Interaction between variants in the CYP2C9 and POR genes and the risk of sulfonylurea-induced hypoglycaemia: A GoDARTS Study

Tanja Dujic; Kaixin Zhou; Louise A. Donnelly; Graham Leese; Colin N. A. Palmer; Ewan R. Pearson

doi:10.1111/dom.13046

Interaction between variants in the CYP2C9 and POR genes and the risk of sulfonylurea-induced hypoglycaemia: A GoDARTS Study

Tanja Dujic, Kaixin Zhou, Louise A. Donnelly, Graham Leese, Colin N. A. Palmer, Ewan R. Pearson (Lead / Corresponding author)

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Abstract

Data on the association of CYP2C9 genetic polymorphisms with sulfonylurea (SU)-induced hypoglycaemia (SH) are inconsistent. Recent studies showed that variants in P450 oxidoreductase (POR) gene could affect CYP2C9 activity. In this study, we explored the effects of POR*28 and combined CYP2C9*2 and CYP2C9*3 genotypes, on SH and the efficacy of SU treatment in type 2 diabetes. A total of 1,770 patients were included in the analysis of SU efficacy assessed as the combined outcome of the HbA1c reduction and prescribed SU daily dose. Sixty nine patients with severe SH were compared with 311 control patients. The number of CYP2C9 deficient alleles was associated with nearly three-fold higher odds of hypoglycaemia (OR=2.81, 95%CI 1.30-6.09, P=0.009) and better response to SU treatment (β = -0.218, SE=0.074, P=0.003) only in patients carrying POR*1/*1 genotype. Our results indicate that interaction between CYP2C9 and POR genes may be an important determinant of efficacy and severe adverse effects of SU treatment.

Original language	English
Journal	Diabetes, Obesity & Metabolism
Early online date	28 Jun 2017
DOIs	https://doi.org/10.1111/dom.13046
Publication status	Published - 25 Aug 2017

Keywords

hypoglycaemia
pharmacogenetics
sulphonylureas
type 2 diabetes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1111/dom.13046Licence: CC BY

Final Published Version
© 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Final published version, 297 KBLicence: CC BY

Stratified Medicine in Type 2 Diabetes: Insights from the Study of Drug Response (New Investigator Award)
Pearson, E. (Investigator)
16/02/15 → 15/08/21
Project: Research

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title = "Interaction between variants in the CYP2C9 and POR genes and the risk of sulfonylurea-induced hypoglycaemia: A GoDARTS Study",

abstract = "Data on the association of CYP2C9 genetic polymorphisms with sulfonylurea (SU)-induced hypoglycaemia (SH) are inconsistent. Recent studies showed that variants in P450 oxidoreductase (POR) gene could affect CYP2C9 activity. In this study, we explored the effects of POR*28 and combined CYP2C9*2 and CYP2C9*3 genotypes, on SH and the efficacy of SU treatment in type 2 diabetes. A total of 1,770 patients were included in the analysis of SU efficacy assessed as the combined outcome of the HbA1c reduction and prescribed SU daily dose. Sixty nine patients with severe SH were compared with 311 control patients. The number of CYP2C9 deficient alleles was associated with nearly three-fold higher odds of hypoglycaemia (OR=2.81, 95%CI 1.30-6.09, P=0.009) and better response to SU treatment (β = -0.218, SE=0.074, P=0.003) only in patients carrying POR*1/*1 genotype. Our results indicate that interaction between CYP2C9 and POR genes may be an important determinant of efficacy and severe adverse effects of SU treatment.",

keywords = "hypoglycaemia, pharmacogenetics, sulphonylureas, type 2 diabetes",

author = "Tanja Dujic and Kaixin Zhou and Donnelly, {Louise A.} and Graham Leese and Palmer, {Colin N. A.} and Pearson, {Ewan R.}",

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T2 - A GoDARTS Study

AU - Dujic, Tanja

AU - Zhou, Kaixin

AU - Donnelly, Louise A.

AU - Leese, Graham

AU - Palmer, Colin N. A.

AU - Pearson, Ewan R.

N1 - Funding: Wellcome Trust New Investigator Award (102820/Z/13/Z).

PY - 2017/8/25

Y1 - 2017/8/25

N2 - Data on the association of CYP2C9 genetic polymorphisms with sulfonylurea (SU)-induced hypoglycaemia (SH) are inconsistent. Recent studies showed that variants in P450 oxidoreductase (POR) gene could affect CYP2C9 activity. In this study, we explored the effects of POR*28 and combined CYP2C9*2 and CYP2C9*3 genotypes, on SH and the efficacy of SU treatment in type 2 diabetes. A total of 1,770 patients were included in the analysis of SU efficacy assessed as the combined outcome of the HbA1c reduction and prescribed SU daily dose. Sixty nine patients with severe SH were compared with 311 control patients. The number of CYP2C9 deficient alleles was associated with nearly three-fold higher odds of hypoglycaemia (OR=2.81, 95%CI 1.30-6.09, P=0.009) and better response to SU treatment (β = -0.218, SE=0.074, P=0.003) only in patients carrying POR*1/*1 genotype. Our results indicate that interaction between CYP2C9 and POR genes may be an important determinant of efficacy and severe adverse effects of SU treatment.

AB - Data on the association of CYP2C9 genetic polymorphisms with sulfonylurea (SU)-induced hypoglycaemia (SH) are inconsistent. Recent studies showed that variants in P450 oxidoreductase (POR) gene could affect CYP2C9 activity. In this study, we explored the effects of POR*28 and combined CYP2C9*2 and CYP2C9*3 genotypes, on SH and the efficacy of SU treatment in type 2 diabetes. A total of 1,770 patients were included in the analysis of SU efficacy assessed as the combined outcome of the HbA1c reduction and prescribed SU daily dose. Sixty nine patients with severe SH were compared with 311 control patients. The number of CYP2C9 deficient alleles was associated with nearly three-fold higher odds of hypoglycaemia (OR=2.81, 95%CI 1.30-6.09, P=0.009) and better response to SU treatment (β = -0.218, SE=0.074, P=0.003) only in patients carrying POR*1/*1 genotype. Our results indicate that interaction between CYP2C9 and POR genes may be an important determinant of efficacy and severe adverse effects of SU treatment.

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KW - sulphonylureas

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JO - Diabetes, Obesity & Metabolism

JF - Diabetes, Obesity & Metabolism

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Interaction between variants in the CYP2C9 and POR genes and the risk of sulfonylurea-induced hypoglycaemia: A GoDARTS Study

Abstract

Keywords

UN SDGs

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Stratified Medicine in Type 2 Diabetes: Insights from the Study of Drug Response (New Investigator Award)

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