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  1. Article ; Online: Genetics of PlGF plasma levels highlights a role of its receptors and supports the link between angiogenesis and immunity.

    Ruggiero, Daniela / Nutile, Teresa / Nappo, Stefania / Tirozzi, Alfonsina / Bellenguez, Celine / Leutenegger, Anne-Louise / Ciullo, Marina

    Scientific reports

    2021  Volume 11, Issue 1, Page(s) 16821

    Abstract: Placental growth factor (PlGF) is a member of the vascular endothelial growth factor family and is involved in bone marrow-derived cell activation, endothelial stimulation and pathological angiogenesis. High levels of PlGF have been observed in several ... ...

    Abstract Placental growth factor (PlGF) is a member of the vascular endothelial growth factor family and is involved in bone marrow-derived cell activation, endothelial stimulation and pathological angiogenesis. High levels of PlGF have been observed in several pathological conditions especially in cancer, cardiovascular, autoimmune and inflammatory diseases. Little is known about the genetics of circulating PlGF levels. Indeed, although the heritability of circulating PlGF levels is around 40%, no studies have assessed the relation between PlGF plasma levels and genetic variants at a genome-wide level. In the current study, PlGF plasma levels were measured in a population-based sample of 2085 adult individuals from three isolated populations of South Italy. A GWAS was performed in a discovery cohort (N = 1600), followed by a de novo replication (N = 468) from the same populations. The meta-analysis of the discovery and replication samples revealed one signal significantly associated with PlGF circulating levels. This signal was mapped to the PlGF co-receptor coding gene NRP1, indicating its important role in modulating the PlGF plasma levels. Two additional signals, at the PlGF receptor coding gene FLT1 and RAPGEF5 gene, were identified at a suggestive level. Pathway and TWAS analyses highlighted genes known to be involved in angiogenesis and immune response, supporting the link between these processes and PlGF regulation. Overall, these data improve our understanding of the genetic variation underlying circulating PlGF levels. This in turn could lead to new preventive and therapeutic strategies for a wide variety of PlGF-related pathologies.
    MeSH term(s) Adult ; Cohort Studies ; Female ; Genome-Wide Association Study ; Humans ; Immunity/genetics ; Male ; Meta-Analysis as Topic ; Middle Aged ; Neovascularization, Physiologic/genetics ; Placenta Growth Factor/blood ; Reproducibility of Results ; Signal Transduction/genetics ; Transcription, Genetic
    Chemical Substances Placenta Growth Factor (144589-93-5)
    Language English
    Publishing date 2021-08-19
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-021-96256-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Detecting the dominance component of heritability in isolated and outbred human populations.

    Herzig, Anthony F / Nutile, Teresa / Ruggiero, Daniela / Ciullo, Marina / Perdry, Hervé / Leutenegger, Anne-Louise

    Scientific reports

    2018  Volume 8, Issue 1, Page(s) 18048

    Abstract: Inconsistencies between published estimates of dominance heritability between studies of human genetic isolates and human outbred populations incite investigation into whether such differences result from particular trait architectures or specific ... ...

    Abstract Inconsistencies between published estimates of dominance heritability between studies of human genetic isolates and human outbred populations incite investigation into whether such differences result from particular trait architectures or specific population structures. We analyse simulated datasets, characteristic of genetic isolates and of unrelated individuals, before analysing the isolate of Cilento for various commonly studied traits. We show the strengths of using genetic relationship matrices for variance decomposition over identity-by-descent based methods in a population isolate and that heritability estimates in isolates will avoid the downward biases that may occur in studies of samples of unrelated individuals; irrespective of the simulated distribution of causal variants. Yet, we also show that precise estimates of dominance in isolates are demonstrably problematic in the presence of shared environmental effects and such effects should be accounted for. Nevertheless, we demonstrate how studying isolates can help determine the existence or non-existence of dominance for complex traits, and we find strong indications of non-zero dominance for low-density lipoprotein level in Cilento. Finally, we recommend future study designs to analyse trait variance decomposition from ensemble data across multiple population isolates.
    MeSH term(s) Genes, Dominant/physiology ; Genetic Variation ; Humans ; Models, Genetic ; Models, Theoretical ; Multifactorial Inheritance/genetics ; Phenotype ; Population Dynamics ; Quantitative Trait, Heritable ; Reproduction/physiology ; Reproductive Isolation
    Language English
    Publishing date 2018-12-21
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-018-36050-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Strategies for phasing and imputation in a population isolate.

