A novel chromosome 5 locus interacting with sodium intake was associated with increased MEF2C-AS1 expression and VEGF-A plasma protein concentrations (P=6x10-7).
Meta-Analysis (n=40,570)
Yes
The MEF2C-VEGFA pathway is highlighted as a candidate pathway for salt-mediated blood pressure traits, potentially influencing endothelial function and angiogenesis.
p-value: p=6x10-7
Objective: Dietary salt intake remains an important modifiable risk factor for both hypertension and associated cardiovascular disease. Large population-based cohort studies enable a hypothesis free approach to identifying key genetic and pathophysiological drivers of salt-mediated blood pressure (BP) traits.Design and method: Genome-wide gene-environment interaction analyses of sodium mediated BP traits were conducted using the UK biobank and EPIC Norfolk cohorts. A meta-analysis of both cohorts identified a single genome-wide significant interaction locus on chromosome 5. In order to identify the underlying causal pathway, computational fine mapping and colocalization analysis with expression quantitative trait locus (eQTL) data was conducted to identify single nucleotide polymorphisms (SNP) within this locus that are associated with both a SNPxsodium excretion interaction and altered RNA expression of nearby genes. A proteome wide scan (N=40,570 individuals, n=2907 proteins) was then conducted to delineate the potential downstream effects of altered RNA expression. We utilized available normalized protein expression (NPX) data from the UK Biobank using linear regression to test the association between the lead SNP and NPX values. Results: MEF2C and MEF2C-AS1 were the closest mapped genes to the locus identified in our genome-wide interaction analysis. Significant eQTL associations for both genes were observed for SNPs within this locus. Fine-mapping and colocalization analysis indicated a colocalization with altered MEF2C-AS1 RNA expression in arterial and muscular tissue. In proteomic analysis, the 10 proteins that met the false discovery rate significance threshold (q < 0.05), only VEGFA (P = 6x10-7)had a clear experimentally established link both to MEF2C-AS1 and salt mediated BP traits. Conclusions: A meta-analysis of a gene-by-sodium interaction studies identified a novel locus on chromosome 5. This locus is associated with increased expression of MEF2C-AS1 in vascular tissue and increased VEGF-A plasma protein concentrations. Genetic variation at this locus may therefore contribute to salt-mediated BP traits by influencing endothelial function and angiogenesis. This hypothesis generating analysis highlights MEF2C-VEGFA as a candidate pathway for salt mediated blood pressure traits worthy of further investigation.
Murray et al. (Fri,) conducted a meta-analysis in Salt-mediated blood pressure traits (n=40,570). Gene-by-sodium interaction at chromosome 5 locus was evaluated on Association between lead SNP and normalized protein expression values (p=6x10-7). A novel chromosome 5 locus interacting with sodium intake was associated with increased MEF2C-AS1 expression and VEGF-A plasma protein concentrations (P=6x10-7).