Department of Clinical Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA.
Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH, 44272, USA.
Pharm Res. 2023 Nov;40(11):2525-2531. doi: 10.1007/s11095-023-03558-1. Epub 2023 Jul 10.
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.
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.
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 TPMT3A and TPMT3C alleles, showed no additional independent signals. Mean TPMT expression is significantly higher in wildtype donors compared to those carrying the known TPMT alleles, including TPMT3A, TPMT3C, and TPMT*24 (0.107 ± 0.028 vs. 0.052 ± 0.014 pmol/mg total protein, P = 2.2 × 10). 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).
The GWAS identified 31 SNPs associated with TPMT protein expression in human livers. Hepatic TPMT protein expression was significantly lower in subjects carrying the TPMT3A, TPMT3C, 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.
硫嘌呤甲基转移酶（TPMT）基因中的多态性与 TPMT 活性降低有关，但关于它们对人肝 TPMT 蛋白表达的影响知之甚少。本项目旨在进行全基因组关联研究（GWAS），以鉴定与人类肝脏中 TPMT 蛋白表达改变相关的单核苷酸多态性（SNP），并确定人口统计学因素是否影响肝 TPMT 蛋白表达。
使用全基因组基因分型面板对 287 个人肝样本进行基因分型，并使用 Data-Independent Acquisition 蛋白质组学方法定量检测 TPMT 蛋白的表达。
发现 31 个 SNP 与人类肝脏中 TPMT 蛋白的差异表达相关。进一步分析，在 rs1142345 条件下，与 TPMT3A 和 TPMT3C 等位基因相关的 SNP，没有发现其他独立信号。与携带已知 TPMT 等位基因（包括 TPMT3A、TPMT3C 和 TPMT*24）的个体相比，野生型供体的 TPMT 表达明显更高，平均值分别为 0.107 ± 0.028 与 0.052 ± 0.014 pmol/mg 总蛋白（P = 2.2×10）。在去除携带已知 TPMT 变体的样本后，欧洲血统供体的表达明显高于非洲血统供体（0.109 ± 0.026 与 0.090 ± 0.041 pmol/mg 总蛋白，P = 0.020）。
GWAS 鉴定出 31 个与人类肝脏中 TPMT 蛋白表达相关的 SNP。与非携带者相比，携带 TPMT3A、TPMT3C 和 TPMT*24 等位基因的个体的 TPMT 蛋白表达明显较低。欧洲血统与非洲血统相比，肝 TPMT 蛋白表达明显较高，与已知的 TPMT 变体无关。