    Herzig, Anthony Francis / Nutile, Teresa / Babron, Marie-Claude / Ciullo, Marina / Bellenguez, Céline / Leutenegger, Anne-Louise

    Genetic epidemiology

    2018  Volume 42, Issue 2, Page(s) 201–213

    Abstract: In the search for genetic associations with complex traits, population isolates offer the advantage of reduced genetic and environmental heterogeneity. In addition, cost-efficient next-generation association approaches have been proposed in these ... ...

    Abstract In the search for genetic associations with complex traits, population isolates offer the advantage of reduced genetic and environmental heterogeneity. In addition, cost-efficient next-generation association approaches have been proposed in these populations where only a subsample of representative individuals is sequenced and then genotypes are imputed into the rest of the population. Gene mapping in such populations thus requires high-quality genetic imputation and preliminary phasing. To identify an effective study design, we compare by simulation a range of phasing and imputation software and strategies. We simulated 1,115,604 variants on chromosome 10 for 477 members of the large complex pedigree of Campora, a village within the established isolate of Cilento in southern Italy. We assessed the phasing performance of identical by descent based software ALPHAPHASE and SLRP, LD-based software SHAPEIT2, SHAPEIT3, and BEAGLE, and new software EAGLE that combines both methodologies. For imputation we compared IMPUTE2, IMPUTE4, MINIMAC3, BEAGLE, and new software PBWT. Genotyping errors and missing genotypes were simulated to observe their effects on the performance of each software. Highly accurate phased data were achieved by all software with SHAPEIT2, SHAPEIT3, and EAGLE2 providing the most accurate results. MINIMAC3, IMPUTE4, and IMPUTE2 all performed strongly as imputation software and our study highlights the considerable gain in imputation accuracy provided by a genome sequenced reference panel specific to the population isolate.
    MeSH term(s) Algorithms ; Chromosomes, Human, Pair 10/genetics ; Female ; Founder Effect ; Genetics, Population ; Genome, Human/genetics ; Haplotypes/genetics ; Humans ; Italy ; Linkage Disequilibrium/genetics ; Male ; Models, Genetic ; Pedigree ; Phenotype ; Research Design ; Software
    Language English
    Publishing date 2018
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 605785-8
    ISSN 1098-2272 ; 0741-0395
    ISSN (online) 1098-2272
    ISSN 0741-0395
    DOI 10.1002/gepi.22109
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  4. Article: Whole Exome Sequencing Study of Parkinson Disease and Related Endophenotypes in the Italian Population.

    Gialluisi, Alessandro / Reccia, Mafalda Giovanna / Tirozzi, Alfonsina / Nutile, Teresa / Lombardi, Alessia / De Sanctis, Claudia / Varanese, Sara / Pietracupa, Sara / Modugno, Nicola / Simeone, Antonio / Ciullo, Marina / Esposito, Teresa

    Frontiers in neurology

    2020  Volume 10, Page(s) 1362

    Abstract: Parkinson Disease (PD) is a complex neurodegenerative disorder characterized by large genetic heterogeneity and missing heritability. Since the genetic background of PD can partly vary among ethnicities and neurological scales have been scarcely ... ...

