Genetic linkage of serum homocysteine in Dominican families: the Family Study of Stroke Risk and Carotid Atherosclerosis.

BACKGROUND AND PURPOSE: Homocysteine levels are determined by genetic and environmental factors. Several studies have linked high plasma levels of total homocysteine to the increased risk of cardiovascular disease, stroke, and many other conditions. However, the exact mechanism of documented and novel total homocysteine quantitative trait loci to that risk is unknown.

METHODS

We have performed linkage analysis in 100 high-risk Dominican families with 1362 members. Probands were selected from the population-based Northern Manhattan Study. A set of 405 microsatellite markers was used to screen the whole genome. Variance components analysis was used to detect evidence for linkage after adjusting for stroke risk factors. Ordered-subset analysis based on Dominican Republic enrollment was conducted.

RESULTS

Total homocysteine levels had a heritability of 0.44 (P<0.0001). The most significant evidence for linkage was found at chromosome 17q24 (maximum logarithm of odds [MLOD]=2.66, P=0.0005) with a peak at D17S2193 and was significantly increased in a subset of families with a high proportion of Dominican Republic enrollment (MLOD=3.92, P=0.0022). Additionally, modest evidence for linkage was found at chromosome 2p21 (MLOD=1.77, P=0.0033) with a peak at D2S1356 and was significantly increased in a subset of families with a low proportion of Dominican Republic enrollment (MLOD=2.82, P=0.0097).

CONCLUSIONS

We found a strong evidence for novel quantitative trait loci on chromosomes 2 and 17 for total homocysteine plasma levels in Dominican families. Our family study provides essential data for a better understanding of the genetic mechanisms associated with elevated total homocysteine levels leading to cardiovascular disease after accounting for environmental risk factors.