Although numerous genetic studies have been performed, only 0.9% of blood pressure phenotypic variance has been elucidated. This phenomenon could be partially due to epistatic interactions. Our aim was to identify epistatic interaction(s) associated with blood pressure levels in a pre-planned two-phase approach.In a discovery cohort composed of 3,600 French individuals, we found rs6046A allele in F7 associated with decreased blood pressure levels (P≤3.7×10(-3)) and rs5355T allele in SELE associated with decreased diastolic blood pressure levels (P = 5×10(-3)). Both variants interacted in order to influence blood pressure levels (P≤0.048). This interaction was replicated with systolic blood pressure in 4,620 additional European individuals (P = 0.03). Similarly, in this replication cohort, rs6046A was associated with decreased blood pressure levels (P≤8.5×10(-4)). Furthermore, in peripheral blood mononuclear cells of a subsample of 90 supposed healthy individuals, we found rs6046A positively associated with NAMPT mRNA levels (P≤9.1×10(-5)), suggesting an eventual involvement of NAMPT expression in blood pressure regulation. Confirming this hypothesis, further transcriptomic analyses showed that increased NAMPT mRNA levels were positively correlated with ICAM1, SELL, FPR1, DEFA1-3, and LL-37 genes expression (P≤5×10(-3)). The last two mRNA levels were positively associated with systolic blood pressure levels (P≤0.01) and explained 4% of its phenotypic variation.These findings reveal the importance of epistatic interactions in blood pressure genetics and give new insights for the role of inflammation in its complex regulation.