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1. Potential Pathogenetic Role of Antimicrobial Peptides Carried by Extracellular Vesicles in an in vitro Psoriatic Model

Author

Capriotti L, Iuliano M, Lande R, Frasca L, Falchi M, Rosa P, Mangino G, and Romeo G

Subjects
extracellular vesicles, antimicrobial peptides, cytokines, keratinocytes, pathogenesis of psoriasis, comorbidities, Pathology, RB1-214, Therapeutics. Pharmacology, RM1-950
Abstract

Lorena Capriotti,1,* Marco Iuliano,1,* Roberto Lande,2 Loredana Frasca,2 Mario Falchi,3 Paolo Rosa,1 Giorgio Mangino,1 Giovanna Romeo1 1Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome – Polo Pontino, Latina, Italy; 2Pharmacological Research and Experimental Therapy Section, National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy; 3National AIDS Center, Istituto Superiore di Sanità, Rome, Italy*These authors contributed equally to this workCorrespondence: Giorgio Mangino, Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome – Polo Pontino, C.so della Repubblica, 79, Latina, 04100, Italy, Tel +39 0773 1757271, Email giorgio.mangino@uniroma1.itPurpose: Extracellular Vesicles (EVs) are a heterogeneous group of cell-derived membranous nanoparticles involved in several physiopathological processes. EVs play a crucial role in the definition of the extracellular microenvironment through the transfer of their cargo. Psoriasis is a prototypical chronic inflammatory disease characterized by several secreted mediators, among which antimicrobial peptides (AMPs) are considered pivotal in the development of the psoriatic inflammatory microenvironment. The role of EVs in the pathogenesis of psoriasis has not been elucidated yet, even if emerging evidence demonstrated that interleukin-17A (IL-17A), the psoriasis-related principal cytokine, modifies EVs release and cargo content. The aim of this work was to analyze whether, besides IL-17A, other psoriasis-related cytokines (ie, IFN-γ, TNF-α, IL-22 and IL-23) could affect EVs release and their AMPs mRNAs cargo as well as to analyze the potential biological effect due to EVs internalization by different acceptor cells.Methods: Nanoparticle tracking analysis (NTA) was performed on supernatants of HaCaT cells stimulated with IL-17A, IFN-γ, TNF-α, IL-22 or IL-23 to enumerate EVs. Real-Time RT-PCR was used for gene expression analysis in cells and EVs. Confocal microscopy and Flow cytometry were used to, respectively, study Netosis and EVs internalization.Results: IL-17A and IFN-γ increased EVs release by HaCaT cells. All the tested cytokines modulated AMPs mRNA expression in parental cells and in their respective EVs. S100A12 and hBD2 mRNAs were upregulated following IL-17A and IL-22 treatments. Interestingly, EVs derived from cytokine treated HaCaT cells induced Netosis in freshly isolated neutrophils. Upregulation of S100A12 and hBD2 mRNA was also detectable in acceptor cells incubated with EVs derived from cells treated with psoriasis-related cytokines.Conclusion: The obtained results highlighted the role of EVs in the composition of psoriasis-associated secretome and microenvironment also suggesting the EV involvement in the spreading of the disease mediators and in the possible associated comorbidities.Keywords: extracellular vesicles, antimicrobial peptides, cytokines, keratinocytes, pathogenesis of psoriasis, comorbidities

Published
2022

2. A Fecal Metabolite Signature of Impaired Fasting Glucose: Results From Two Independent Population-Based Cohorts

Author

Nogal, A, Tettamanzi, F, Dong, Q, Louca, P, Visconti, A, Christiansen, C, Breuninger, T, Linseisen, J, Grallert, H, Wawro, N, Asnicar, F, Wong, K, Baleanu, A, Michelotti, G, Segata, N, Falchi, M, Peters, A, Franks, P, Bagnardi, V, Spector, T, Bell, J, Gieger, C, Valdes, A, Menni, C, Nogal A., Tettamanzi F., Dong Q., Louca P., Visconti A., Christiansen C., Breuninger T., Linseisen J., Grallert H., Wawro N., Asnicar F., Wong K., Baleanu A. -F., Michelotti G. A., Segata N., Falchi M., Peters A., Franks P. W., Bagnardi V., Spector T. D., Bell J. T., Gieger C., Valdes A. M., Menni C., Nogal, A, Tettamanzi, F, Dong, Q, Louca, P, Visconti, A, Christiansen, C, Breuninger, T, Linseisen, J, Grallert, H, Wawro, N, Asnicar, F, Wong, K, Baleanu, A, Michelotti, G, Segata, N, Falchi, M, Peters, A, Franks, P, Bagnardi, V, Spector, T, Bell, J, Gieger, C, Valdes, A, Menni, C, Nogal A., Tettamanzi F., Dong Q., Louca P., Visconti A., Christiansen C., Breuninger T., Linseisen J., Grallert H., Wawro N., Asnicar F., Wong K., Baleanu A. -F., Michelotti G. A., Segata N., Falchi M., Peters A., Franks P. W., Bagnardi V., Spector T. D., Bell J. T., Gieger C., Valdes A. M., and Menni C.

Abstract

Prediabetes is a metabolic condition associated with gut mi-crobiome composition, although mechanisms remain elu-sive. We searched for fecal metabolites, a readout of gut microbiome function, associated with impaired fasting glucose (IFG) in 142 individuals with IFG and 1,105 healthy individuals from the UK Adult Twin Registry (TwinsUK). We used the Cooperative Health Research in the Region of Augsburg (KORA) cohort (318 IFG individuals, 689 healthy individuals) to replicate our findings. We linearly combined eight IFG-positively associated metabolites (1-methylxantine, nicoti-nate, glucuronate, uridine, cholesterol, serine, caffeine, and protoporphyrin IX) into an IFG-metabolite score, which was significantly associated with higher odds ratios (ORs) for IFG (TwinsUK: OR 3.9 [95% CI 3.02–5.02], P < 0.0001, KORA: OR 1.3 [95% CI 1.16–1.52], P < 0.0001) and incident type 2 diabetes (T2D; TwinsUK: hazard ratio 4 [95% CI 1.97–8], P = 0.0002). Although these are host-produced me-tabolites, we found that the gut microbiome is strongly associated with their fecal levels (area under the curve >70%). Abundances of Faecalibacillus intestinalis, Dorea formicigenerans, Ruminococcus torques, and Dorea sp. AF24-7LB were positively associated with IFG, and such associations were partially mediated by 1-methylxanthine and nicotinate (variance accounted for mean 14.4% [SD 5.1], P < 0.05). Our results suggest that the gut microbiome is linked to prediabetes not only via the production of microbial metabolites but also by affecting intestinal absorption/excretion of host-produced metabolites and xenobiotics, which are correlated with the risk of IFG. Fecal metabolites enable modeling of another mechanism of gut microbiome effect on prediabetes and T2D onset.

Published
2023

3. Native/citrullinated LL37-specific T-cells help autoantibody production in Systemic Lupus Erythematosus

Author

Lande, R., Palazzo, R., Gestermann, N., Jandus, C., Falchi, M., Spadaro, F., Riccieri, V., James, E. A., Butera, A., Boirivant, M., Feldmeyer, L., Surbeck, I., Di Lucca, J., Stuber, F., Spinelli, F. R., Botti, E., Marinari, B., Bianchi, L., Pica, R., Cerbelli, B., Giannakakis, K., Auteri, S. E., Daniels, I., Durrant, L. G., Horstman, S., Costanzo, A., Romero, P., Alessandri, C., Conti, F., Valesini, G., Gilliet, M., Chizzolini, C., and Frasca, L.

