Genetic and environmental influences on plasma homocysteine: results from a Danish twin study.
BACKGROUND
Increased plasma homocysteine has been linked to many clinical conditions including atherosclerosis and ischemic stroke. We assessed the genetic and environmental influences on homocysteine in adult twins and tested the influence of 3 candidate polymorphisms.


METHODS
Homocysteine was analyzed in 1206 healthy twins, who were genotyped for 3 polymorphisms: MTHFR 677C>T, MTR 2756A>G, and NNMT (dbSNP: rs694539). To perform quantitative trait linkage analysis of the MTHFR locus, the genotyping was supplemented with 2 genetic markers localized on each site of the MTHFR locus. The twin data were analyzed using biometric structural equation models as well as a combined association and linkage analysis in 2 age cohorts.


RESULTS
Age, sex, and MTHFR genotype have a significant impact on homocysteine concentrations, whereas the other genotypes were not associated with homocysteine concentrations. The variance in homocysteine could be solely ascribed to additive genetic and nonshared environmental factors, with an estimated additive genetic proportion of total variation at age 18-39 years of 0.63 (95% CI, 0.53-0.71) and at age 40-65 years of 0.27 (95% CI, 0.10-0.41). The impact of the MTHFR locus is estimated to explain 53% (95% CI, 0.07-0.67) of the total phenotypic variation in persons 18-39 years old and 24% (95% CI, 0.00-0.39) in persons 40-65 years old, i.e., almost all additive genetic variance.


CONCLUSIONS
Homocysteine concentrations have a high heritability that decreases with age. The MTHFR gene locus is responsible for almost all the variation attributable to genetic factors, leaving very little influence of other genetic variations.
Bathum
Lise
L
Department of Biochemistry, Pharmacology and Genetics, Odense University Hospital, Odense, Denmark. lisebathum@dadlnet.dk
Petersen
Inge
I
Christiansen
Lene
L
Konieczna
Agnieszka
A
Sørensen
Thorkild I A
TI
Kyvik
Kirsten O
KO
D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D004777:Environment; D005260:Female; D008040:Genetic Linkage; D005819:Genetic Markers; D005838:Genotype; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D050903:Nicotinamide N-Methyltransferase / Q000235:genetics*; D011110:Polymorphism, Genetic; D012737:Sex Factors; D014427:Twins / Q000235:genetics*
D005819:Genetic Markers; D006710:Homocysteine; D042965:Methylenetetrahydrofolate Reductase (NADPH2); C494406:NNMT protein, human; D050903:Nicotinamide N-Methyltransferase; D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase