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 V_Leiden 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 Ibα gene, for which the C allele is thought to increase translation, and to increase GPIbα 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.