    Abstract Parkinson Disease (PD) is a complex neurodegenerative disorder characterized by large genetic heterogeneity and missing heritability. Since the genetic background of PD can partly vary among ethnicities and neurological scales have been scarcely investigated in a PD setting, we performed an exploratory Whole Exome Sequencing (WES) analysis of 123 PD patients from mainland Italy, investigating scales assessing motor (UPDRS), cognitive (MoCA), and other non-motor symptoms (NMS). We performed variant prioritization, followed by targeted association testing of prioritized variants in 446 PD cases and 211 controls. Then we ran Exome-Wide Association Scans (EWAS) within sequenced PD cases (
    Language English
    Publishing date 2020-01-10
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2564214-5
    ISSN 1664-2295
    ISSN 1664-2295
    DOI 10.3389/fneur.2019.01362
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Identification of sixteen novel candidate genes for late onset Parkinson's disease.

    Gialluisi, Alessandro / Reccia, Mafalda Giovanna / Modugno, Nicola / Nutile, Teresa / Lombardi, Alessia / Di Giovannantonio, Luca Giovanni / Pietracupa, Sara / Ruggiero, Daniela / Scala, Simona / Gambardella, Stefano / Iacoviello, Licia / Gianfrancesco, Fernando / Acampora, Dario / D'Esposito, Maurizio / Simeone, Antonio / Ciullo, Marina / Esposito, Teresa

    Molecular neurodegeneration

    2021  Volume 16, Issue 1, Page(s) 35

    Abstract: Background: Parkinson's disease (PD) is a neurodegenerative movement disorder affecting 1-5% of the general population for which neither effective cure nor early diagnostic tools are available that could tackle the pathology in the early phase. Here we ... ...

    Abstract Background: Parkinson's disease (PD) is a neurodegenerative movement disorder affecting 1-5% of the general population for which neither effective cure nor early diagnostic tools are available that could tackle the pathology in the early phase. Here we report a multi-stage procedure to identify candidate genes likely involved in the etiopathogenesis of PD.
    Methods: The study includes a discovery stage based on the analysis of whole exome data from 26 dominant late onset PD families, a validation analysis performed on 1542 independent PD patients and 706 controls from different cohorts and the assessment of polygenic variants load in the Italian cohort (394 unrelated patients and 203 controls).
    Results: Family-based approach identified 28 disrupting variants in 26 candidate genes for PD including PARK2, PINK1, DJ-1(PARK7), LRRK2, HTRA2, FBXO7, EIF4G1, DNAJC6, DNAJC13, SNCAIP, AIMP2, CHMP1A, GIPC1, HMOX2, HSPA8, IMMT, KIF21B, KIF24, MAN2C1, RHOT2, SLC25A39, SPTBN1, TMEM175, TOMM22, TVP23A and ZSCAN21. Sixteen of them have not been associated to PD before, were expressed in mesencephalon and were involved in pathways potentially deregulated in PD. Mutation analysis in independent cohorts disclosed a significant excess of highly deleterious variants in cases (p = 0.0001), supporting their role in PD. Moreover, we demonstrated that the co-inheritance of multiple rare variants (≥ 2) in the 26 genes may predict PD occurrence in about 20% of patients, both familial and sporadic cases, with high specificity (> 93%; p = 4.4 × 10
    Conclusions: Besides confirming the extreme genetic heterogeneity of PD, these data provide novel insights into the genetic of the disease and may be relevant for its prediction, diagnosis and treatment.
    MeSH term(s) Adult ; Age of Onset ; Aged ; Female ; Genetic Predisposition to Disease/genetics ; Humans ; Male ; Middle Aged ; Parkinson Disease/genetics ; Pedigree ; Exome Sequencing/methods
    Language English
    Publishing date 2021-06-21
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2244557-2
    ISSN 1750-1326 ; 1750-1326
    ISSN (online) 1750-1326
    ISSN 1750-1326
    DOI 10.1186/s13024-021-00455-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Exome-wide association study of levodopa-induced dyskinesia in Parkinson's disease.

