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Comparative Study
. 2010 Jul;41(7):1356-62.
doi: 10.1161/STROKEAHA.109.573626. Epub 2010 May 20.

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

David Della-Morte  1 , Ashley Beecham, Tatjana Rundek, Susan Slifer, Bernadette Boden-Albala, Mark S McClendon, Susan H Blanton, Ralph L Sacco
Affiliations
Comparative Study

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

David Della-Morte et al. Stroke. 2010 Jul.

Abstract

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.

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Figures

Figure 1
Figure 1
Multipoint linkage plots for tHcy. Map distance in CM is depicted on the X-axis and LOD scores on the Y-axis.
Figure 2
Figure 2
(a): Multipoint linkage plot for tHcy on chromosome 2, including OSA for a subset of families with the smallest proportion of DR enrollment. (b): Multipoint linkage plot for tHcy on chromosome 17, including OSA for a subset of families with the largest proportion of DR enrollment.
Figure 2
Figure 2
(a): Multipoint linkage plot for tHcy on chromosome 2, including OSA for a subset of families with the smallest proportion of DR enrollment. (b): Multipoint linkage plot for tHcy on chromosome 17, including OSA for a subset of families with the largest proportion of DR enrollment.
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