Published
2020
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4. The autophagic protein FYCO1 controls TNFRSF10/TRAIL receptor induced apoptosis and is inactivated by CASP8 (caspase 8)

Author

Coppola, V., Marino, Ilaria, Warnken, U., Falchi, M., Pasquini, L., Biffoni, M., De Maria Marchiano, Ruggero, Haas, Tobias Longin, Marino I., De Maria R. (ORCID:0000-0003-2255-0583), Haas T. L. (ORCID:0000-0003-2336-0263), Coppola, V., Marino, Ilaria, Warnken, U., Falchi, M., Pasquini, L., Biffoni, M., De Maria Marchiano, Ruggero, Haas, Tobias Longin, Marino I., De Maria R. (ORCID:0000-0003-2255-0583), and Haas T. L. (ORCID:0000-0003-2336-0263)

Abstract

Apoptosis is a tightly controlled cell death program executed by proteases, the so-called caspases. It plays an important role in tissue homeostasis and is often dysregulated in cancer. Here, we identified FYCO1, a protein that promotes microtubule plus end-directed transport of autophagic and endosomal vesicles as a molecular interaction partner of activated CASP8 (caspase 8). The absence of FYCO1 sensitized cells to basal and TNFSF10/TRAIL-induced apoptosis by receptor accumulation and stabilization of the Death Inducing Signaling Complex (DISC). Loss of FYCO1 resulted in impaired transport of TNFRSF10B/TRAIL-R2/DR5 (TNF receptor superfamily member 10b) to the lysosomes in TNFSF10/TRAIL-stimulated cells. More in detail, we show that FYCO1 interacted via its C-terminal GOLD domain with the CCZ1-MON1A complex, which is necessary for RAB7A activation and for the fusion of autophagosomal/endosomal vesicles with lysosomes. We demonstrated that FYCO1 is a novel and specific CASP8 substrate. The cleavage at aspartate 1306 resulted in the release of the C-terminal GOLD domain, inactivating FYCO1 function, and allowing for the progression of apoptosis. Furthermore, the lack of FYCO1 resulted in a stronger and prolonged formation of the TNFRSF1A/TNF-R1 signaling complex. Thus, FYCO1 limits the ligand-induced and steady-state signaling of TNFR-superfamily members, providing a control mechanism that fine-tunes both apoptotic and inflammatory answers. Abbreviations: AP: affinity purification; CHX: cycloheximide; co-IP: co-immunoprecipitation; CRISPR: clustered regularly interspaced short palindromic repeats; DISC: death-inducing signaling complex; DR: death receptors; doxy: doxycycline; GEF: guanine nucleotide exchange factor; ind: inducible; KD: knockdown; KO: knockout; MS: mass spectrometry; shRNA: short hairpin RNA; siRNA: small interfering RNA; TIP: two-step co-immunoprecipitation; WB: western blot.

Published
2023

5. Association analyses of rare variants identify two genes associated with refractive error

Author

Patasova, K., Haarman, A.E.G., Musolf, A.M., Mahroo, O.A., Rahi, J.S., Falchi, M., Verhoeven, V.J.M., Bailey-Wilson, J.E., Klaver, C.C.W., Duggal, P., Klein, A., Guggenheim, J.A., Hammond, C.J., Hysi, P.G., Patasova, K., Haarman, A.E.G., Musolf, A.M., Mahroo, O.A., Rahi, J.S., Falchi, M., Verhoeven, V.J.M., Bailey-Wilson, J.E., Klaver, C.C.W., Duggal, P., Klein, A., Guggenheim, J.A., Hammond, C.J., and Hysi, P.G.

Abstract

Contains fulltext : 282599.pdf (Publisher’s version ) (Open Access), PURPOSE: Genetic variants identified through population-based genome-wide studies are generally of high frequency, exerting their action in the central part of the refractive error spectrum. However, the power to identify associations with variants of lower minor allele frequency is greatly reduced, requiring considerable sample sizes. Here we aim to assess the impact of rare variants on genetic variation of refractive errors in a very large general population cohort. METHODS: Genetic association analyses of non-cyclopaedic autorefraction calculated as mean spherical equivalent (SPHE) used whole-exome sequence genotypic information from 50,893 unrelated participants in the UK Biobank of European ancestry. Gene-based analyses tested for association with SPHE using an optimised SNP-set kernel association test (SKAT-O) restricted to rare variants (minor allele frequency < 1%) within protein-coding regions of the genome. All models were adjusted for age, sex and common lead variants within the same locus reported by previous genome-wide association studies. Potentially causal markers driving association at significant loci were elucidated using sensitivity analyses by sequentially dropping the most associated variants from gene-based analyses. RESULTS: We found strong statistical evidence for association of SPHE with the SIX6 (p-value = 2.15 x 10-10, or Bonferroni-Corrected p = 4.41x10-06) and the CRX gene (p-value = 6.65 x 10-08, or Bonferroni-Corrected p = 0.001). The SIX6 gene codes for a transcription factor believed to be critical to the eye, retina and optic disc development and morphology, while CRX regulates photoreceptor specification and expression of over 700 genes in the retina. These novel associations suggest an important role of genes involved in eye morphogenesis in refractive error. CONCLUSION: The results of our study support previous research highlighting the importance of rare variants to the genetic risk of refractive error. We explain some of the o

Published
2022

10. Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4

Author

Grosche, S, Marenholz, I, Esparza-Gordillo, J, Arnau-Soler, A, Pairo-Castineira, E, Rueschendorf, F, Ahluwalia, TS, Almqvist, C, Arnold, A, Baurecht, H, Bisgaard, H, Bonnelykke, K, Brown, SJ, Bustamante, M, Curtin, JA, Custovic, A, Dharmage, SC, Esplugues, A, Falchi, M, Fernandez-Orth, D, Ferreira, MAR, Franke, A, Gerdes, S, Gieger, C, Hakonarson, H, Holt, PG, Homuth, G, Hubner, N, Hysi, PG, Jarvelin, M-R, Karlsson, R, Koppelman, GH, Lau, S, Lutz, M, Magnusson, PKE, Marks, GB, Mueller-Nurasyid, M, Noethen, MM, Paternoster, L, Pennell, CE, Peters, A, Rawlik, K, Robertson, CF, Rodriguez, E, Sebert, S, Simpson, A, Sleiman, PMA, Standl, M, Stoelzl, D, Strauch, K, Szwajda, A, Tenesa, A, Thompson, PJ, Ullemar, V, Visconti, A, Vonk, JM, Wang, CA, Weidinger, S, Wielscher, M, Worth, CL, Xu, C-J, Lee, Y-A, Grosche, S, Marenholz, I, Esparza-Gordillo, J, Arnau-Soler, A, Pairo-Castineira, E, Rueschendorf, F, Ahluwalia, TS, Almqvist, C, Arnold, A, Baurecht, H, Bisgaard, H, Bonnelykke, K, Brown, SJ, Bustamante, M, Curtin, JA, Custovic, A, Dharmage, SC, Esplugues, A, Falchi, M, Fernandez-Orth, D, Ferreira, MAR, Franke, A, Gerdes, S, Gieger, C, Hakonarson, H, Holt, PG, Homuth, G, Hubner, N, Hysi, PG, Jarvelin, M-R, Karlsson, R, Koppelman, GH, Lau, S, Lutz, M, Magnusson, PKE, Marks, GB, Mueller-Nurasyid, M, Noethen, MM, Paternoster, L, Pennell, CE, Peters, A, Rawlik, K, Robertson, CF, Rodriguez, E, Sebert, S, Simpson, A, Sleiman, PMA, Standl, M, Stoelzl, D, Strauch, K, Szwajda, A, Tenesa, A, Thompson, PJ, Ullemar, V, Visconti, A, Vonk, JM, Wang, CA, Weidinger, S, Wielscher, M, Worth, CL, Xu, C-J, and Lee, Y-A

Abstract

Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema.

Published
2021

11. Symptom clusters in COVID-19 : A potential clinical prediction tool from the COVID Symptom Study app

Author

Sudre, C. H., Lee, K. A., Lochlainn, M. N., Varsavsky, T., Murray, B., Graham, M. S., Menni, C., Modat, M., Bowyer, R. C. E., Nguyen, L. H., Drew, D. A., Joshi, A. D., Ma, W., Guo, C. G., Lo, C. H., Ganesh, S., Buwe, A., Pujol, J. C., du Cadet, J. L., Visconti, A., Freidin, M. B., El-Sayed Moustafa, J. S., Falchi, M., Davies, R., Gomez, M. F., Fall, Tove, Cardoso, M. J., Wolf, J., Franks, P. W., Chan, A. T., Spector, T. D., Steves, C. J., Ourselin, S., Sudre, C. H., Lee, K. A., Lochlainn, M. N., Varsavsky, T., Murray, B., Graham, M. S., Menni, C., Modat, M., Bowyer, R. C. E., Nguyen, L. H., Drew, D. A., Joshi, A. D., Ma, W., Guo, C. G., Lo, C. H., Ganesh, S., Buwe, A., Pujol, J. C., du Cadet, J. L., Visconti, A., Freidin, M. B., El-Sayed Moustafa, J. S., Falchi, M., Davies, R., Gomez, M. F., Fall, Tove, Cardoso, M. J., Wolf, J., Franks, P. W., Chan, A. T., Spector, T. D., Steves, C. J., and Ourselin, S.

