title: A Longitudinal HbA1c Model Elucidates Genes Linked to Disease Progression on Metformin.
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.
authors.affiliation: University of California, San Francisco, San Francisco, California, USA.
authors.forename: S
authors.initials: S
authors.lastname: Goswami
authors.affiliation: University of California, San Francisco, San Francisco, California, USA.
authors.forename: S W
authors.initials: SW
authors.lastname: Yee
authors.affiliation: Kaiser Permanente Northern California, Oakland, California, USA.
authors.forename: F
authors.initials: F
authors.lastname: Xu
authors.affiliation: Kaiser Permanente Northern California, Oakland, California, USA.
authors.forename: S B
authors.initials: SB
authors.lastname: Sridhar
authors.affiliation: Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Mosley
authors.affiliation: RIKEN Institute, Center for Genomic Medicine, Saitama, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: RIKEN Institute, Center for Genomic Medicine, Saitama, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kubo
authors.affiliation: RIKEN Institute, Center for Genomic Medicine, Saitama, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Maeda
authors.affiliation: Kaiser Permanente Georgia, Atlanta, Georgia, USA.|Center for Biomedical Informatics, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Davis
authors.affiliation: Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Roden
authors.affiliation: Kaiser Permanente Northern California, Oakland, California, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Hedderson
authors.affiliation: University of California, San Francisco, San Francisco, California, USA. Kathy.giacomini@ucsf.edu.
authors.forename: K M
authors.initials: KM
authors.lastname: Giacomini
authors.affiliation: University of California, San Francisco, San Francisco, California, USA. rada.savic@ucsf.edu.
authors.forename: R M
authors.initials: RM
authors.lastname: Savic
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D008137:Longitudinal Studies; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D017711:Nonlinear Dynamics; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D000075102:Organic Cation Transporter 2; D000071184:Pharmacogenomic Variants / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D025521:Tumor Suppressor Proteins; D055815:Young Adult
chemical_list: D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D008565:Membrane Proteins; D008687:Metformin; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D025521:Tumor Suppressor Proteins; C477880:CSMD1 protein, human; C491013:SLC22A2 protein, human; C517652:hemoglobin A1c protein, human