A Longitudinal HbA1c Model Elucidates Genes Linked to Disease Progression on Metformin

Clin Pharmacol Ther. 2016 Nov;100(5):537-547. doi: 10.1002/cpt.428. Epub 2016 Sep 23.

Abstract

One-third of type-2 diabetic patients respond poorly to metformin. Despite extensive research, the impact of genetic and nongenetic factors on long-term outcome is unknown. In this study we combine nonlinear mixed effect modeling with computational genetic methodologies to identify predictors of long-term response. In all, 1,056 patients contributed their genetic, demographic, and long-term HbA1c data. The top nine variants (of 12,000 variants in 267 candidate genes) accounted for approximately one-third of the variability in the disease progression parameter. Average serum creatinine level, age, and weight were determinants of symptomatic response; however, explaining negligible variability. Two single nucleotide polymorphisms (SNPs) in CSMD1 gene (rs2617102, rs2954625) and one SNP in a pharmacologically relevant SLC22A2 gene (rs316009) influenced disease progression, with minor alleles leading to less and more favorable outcomes, respectively. Overall, our study highlights the influence of genetic factors on long-term HbA1c response and provides a computational model, which when validated, may be used to individualize treatment.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / metabolism*
  • Disease Progression*
  • Female
  • Glycated Hemoglobin A / metabolism*
  • Humans
  • Hypoglycemic Agents / therapeutic use
  • Longitudinal Studies
  • Male
  • Membrane Proteins / genetics*
  • Metformin / therapeutic use*
  • Middle Aged
  • Nonlinear Dynamics
  • Organic Cation Transport Proteins / genetics*
  • Organic Cation Transporter 2
  • Pharmacogenomic Variants / genetics*
  • Polymorphism, Single Nucleotide / genetics
  • Young Adult

Substances

  • CSMD1 protein, human
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Membrane Proteins
  • Organic Cation Transport Proteins
  • Organic Cation Transporter 2
  • SLC22A2 protein, human
  • hemoglobin A1c protein, human
  • Metformin