Abstract

As no one symptom can predict disease severity or the need for dedicated medical support in coronavirus disease 2019 (COVID-19), we asked whether documenting symptom time series over the first few days informs outcome. Unsupervised time series clustering over symptom presentation was performed on data collected from a training dataset of completed cases enlisted early from the COVID Symptom Study Smartphone application, yielding six distinct symptom presenta- tions. Clustering was validated on an independent replication dataset between 1 and 28 May 2020. Using the first 5 days of symptom logging, the ROC-AUC (receiver operating characteristic – area under the curve) of need for respiratory sup- port was 78.8%, substantially outperforming personal characteristics alone (ROC-AUC 69.5%). Such an approach could be used to monitor at-risk patients and predict medical resource requirements days before they are required.

Published
2021
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12. Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4

Author

Grosche, S. (Sarah), Marenholz, I. (Ingo), Esparza-Gordillo, J. (Jorge), Arnau-Soler, A. (Aleix), Pairo-Castineira, E. (Erola), Rueschendorf, F. (Franz), Ahluwalia, T. S. (Tarunveer S.), Almqvist, C. (Catarina), Arnold, A. (Andreas), Baurecht, H. (Hansjoerg), Bisgaard, H. (Hans), Bonnelykke, K. (Klaus), Brown, S. J. (Sara J.), Bustamante, M. (Mariona), Curtin, J. A. (John A.), Custovic, A. (Adnan), Dharmage, S. C. (Shyamali C.), Esplugues, A. (Ana), Falchi, M. (Mario), Fernandez-Orth, D. (Dietmar), Ferreira, M. A. (Manuel A. R.), Franke, A. (Andre), Gerdes, S. (Sascha), Gieger, C. (Christian), Hakonarson, H. (Hakon), Holt, P. G. (Patrick G.), Homuth, G. (Georg), Hubner, N. (Norbert), Hysi, P. G. (Pirro G.), Järvelin, M.-R. (Marjo-Riitta), Karlsson, R. (Robert), Koppelman, G. H. (Gerard H.), Lau, S. (Susanne), Lutz, M. (Manuel), Magnusson, P. K. (Patrik K. E.), Marks, G. B. (Guy B.), Mueller-Nurasyid, M. (Martina), Noethen, M. M. (Markus M.), Paternoster, L. (Lavinia), Pennell, C. E. (Craig E.), Peters, A. (Annette), Rawlik, K. (Konrad), Robertson, C. F. (Colin F.), Rodriguez, E. (Elke), Sebert, S. (Sylvain), Simpson, A. (Angela), Sleiman, P. M. (Patrick M. A.), Standl, M. (Marie), Stoelzl, D. (Dora), Strauch, K. (Konstantin), Szwajda, A. (Agnieszka), Tenesa, A. (Albert), Thompson, P. J. (Philip J.), Ullemar, V. (Vilhelmina), Visconti, A. (Alessia), Vonk, J. M. (Judith M.), Wang, C. A. (Carol A.), Weidinger, S. (Stephan), Wielscher, M. (Matthias), Worth, C. L. (Catherine L.), Xu, C.-J. (Chen-Jian), Lee, Y.-A. (Young-Ae), Grosche, S. (Sarah), Marenholz, I. (Ingo), Esparza-Gordillo, J. (Jorge), Arnau-Soler, A. (Aleix), Pairo-Castineira, E. (Erola), Rueschendorf, F. (Franz), Ahluwalia, T. S. (Tarunveer S.), Almqvist, C. (Catarina), Arnold, A. (Andreas), Baurecht, H. (Hansjoerg), Bisgaard, H. (Hans), Bonnelykke, K. (Klaus), Brown, S. J. (Sara J.), Bustamante, M. (Mariona), Curtin, J. A. (John A.), Custovic, A. (Adnan), Dharmage, S. C. (Shyamali C.), Esplugues, A. (Ana), Falchi, M. (Mario), Fernandez-Orth, D. (Dietmar), Ferreira, M. A. (Manuel A. R.), Franke, A. (Andre), Gerdes, S. (Sascha), Gieger, C. (Christian), Hakonarson, H. (Hakon), Holt, P. G. (Patrick G.), Homuth, G. (Georg), Hubner, N. (Norbert), Hysi, P. G. (Pirro G.), Järvelin, M.-R. (Marjo-Riitta), Karlsson, R. (Robert), Koppelman, G. H. (Gerard H.), Lau, S. (Susanne), Lutz, M. (Manuel), Magnusson, P. K. (Patrik K. E.), Marks, G. B. (Guy B.), Mueller-Nurasyid, M. (Martina), Noethen, M. M. (Markus M.), Paternoster, L. (Lavinia), Pennell, C. E. (Craig E.), Peters, A. (Annette), Rawlik, K. (Konrad), Robertson, C. F. (Colin F.), Rodriguez, E. (Elke), Sebert, S. (Sylvain), Simpson, A. (Angela), Sleiman, P. M. (Patrick M. A.), Standl, M. (Marie), Stoelzl, D. (Dora), Strauch, K. (Konstantin), Szwajda, A. (Agnieszka), Tenesa, A. (Albert), Thompson, P. J. (Philip J.), Ullemar, V. (Vilhelmina), Visconti, A. (Alessia), Vonk, J. M. (Judith M.), Wang, C. A. (Carol A.), Weidinger, S. (Stephan), Wielscher, M. (Matthias), Worth, C. L. (Catherine L.), Xu, C.-J. (Chen-Jian), and Lee, Y.-A. (Young-Ae)

Abstract

Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema.

Published
2021

13. Theratyping cystic fibrosis in vitro in ALI culture and organoid models generated from patient-derived nasal epithelial conditionally reprogrammed stem cells

Author

Sette, Giovanni, Cicero, S. L., Blacona, G., Pierandrei, S., Bruno, Sabina Maria, Salvati, Valentina, Castelli, Andrea Giuliano, Falchi, M., Fabrizzi, B., Cimino, Giovanni, De Maria Marchiano, Ruggero, Biffoni, M., Eramo, A., Lucarelli, M., Sette G., Bruno S. M., Salvati V., Castelli G., Cimino G., De Maria R. (ORCID:0000-0003-2255-0583), Sette, Giovanni, Cicero, S. L., Blacona, G., Pierandrei, S., Bruno, Sabina Maria, Salvati, Valentina, Castelli, Andrea Giuliano, Falchi, M., Fabrizzi, B., Cimino, Giovanni, De Maria Marchiano, Ruggero, Biffoni, M., Eramo, A., Lucarelli, M., Sette G., Bruno S. M., Salvati V., Castelli G., Cimino G., and De Maria R. (ORCID:0000-0003-2255-0583)

Abstract

Question Cystic fibrosis (CF) is due to pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Recent improvements have enabled pharmacological therapy aiming at restoring mutated CFTR expression and function. CFTR "modulators"have revolutionised the CF therapeutic landscape, particularly the last approved, Trikafta. This drug combination is indicated by the United States Food and Drug Administration and very recently by the European Medicines Agency for genotypes carrying at least one copy of CFTR with the F508del pathogenic variant. However, several genotypes are not yet eligible for Trikafta treatment. Materials/patients and methods We exploited an innovative cellular approach allowing highly efficient in vitro expansion of airway epithelial stem cells (AESCs) through conditional reprogramming from nasal brushing of CF patients. This approach, coupled to the development of AESC-derived personalised disease models, as organoids and air-liquid interface (ALI) cultures, revealed highly suitable for CFTR pharmacological testing. Results and answer to the question We fully validated the experimental models and implemented the CFTR functional assays and biochemical CFTR protein characterisation, which allowed the evaluation of the efficacy of clinically available modulators in restoring CFTR maturation and function of each patientderived "avatar"(theratyping). F508del homozygous genotypes, used as controls, confirmed the higher clinical activity of Trikafta in comparison with older modulators. In addition, Trikafta showed its efficacy on three rare genotypes previously not eligible for treatment with modulators, opening the way to clinical translation. Finally, encouraging results for innovative drug combinations were obtained.

