Renal Mechanisms of Association between Fibroblast Growth Factor 1 and Blood Pressure

Fibroblast growth factor 1 gene - FGF1 - is expressed primarily in the kidney and is postulated to contribute to hypertension. However, the biological mechanisms underlying the association between FGF1 and blood pressure regulation remain unknown. We report that the major allele of FGF1 single nucleotide polymorphism rs152524 was associated in a dose-dependent manner not only with systolic blood pressure (P=9.65x10-5) and diastolic blood pressure (7.61x10-3) in a meta-analysis of 14364 individuals but also with renal expression of FGF1 mRNA in 126 human kidneys (9.0x10-3). Next-generation RNA-sequencing revealed that renal upregulation of FGF1 expression globally and of each of its 3 mRNA isoforms individually is associated with higher blood pressure. FGF1-stratified co-expression analysis in 2 separate collections of human kidneys identified 126 FGF1 partner mRNAs, of which 71 and 63 showed at least nominal association with systolic and diastolic blood pressure, respectively. Of those, 7 mRNAs in 5 genes (MME, PTPRO, REN, SLC12A3 and WNK1) had strong prior annotation to blood pressure or hypertension. MME (that encodes an enzyme responsible for degradation of circulating natriuretic peptides) showed the strongest differential co-expression with FGF1 between hypertensive and normotensive kidneys. Higher level of renal FGF1 expression was associated with lower circulating levels of atrial and brain natriuretic peptides. These findings indicate that FGF1expression in the kidney is at least under partial genetic control and that renal expression of several FGF1 partner genes in natriuretic peptides catabolism pathway, reninangiotensin cascade and sodium handling network may explain the association between FGF1 and blood pressure

52 Genetic Loci Influencing Myocardial Mass.

BACKGROUND: Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. OBJECTIVES: This meta-analysis sought to gain insights into the genetic determinants of myocardial mass. METHODS: We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment. RESULTS: We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10(-8). These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo. CONCLUSIONS: Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets