Liberating R169 promotes anticoagulant protein C

useful predictors of the thromboembolic disease of an individual. One of the more striking results in the article by de Haan et al is the apparent ineffectiveness of a risk score composed of 31 SNPs compared with another composed of only 5 SNPs with the highest individual odds ratio for venous thrombosis (Factor V Leiden, PT G20210A, A1 blood group, 1 SNP in the Fibrinogen gene, 1 in the Factor XI gene). 1 Remarkably, these 5 genetic variants have a direct or indirect functional effect on hemostatic proteins, highlighting the role of coagulation on thrombosis risk. Considering that all 31 SNPs are independently associated with thrombotic risk, although sometimes small, a better predictive power should be expected when increasing the number of SNPs in the model. We hypothesize 2 explanations for this paradox. Perhaps some of the proposed SNPs are false-positive. More likely, new and more powerful mathematical tools to integrate all of this multiplicity of genetic information are needed. To date, only classical methods of logistic regression have been applied. These methods are unable to cope with the interaction among risk factors. It is also possible that other variables play an important role in thrombotic risk. In this sense, a limitation to the study by de Haan et al is the exclusive use of common genetic variants in the analysis of the risk. Using these variants, only a very small portion of the disease susceptibility is explained and this is one of the more frustrating findings of the giant genomic studies published to date. One germane question is where the "missing heritability" underlying the complex and common diseases lies. Very probably, other rarer genetic variants, of the utmost importance at the individual level, must be included in the risk score of venous thromboembolic disease.