Blood, 15 September 2002, Vol. 100, No. 6, pp. 1933-1933
Starting out right: Kozak sequences and clots
Understanding genetic risk factors for thrombotic disorders
presents a challenge: exactly how does a given polymorphism lead to
thrombosis risk? A straightforward answer presents itself when polymorphisms affect coding sequences, for example factor
VLeiden and resistance to activated protein C. Other
polymorphisms have less obvious effects. The prothrombin gene's
20210A>G polymorphism affects only the 3' untranslated region, leading
to more efficient processing of prothrombin mRNA and higher prothrombin
levels, but the relationship between this observation and subsequent
thrombosis remains speculative.
Now González-Conejero and colleagues (page 2081) provide evidence
that links a 5' untranslated polymorphism in the translation initiation
sequence (Kozak consensus site) of the annexin V gene (
1C>T) to
reduction in myocardial infarction (MI) risk in a Mediterranean population. The 1T allele was present in 23% of controls but only
13% of young MI survivors. Annexin V cDNA constructs containing the
1T allele were translated in vitro 1.4 times as efficiently as
constructs with the 1C allele. Circulating levels of annexin V were
almost twice as high in subjects carrying the T allele as levels in
those homozygous for C. The authors propose that the higher circulating
annexin V may protect against thrombosis by binding to prothrombotic,
negatively charged phospholipids exposed on platelet surfaces during
activation, as demonstrated by others.
This is not the first analysis of Kozak sequence polymorphism in a
coagulation gene related to thrombosis risk. Frank and colleagues
(Blood. 2001;97:875-879) studied a Kozak polymorphism in the
glycoprotein Ib
gene, for which the C allele is thought to increase
translation, and to increase GPIb receptor levels on platelets.
Significant changes in risk were not established in a cohort of young
women with stroke or MI.
Candidate gene polymorphisms are now easy to come by.
González-Conejero et al have set a high standard by coupling
epidemiology with demonstration of plausible biology and an underlying
molecular mechanism. The significance of this polymorphism in other
populations remains to be established, and studies on the putative
protective effect of circulating annexin V are now needed to test
this interesting hypothesis.
Ellis Neufeld
Children's Hospital,
Boston
