Abstract：
BACKGROUND: 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.
CONCLUSIONS: 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).
CONCLUSIONS: 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.
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.
CONCLUSIONS: 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).
CONCLUSIONS: 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.
摘要：
背景：硫嘌呤S-甲基转移酶（TPMT）基因的多态性与TPMT活性降低有关，但对其对肝脏中TPMT蛋白表达的影响知之甚少。该项目将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），并确定人口统计学是否影响肝脏TPMT蛋白表达。
方法:使用全基因组基因分型组对人肝脏样品(n=287)进行基因分型,并使用数据独立采集蛋白质组学方法对TPMT蛋白表达进行定量。
结论：发现31个SNP与人肝脏中TPMT蛋白的差异表达有关。后续分析，调节rs1142345，一个与TPMT*3A和TPMT*3C等位基因相关的SNP，没有显示额外的独立信号。与携带已知TPMT等位基因的那些相比，野生型供体的平均TPMT表达明显更高。包括TPMT*3A，TPMT*3C,和TPMT*24(0.107±0.028vs.0.052±0.014pmol/mg总蛋白，P=2.2×10-16)。取出携带已知TPMT变体的样品后，欧洲血统捐赠者的表达明显高于非洲血统捐赠者（0.109±0.026vs.0.090±0.041pmol/mg总蛋白，P=0.020)。
结论：GWAS在人肝脏中鉴定出31个与TPMT蛋白表达相关的SNP。携带TPMT*3A的受试者肝脏TPMT蛋白表达显著降低，TPMT*3C,和TPMT*24等位基因与非携带者相比。欧洲血统与显著高于非洲血统的肝TPMT蛋白表达相关,独立于已知的TPMT变体。
方法:使用全基因组基因分型组对人肝脏样品(n=287)进行基因分型,并使用数据独立采集蛋白质组学方法对TPMT蛋白表达进行定量。
结论：发现31个SNP与人肝脏中TPMT蛋白的差异表达有关。后续分析，调节rs1142345，一个与TPMT*3A和TPMT*3C等位基因相关的SNP，没有显示额外的独立信号。与携带已知TPMT等位基因的那些相比，野生型供体的平均TPMT表达明显更高。包括TPMT*3A，TPMT*3C,和TPMT*24(0.107±0.028vs.0.052±0.014pmol/mg总蛋白，P=2.2×10-16)。取出携带已知TPMT变体的样品后，欧洲血统捐赠者的表达明显高于非洲血统捐赠者（0.109±0.026vs.0.090±0.041pmol/mg总蛋白，P=0.020)。
结论：GWAS在人肝脏中鉴定出31个与TPMT蛋白表达相关的SNP。携带TPMT*3A的受试者肝脏TPMT蛋白表达显著降低，TPMT*3C,和TPMT*24等位基因与非携带者相比。欧洲血统与显著高于非洲血统的肝TPMT蛋白表达相关,独立于已知的TPMT变体。
