Variation in TCF7L2 Influences Therapeutic Response to Sulfonylureas

A GoDARTs Study

  1. Ewan R. Pearson1,
  2. Louise A. Donnelly2,
  3. Charlotte Kimber3,
  4. Adrian Whitley3,
  5. Alex S.F. Doney1,
  6. Mark I. McCarthy4,
  7. Andrew T. Hattersley5,
  8. Andrew D. Morris1 and
  9. Colin N.A. Palmer3
  1. 1Division of Medicine and Therapeutics, University of Dundee, Dundee, U.K
  2. 2Health Informatics Centre, University of Dundee, Dundee, U.K
  3. 3Population Pharmacogenetics Group, Biomedical Research Centre, University of Dundee, Dundee, U.K
  4. 4Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford, U.K
  5. 5Institute of Biomedical Sciences, Peninsula Medical School, Plymouth, U.K
  1. Address correspondence and reprint requests to Ewan Pearson, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, Ninewells Avenue, Dundee, DD1 9SY, U.K. E-mail: e.pearson{at}chs.dundee.ac.uk

Abstract

OBJECTIVE— There is considerable interindividual variation in sulfonylurea response in type 2 diabetes. Transcription factor 7-like 2 (TCF7L2) variants have been identified to be strongly associated with type 2 diabetes risk, probably due to decreased β-cell function. We hypothesized that variation in TCF7L2 would influence response to sulfonylureas but not metformin. We studied the effect of TCF7L2 rs12255372 and rs7903146 genotypes on glycemic response.

RESEARCH DESIGN AND METHODS— The DARTS/MEMO (Diabetes Audit and Research Tayside/Medicines Monitoring Unit) collaboration database includes prescribing, biochemistry, and clinical phenotype of all patients with diabetes within Tayside, Scotland, from 1992. Of these, the TCF7L2 genotype was determined in 4,469 patients with type 2 diabetes recruited to GoDARTS (Genetics of Diabetes Audit and Research Tayside) between 1997 and July 2006. A total of 901 incident sulfonylurea users and 945 metformin users were identified. A logistic regression was used with treatment failure defined as an A1C >7% within 3–12 months after treatment initiation. Covariates included the TCF7L2 genotype, BMI, sex, age diagnosed, drug adherence, and drug dose. A1C pretreatment was available in a subset of patients (sulfonylurea n = 579; metformin n = 755).

RESULTS— Carriers of the risk allele were less likely to respond to sulfonylureas with an odds ratio (OR) for failure of 1.95 (95% CI 1.23–3.06; P = 0.005), comparing rs12255372 T/T vs. G/G. Including the baseline A1C strengthened this association (OR 2.16 [95% CI 1.21–3.86], P = 0.009). A similar, although slightly weaker, association was seen with rs7903146. No association was seen between metformin response and either single nucleotide polymorphism, after adjustment for baseline A1C.

CONCLUSIONS— TCF7L2 variants influence therapeutic response to sulfonylureas but not metformin. This study establishes that genetic variation can alter response to therapy in type 2 diabetes.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 22 May 2007. DOI: 10.2337/db07-0440.

  • E.R.P. and L.A.D. contributed equally to this work.

  • Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0440.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted May 18, 2007.
    • Received March 30, 2007.
| Table of Contents

This Article

  1. Diabetes vol. 56 no. 8 2178-2182
  1. Online-Only Appendix
  2. All Versions of this Article:
    1. db07-0440v1
    2. 56/8/2178 most recent