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

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

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

Pro- and anti-angiogenic VEGF mRNAs in autoimmune thyroid diseases

<p>The aim of this study was to assess the relationships between five different splice isoforms of VEGF mRNA and its plasma levels in individuals treated for autoimmune thyroid diseases (AITD); mainly Graves’ disease (GD) and Hashimoto’s thyroiditis (HT). In a population from Tunisia, levels of thyroid hormones and antibodies were quantified simultaneously with plasma VEGF and VEGF mRNA isoforms after a period of 6 months of patients’ treatment. Plasma VEGF was measured in 110 AITD patients (21 GD and 89 HT patients). VEGF isoforms (VEGF121, VEGF165, VEGF145 and VEGF189 pro-angiogenic isoforms and VEGF165b anti-angiogenic isoform) in peripheral blood mononuclear cells were quantified in 71 patients (20 GD and 51 HT patients) and 86 healthy controls. Decreased levels of VEGF189 mRNA were observed in AITD compared to controls. VEGF165 was increased in GD patients compared to controls and the VEGF165b was increased in HT patients compared to GD. We observed increased levels of VEGF165b in hypothyroid AITD patients after treatment. We have also shown that the VEGF145 isoform levels were determined by FT4 in all patients and by the thyroid status after 6 months of treatment only in HT patients. An association was observed for VEGF165 mRNA levels with anti-TPO antibodies in all patients. Finally, FT4 was associated with VEGF plasma levels but only in healthy controls. In conclusion, this descriptive study highlights the specificity of VEGF mRNA isoforms in AITD, a fact underlining the need for novel clinical trials and the development of personalised theranostic approaches.</p

Effect of SNPs rs6921438 and rs10738760 on variation in quantitative traits related to T2D complications in type 2 diabetic participants from the Corbeil and Diab2-Néphrogène (D2NG) studies.

*<p>Per X-allele effect size: coefficient β from additive linear regression models adjusted for T2D duration and gender.</p><p>Data are presented as mean ± standard deviation or median (interquartile range). Data for ACR were logarithmically transformed before statistical analysis.</p><p><b><i>eGFR</i></b>, estimated glomerular filtration rate using modification of diet in renal disease (MDRD) formula; <b><i>ACR</i></b>, urinary albumin/creatinine ratio; <b><i>T2D</i></b>, type 2 diabetes; <b><i>SE</i></b>, standard error; <b><i>CI</i></b>, confidence interval; <b><i>P</i></b>, P-value.</p

Case numbers needed for reaching a statistical power of 80% according to the expected odds ratio or effect.

<p>Only statistical power of association analyses with a P-value above 0.05 was analysed.</p><p><b><i>β</i></b>, effect size; <b><i>OR</i></b>, odds ratio; <b><i>NA</i></b>, not applicable; <b><i>eGFR</i></b>, estimated glomerular filtration rate using modification of diet in renal disease (MDRD) formula; <b><i>ACR</i></b>, urinary albumin/creatinine ratio.</p

Association of SNPs rs6921438 and rs10738760 with T2D risk in two European case-control studies.

*<p>OR from additive logistic regression models adjusted for age and gender.</p><p><b><i>T2D</i></b>, type 2 diabetes; <b><i>OR</i></b>, odds ratio; <b><i>CI</i></b>, confidence interval; <b><i>P</i></b>, P-value.</p