Published
2021

19. Publisher Correction: Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability (Nature Genetics, (2018), 50, 5, (652-656), 10.1038/s41588-018-0100-5)

Author

Hysi P. G., Valdes A. M., Liu F., Furlotte N. A., Evans D. M., Bataille V., Visconti A., Hemani G., McMahon G., Ring S. M., Smith G. D., Duffy D. L., Zhu G., Gordon S. D., Medland S. E., Lin B. D., Willemsen G., Jan Hottenga J., Vuckovic D., Girotto G., Gandin I., Sala C., Concas M. P., Brumat M., Gasparini P., Toniolo D., Cocca M., Robino A., Yazar S., Hewitt A. W., Chen Y., Zeng C., Uitterlinden A. G., Ikram M. A., Hamer M. A., van Duijn C. M., Nijsten T., Mackey D. A., Falchi M., Boomsma D. I., Martin N. G., Hinds D. A., Kayser M., Spector T. D., Hysi, P. G., Valdes, A. M., Liu, F., Furlotte, N. A., Evans, D. M., Bataille, V., Visconti, A., Hemani, G., Mcmahon, G., Ring, S. M., Smith, G. D., Duffy, D. L., Zhu, G., Gordon, S. D., Medland, S. E., Lin, B. D., Willemsen, G., Jan Hottenga, J., Vuckovic, D., Girotto, G., Gandin, I., Sala, C., Concas, M. P., Brumat, M., Gasparini, P., Toniolo, D., Cocca, M., Robino, A., Yazar, S., Hewitt, A. W., Chen, Y., Zeng, C., Uitterlinden, A. G., Ikram, M. A., Hamer, M. A., van Duijn, C. M., Nijsten, T., Mackey, D. A., Falchi, M., Boomsma, D. I., Martin, N. G., Hinds, D. A., Kayser, M., and Spector, T. D.

Subjects
Publisher correction
Abstract

N/A

Published
2019

20. Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4

Author

Grosche, S. (Sarah), Marenholz, I. (Ingo), Esparza-Gordillo, J. (Jorge), Arnau-Soler, A. (Aleix), Pairo-Castineira, E. (Erola), Rueschendorf, F. (Franz), Ahluwalia, T. S. (Tarunveer S.), Almqvist, C. (Catarina), Arnold, A. (Andreas), Baurecht, H. (Hansjoerg), Bisgaard, H. (Hans), Bonnelykke, K. (Klaus), Brown, S. J. (Sara J.), Bustamante, M. (Mariona), Curtin, J. A. (John A.), Custovic, A. (Adnan), Dharmage, S. C. (Shyamali C.), Esplugues, A. (Ana), Falchi, M. (Mario), Fernandez-Orth, D. (Dietmar), Ferreira, M. A. (Manuel A. R.), Franke, A. (Andre), Gerdes, S. (Sascha), Gieger, C. (Christian), Hakonarson, H. (Hakon), Holt, P. G. (Patrick G.), Homuth, G. (Georg), Hubner, N. (Norbert), Hysi, P. G. (Pirro G.), Järvelin, M.-R. (Marjo-Riitta), Karlsson, R. (Robert), Koppelman, G. H. (Gerard H.), Lau, S. (Susanne), Lutz, M. (Manuel), Magnusson, P. K. (Patrik K. E.), Marks, G. B. (Guy B.), Mueller-Nurasyid, M. (Martina), Noethen, M. M. (Markus M.), Paternoster, L. (Lavinia), Pennell, C. E. (Craig E.), Peters, A. (Annette), Rawlik, K. (Konrad), Robertson, C. F. (Colin F.), Rodriguez, E. (Elke), Sebert, S. (Sylvain), Simpson, A. (Angela), Sleiman, P. M. (Patrick M. A.), Standl, M. (Marie), Stoelzl, D. (Dora), Strauch, K. (Konstantin), Szwajda, A. (Agnieszka), Tenesa, A. (Albert), Thompson, P. J. (Philip J.), Ullemar, V. (Vilhelmina), Visconti, A. (Alessia), Vonk, J. M. (Judith M.), Wang, C. A. (Carol A.), Weidinger, S. (Stephan), Wielscher, M. (Matthias), Worth, C. L. (Catherine L.), Xu, C.-J. (Chen-Jian), Lee, Y.-A. (Young-Ae), and Groningen Research Institute for Asthma and COPD (GRIAC)

Subjects
Sodium-Hydrogen Exchangers, Genotype, Eczema, Gene Expression, Genetic predisposition to disease, Dual Specificity Phosphatase 1, Rare variants, Matrix Attachment Region Binding Proteins, Polymorphism, Single Nucleotide, Genome-wide association studies, Article, Cytokine Receptor Common beta Subunit, Skin diseases, Rare Diseases, Cardiovascular and Metabolic Diseases, Humans, Receptor, Notch4, Genome-Wide Association Study, Atopic dermatitis
Abstract

Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema., Genetic studies of eczema to date have mostly explored common genetic variation. Here, the authors perform a large meta-analysis for common and rare variants and discover 8 loci associated with eczema. Over 20% of the heritability of the condition is attributable to rare variants.

Published
2020

21. Current tobacco smoking and risk from COVID-19: results from a population symptom app in over 2.4 million people

Author

Hopkinson, NS, Rossi, N, El-Sayed Moustafa, J, Laverty, AA, Quint, JK, Freydin, MB, Visconti, A, Murray, B, Modat, M, Ourselin, S, Small, K, Davies, R, Wolf, J, Spector, T, Steves, CJ, and Falchi, M

Abstract

Background The association between current tobacco smoking, the risk of developing COVID-19 and the severity of illness is an important information gap. Methods UK users of the COVID Symptom Study app provided baseline data including demographics, anthropometrics, smoking status and medical conditions, were asked to log symptoms daily from 24th March 2020 to 23rd April 2020. Participants reporting that they did not feel physically normal were taken through a series of questions, including 14 potential COVID-19 symptoms and any hospital attendance. The main study outcome was the association between current smoking and the development of “classic” symptoms of COVID-19 during the pandemic defined as fever, new persistent cough and breathlessness. The number of concurrent COVID-19 symptoms was used as a proxy for severity. In addition, association of subcutaneous adipose tissue expression of ACE2, both the receptor for SARS-CoV-2 and a potential mediator of disease severity, with smoking status was assessed in a subset of 541 twins from the TwinsUK cohort. Results Data were available on 2,401,982 participants, mean(SD) age 43.6(15.1) years, 63.3% female, overall smoking prevalence 11.0%. 834,437 (35%) participants reported being unwell and entered one or more symptoms. Current smokers were more likely to develop symptoms suggesting a diagnosis of COVID-19; classic symptoms adjusted OR[95%CI] 1.14[1.10 to 1.18]; >5 symptoms 1.29[1.26 to 1.31]; >10 symptoms 1.50[1.42 to 1.58]. Smoking was associated with reduced ACE2 expression in adipose tissue (Beta(SE)=-0.395(0.149); p=7.01×10-3). Interpretation These data are consistent with smokers having an increased risk from COVID-19. Funding Zoe provided in kind support for all aspects of building, running and supporting the app and service to all users worldwide. The study was also supported by grants from the Wellcome Trust, UK Research and Innovation and British Heart Foundation.

