Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 126-133 |
| Number of pages | 8 |
| Journal | Molecular Genetics and Metabolism |
| Volume | 102 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 2011 |
Fingerprint
Keywords
- Betaine-homocysteine methyltransferase
- BHMT
- BHMT2
- Genotype-phenotype correlation
- Hepatic tissue
- Single nucleotide polymorphisms
- SNPs
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Genetics
- Endocrinology
- Endocrinology, Diabetes and Metabolism
Cite this
Betaine-homocysteine methyltransferase : Human liver genotype-phenotype correlation. / Feng, Qiping; Kalari, Krishna R; Fridley, Brooke L.; Jenkins, Gregory; Ji, Yuan; Abo, Ryan; Hebbring, Scott; Zhang, Jianping; Nye, Monica D.; Leeder, J. Steven; Weinshilboum, Richard M.
In: Molecular Genetics and Metabolism, Vol. 102, No. 2, 02.2011, p. 126-133.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Betaine-homocysteine methyltransferase
T2 - Human liver genotype-phenotype correlation
AU - Feng, Qiping
AU - Kalari, Krishna R
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
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 - Betaine-homocysteine methyltransferase
KW - BHMT
KW - BHMT2
KW - Genotype-phenotype correlation
KW - Hepatic tissue
KW - Single nucleotide polymorphisms
KW - SNPs
UR - http://www.scopus.com/inward/record.url?scp=78651418868&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78651418868&partnerID=8YFLogxK
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 -