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Effects and interaction of single nucleotide polymorphisms at the pharmacokinetic/pharmacodynamic site: insights from the Rotterdam study into metformin clinical response and dose titration

The Pharmacogenomics Journal volume 24, Article number: 31 (2024) Cite this article

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Abstract

Our study investigated the impact of genetic variations on metformin glycemic response in a cohort from the Rotterdam Study, comprising 14,926 individuals followed for up to 27 years. Among 1285 metformin users of European ancestry, using linear mixed models, we analyzed the association of single nucleotide polymorphisms (SNPs) and a Polygenic Risk Score (PRS) with glycemic response, measured by changes in metformin dosage or HbA1c levels. While individual genetic variants showed no significant association, rs622342 on SLC2A1 correlated with increased glycemic response only in metformin monotherapy patients (β = −2.09, P-value < 0.001). The collective effect of variants, as represented by PRS, weakly correlated with changes in metformin dosage (β = 0.023, P-value = 0.027). Synergistic interaction was observed between rs7124355 and rs8192675. Our findings suggest that while higher PRS correlates with increased metformin dosage, its modest effect size limits clinical utility, emphasizing the need for future research in diverse populations to refine genetic risk models.

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Fig. 1: Forest plot for an individual association of each genetic variant with changes in HbA1c levels.
Fig. 2: SNP-SNP interactions and metformin prescribed daily dosage.

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Data availability

Data generated by the authors or analyzed during the study are available upon request. Requests should be directed toward the management team of the Rotterdam Study (secretariat.epi@erasmusmc.nl), which has a protocol for approving data requests. Because of restrictions based on privacy regulations and informed consent of the participants, data cannot be made freely available in a public repository.

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Acknowledgements

The authors thank the staff and participants of the Rotterdam study, NIHES, and the Epidemiology department of Erasmus MC for their important contributions.

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Authors and Affiliations

  1. Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands

    Soroush Mohammadi Jouabadi, Payam Peymani, Mitra Nekouei Shahraki, Bruno H. Stricker & Fariba Ahmadizar

  2. Division of Vascular Disease and Pharmacology, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands

    Soroush Mohammadi Jouabadi & Anton J. M. Roks

  3. College of pharmacy, University of Manitoba, Winnipeg, MB, Canada

    Payam Peymani

  4. Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands

    Jeroen G. J. van Rooij & Linda Broer

  5. Department of Data Science and Biostatistics, Julius Global Health, University Medical Center Utrecht, Utrecht, The Netherlands

    Fariba Ahmadizar

  6. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Fariba Ahmadizar

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Contributions

SMJ, FA, PP, and BHS were involved in conceptualization, design, and study conduction. SMJ and MNS performed the statistical analysis and JVR and LB were involved in the methodology. SMJ drafted the first version of the manuscript and all authors edited, reviewed, and approved the final version of the manuscript. FA is the guarantor of this work and, as such, had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Data are available upon reasonable request.

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Correspondence to Soroush Mohammadi Jouabadi.

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Competing interests

This project has received funding from the Inspectorate of Healthcare and the Innovative Medicines Initiative 2 Joint Undertaking (grant agreement No 116030: TransQST-consortium). This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.

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Mohammadi Jouabadi, S., Peymani, P., Nekouei Shahraki, M. et al. Effects and interaction of single nucleotide polymorphisms at the pharmacokinetic/pharmacodynamic site: insights from the Rotterdam study into metformin clinical response and dose titration. Pharmacogenomics J 24, 31 (2024). https://doi.org/10.1038/s41397-024-00352-z

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