Published
2020

22. Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility

Author

Landi MT, Bishop DT, MacGregor S, Machiela MJ, Stratigos AJ, Ghiorzo P, Brossard M, Calista D, Choi J, Fargnoli MC, Zhang T, Rodolfo M, Trower AJ, Menin C, Martinez J, Hadjisavvas A, Song L, Stefanaki I, Scolyer R, Yang R, Goldstein AM, Potrony M, Kypreou KP, Pastorino L, Queirolo P, Pellegrini C, Cattaneo L, Zawistowski M, Gimenez-Xavier P, Rodriguez A, Elefanti L, Manoukian S, Rivoltini L, Smith BH, Loizidou MA, Del Regno L, Massi D, Mandala M, Khosrotehrani K, Akslen LA, Amos CI, Andresen PA, Avril MF, Azizi E, Soyer HP, Bataille V, Dalmasso B, Bowdler LM, Burdon KP, Chen WV, Codd V, Craig JE, Debniak T, Falchi M, Fang S, Friedman E, Simi S, Galan P, Garcia-Casado Z, Gillanders EM, Gordon S, Green A, Gruis NA, Hansson J, Harland M, Harris J, Helsing P, Henders A, Hocevar M, Höiom V, Hunter D, Ingvar C, Kumar R, Lang J, Lathrop GM, Lee JE, Li X, Lubinski J, Mackie RM, Malt M, Malvehy J, McAloney K, Mohamdi H, Molven A, Moses EK, Neale RE, Novakovic S, Nyholt DR, Olsson H, Orr N, Fritsche LG, Puig-Butille JA, Qureshi AA, Radford-Smith GL, Randerson-Moor J, Requena C, Rowe C, Samani NJ, Sanna M, Schadendorf D, Schulze HJ, Simms LA, Smithers M, Song F, Swerdlow AJ, van der Stoep N, Kukutsch NA, Visconti A, Wallace L, Ward SV, Wheeler L, Sturm RA, Hutchinson A, Jones K, Malasky M, Vogt A, Zhou W, Pooley KA, Elder DE, Han J, Hicks B, Hayward NK, Kanetsky PA, Brummett C, Montgomery GW, Olsen CM, Hayward C, Dunning AM, Martin NG, Evangelou E, Mann GJ, Long G, Pharoah PDP, Easton DF, Barrett JH, Cust AE, Abecasis G, Duffy DL, Whiteman DC, Gogas H, De Nicolo A, Tucker MA, Newton-Bishop JA, GenoMEL Consortium, Q-MEGA and QTWIN Investigators, ATHENS Melanoma Study Group, 23andMe, SDH Study Group, IBD Investigators, Essen-Heidelberg Investigators, AMFS Investigators, MelaNostrum Consortium, Peris K, Chanock SJ, Demenais F, Brown KM, Puig S, Nagore E, Shi J, Iles MM, and Law MH

Abstract

Meta-analysis of 36,760 cases and 375,188 controls identifies 54 loci associated with susceptibility to cutaneous melanoma. Further analysis combining nevus count and hair color GWAS results provide insights into the genetic architecture of melanoma. Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 x 10(-8)) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.

Published
2020

23. Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility

Author

Landi, M.T. Bishop, D.T. MacGregor, S. Machiela, M.J. Stratigos, A.J. Ghiorzo, P. Brossard, M. Calista, D. Choi, J. Fargnoli, M.C. Zhang, T. Rodolfo, M. Trower, A.J. Menin, C. Martinez, J. Hadjisavvas, A. Song, L. Stefanaki, I. Scolyer, R. Yang, R. Goldstein, A.M. Potrony, M. Kypreou, K.P. Pastorino, L. Queirolo, P. Pellegrini, C. Cattaneo, L. Zawistowski, M. Gimenez-Xavier, P. Rodriguez, A. Elefanti, L. Manoukian, S. Rivoltini, L. Smith, B.H. Loizidou, M.A. Del Regno, L. Massi, D. Mandala, M. Khosrotehrani, K. Akslen, L.A. Amos, C.I. Andresen, P.A. Avril, M.-F. Azizi, E. Soyer, H.P. Bataille, V. Dalmasso, B. Bowdler, L.M. Burdon, K.P. Chen, W.V. Codd, V. Craig, J.E. Dębniak, T. Falchi, M. Fang, S. Friedman, E. Simi, S. Galan, P. Garcia-Casado, Z. Gillanders, E.M. Gordon, S. Green, A. Gruis, N.A. Hansson, J. Harland, M. Harris, J. Helsing, P. Henders, A. Hočevar, M. Höiom, V. Hunter, D. Ingvar, C. Kumar, R. Lang, J. Lathrop, G.M. Lee, J.E. Li, X. Lubiński, J. Mackie, R.M. Malt, M. Malvehy, J. McAloney, K. Mohamdi, H. Molven, A. Moses, E.K. Neale, R.E. Novaković, S. Nyholt, D.R. Olsson, H. Orr, N. Fritsche, L.G. Puig-Butille, J.A. Qureshi, A.A. Radford-Smith, G.L. Randerson-Moor, J. Requena, C. Rowe, C. Samani, N.J. Sanna, M. Schadendorf, D. Schulze, H.-J. Simms, L.A. Smithers, M. Song, F. Swerdlow, A.J. van der Stoep, N. Kukutsch, N.A. Visconti, A. Wallace, L. Ward, S.V. Wheeler, L. Sturm, R.A. Hutchinson, A. Jones, K. Malasky, M. Vogt, A. Zhou, W. Pooley, K.A. Elder, D.E. Han, J. Hicks, B. Hayward, N.K. Kanetsky, P.A. Brummett, C. Montgomery, G.W. Olsen, C.M. Hayward, C. Dunning, A.M. Martin, N.G. Evangelou, E. Mann, G.J. Long, G. Pharoah, P.D.P. Easton, D.F. Barrett, J.H. Cust, A.E. Abecasis, G. Duffy, D.L. Whiteman, D.C. Gogas, H. De Nicolo, A. Tucker, M.A. Newton-Bishop, J.A. Peris, K. Chanock, S.J. Demenais, F. Brown, K.M. Puig, S. Nagore, E. Shi, J. Iles, M.M. Law, M.H. GenoMEL Consortium Q-MEGA QTWIN Investigators ATHENS Melanoma Study Group 23andMe The SDH Study Group IBD Investigators Essen-Heidelberg Investigators AMFS Investigators MelaNostrum Consortium

Abstract

Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10−8) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis. © 2020, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Published
2020