    König, Eva / Nicoletti, Alessandra / Pattaro, Cristian / Annesi, Grazia / Melotti, Roberto / Gialluisi, Alessandro / Schwienbacher, Christine / Picard, Anne / Blankenburg, Hagen / Pichler, Irene / Modugno, Nicola / Ciullo, Marina / Esposito, Teresa / Domingues, Francisco S / Hicks, Andrew A / Zappia, Mario / Pramstaller, Peter P

    Scientific reports

    2021  Volume 11, Issue 1, Page(s) 19582

    Abstract: Levodopa is the standard long-term dopamine replacement therapy to treat Parkinson's disease (PD) symptoms. With time, levodopa may induce debilitating dyskinesias (LID), the treatment of which represents a large clinically unmet need. However, time-to- ... ...

    Abstract Levodopa is the standard long-term dopamine replacement therapy to treat Parkinson's disease (PD) symptoms. With time, levodopa may induce debilitating dyskinesias (LID), the treatment of which represents a large clinically unmet need. However, time-to-LID onset varies between patients, reflecting a possible genetic component. We performed an hypothesis-free whole-exome sequencing (WES)-based screening of time-to-LID onset and attempted replication of previously published candidate gene studies. A WES association analysis was carried out in 134 PD patients in a meta-analytical framework. Replication was attempted in an independent study of 97 PD patients. Variants from previously reported candidate genes (OPRM1, COMT, BDNF) were also specifically examined. We significantly replicated, for the first time, an association of variant rs1799971 in the OPRM1 gene with time-to-LID onset. Furthermore, we identified two novel potentially functional variants, in the MAD2L2 (rs2233019) and MAP7 (rs35350783) genes, which were significantly associated at the discovery stage. In the replication study, the two variants showed direction-consistent effects but did not achieve the replication significance threshold. Our study provides the first WES results for time-to-LID onset, where we replicate association at OPRM1, and suggest new variants in MAD2L2 and MAP7 genes that are significant in discovery, but require larger datasets for replication. The results are being made publicly available to allow for independent external validation.
    MeSH term(s) Aged ; Alleles ; Biomarkers ; Disease Susceptibility ; Dyskinesia, Drug-Induced/diagnosis ; Dyskinesia, Drug-Induced/etiology ; Female ; Gene Frequency ; Humans ; Levodopa/adverse effects ; Male ; Middle Aged ; Odds Ratio ; Parkinson Disease/diagnosis ; Parkinson Disease/etiology ; Symptom Assessment ; Whole Exome Sequencing
    Chemical Substances Biomarkers ; Levodopa (46627O600J)
    Language English
    Publishing date 2021-10-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-021-99393-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: SNP-based linkage analysis in extended pedigrees: comparison between two alternative approaches.

    Saint-Pierre, Aude / D'Elia, Yuri / Ciullo, Marina / Pramstaller, Peter P / Pattaro, Cristian

    Human heredity

    2014  Volume 78, Issue 1, Page(s) 27–37

    Abstract: Background: Linkage analysis on extended pedigrees is often challenged by the high computational demand of exact identity-by-descent (IBD) matrix reconstruction. When such an analysis becomes not feasible, two alternative solutions are contrasted: a ... ...

