The 894 G > T variant of endothelial nitric oxide synthase (eNOS) increases the risk of recurrent venous thrombosis through interaction with elevated homocysteine levels.
BACKGROUND
Venous thrombosis is a multicausal disease involving both genetic as well as acquired risk factors. Hyperhomocysteinemia is associated with a 2-fold increased risk of recurrent venous thrombosis (RVT). Recently, the 894 G > T variant of endothelial nitric oxide synthase (eNOS) was postulated to be associated with hyperhomocysteinemia.


OBJECTIVE
We hypothesized an interrelation of hyperhomocysteinemia, the eNOS 894 G > T variant and RVT risk.


METHODS
The eNOS 894 G > T variant was studied in 170 cases with a history of RVT and 433 controls from the general population.


RESULTS
The eNOS 894 TT genotype may increase RVT risk [odds ratio (OR) 1.3 (0.7-2.6)], but no association of the eNOS 894 G > T variant with elevated homocysteine was found in controls. Interestingly, in RVT cases the coexistence of both the 894 TT genotype and elevated tHcy levels (> 90th percentile) was more frequently present than in controls, which led to a substantially increased risk of recurrent venous thrombosis [fasting tHcy OR 5.3 (1.1-24.1), postload tHcy OR 6.5 (1.6-29.5)].


CONCLUSIONS
The results of the present study demonstrate that the eNOS 894 G > T variation interacts with elevated tHcy levels, leading to an increased risk of recurrent thrombotic events. This interaction points in the direction of S-nitrosation as a mechanism by which homocysteine exerts its detrimental effects on the hemostatic system.
Heil
S G
SG
Department of Endocrinology, University Medical Center Nijmegen, Nijmegen, The Netherlands.
Den Heijer
M
M
Van Der Rijt-Pisa
B J M
BJ
Kluijtmans
L A J
LA
Blom
H J
HJ
D016022:Case-Control Studies; D005838:Genotype; D006710:Homocysteine / Q000378:metabolism; D006801:Humans; D020138:Hyperhomocysteinemia / Q000150:complications* / Q000453:epidemiology; D017720:Molecular Epidemiology; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III; D015538:Nitrosation; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012008:Recurrence; D012306:Risk; D020246:Venous Thrombosis / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*
D006710:Homocysteine; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III