The heritability of plasma homocysteine, and the influence of genetic variation in the homocysteine methylation pathway.

BACKGROUND

The extent of genetic influence on plasma homocysteine, a risk factor for ischaemic heart disease, is uncertain. Many association studies have investigated common polymorphisms and their role in hyperhomocysteinaemia, but only the thermolabile variant of methylene tetrahydrofolate reductase (MTHFR) has shown an association (small but robust).

AIM

To estimate the heritability of plasma homocysteine and the contributions of well-studied common SNPs in the three main candidate genes in the homocysteine methylation pathway.

DESIGN

Twin study.

METHODS

We studied 216 monozygotic and 790 dizygotic pairs of twins; all were women. Blood was collected after overnight fasting for measurement of homocysteine, folate, vitamin B12, and extraction of DNA. Heritability was estimated by structural modelling, including correction for known environmental influences, particularly serum folate. The frequency of a common coding SNP in MTHFR and methionine synthase (MTR), and two coding SNPs in methionine synthase reductase (MTRR) were measured in dizygotic twins by ABI 7700 Sequence Detection, and the contribution of each to homocysteine variance was determined.

RESULTS

The heritability of homocysteine was 57% (95%CI 51-63%). The highest contribution to homocysteine was serum folate, accounting for 10.13% of variance. This was twice the total genetic contribution of 4.56%, and only the C1763T SNP of MTRR showed significant association with homocysteine.

DISCUSSION

Homocysteine has one of the highest heritabilities of common risk factors for ischaemic heart disease. This is not accounted for by the commonly studied SNPs in MTHFR, MTR and MTRR.