Abstract
The fibroblast growth factor 1 (FGF1) gene is expressed primarily in the kidney and may contribute to hypertension. However, the biologic mechanisms underlying the association between FGF1 and BP regulation remain unknown. We report that the major allele of FGF1 single nucleotide polymorphism rs152524 was associated in a dose-dependent manner with systolic BP (P = 9.65 × 10(-5)) and diastolic BP (P = 7.61 × 10(-3)) in a meta-analysis of 14,364 individuals and with renal expression of FGF1 mRNA in 126 human kidneys (P=9.0 × 10(-3)). Next-generation RNA sequencing revealed that upregulated renal expression of FGF1 or of each of the three FGF1 mRNA isoforms individually was associated with higher BP. FGF1-stratified coexpression analysis in two separate collections of human kidneys identified 126 FGF1 partner mRNAs, of which 71 and 63 showed at least nominal association with systolic and diastolic BP, respectively. Of those mRNAs, seven mRNAs in five genes (MME, PTPRO, REN, SLC12A3, and WNK1) had strong prior annotation to BP or hypertension. MME, which encodes an enzyme that degrades circulating natriuretic peptides, showed the strongest differential coexpression with FGF1 between hypertensive and normotensive kidneys. Furthermore, higher level of renal FGF1 expression was associated with lower circulating levels of atrial and brain natriuretic peptides. These findings indicate that FGF1 expression in the kidney is at least under partial genetic control and that renal expression of several FGF1 partner genes involved in the natriuretic peptide catabolism pathway, renin-angiotensin cascade, and sodium handling network may explain the association between FGF1 and BP.
Highlights
Major Allele of rs152524 Is Associated with Upregulation of fibroblast growth factor 1 (FGF1) mRNA in the Human Kidney Clinical characteristics of 126 TRANSLATE Study individuals with informative genotype included in quantitative real-time PCR analysis of renal FGF1 are given in Table 1. rs152524 was associated with renal expression of total FGF1—compared with the reference genotype, carriers of one and two copies of the major allele of rs152524 had 1.8and 2.7-fold higher levels of FGF1 mRNA in the kidney (P=0.009) (Figure 2)
Through next-generation RNA sequencing we have characterized the diversity of renal FGF1 mRNAs and quantified the extent of their overexpression in the hypertensive kidney
Through coexpression analysis we have identified the network of FGF1 partner transcripts and genes that may explain how upregulation of FGF1 mRNA in the kidney could relate to BP elevation
Summary
Renal mechanisms.[3,4,5,6,7] Two of these variants map to the same fibroblast growth factor 1 signaling cascade—a pathway increasingly recognized as an important player in the cardiovascular system.[6,7] common alleles of fibroblast growth factor 1 (FGF1) gene and its chaperone molecule gene (fibroblast growth factor binding molecule, FGFBP1) cosegregated with familial susceptibility to hypertension in our previous studies.[6,7] The central gene of this pathway—FGF1—was upregulated at both mRNA and protein level in the hypertensive kidney.[6,7] The recent large-scale genetic analysis showed that genetic score composed of FGF1 signaling pathway single nucleotide polymorphisms (SNPs) provides a better explanation for variance in hypertension risk than the score calculated using a similar number of top variants identified by a genome-wide association study.[8]. The exact biologic cause of the association between FGF1 and BP regulation remains unknown. We examined the association between a common SNP of FGF1 and BP in a meta-analysis of approximately 15,000 individuals from five populations of white European ancestry. We explored an effect of this SNP on expression of FGF1 mRNA in the largest to date analysis of 126 human kidneys collected in the TRANScriptome of renaL humAn TissuE (TRANSLATE) Study. Through next-generation RNA sequencing of human renal tissue we have investigated the network of most likely renal partner genes and transcripts of FGF1. Through further clinical association studies, in silico analyses and the investigations of biochemical read-outs of the most relevant partner molecules we have identified a biologically plausible network of transcripts that can mediate renal FGF1-related BP effect
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