TY - JOUR
T1 - Betaine-homocysteine methyltransferase
T2 - Human liver genotype-phenotype correlation
AU - Feng, Qiping
AU - Kalari, Krishna
AU - Fridley, Brooke L.
AU - Jenkins, Gregory
AU - Ji, Yuan
AU - Abo, Ryan
AU - Hebbring, Scott
AU - Zhang, Jianping
AU - Nye, Monica D.
AU - Leeder, J. Steven
AU - Weinshilboum, Richard M.
N1 - Funding Information:
This work was supported in part by National Institutes of Health (NIH) grants R01 GM28157 and U01 GM61388 (The Pharmacogenetics Research Network) as well as a PhRMA Foundation “Center of Excellence in Clinical Pharmacology” Award. Our use of samples obtained from the “Laboratory of Developmental Biology” was supported by NIH Award 5R24HD000836 from the Eunice Kennedy Shriver NICHD. The content of this manuscript does not necessarily represent the official views of the Eunice Kennedy Shriver NICHD of the NIH. We thank Luanne Wussow for her assistance with the preparation of this manuscript. Human tissue was obtained from the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore, MD. The role of the NICHD brain and Tissue Bank is to distribute tissue, and therefore, cannot endorse the studies performed or the interpretation of results. The project entitled ‘Laboratory of Developmental Biology’ was supported by NIH Award Number 5R24HD000836 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development. The content does not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. Appendix A
PY - 2011/2
Y1 - 2011/2
N2 - 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 28. kb 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.
AB - 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 28. kb 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.
KW - BHMT
KW - BHMT2
KW - Betaine-homocysteine methyltransferase
KW - Genotype-phenotype correlation
KW - Hepatic tissue
KW - SNPs
KW - Single nucleotide polymorphisms
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U2 - 10.1016/j.ymgme.2010.10.010
DO - 10.1016/j.ymgme.2010.10.010
M3 - Article
C2 - 21093336
AN - SCOPUS:78651418868
VL - 102
SP - 126
EP - 133
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
SN - 1096-7192
IS - 2
ER -