26. A reference map of potential determinants for the human serum metabolome

Author

Bar, N., Korem, T., Weissbrod, O., Zeevi, D., Rothschild, D., Leviatan, S., Kosower, N., Lotan-Pompan, M., Weinberger, A., Le Roy, C. I., Menni, C., Visconti, A., Falchi, M., Spector, T. D., Vestergaard, H., Arumugam, M., Hansen, T., Allin, K., Hong, Mun-Gwan, Schwenk, Jochen M., Häussler, Ragna S., Dale, Matilda, Giorgino, T., Rodriquez, M., Perry, M., Nice, R., McDonald, T., Hattersley, A., Jones, A., Graefe-Mody, U., Baum, P., Grempler, R., Thomas, C. E., Masi, F. D., Brorsson, C. A., Mazzoni, G., Allesøe, R., Rasmussen, S., Gudmundsdóttir, V., Nielsen, A. M., Banasik, K., Tsirigos, K., Nilsson, B., Pedersen, H., Brunak, S., Karaderi, T., Lundgaard, A. T., Johansen, J., Gupta, R., Sackett, P. W., Tillner, J., Lehr, T., Scherer, N., Dings, C., Sihinevich, I., Loftus, H., Cabrelli, L., McEvoy, D., Mari, A., Bizzotto, R., Tura, A., ’t Hart, L., Dekkers, K., Leeuwen, N., Slieker, R., Rutters, F., Beulens, J., Nijpels, G., Koopman, A., Oort, S., Groeneveld, L., Groop, L., Elders, P., Viñuela, A., Ramisch, A., Dermitzakis, E., Ehrhardt, B., Jennison, C., Froguel, P., Canouil, M., Boneford, A., McVittie, I., Wake, D., Frau, F., Staerfeldt, H. -H, Adragni, K., Thomas, M., Wu, H., Pavo, I., Steckel-Hamann, B., Thomsen, H., Giordano, G. N., Fitipaldi, H., Ridderstråle, M., Kurbasic, A., Pasdar, N. A., Pomares-Millan, H., Mutie, P., Koivula, R., McRobert, N., McCarthy, M., Wesolowska-Andersen, A., Mahajan, A., Abdalla, M., Fernandez, J., Holl, R., Heggie, A., Deshmukh, H., Hennige, A., Bianzano, S., Thorand, B., Sharma, S., Grallert, H., Adam, J., Troll, M., Fritsche, A., Hill, A., Thorne, C., Hudson, M., Kuulasmaa, T., Vangipurapu, J., Laakso, M., Cederberg, H., Kokkola, T., Jiao, Y., Gough, S., Robertson, N., Verkindt, H., Raverdi, V., Caiazzo, R., Pattou, F., White, M., Donnelly, L., Brown, A., Palmer, C., Davtian, D., Dawed, A., Forgie, I., Pearson, E., Ruetten, H., Musholt, P., Bell, J., Thomas, E. L., Whitcher, B., Haid, M., Nicolay, C., Mourby, M., Kaye, J., Shah, N., Teare, H., Frost, G., Jablonka, B., Uhlen, M., Eriksen, R., Vogt, J., Dutta, A., Jonsson, A., Engelbrechtsen, L., Forman, A., Sondertoft, N., de Preville, N., Baltauss, T., Walker, M., Gassenhuber, J., Klintenberg, M., Bergstrom, M., Ferrer, J., Adamski, J., Franks, P. W., Pedersen, O., Segal, E., consortium, The IMI DIRECT, Bar, N., Korem, T., Weissbrod, O., Zeevi, D., Rothschild, D., Leviatan, S., Kosower, N., Lotan-Pompan, M., Weinberger, A., Le Roy, C. I., Menni, C., Visconti, A., Falchi, M., Spector, T. D., Vestergaard, H., Arumugam, M., Hansen, T., Allin, K., Hong, Mun-Gwan, Schwenk, Jochen M., Häussler, Ragna S., Dale, Matilda, Giorgino, T., Rodriquez, M., Perry, M., Nice, R., McDonald, T., Hattersley, A., Jones, A., Graefe-Mody, U., Baum, P., Grempler, R., Thomas, C. E., Masi, F. D., Brorsson, C. A., Mazzoni, G., Allesøe, R., Rasmussen, S., Gudmundsdóttir, V., Nielsen, A. M., Banasik, K., Tsirigos, K., Nilsson, B., Pedersen, H., Brunak, S., Karaderi, T., Lundgaard, A. T., Johansen, J., Gupta, R., Sackett, P. W., Tillner, J., Lehr, T., Scherer, N., Dings, C., Sihinevich, I., Loftus, H., Cabrelli, L., McEvoy, D., Mari, A., Bizzotto, R., Tura, A., ’t Hart, L., Dekkers, K., Leeuwen, N., Slieker, R., Rutters, F., Beulens, J., Nijpels, G., Koopman, A., Oort, S., Groeneveld, L., Groop, L., Elders, P., Viñuela, A., Ramisch, A., Dermitzakis, E., Ehrhardt, B., Jennison, C., Froguel, P., Canouil, M., Boneford, A., McVittie, I., Wake, D., Frau, F., Staerfeldt, H. -H, Adragni, K., Thomas, M., Wu, H., Pavo, I., Steckel-Hamann, B., Thomsen, H., Giordano, G. N., Fitipaldi, H., Ridderstråle, M., Kurbasic, A., Pasdar, N. A., Pomares-Millan, H., Mutie, P., Koivula, R., McRobert, N., McCarthy, M., Wesolowska-Andersen, A., Mahajan, A., Abdalla, M., Fernandez, J., Holl, R., Heggie, A., Deshmukh, H., Hennige, A., Bianzano, S., Thorand, B., Sharma, S., Grallert, H., Adam, J., Troll, M., Fritsche, A., Hill, A., Thorne, C., Hudson, M., Kuulasmaa, T., Vangipurapu, J., Laakso, M., Cederberg, H., Kokkola, T., Jiao, Y., Gough, S., Robertson, N., Verkindt, H., Raverdi, V., Caiazzo, R., Pattou, F., White, M., Donnelly, L., Brown, A., Palmer, C., Davtian, D., Dawed, A., Forgie, I., Pearson, E., Ruetten, H., Musholt, P., Bell, J., Thomas, E. L., Whitcher, B., Haid, M., Nicolay, C., Mourby, M., Kaye, J., Shah, N., Teare, H., Frost, G., Jablonka, B., Uhlen, M., Eriksen, R., Vogt, J., Dutta, A., Jonsson, A., Engelbrechtsen, L., Forman, A., Sondertoft, N., de Preville, N., Baltauss, T., Walker, M., Gassenhuber, J., Klintenberg, M., Bergstrom, M., Ferrer, J., Adamski, J., Franks, P. W., Pedersen, O., Segal, E., and consortium, The IMI DIRECT

Abstract

The serum metabolome contains a plethora of biomarkers and causative agents of various diseases, some of which are endogenously produced and some that have been taken up from the environment1. The origins of specific compounds are known, including metabolites that are highly heritable2,3, or those that are influenced by the gut microbiome4, by lifestyle choices such as smoking5, or by diet6. However, the key determinants of most metabolites are still poorly understood. Here we measured the levels of 1,251 metabolites in serum samples from a unique and deeply phenotyped healthy human cohort of 491 individuals. We applied machine-learning algorithms to predict metabolite levels in held-out individuals on the basis of host genetics, gut microbiome, clinical parameters, diet, lifestyle and anthropometric measurements, and obtained statistically significant predictions for more than 76% of the profiled metabolites. Diet and microbiome had the strongest predictive power, and each explained hundreds of metabolites—in some cases, explaining more than 50% of the observed variance. We further validated microbiome-related predictions by showing a high replication rate in two geographically independent cohorts7,8 that were not available to us when we trained the algorithms. We used feature attribution analysis9 to reveal specific dietary and bacterial interactions. We further demonstrate that some of these interactions might be causal, as some metabolites that we predicted to be positively associated with bread were found to increase after a randomized clinical trial of bread intervention. Overall, our results reveal potential determinants of more than 800 metabolites, paving the way towards a mechanistic understanding of alterations in metabolites under different conditions and to designing interventions for manipulating the levels of circulating metabolites., QC 20211001

Published
2020
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27. A new highly penetrant form of obesity due to deletions on chromosome 16p11.2

Author

Walters, R. G., Jacquemont, S., Valsesia, A., de Smith, A. J., Martinet, D., Andersson, J., Falchi, M., Chen, F., Andrieux, J., Lobbens, S., Delobel, B., Stutzmann, F., El-Sayed Moustafa, J. S., Chèvre, J.-C., Lecoeur, C., Vatin, V., Bouquillon, S., Buxton, J. L., Boute, O., Holder-Espinasse, M., Cuisset, J.-M., Lemaitre, M.-P., Ambresin, A.-E., Brioschi, A., Gaillard, M., Giusti, V., Fellmann, F., Ferrarini, A., Hadjikhani, N., Campion, D., Guilmatre, A., Goldenberg, A., Calmels, N., Mandel, J.-L., Le Caignec, C., David, A., Isidor, B., Cordier, M.-P., Dupuis-Girod, S., Labalme, A., Sanlaville, D., Béri-Dexheimer, M., Jonveaux, P., Leheup, B., Õunap, K., Bochukova, E. G., Henning, E., Keogh, J., Ellis, R. J., MacDermot, K. D., van Haelst, M. M., Vincent-Delorme, C., Plessis, G., Touraine, R., Philippe, A., Malan, V., Mathieu-Dramard, M., Chiesa, J., Blaumeiser, B., Kooy, R. F., Caiazzo, R., Pigeyre, M., Balkau, B., Sladek, R., Bergmann, S., Mooser, V., Waterworth, D., Reymond, A., Vollenweider, P., Waeber, G., Kurg, A., Palta, P., Esko, T., Metspalu, A., Nelis, M., Elliott, P., Hartikainen, A.-L., McCarthy, M. I., Peltonen, L., Carlsson, L., Jacobson, P., Sjöström, L., Huang, N., Hurles, M. E., OʼRahilly, S., Farooqi, I. S., Männik, K., Jarvelin, M.-R., Pattou, F., Meyre, D., Walley, A. J., Coin, L. J. M., Blakemore, A. I. F., Froguel, P., and Beckmann, J. S.

