Genetic and lifestyle variables associated with homocysteine concentrations and the distribution of folate derivatives in healthy premenopausal women.
BACKGROUND
Low folate and high homocysteine (Hcy) concentrations are associated with pregnancy-related pathologies such as spina bifida. Polymorphisms in folate/Hcy metabolic enzymes may contribute to this potentially pathogenic biochemical phenotype.


METHODS
The study comprised 26 Caucasian and 23 African-American premenopausal women. Subjects gave fasting blood samples for biochemical phenotyping and genotyping. Total Hcy (tHcy) and both plasma and red blood cell (RBC) folate derivatives (i.e. tetrahydrofolate [THF], 5-methylTHF [5-MTHF], and 5,10-methenylTHF [5,10-MTHF]) were measured using stable isotope dilution liquid chromatography, multiple reaction monitoring, and mass spectrometry. Eleven polymorphisms from nine folate/Hcy pathway genes were genotyped. Tests of association between genetic, lifestyle, and biochemical variables were applied.


RESULTS
In African American women, tHcy concentrations were associated (p < 0.05) with total RBC folate, RBC 5-MTHF, B(12), and polymorphisms in methionine synthase (MTR) and thymidylate synthase (TYMS). In Caucasian women, tHcy concentrations were not associated with total folate levels, but were associated (p < 0.05) with RBC THF, ratios of RBC 5-MTHF:THF, and polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR) and MTR. In African Americans, folate derivative levels were associated with smoking, B(12), and polymorphisms in MTR, TYMS, methionine synthase reductase (MTRR), and reduced folate carrier1 (RFC1). In Caucasians, folate derivative levels were associated with vitamin use, B(12), and polymorphisms in MTHFR, TYMS, and RFC1.


CONCLUSIONS
Polymorphisms in the folate/Hcy pathway are associated with tHcy and folate derivative levels. In African American and Caucasian women, different factors are associated with folate/Hcy phenotypes and may contribute to race-specific differences in the risks of a range of pregnancy-related pathologies.
Summers
Carolyn M
CM
Centers for Cancer Pharmacology, Pharmacogenetics, and Excellence in Environmental Toxicology, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Mitchell
Laura E
LE
Stanislawska-Sachadyn
Anna
A
Baido
Shirley F
SF
Blair
Ian A
IA
Von Feldt
Joan M
JM
Whitehead
Alexander S
AS
D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics; D000293:Adolescent; D000328:Adult; D001741:Black or African American / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D019587:Dietary Supplements; D004912:Erythrocytes / Q000737:chemistry; D005260:Female; D056726:Genetic Association Studies; D006710:Homocysteine / Q000097:blood* / Q000235:genetics; D006801:Humans; D007223:Infant; D008019:Life Style; D026901:Membrane Transport Proteins / Q000235:genetics; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011247:Pregnancy; D017697:Premenopause / Q000235:genetics / Q000378:metabolism*; D016135:Spinal Dysraphism / Q000453:epidemiology / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D013763:Tetrahydrofolates / Q000032:analysis; D013940:Thymidylate Synthase / Q000235:genetics; D014815:Vitamins / Q000008:administration & dosage; D044465:White People / Q000235:genetics; D055815:Young Adult
D026901:Membrane Transport Proteins; C120043:SLC19A2 protein, human; D013763:Tetrahydrofolates; D014815:Vitamins; D006710:Homocysteine; C030371:5,6,7,8-tetrahydrofolic acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; D013940:Thymidylate Synthase