    Abstract Background: Linkage analysis on extended pedigrees is often challenged by the high computational demand of exact identity-by-descent (IBD) matrix reconstruction. When such an analysis becomes not feasible, two alternative solutions are contrasted: a full pedigree analysis based on approximate IBD estimation versus a pedigree splitting followed by exact IBD estimation. A multiple splitting (MS) approach, which combines linkage results across different splitting configurations, has been proposed to increase the power of single-split solutions.
    Methods: To assess whether MS can achieve a comparable power to a full pedigree analysis, we compared the power of linkage on a very large pedigree in both simulated and real-case scenarios, using variance components linkage analysis of a dense SNP array.
    Results: Our results confirm that the power to detect linkage is affected by the pedigree size. The MS approach showed higher power than the single-split analysis, but it was substantially less powerful than the full pedigree approach in both scenarios, at any level of significance and variance explained by a quantitative trait locus.
    Conclusion: The MS approach should always be preferred to analyses based on a single split but, when adequate computational resources are available, a full pedigree analysis is better than the MS analysis. Rather than focusing on how to best split a pedigree, it might be more valuable to identify computational solutions that can make the IBD estimation of dense-marker maps practically feasible, thus allowing a full pedigree analysis.
    MeSH term(s) Chromosome Mapping/methods ; Computer Simulation ; Female ; Genetic Linkage ; Genetics, Population/methods ; Genotype ; Humans ; Lod Score ; Male ; Models, Genetic ; Pedigree ; Polymorphism, Single Nucleotide ; Quantitative Trait Loci/genetics
    Language English
    Publishing date 2014
    Publishing country Switzerland
    Document type Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2424-7
    ISSN 1423-0062 ; 0001-5652
    ISSN (online) 1423-0062
    ISSN 0001-5652
    DOI 10.1159/000360623
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: SNP-Based Linkage Analysis in Extended Pedigrees: Comparison between Two Alternative Approaches

    Saint-Pierre, Aude / D'Elia, Yuri / Ciullo, Marina / Pramstaller, Peter P. / Pattaro, Cristian

    Human Heredity

    2014  Volume 78, Issue 1, Page(s) 27–37

    Abstract: Background: Linkage analysis on extended pedigrees is often challenged by the high computational demand of exact identity-by-descent (IBD) matrix reconstruction. When such an analysis becomes not feasible, two alternative solutions are contrasted: a full ...

    Institution INSERM U1078, Etablissement Français du Sang, Brest, France Center for Biomedicine, European Academy of Bolzano (EURAC), Bolzano, Italy - affiliated Institute of the University of Lübeck, Lübeck, Germany Institute of Genetics and Biophysics ‘A. Buzzati-Traverso', CNR Naples, Naples, Italy Department of Neurology, University of Lübeck, Lübeck, Germany Department of Neurology, Central Hospital, Bolzano, Italy
    Abstract Background: Linkage analysis on extended pedigrees is often challenged by the high computational demand of exact identity-by-descent (IBD) matrix reconstruction. When such an analysis becomes not feasible, two alternative solutions are contrasted: a full pedigree analysis based on approximate IBD estimation versus a pedigree splitting followed by exact IBD estimation. A multiple splitting (MS) approach, which combines linkage results across different splitting configurations, has been proposed to increase the power of single-split solutions. Methods: To assess whether MS can achieve a comparable power to a full pedigree analysis, we compared the power of linkage on a very large pedigree in both simulated and real-case scenarios, using variance components linkage analysis of a dense SNP array. Results: Our results confirm that the power to detect linkage is affected by the pedigree size. The MS approach showed higher power than the single-split analysis, but it was substantially less powerful than the full pedigree approach in both scenarios, at any level of significance and variance explained by a quantitative trait locus. Conclusion: The MS approach should always be preferred to analyses based on a single split but, when adequate computational resources are available, a full pedigree analysis is better than the MS analysis. Rather than focusing on how to best split a pedigree, it might be more valuable to identify computational solutions that can make the IBD estimation of dense-marker maps practically feasible, thus allowing a full pedigree analysis.
    Keywords Extended pedigrees ; SNP ; Linkage analysis
    Language English
    Publishing date 2014-06-21
    Publisher S. Karger AG
    Publishing place Basel, Switzerland
    Document type Article
    Note Original Paper
    ZDB-ID 2424-7
    ISSN 1423-0062 ; 0001-5652
    ISSN (online) 1423-0062
    ISSN 0001-5652
    DOI 10.1159/000360623
    Database Karger publisher's database

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  9. Article ; Online: Genetic and environmental factors influencing the Placental Growth Factor (PGF) variation in two populations.