Published
2010
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28. Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways (vol 9, 4774, 2018)

Author

Duffy, DL, Zhu, G, Li, X, Sanna, M, Iles, MM, Jacobs, LC, Evans, DM, Yazar, S, Beesley, J, Law, MH, Kraft, P, Visconti, A, Taylor, JC, Liu, F, Wright, MJ, Henders, AK, Bowdler, L, Glass, D, Ikram, MA, Uitterlinden, AG, Madden, PA, Heath, AC, Nelson, EC, Green, AC, Chanock, S, Barrett, JH, Brown, MA, Hayward, NK, MacGregor, S, Sturm, RA, Hewitt, AW, Kayser, M, Hunter, DJ, Bishop, JAN, Spector, TD, Montgomery, GW, Mackey, DA, Smith, GD, Nijsten, TE, Bishop, DT, Bataille, V, Falchi, M, Han, J, Martin, NG, Lee, JE, Brossard, M, Moses, EK, Song, F, Kumar, R, Easton, DF, Pharoah, PDP, Swerdlow, AJ, Kypreou, KP, Harland, M, Randerson-Moor, J, Akslen, LA, Andresen, PA, Avril, M-F, Azizi, E, Scarra, GB, Brown, KM, Debniak, T, Elder, DE, Fang, S, Friedman, E, Galan, P, Ghiorzo, P, Gillanders, EM, Goldstein, AM, Gruis, NA, Hansson, J, Helsing, P, Hocevar, M, Hoiom, V, Ingvar, C, Kanetsky, PA, Chen, WV, Landi, MT, Lang, J, Lathrop, GM, Lubinski, J, Mackie, RM, Mann, GJ, Molven, A, Novakovic, S, Olsson, H, Puig, S, Puig-Butille, JA, Radford-Smith, GL, van der Stoep, N, van Doorn, R, Whiteman, DC, Craig, JE, Schadendorf, D, Simms, LA, Burdon, KP, Nyholt, DR, Pooley, KA, Orr, N, Stratigos, AJ, Cust, AE, Ward, SV, Schulze, H-J, Dunning, AM, Demenais, F, Amos, CI, Duffy, DL, Zhu, G, Li, X, Sanna, M, Iles, MM, Jacobs, LC, Evans, DM, Yazar, S, Beesley, J, Law, MH, Kraft, P, Visconti, A, Taylor, JC, Liu, F, Wright, MJ, Henders, AK, Bowdler, L, Glass, D, Ikram, MA, Uitterlinden, AG, Madden, PA, Heath, AC, Nelson, EC, Green, AC, Chanock, S, Barrett, JH, Brown, MA, Hayward, NK, MacGregor, S, Sturm, RA, Hewitt, AW, Kayser, M, Hunter, DJ, Bishop, JAN, Spector, TD, Montgomery, GW, Mackey, DA, Smith, GD, Nijsten, TE, Bishop, DT, Bataille, V, Falchi, M, Han, J, Martin, NG, Lee, JE, Brossard, M, Moses, EK, Song, F, Kumar, R, Easton, DF, Pharoah, PDP, Swerdlow, AJ, Kypreou, KP, Harland, M, Randerson-Moor, J, Akslen, LA, Andresen, PA, Avril, M-F, Azizi, E, Scarra, GB, Brown, KM, Debniak, T, Elder, DE, Fang, S, Friedman, E, Galan, P, Ghiorzo, P, Gillanders, EM, Goldstein, AM, Gruis, NA, Hansson, J, Helsing, P, Hocevar, M, Hoiom, V, Ingvar, C, Kanetsky, PA, Chen, WV, Landi, MT, Lang, J, Lathrop, GM, Lubinski, J, Mackie, RM, Mann, GJ, Molven, A, Novakovic, S, Olsson, H, Puig, S, Puig-Butille, JA, Radford-Smith, GL, van der Stoep, N, van Doorn, R, Whiteman, DC, Craig, JE, Schadendorf, D, Simms, LA, Burdon, KP, Nyholt, DR, Pooley, KA, Orr, N, Stratigos, AJ, Cust, AE, Ward, SV, Schulze, H-J, Dunning, AM, Demenais, F, and Amos, CI

Abstract

The original version of this Article contained errors in the spelling of the authors Fan Liu and M. Arfan Ikram, which were incorrectly given as Fan Lui and Arfan M. Ikram. In addition, the original version of this Article also contained errors in the author affiliations which are detailed in the associated Publisher Correction.

Published
2019

29. A novel oral micellar fenretinide formulation with enhanced bioavailability and antitumour activity against multiple tumours from cancer stem cells

Author

Orienti, I., Salvati, Valentina, Sette, Giovanni, Zucchetti, M., Bongiorno-Borbone, L., Peschiaroli, A., Zolla, L., Francescangeli, F., Ferrari, M., Matteo, C., Bello, E., Di Virgilio, A., Falchi, M., De Angelis, M. L., Baiocchi, M., Melino, G., De Maria Marchiano, Ruggero, Zeuner, A., Eramo, A., Salvati V., Sette G., De Maria R. (ORCID:0000-0003-2255-0583), Orienti, I., Salvati, Valentina, Sette, Giovanni, Zucchetti, M., Bongiorno-Borbone, L., Peschiaroli, A., Zolla, L., Francescangeli, F., Ferrari, M., Matteo, C., Bello, E., Di Virgilio, A., Falchi, M., De Angelis, M. L., Baiocchi, M., Melino, G., De Maria Marchiano, Ruggero, Zeuner, A., Eramo, A., Salvati V., Sette G., and De Maria R. (ORCID:0000-0003-2255-0583)

Abstract

Background: An increasing number of anticancer agents has been proposed in recent years with the attempt to overcome treatment-resistant cancer cells and particularly cancer stem cells (CSC), the major culprits for tumour resistance and recurrence. However, a huge obstacle to treatment success is the ineffective delivery of drugs within the tumour environment due to limited solubility, short circulation time or inconsistent stability of compounds that, together with concomitant dose-limiting systemic toxicity, contribute to hamper the achievement of therapeutic drug concentrations. The synthetic retinoid Fenretinide (4-hydroxy (phenyl)retinamide; 4-HPR) formerly emerged as a promising anticancer agent based on pre-clinical and clinical studies. However, a major limitation of fenretinide is traditionally represented by its poor aqueous solubility/bioavailability due to its hydrophobic nature, that undermined the clinical success of previous clinical trials. Methods: Here, we developed a novel nano-micellar fenretinide formulation called bionanofenretinide (Bio-nFeR), based on drug encapsulation in an ion-pair stabilized lipid matrix, with the aim to raise fenretinide bioavailability and antitumour efficacy. Results: Bio-nFeR displayed marked antitumour activity against lung, colon and melanoma CSC both in vitro and in tumour xenografts, in absence of mice toxicity. Bio-nFeR is suitable for oral administration, reaching therapeutic concentrations within tumours and an unprecedented therapeutic activity in vivo as single agent. Conclusion: Altogether, our results indicate Bio-nFeR as a novel anticancer agent with low toxicity and high activity against tumourigenic cells, potentially useful for the treatment of solid tumours of multiple origin.

Published
2019

31. Genome-wide association study in 176,678 Europeans reveals genetic loci for tanning response to sun exposure

Author

Visconti, A, Duffy, DL, Liu, Fan, Zhu, G, Wu, WT, Chen, Y, Hysi, PG, Zeng, CQ, Sanna, M, Iles, MM, Kanetsky, PA, Demenais, F, Hamer, Merel, Uitterlinden, André, Ikram, Arfan, Nijsten, Tamar, Martin, NG, Kayser, Manfred, Spector, TD, Han, JL, Bataille, V, Falchi, M, Genetic Identification, Dermatology, Epidemiology, and Internal Medicine

Subjects
Adult, Male, Neoplasms, Radiation-Induced, Skin Neoplasms, SUSCEPTIBILITY LOCI, Science, Sunburn, Polymorphism, Single Nucleotide, White People, Article, Sex Factors, Risk Factors, MD Multidisciplinary, HAIR, Humans, COLOR, Genetic Predisposition to Disease, Prospective Studies, lcsh:Science, Hair Color, skin and connective tissue diseases, Melanoma, METAANALYSIS, Aged, Suntan, Science & Technology, SKIN-CANCER, IDENTIFICATION, integumentary system, Chromosome Mapping, Middle Aged, Radiation Exposure, United Kingdom, Neoplasm Proteins, Multidisciplinary Sciences, Phenotype, Receptors, Aryl Hydrocarbon, Genetic Loci, Science & Technology - Other Topics, PIGMENTATION, lcsh:Q, Female, SQUAMOUS-CELL CARCINOMA, Carrier Proteins, human activities, TRAITS, Genome-Wide Association Study
Abstract

The skin’s tendency to sunburn rather than tan is a major risk factor for skin cancer. Here we report a large genome-wide association study of ease of skin tanning in 176,678 subjects of European ancestry. We identify significant association with tanning ability at 20 loci. We confirm previously identified associations at six of these loci, and report 14 novel loci, of which ten have never been associated with pigmentation-related phenotypes. Our results also suggest that variants at the AHR/AGR3 locus, previously associated with cutaneous malignant melanoma the underlying mechanism of which is poorly understood, might act on disease risk through modulation of tanning ability., The skin’s tanning response to sun exposure shows great interindividual variability. Here, Visconti et al. perform a genome-wide association study for ease of skin tanning and identify 20 genetic loci, ten of which had not previously been associated with pigmentation-related traits.

