Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
Mol Genet Metab. 2011 Feb;102(2):126-33. doi: 10.1016/j.ymgme.2010.10.010. Epub 2010 Oct 21.
Betaine-homocysteine methyltransferase (BHMT) catalyzes the remethylation of homocysteine. BHMT is highly expressed in the human liver. In the liver, BHMT catalyzes up to 50% of homocysteine metabolism. Understanding the relationship between BHMT genetic polymorphisms and function might increase our understanding of the role of this reaction in homocysteine remethylation and in S-adenosylmethionine-dependent methylation. To help achieve those goals, we measured levels of BHMT enzyme activity and immunoreactive protein in 268 human hepatic surgical biopsy samples from adult subjects as well as 73 fetal hepatic tissue samples obtained at different gestational ages. BHMT protein levels were correlated significantly (p<0.001) with levels of enzyme activity in both fetal and adult tissues, but both were decreased in fetal tissue when compared with levels in the adult hepatic biopsies. To determine possible genotype-phenotype correlations, 12 tag SNPs for BHMT and the closely related BHMT2 gene were selected from SNPs observed during our own gene resequencing studies as well as from HapMap. These SNPs data were used to genotype DNA from the adult hepatic surgical biopsy samples, and genotype-phenotype association analysis was performed. Three SNPs (rs41272270, rs16876512, and rs6875201), located 28kb upstream, in the 5'-UTR and in intron 1 of BHMT, respectively, were significantly correlated with both BHMT activity (p=3.41E-8, 2.55E-9 and 2.46E-10, respectively) and protein levels (p=5.78E-5, 1.08E-5 and 6.92E-6, respectively). We also imputed 230 additional SNPs across the BHMT and BHMT2 genes, identifying an additional imputed SNP, rs7700790, that was also highly associated with hepatic BHMT enzyme activity and protein. However, none of the 3 genotyped or one imputed SNPs displayed a "shift" during electrophoretic mobility shift assays. These observations may help us to understand individual variation in the regulation of BHMT in the human liver and its possible relationship to variation in methylation.
甜菜碱同型半胱氨酸甲基转移酶（BHMT）催化同型半胱氨酸的再甲基化。BHMT 在人类肝脏中表达水平较高。在肝脏中，BHMT 催化高达 50%的同型半胱氨酸代谢。了解 BHMT 遗传多态性与功能之间的关系，可能有助于我们了解该反应在同型半胱氨酸再甲基化和 S-腺苷甲硫氨酸依赖性甲基化中的作用。为了实现这些目标，我们测量了 268 例成人肝外科活检样本和 73 例不同胎龄胎儿肝组织样本中 BHMT 酶活性和免疫反应性蛋白的水平。BHMT 蛋白水平与胎儿和成人组织中的酶活性显著相关（p<0.001），但与成人肝活检相比，胎儿组织中的酶活性均降低。为了确定可能的基因型-表型相关性，我们从我们自己的基因重测序研究以及 HapMap 中观察到的 BHMT 和密切相关的 BHMT2 基因的 12 个标记 SNP 中选择了 12 个 BHMT 标签 SNP 和 BHMT2 基因。这些 SNP 数据用于对成人肝外科活检样本的 DNA 进行基因分型，并进行基因型-表型关联分析。三个 SNP（rs41272270、rs16876512 和 rs6875201）分别位于 BHMT 的 28kb 上游、5'UTR 和内含子 1 中，与 BHMT 活性（p=3.41E-8、2.55E-9 和 2.46E-10）和蛋白水平（p=5.78E-5、1.08E-5 和 6.92E-6）显著相关。我们还在 BHMT 和 BHMT2 基因中推断了 230 个额外的 SNP，鉴定出一个额外的推断 SNP rs7700790，该 SNP 也与肝 BHMT 酶活性和蛋白高度相关。然而，在电泳迁移率变动分析中，没有一个基因型或一个推断的 SNP 显示出“移位”。这些观察结果可能有助于我们了解人类肝脏中 BHMT 调节的个体差异及其与甲基化变异的可能关系。