    Sorice, Rossella / Ruggiero, Daniela / Nutile, Teresa / Aversano, Mario / Husemoen, Lotte / Linneberg, Allan / Bourgain, Catherine / Leutenegger, Anne-Louise / Ciullo, Marina

    PloS one

    2012  Volume 7, Issue 8, Page(s) e42537

    Abstract: Placental Growth Factor (PGF) is a key molecule in angiogenesis. Several studies have revealed an important role of PGF primarily in pathological conditions (e.g.: ischaemia, tumour formation, cardiovascular diseases and inflammatory processes) ... ...

    Abstract Placental Growth Factor (PGF) is a key molecule in angiogenesis. Several studies have revealed an important role of PGF primarily in pathological conditions (e.g.: ischaemia, tumour formation, cardiovascular diseases and inflammatory processes) suggesting its use as a potential therapeutic agent. However, to date, no information is available regarding the genetics of PGF variability. Furthermore, even though the effect of environmental factors (e.g.: cigarette smoking) on angiogenesis has been explored, no data on the influence of these factors on PGF levels have been reported so far. Here we have first investigated PGF variability in two cohorts focusing on non-genetic risk factors: a study sample from two isolated villages in the Cilento region, South Italy (N=871) and a replication sample from the general Danish population (N=1,812). A significant difference in PGF mean levels was found between the two cohorts. However, in both samples, we observed a strong correlation of PGF levels with ageing and sex, men displaying PGF levels significantly higher than women. Interestingly, smoking was also found to influence the trait in the two populations, although differently. We have then focused on genetic risk factors. The association between five single nucleotide polymorphisms (SNPs) located in the PGF gene and the plasma levels of the protein was investigated. Two polymorphisms (rs11850328 and rs2268614) were associated with the PGF plasma levels in the Cilento sample and these associations were strongly replicated in the Danish sample. These results, for the first time, support the hypothesis of the presence of genetic and environmental factors influencing PGF plasma variability.
    MeSH term(s) Denmark ; Female ; Genetics, Population ; Genotype ; Humans ; Male ; Placenta Growth Factor ; Polymorphism, Single Nucleotide ; Pregnancy Proteins/genetics ; Quality Control
    Chemical Substances PGF protein, human ; Pregnancy Proteins ; Placenta Growth Factor (144589-93-5)
    Language English
    Publishing date 2012-08-20
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0042537
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Genetic variants modulating CRIPTO serum levels identified by genome-wide association study in Cilento isolates.

    Ruggiero, Daniela / Nappo, Stefania / Nutile, Teresa / Sorice, Rossella / Talotta, Francesco / Giorgio, Emilia / Bellenguez, Celine / Leutenegger, Anne-Louise / Liguori, Giovanna L / Ciullo, Marina

    PLoS genetics

    2015  Volume 11, Issue 1, Page(s) e1004976

    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- ... ...

    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.
    MeSH term(s) Adult ; Aged ; Cell Movement/genetics ; Cell Proliferation/genetics ; Embryonic Development/genetics ; Epithelial-Mesenchymal Transition/genetics ; Female ; GPI-Linked Proteins/blood ; GPI-Linked Proteins/genetics ; Gene Expression Regulation ; Genome-Wide Association Study ; Humans ; Intercellular Signaling Peptides and Proteins/blood ; Intercellular Signaling Peptides and Proteins/genetics ; Italy ; Middle Aged ; Neoplasm Proteins/blood ; Neoplasm Proteins/genetics ; Neoplasms/blood ; Neoplasms/genetics ; Transcription Factor AP-1/genetics ; Transforming Growth Factor beta
    Chemical Substances GPI-Linked Proteins ; Intercellular Signaling Peptides and Proteins ; Neoplasm Proteins ; TDGF1 protein, human ; Transcription Factor AP-1 ; Transforming Growth Factor beta
    Language English
    Publishing date 2015-01-28
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2186725-2
    ISSN 1553-7404 ; 1553-7390
    ISSN (online) 1553-7404
    ISSN 1553-7390
    DOI 10.1371/journal.pgen.1004976
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