, PCK1 rs4810083, PPARGC1A rs10213440, HNF1A rs11086926, and CAPN10 rs3792269 variants were genotyped. The outcomes of the study were treatment success defined by achieving HbA1c <7 % and absolute reduction in HbAlc after 6-month metformin therapy. The relationships between genotypes and outcomes were evaluated in multivariate logistic and linear models. The level of statistical significance after Bonferroni correction was predefined as p<0.0083.
  
  
  RESULTS
  The minor G-allele of CAPN10 rs3792269 A>G polymorphism was significantly associated with less treatment success with an odds ratio of 0.27 (95 % CI 0.12-0.62, p=0.002) per variant allele. When the reduction in HbA1c was analyzed as a quantitative trait, G-allele was nominally associated with a smaller reduction in HbA1c (per allele β=-0.26, 95 % CI -0.50 to -0.02, p=0.032). The reduction in HbA1c in minor allele carriers (24 % of study population) was smaller by 0.3 % in comparison with the major allele homozygotes.
  
  
  CONCLUSIONS
  The present study provides the first observation of an association between a variant in CAPN10 gene and the response to metformin therapy in patients with type 2 diabetes. This observation needs to be replicated in further studies in different populations.
authors.affiliation: Department of Internal Medicine 4, Faculty of Medicine, P. J. Šafárik University, Rastislavova 43, 04190, Košice, Slovakia, ivan.tkac@upjs.sk.
authors.forename: Ivan
authors.initials: I
authors.lastname: Tkáč
authors.forename: Martin
authors.initials: M
authors.lastname: Javorský
authors.forename: Lucia
authors.initials: L
authors.lastname: Klimčáková
authors.forename: Jozef
authors.initials: J
authors.lastname: Židzik
authors.forename: Igor
authors.initials: I
authors.lastname: Gaľa
authors.forename: Eva
authors.initials: E
authors.lastname: Babjaková
authors.forename: Zbynek
authors.initials: Z
authors.lastname: Schroner
authors.forename: Mária
authors.initials: M
authors.lastname: Štolfová
authors.forename: Hana
authors.initials: H
authors.lastname: Hermanová
authors.forename: Viera
authors.initials: V
authors.lastname: Habalová
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000235:genetics; D002154:Calpain / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006442:Glycated Hemoglobin / Q000032:analysis; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D002154:Calpain; D006442:Glycated Hemoglobin; D051538:Hepatocyte Nuclear Factor 1-alpha; D007004:Hypoglycemic Agents; D047908:Intracellular Signaling Peptides and Proteins; D008687:Metformin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; C496487:HNF1A protein, human; C486497:PPARGC1A protein, human; C517652:hemoglobin A1c protein, human; C109790:STK11 protein, human; C526180:PRKAA1 protein, human; C415197:calpain 10; C521898:PCK1 protein, human