Pearson’s correlations between <i>NAMPT, ICAM1, SELL, FPR1, DEFA1-3</i> and <i>LL-37</i> genes expression.

<p>Only Significant correlations are shown (P≤5×10⁻³).</p><p>All genes expression were normalized to <i>POL2RA</i> mRNA levels.</p><p>r: Pearson’s correlation coefficient, P: P-value.</p

Characteristics of studied individuals.

<p>BMI: body mass index, BP: blood pressure, SBP: systolic blood pressure, DBP: diastolic blood pressure, MAF: minor allele frequency.</p

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

<div><h3>Background</h3><p>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.</p> <h3>Methods and Results</h3><p>In a discovery cohort composed of 3,600 French individuals, we found rs6046A allele in <em>F7</em> associated with decreased blood pressure levels (P≤3.7×10⁻³) and rs5355T allele in <em>SELE</em> 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 <em>NAMPT</em> mRNA levels (P≤9.1×10⁻⁵), suggesting an eventual involvement of <em>NAMPT</em> expression in blood pressure regulation. Confirming this hypothesis, further transcriptomic analyses showed that increased <em>NAMPT</em> mRNA levels were positively correlated with <em>ICAM1</em>, <em>SELL</em>, <em>FPR1</em>, <em>DEFA1-3</em>, and <em>LL-37</em> 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.</p> <h3>Conclusion</h3><p>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.</p> </div

Genetic variants associated with blood pressure.

*<p>: Log10 transformed values.</p><p>Beta coefficients are shown for significant associations.</p><p>Chr: chromosome, SNP: single nucleotide polymorphism, MAF: minor allele frequency, Beta: coefficient in the linear regression model, BP: blood pressure, P_meta: P meta-analysis, SBP: systolic blood pressure, DBP: diastolic blood pressure.</p

Blood pressure variations according to rs5355T allele in <i>SELE</i> and rs6046G/A genotypes in <i>F7</i> when compared to rs5355C allele in <i>SELE</i>.

<p>Only significant blood pressure variations are shown.</p><p>BP variations in individuals carrying rs5355T allele in <i>SELE</i> and rs6046GG in <i>F7</i> were compared with carriers of rs5355C allele in <i>SELE</i> and rs6046GG genotype in <i>F7</i>. BP variations in individuals carrying rs5355T allele in <i>SELE</i> and rs6046GA genotype in <i>F7</i> were compared with carriers of rs5355C allele in <i>SELE</i>, rs6046GA genotype in <i>F7</i>. BP variations in carriers of rs5355T allele in <i>SELE</i> and rs6046AA genotype in <i>F7</i> were compared with those carrying rs5355C allele in <i>SELE</i> and rs6046AA genotype in <i>F7</i>.</p><p>DBP: diastolic blood pressure, P*: p value for epistatic interaction model, SBP: systolic blood pressure, BP: blood pressure.</p

Summary of the study and hypothesis for rs5355C>T in <i>SELE</i> and rs6046G>A in <i>F7</i> interaction.

<p>rs6046A allele in <i>F7</i> was associated with decreased BP levels. rs5355C>T in <i>SELE</i> and rs6046G>A in <i>F7</i> interacted in order to alter SBP levels, rs6046A inverted the BP-lowering effect of rs5355T. rs6046A allele in <i>F7</i> was positively associated with increased <i>NAMPT</i> gene expression. <i>NAMPT</i> levels were positively correlated with <i>ICAM1</i>, <i>SELL</i>, <i>FPR1</i> and <i>DEFA1-3</i> genes expression. Only <i>DEFA1-3</i> and <i>LL-37</i> expressions were correlated and associated with SBP levels and explained 4% of its variation.</p