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. 2011 May;22(5):947-55.
doi: 10.1681/ASN.2010080829. Epub 2011 Mar 24.

Pathway analysis shows association between FGFBP1 and hypertension

Maciej Tomaszewski  1 , Fadi J Charchar, Christopher P Nelson, Timothy Barnes, Matthew Denniff, Michael Kaiser, Radoslaw Debiec, Paraskevi Christofidou, Suzanne Rafelt, Pim van der Harst, William Y S Wang, Christine Maric, Ewa Zukowska-Szczechowska, Nilesh J Samani
Affiliations

Pathway analysis shows association between FGFBP1 and hypertension

Maciej Tomaszewski et al. J Am Soc Nephrol. 2011 May.

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=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=0.04 and P=0.001), respectively. By immunohistochemistry, hypertension-related 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.

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Figures

Figure 1.
Figure 1.
FGFBP1 is associated with hypertension: family-based association analysis and gene expression studies. (A) The results of the primary family-based association analysis (the most significant P values) in SHS are shown at the background of molecular interactions within the pathway (image created using the GeneGo software). FGF1, fibroblast growth factor 1; FGF2, fibroblast growth factor 2; FGFBP1, fibroblast growth factor binding protein 1; FGFR1, fibroblast growth factor receptor 1; FGFR2, fibroblast growth factor receptor 2; FGFR3, fibroblast growth factor receptor 3; FGFR4, fibroblast growth factor receptor 4; FIBP, fibroblast growth factor (acidic) intracellular binding protein; SPRY1, sprouty homolog 1, antagonist of FGF signaling; B, binding; A, allosteric effect; IE, influence on expression. (B) FGFBP1 and hypertension: fine mapping analysis in SHS. (Top) −Log-transformed probability values from the family-based association analysis. (Middle) Structure of FGFBP1 gene: 1, first untranslated exon; 2, coding exon; x, intron 1; ←, direction of transcription. (Bottom) LD map (r2 coefficients–based) of FGFBP1 (black corresponds to r2 = 0.8 to 1 − maximal LD, and white corresponds to r2 = 0 to 0.2 − no or weak LD) in SHS. (C) Comparative analysis of FGFBP1 mRNA and protein expression in hypertensive and normotensive kidneys from SRTB. n, number of subjects.
Figure 2.
Figure 2.
FGFBP1 expression is up-regulated in the human hypertensive kidney. FGFBP1 was immunolocalized mainly to glomerulus (g) and juxtaglomerular space. Intensity of FGFBP1 immunostaining in the hypertensive kidney was higher than the normotensive control. pt, proximal tubule, arrows indicate cells that express FGFBP1 (mostly monocytes/macrophages).
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