Functional Epistatic Interaction between rs6046G>A in F7 and rs5355C>T in SELE Modifies Systolic Blood Pressure Levels

Background 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. Methods and Results 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. Conclusion 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.