RT Journal Article
SR Electronic
T1 Human Liver Methionine Cycle: <em>MAT1A</em> and <em>GNMT</em> Gene Resequencing, Functional Genomics, and Hepatic Genotype-Phenotype Correlation
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1984
OP 1992
DO 10.1124/dmd.112.046953
VO 40
IS 10
A1 Ji, Yuan
A1 Nordgren, Kendra K. S.
A1 Chai, Yubo
A1 Hebbring, Scott J.
A1 Jenkins, Gregory D.
A1 Abo, Ryan P.
A1 Peng, Yi
A1 Pelleymounter, Linda L.
A1 Moon, Irene
A1 Eckloff, Bruce W.
A1 Chai, Xiaoshan
A1 Zhang, Jianping
A1 Fridley, Brooke L.
A1 Yee, Vivien C.
A1 Wieben, Eric D.
A1 Weinshilboum, Richard M.
YR 2012
UL http://dmd.aspetjournals.org/content/40/10/1984.abstract
AB The “methionine cycle” plays a critical role in the regulation of concentrations of (S)-adenosylmethionine (AdoMet), the major biological methyl donor. We set out to study sequence variation in genes encoding the enzyme that synthesizes AdoMet in liver, methionine adenosyltransferase 1A (MAT1A) and the major hepatic AdoMet using enzyme, glycine N-methyltransferase (GNMT), as well as functional implications of that variation. We resequenced MAT1A and GNMT using DNA from 288 subjects of three ethnicities, followed by functional genomic and genotype-phenotype correlation studies performed with 268 hepatic biopsy samples. We identified 44 and 42 polymorphisms in MAT1A and GNMT, respectively. Quantitative Western blot analyses for the human liver samples showed large individual variation in MAT1A and GNMT protein expression. Genotype-phenotype correlation identified two genotyped single-nucleotide polymorphisms (SNPs), reference SNP (rs) 9471976 (corrected p = 3.9 × 10−10) and rs11752813 (corrected p = 1.8 × 10−5), and 42 imputed SNPs surrounding GNMT that were significantly associated with hepatic GNMT protein levels (corrected p values &lt; 0.01). Reporter gene studies showed that variant alleles for both genotyped SNPs resulted in decreased transcriptional activity. Correlation analyses among hepatic protein levels for methionine cycle enzymes showed significant correlations between GNMT and MAT1A (p = 1.5 × 10−3) and between GNMT and betaine homocysteine methyltransferase (p = 1.6 × 10−7). Our discovery of SNPs that are highly associated with hepatic GNMT protein expression as well as the “coordinate regulation” of methionine cycle enzyme protein levels provide novel insight into the regulation of this important human liver biochemical pathway.