Pathway Analysis Shows Association between FGFBP1 and Hypertension

Abstract

Variants in the gene encoding fibroblast growth factor 1 (FGF1) co-segregate with familial susceptibility to hypertension, and glomerular upregulation of FGF1 associates with hypertension. To investigate whether variants in other members of the FGF signaling pathway may also associate with hypertension, we genotyped 629 subjects from 207 Polish families with hypertension for 79 single nucleotide polymorphisms in eight genes of this network. Family-based analysis showed that parents transmitted the major allele of the rs16892645 polymorphism in the gene encoding FGF binding protein 1 (FGFBP1) to hypertensive offspring more frequently than expected by chance (P ϭ 0.005). An independent cohort of 807 unrelated Polish subjects validated this association. Furthermore, compared with normotensive subjects, hypertensive subjects had approximately 1.5-and 1.4-fold higher expression of renal FGFBP1 mRNA and protein (P ϭ 0.04 and P ϭ 0.001), respectively. By immunohistochemistry, hypertensionrelated upregulation of FGFBP1 was most apparent in the glomerulus and juxtaglomerular space. Taken together, these data suggest that FGFBP1 associates with hypertension and that systematic analysis of signaling pathways can identify previously undescribed genetic associations. 22: 947-955, 201122: 947-955, . doi: 10.1681 Essential hypertension is a complex, multifactorial, heritable disease. The contribution of genetic factors to the development of hypertension is estimated at 30 to 50%, but the causative alleles and related molecular mechanisms remain largely elusive. However, it is becoming increasingly clear that genes underlying familial susceptibility to essential hypertension may not necessarily reside within the most obvious pathways involved in BP regulation. 1 Indeed, a substantial proportion of novel alleles associated with hypertension and BP in the recent genome-wide association scans map to genes that do not belong to classical systems of BP regulation (such as the sympathetic nervous system or renal sodium handling). 2,3 Fibroblast growth factor (FGF) family is an example of a novel group of mole- J Am Soc Nephrol

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

“…6,7 Indeed, 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.…”

“…In brief, the TRANSLATE Study recruited individuals of white European ancestry eligible for unilateral elective nephrectomy because of noninvasive renal cancer in three reference centers. 7 Small fragments of kidney tissues were collected from the healthy (unaffected by cancer) pole of the kidney and immersed in RNAlater (Ambion, Austin, Texas) immediately after nephrectomy. Information on an additional set of 70 human kidneys characterized by RNA-sequencing used in the replication phase of next-generation RNA-sequencing analysis was obtained from the TCGA database.…”

“…2 Several common variants in genes associated with BP and/or susceptibility to hypertension are also believed to act through the 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 Indeed, 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.…”

“…[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 Indeed, 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 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 Taken together, these data clearly suggest that FGF1 and its partner molecules play a role in genetic susceptibility to hypertension, possibly through kidney-related mechanisms.…”