Role of promoter polymorphisms in the plasma glutathione peroxidase (GPx-3) gene as a risk factor for cerebral venous thrombosis.
OBJECTIVE
Plasma glutathione peroxidase (GPx-3) is a major antioxidant enzyme in plasma and the extracellular space that scavenges reactive oxygen species produced during normal metabolism or after oxidative insult. A deficiency of this enzyme increases extracellular oxidant stress, promotes platelet activation, and may promote oxidative posttranslational modification of fibrinogen. We recently identified a haplotype (H(2)) in the GPx-3 gene promoter that increases the risk of arterial ischemic stroke among children and young adults.


METHODS
The aim of this study is to identify possible relationships between promoter haplotypes in the GPx-3 gene and cerebral venous thrombosis (CVT). We studied the GPx-3 gene promoter from 23 patients with CVT and 123 young controls (18 to 45 years) by single-stranded conformational polymorphism and sequencing analysis.


RESULTS
Over half of CVT patients (52.1%) were heterozygous (H(1)H(2)) or homozygous (H(2)H(2)) carriers of the H(2) haplotype compared with 12.2% of controls, yielding a more than 10-fold independent increase in the risk of CVT (OR=10.7; 95% CI, 2.70 to 42.36; P<0.0001). Among women, the interaction of the H(2) haplotype with hormonal risk factors increased the OR of CVT to almost 70 (P<0.0001).


CONCLUSIONS
These findings show that a novel GPx-3 promoter haplotype is a strong, independent risk factor for CVT. As we have previously shown that this haplotype is associated with a reduction in transcriptional activity, which compromises antioxidant activity and antithrombotic benefits of the enzyme, these results suggest that a deficiency of GPx-3 leads to a cerebral venous thrombophilic state.
Voetsch
Barbara
B
Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, Boston, MA 02115, USA.
Jin
Richard C
RC
Bierl
Charlene
C
Deus-Silva
Leonardo
L
Camargo
Erica C S
EC
Annichino-Bizacchi
Joyce M
JM
Handy
Diane E
DE
Loscalzo
Joseph
J
D000293:Adolescent; D000328:Adult; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005979:Glutathione Peroxidase / Q000097:blood / Q000235:genetics*; D006239:Haplotypes; D006728:Hormones; D006801:Humans; D020767:Intracranial Thrombosis / Q000097:blood / Q000453:epidemiology* / Q000235:genetics*; D016015:Logistic Models; D008875:Middle Aged; D018807:Polymorphism, Single-Stranded Conformational; D011401:Promoter Regions, Genetic / Q000235:genetics; D012307:Risk Factors; D020521:Stroke / Q000097:blood / Q000453:epidemiology / Q000235:genetics; D020246:Venous Thrombosis / Q000097:blood / Q000453:epidemiology* / Q000235:genetics*
D006728:Hormones; C486484:GPX3 protein, human; D005979:Glutathione Peroxidase