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Search for genetic determinants of sulfonylurea efficacy in type 2 diabetic patients from China

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Abstract

Aims/hypothesis

The aim of this study was to investigate whether genetic variance can influence the efficacy of glibenclamide in patients with type 2 diabetes.

Methods

A total of 747 patients with type 2 diabetes was enrolled from the Xiaoke Pills Clinical Trial, which is a double-blind, randomised controlled trial. All the patients had been treated with glibenclamide for 48 weeks, with strict drug dose adjustment and data collection. Treatment failure was confirmed when patients reached the criteria for terminating their participation in the study (fasting blood glucose level ≥7.0 mmol/l on two consecutive tests 4 weeks after reaching the pre-set maximal dose or maximal tolerated dose). Using this cohort, we tested 44 single-nucleotide polymorphisms (SNPs) in 27 gene regions. The genes in our study were involved in the metabolism of sulfonylureas, islet beta cell function, insulin resistance and beta cell growth and differentiation. A logistic regression model was used to evaluate the relationship between genetic variants and treatment failure over a period of 48 weeks.

Results

We found that no SNP reached the significance level of p < 0.00125 if Bonferroni correction was performed for multiple testing in the logistic regression model used in this pharmacogenetic study. Participants with the minor allele C of rs10811661 in CDKN2A/CDKN2B showed a significantly greater reduction in fasting blood glucose (TT vs TC vs CC: 9.3% (0–20.0%) vs 9.2% (0.9–20.5%) vs 12.7% (5.2–24.4%), p = 0.008) after the initial 4 weeks of treatment independent of age, sex and BMI. There was a significant difference in beta cell function among carriers of different genotypes of rs10811661.

Conclusions/interpretation

Our study demonstrated that the CDKN2A/CDKN2B gene may be nominally associated with the efficacy of glibenclamide, and that CDKN2A/CDKN2B is associated with beta cell function.

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Abbreviations

FPG:

Fasting plasma glucose

GWAS:

Genome-wide association study

MAF:

Minor allele frequency

SNP:

Single-nucleotide polymorphism

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Acknowledgements

We thank all the patients and all 15 hospitals for agreeing to join this study.

Funding

This study was supported by Funding National High Technology Research and Development Program (863 program, No. 2012AA02A509 and No. 2006AA02A409), Guangzhou Zhongyi Pharmaceutical, the National Natural Science Fund (No. 81000334) and the National Basic Research Program of China (973 program, No. 2006CB503903).

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

LJ, XH and QR were responsible for the conceptualisation and design of the study and were involved in data acquisition. QR, XH, YT, X. Zhang, XC, X. Zou, SZ, LZ and HL performed the analysis and interpretation of the data. QR, XH and LJ drafted the manuscript. XC, YT, X. Zhang, X. Zou, SZ, LZ and HL revised the manuscript for critical intellectual content. All authors approved the final version of the manuscript. QR and XH had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

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Authors and Affiliations

  1. Department of Endocrinology and Metabolism, Peking University People’s Hospital, No. 11, Xizhimen South Street, Beijing, 100044, People’s Republic of China

    Qian Ren, Xueyao Han, Xiuying Zhang, Xiantong Zou, Xiaoling Cai, Simin Zhang, Lihua Zhang, Hechao Li & Linong Ji

  2. Department of Endocrinology and Metabolism, Hebei People’s Hospital, Heibei, People’s Republic of China

    Yong Tang

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  1. Qian Ren
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  2. Xueyao Han
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Corresponding author

Correspondence to Linong Ji.

Additional information

Qian Ren and Xueyao Han contributed equally to this manuscript.

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Ren, Q., Han, X., Tang, Y. et al. Search for genetic determinants of sulfonylurea efficacy in type 2 diabetic patients from China. Diabetologia 57, 746–753 (2014). https://doi.org/10.1007/s00125-013-3146-z

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