Fibroblast Growth Factor 20 Polymorphisms and Haplotypes Strongly Influence Risk of Parkinson Disease

Department of Medicine and Center for Human Genetics, Duke University Medical Center, Durham, NC 27710, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 07/2004; 74(6):1121-7. DOI: 10.1086/421052
Source: PubMed

ABSTRACT The pathogenic process responsible for the loss of dopaminergic neurons within the substantia nigra of patients with Parkinson disease (PD) is poorly understood. Current research supports the involvement of fibroblast growth factor (FGF20) in the survival of dopaminergic cells. FGF20 is a neurotrophic factor that is preferentially expressed within the substantia nigra of rat brain. The human homologue has been mapped to 8p21.3-8p22, which is within an area of PD linkage revealed through our published genomic screen. To test whether FGF20 influences risk of PD, we genotyped five single-nucleotide polymorphisms (SNPs) lying within the FGF20 gene, in a large family study. We analyzed our sample (644 families) through use of the pedigree disequilibrium test (PDT), the genotype PDT, the multilocus-genotype PDT, and the family-based association test to assess association between risk of PD and alleles, genotypes, multilocus genotypes, and haplotypes. We discovered a highly significant association of PD with one intronic SNP, rs1989754 (P=.0006), and two SNPs, rs1721100 (P=.02) and ss20399075 (P=.0008), located in the 3' regulatory region in our overall sample. Furthermore, we detected a haplotype (A-G-C-C-T) that is positively associated with risk of PD (P=.0003), whereas a second haplotype (A-G-G-G-C) was found to be negatively associated with risk of PD (P=.0009). Our results strongly support FGF20 as a risk factor for PD.

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Available from: Eden R Martin, Sep 27, 2015
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    • "Given that FGFs were classified together purely on a structural basis [1] the diversity in their biological functions and modes of action is not surprising. To date, FGFs have been shown to regulate a myriad of fundamental processes such as cell differentiation, proliferation , morphogenesis and metabolism while aberrant FGF signaling has been linked to pathological conditions of cancer and metabolic disease [1] [2] [3] [4] [5] [6]. "
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    ABSTRACT: Since the discovery of insulin in 1921, protein therapeutics have become vital tools in the treatment of diabetes mellitus. This heritage has been extended with the comparatively recent introduction of recombinant and re-engineered insulins, in addition to the advent of GLP1 agonists. FGF21 represents an example of a novel experimental protein therapy which is able to induce favorable metabolic effects in various species ranging from rodents to man. The aim of this review is to communicate the story of the FGF21 drug discovery path from identification in a functional in vitro screen, to the eventual evaluation of its utility in patients. Given that the development of FGF21 advanced hand-in-hand with rapidly evolving scientific research around this target, we have also attempted to describe our view of recent developments regarding the mechanistic understanding of FGF21 biology.
    Molecular Metabolism 06/2014; 3(3):221-229. DOI:10.1016/j.molmet.2013.12.003
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    • "To reach power to detect these association signals with genome-wide significance, they combined data from their discovery and follow-up stages, and attempted to replicate their findings in the independent study sample of 23andMe [17]. In this combined analysis, four new loci reached genome-wide significance the strongest candidate at these loci are STX1B, FGF20 (which was previously reported in a candidate-gene study performed in a large family [34]), STBD1, and GPNMB. They also were the first to report a genome-wide significant association to the PARK16 locus in Europeans. "
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    ABSTRACT: Parkinson's disease is a common age-related progressive neurodegenerative disorder. Over the last 10 years, advances have been made in our understanding of the etiology of the disease with the greatest insights perhaps coming from genetic studies, including genome-wide association approaches. These large scale studies allow the identification of genomic regions harboring common variants associated to disease risk. Since the first genome-wide association study on sporadic Parkinson's disease performed in 2005, improvements in study design, including the advent of meta-analyses, have allowed the identification of ~21 susceptibility loci. The first loci to be nominated were previously associated to familial PD (SNCA, MAPT, LRRK2) and these have been extensively replicated. For other more recently identified loci (SREBF1, SCARB2, RIT2) independent replication is still warranted. Cumulative risk estimates of associated variants suggest that more loci are still to be discovered. Additional association studies combined with deep re-sequencing of known genome-wide association study loci are necessary to identify the functional variants that drive disease risk. As each of these associated genes and variants are identified they will give insight into the biological pathways involved the etiology of Parkinson's disease. This will ultimately lead to the identification of molecules that can be used as biomarkers for diagnosis and as targets for the development of better, personalized treatment.
    Current Genomics 02/2014; 15(1):2-10. DOI:10.2174/1389202914666131210212745 · 2.34 Impact Factor
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    • "Fgf20, a paracrine Fgf, with neurotrophic activity in cultured dopaminergic neurons (Ohmachi et al., 2000, 2003) has been suggested to play important roles in the development of dopaminergic neurons (Grothe et al., 2004; Takagi et al., 2005; Correia et al., 2007; Shimada et al., 2009). In addition, FGF20 mutations may result in Parkinson's disease (van der Walt et al., 2004; Satake et al., 2007; IPDGC, 2011; Pan et al., 2012; Pihlstrøm et al., 2013; Wang et al., 2013). As these findings indicate that FGF20 may provide useful clues on the etiology and therapy of Parkinson's disease, a succinct review on the roles of FGF20 in dopaminergic neurons and Parkinson's disease has been provided. "
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    ABSTRACT: The fibroblast growth factor (FGF) family comprises 22 members with diverse functions in development and metabolism. Fgf20 was originally identified as a new Fgf preferentially expressed in the substantia nigra pars compacta (SNpc). Fgf20, which acts on proximal cells, significantly enhanced the survival of cultured dopaminergic neurons by activating the mitogen-activated protein kinase (MAPK) pathway through Fgf receptor 1c. In the rat model of Parkinson's disease, Fgf20 afforded significant protection against the loss of dopaminergic neurons. The significant correlation of Parkinson's disease with single-nucleotide polymorphisms in FGF20 indicates that the genetic variability of FGF20 can be a Parkinson's disease risk. Neural and embryonic stem (ES) cells have been considered as cell resources for restorative transplantation strategies in Parkinson's disease. Fgf20 promoted the differentiation of these stem cells into dopaminergic neurons, which attenuated neurological symptoms in animal models of Parkinson's disease. These findings indicate the importance of FGF20 for the differentiation and survival of dopaminergic neurons and the etiology and therapy of Parkinson's disease.
    Frontiers in Molecular Neuroscience 05/2013; 6:15. DOI:10.3389/fnmol.2013.00015 · 4.08 Impact Factor
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