title: Genetic variants modulating CRIPTO serum levels identified by genome-wide association study in Cilento isolates.
abstract: Cripto, the founding member of the EGF-CFC genes, plays an essential role in embryo development and is involved in cancer progression. Cripto is a GPI-anchored protein that can interact with various components of multiple signaling pathways, such as TGF-β, Wnt and MAPK, driving different processes, among them epithelial-mesenchymal transition, cell proliferation, and stem cell renewal. Cripto protein can also be cleaved and released outside the cell in a soluble and still active form. Cripto is not significantly expressed in adult somatic tissues and its re-expression has been observed associated to pathological conditions, mainly cancer. Accordingly, CRIPTO has been detected at very low levels in the plasma of healthy volunteers, whereas its levels are significantly higher in patients with breast, colon or glioblastoma tumors. These data suggest that CRIPTO levels in human plasma or serum may have clinical significance. However, very little is known about the variability of serum levels of CRIPTO at a population level and the genetic contribution underlying this variability remains unknown. Here, we report the first genome-wide association study of CRIPTO serum levels in isolated populations (n = 1,054) from Cilento area in South Italy. The most associated SNPs (p-value<5*10-8) were all located on chromosome 3p22.1-3p21.3, in the CRIPTO gene region. Overall six CRIPTO associated loci were replicated in an independent sample (n = 535). Pathway analysis identified a main network including two other genes, besides CRIPTO, in the associated regions, involved in cell movement and proliferation. The replicated loci explain more than 87% of the CRIPTO variance, with 85% explained by the most associated SNP. Moreover, the functional analysis of the main associated locus identified a causal variant in the 5'UTR of CRIPTO gene which is able to strongly modulate CRIPTO expression through an AP-1-mediate transcriptional regulation.
authors: Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, Naples, Italy.
authors: Daniela
authors: D
authors: Ruggiero
authors: Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, Naples, Italy.
authors: Stefania
authors: S
authors: Nappo
authors: Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, Naples, Italy.
authors: Teresa
authors: T
authors: Nutile
authors: Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, Naples, Italy.
authors: Rossella
authors: R
authors: Sorice
authors: Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, Naples, Italy.
authors: Francesco
authors: F
authors: Talotta
authors: Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, Naples, Italy.
authors: Emilia
authors: E
authors: Giorgio
authors: Institut Pasteur de Lille, Lille, France; Inserm, U744, Lille, France; Université Lille-Nord de France, Lille, France.
authors: Celine
authors: C
authors: Bellenguez
authors: Inserm, U946, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, IUH, UMR-S 946, Paris, France.
authors: Anne-Louise
authors: AL
authors: Leutenegger
authors: Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, Naples, Italy.
authors: Giovanna L
authors: GL
authors: Liguori
authors: Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, Naples, Italy.
authors: Marina
authors: M
authors: Ciullo
mesh_terms: D000328:Adult; D000368:Aged; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics*; D047108:Embryonic Development / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D058851:GPI-Linked Proteins / Q000097:blood / Q000235:genetics*; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000235:genetics*; D007558:Italy; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000097:blood / Q000235:genetics*; D009369:Neoplasms / Q000097:blood / Q000235:genetics*; D018808:Transcription Factor AP-1 / Q000235:genetics; D016212:Transforming Growth Factor beta
chemical_list: D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; C070636:TDGF1 protein, human; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta
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