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Genome-Wide Association Study for the Genetic Determinants of Thiopurine Methyltransferase Protein Expression in Human Livers and Racial Differences

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Abstract

Introduction

Polymorphisms in the Thiopurine S-Methyltransferase (TPMT) gene are associated with decreased TPMT activity, but little is known about their impact on TPMT protein expression in the liver. This project is to conduct a genome-wide association study (GWAS) to identify single nucleotide polymorphisms (SNPs) associated with altered TPMT protein expression in human livers and to determine if demographics affect hepatic TPMT protein expression.

Methods

Human liver samples (n = 287) were genotyped using a whole genome genotyping panel and quantified for TPMT protein expression using a Data-Independent Acquisition proteomics approach.

Results and Discussion

Thirty-one SNPs were found to be associated with differential expression of TPMT protein in the human livers. Subsequent analysis, conditioning on rs1142345, a SNP associated with the TPMT*3A and TPMT*3C alleles, showed no additional independent signals. Mean TPMT expression is significantly higher in wildtype donors compared to those carrying the known TPMT alleles, including TPMT*3A, TPMT*3C, and TPMT*24 (0.107 ± 0.028 vs. 0.052 ± 0.014 pmol/mg total protein, P = 2.2 × 10−16). After removing samples carrying the known TPMT variants, European ancestry donors exhibited significantly higher expression than African ancestry donors (0.109 ± 0.026 vs. 0.090 ± 0.041 pmol/mg total protein, P = 0.020).

Conclusion

The GWAS identified 31 SNPs associated with TPMT protein expression in human livers. Hepatic TPMT protein expression was significantly lower in subjects carrying the TPMT*3A, TPMT*3C, and TPMT*24 alleles compared to non-carriers. European ancestry was associated with significantly higher hepatic TPMT protein expression than African ancestry, independent of known TPMT variants.

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Authors and Affiliations

  1. Department of Clinical Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA

    Logan S. Smith & Hao-Jie Zhu

  2. Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH, 44272, USA

    Xinwen Wang

  3. Bristol Myers Squibb, 3401 Princeton Pike, Lawrence Township, NJ, 08648, USA

    Jian Shi

  4. Department of Computational Medicine and Bioinformatics, Medical School, University of Michigan, Ann Arbor, MI, USA

    Bing He

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  1. Logan S. Smith
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Correspondence to Hao-Jie Zhu.

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Smith, L.S., Wang, X., Shi, J. et al. Genome-Wide Association Study for the Genetic Determinants of Thiopurine Methyltransferase Protein Expression in Human Livers and Racial Differences. Pharm Res 40, 2525–2531 (2023). https://doi.org/10.1007/s11095-023-03558-1

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  • DOI: https://doi.org/10.1007/s11095-023-03558-1

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