Published
2018
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32. Genome-wide association study in 176,678 Europeans reveals genetic loci for tanning response to sun exposure

Author

Visconti, A. (Alessia), Duffy, D.L. (David), Liu, F. (Fan), Zhu, G. (Gu), Wu, W. (Wenting), Yan, C. (Chen), Hysi, P.G. (Pirro), Zeng, C. (Changqing), Sanna, M. (Marianna), Iles, M.M. (Mark M.), Kanetsky, P.P. (Peter P.), Demenais, F. (Florence), Hamer, M.A. (Merel), Uitterlinden, A.G. (André), Ikram, M.A. (Arfan), Nijsten, T.E.C. (Tamar), Martin, N.G. (Nicholas), Kayser, M.H. (Manfred), Spector, T.D. (Timothy), Han, J. (Jiali), Bataille, V. (Veronique), Falchi, M. (Mario), Visconti, A. (Alessia), Duffy, D.L. (David), Liu, F. (Fan), Zhu, G. (Gu), Wu, W. (Wenting), Yan, C. (Chen), Hysi, P.G. (Pirro), Zeng, C. (Changqing), Sanna, M. (Marianna), Iles, M.M. (Mark M.), Kanetsky, P.P. (Peter P.), Demenais, F. (Florence), Hamer, M.A. (Merel), Uitterlinden, A.G. (André), Ikram, M.A. (Arfan), Nijsten, T.E.C. (Tamar), Martin, N.G. (Nicholas), Kayser, M.H. (Manfred), Spector, T.D. (Timothy), Han, J. (Jiali), Bataille, V. (Veronique), and Falchi, M. (Mario)

Abstract

The skin's tendency to sunburn rather than tan is a major risk factor for skin cancer. Here we report a large genome-wide association study of ease of skin tanning in 176,678 subjects of European ancestry. We identify significant associat

Published
2018
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33. Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways

Author

Duffy, DL, Zhu, G, Li, X, Sanna, M, Iles, MM, Jacobs, LC, Evans, DM, Yazar, S, Beesley, J, Law, MH, Kraft, P, Visconti, A, Taylor, JC, Lui, F, Wright, MJ, Henders, AK, Bowdler, L, Glass, D, Ikram, AM, Uitterlinden, AG, Madden, PA, Heath, AC, Nelson, EC, Green, AC, Chanock, S, Barrett, JH, Brown, MA, Hayward, NK, MacGregor, S, Sturm, RA, Hewitt, AW, Kayser, M, Hunter, DJ, Bishop, JAN, Spector, TD, Montgomery, GW, Mackey, DA, Smith, GD, Nijsten, TE, Bishop, DT, Bataille, V, Falchi, M, Han, J, Martins, NG, Duffy, DL, Zhu, G, Li, X, Sanna, M, Iles, MM, Jacobs, LC, Evans, DM, Yazar, S, Beesley, J, Law, MH, Kraft, P, Visconti, A, Taylor, JC, Lui, F, Wright, MJ, Henders, AK, Bowdler, L, Glass, D, Ikram, AM, Uitterlinden, AG, Madden, PA, Heath, AC, Nelson, EC, Green, AC, Chanock, S, Barrett, JH, Brown, MA, Hayward, NK, MacGregor, S, Sturm, RA, Hewitt, AW, Kayser, M, Hunter, DJ, Bishop, JAN, Spector, TD, Montgomery, GW, Mackey, DA, Smith, GD, Nijsten, TE, Bishop, DT, Bataille, V, Falchi, M, Han, J, and Martins, NG

Abstract

The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B, DOCK8, and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis.

Published
2018

34. Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability

Author

Hysi, PG, Valdes, AM, Liu, F, Furlotte, NA, Evans, DM, Bataille, V, Visconti, A, Hemani, G, McMahon, G, Ring, SM, Smith, GD, Duffy, DL, Zhu, G, Gordon, SD, Medland, SE, Lin, BD, Willemsen, G, Hottenga, JJ, Vuckovic, D, Girotto, G, Gandin, I, Sala, C, Concas, MP, Brumat, M, Gasparini, P, Toniolo, D, Cocca, M, Robino, A, Yazar, S, Hewitt, AW, Chen, Y, Zeng, C, Uitterlinden, AG, Ikram, MA, Hamer, MA, van Duijn, CM, Nijsten, T, Mackey, DA, Falchi, M, Boomsma, DI, Martin, NG, Hinds, DA, Kayser, M, Spector, TD, Hysi, PG, Valdes, AM, Liu, F, Furlotte, NA, Evans, DM, Bataille, V, Visconti, A, Hemani, G, McMahon, G, Ring, SM, Smith, GD, Duffy, DL, Zhu, G, Gordon, SD, Medland, SE, Lin, BD, Willemsen, G, Hottenga, JJ, Vuckovic, D, Girotto, G, Gandin, I, Sala, C, Concas, MP, Brumat, M, Gasparini, P, Toniolo, D, Cocca, M, Robino, A, Yazar, S, Hewitt, AW, Chen, Y, Zeng, C, Uitterlinden, AG, Ikram, MA, Hamer, MA, van Duijn, CM, Nijsten, T, Mackey, DA, Falchi, M, Boomsma, DI, Martin, NG, Hinds, DA, Kayser, M, and Spector, TD

Abstract

Hair color is one of the most recognizable visual traits in European populations and is under strong genetic control. Here we report the results of a genome-wide association study meta-analysis of almost 300,000 participants of European descent. We identified 123 autosomal and one X-chromosome loci significantly associated with hair color; all but 13 are novel. Collectively, single-nucleotide polymorphisms associated with hair color within these loci explain 34.6% of red hair, 24.8% of blond hair, and 26.1% of black hair heritability in the study populations. These results confirm the polygenic nature of complex phenotypes and improve our understanding of melanin pigment metabolism in humans.

Published
2018

35. Conditionally reprogrammed cells (CRC) methodology does not allow the in vitro expansion of patient-derived primary and metastatic lung cancer cells.

Author

Sette, Giovanni, Salvati, Valentina, Giordani, I, Pilozzi, E, Quacquarini, D, Duranti, E, De Nicola, F, Pallocca, M, Fanciulli, M, Falchi, M, Pallini, Roberto, De Maria Marchiano, Ruggero, Eramo, Adriana, Sette G, Salvati V, Pallini R (ORCID:0000-0002-4611-8827), De Maria Marchiano R (ORCID:0000-0003-2255-0583), Sette, Giovanni, Salvati, Valentina, Giordani, I, Pilozzi, E, Quacquarini, D, Duranti, E, De Nicola, F, Pallocca, M, Fanciulli, M, Falchi, M, Pallini, Roberto, De Maria Marchiano, Ruggero, Eramo, Adriana, Sette G, Salvati V, Pallini R (ORCID:0000-0002-4611-8827), and De Maria Marchiano R (ORCID:0000-0003-2255-0583)

Abstract

Availability of tumor and non-tumor patient-derived models would promote the development of more effective therapeutics for Non Small Cell Lung Cancer (NSCLC). Recently, conditionally reprogrammed cells (CRC) methodology demonstrated exceptional potential for the expansion of epithelial cells from patient tissues. However, the possibility to expand patient-derived lung cancer cells using CRC protocols is controversial. Here, we used CRC approach to expand cells from non-tumoral and tumor biopsies of patients with primary or metastatic NSCLC as well as pulmonary metastases of colorectal or breast cancers. CRC cultures were obtained from both tumor and non-malignant tissues with extraordinary high efficiency. Tumor cells were tracked in vitro through tumorigenicity assay, monitoring of tumor-specific genetic alterations and marker expression. Cultures were composed of EpCAM+ lung epithelial cells lacking tumorigenic potential. NSCLC biopsies-derived cultures rapidly lost patient-specific genetic mutations or tumor antigens. Similarly, pulmonary metastases of colon or breast cancer generated CRC cultures of lung epithelial cells. All CRC cultures examined displayed epithelial lung stem cell phenotype and function. In contrast, brain metastatic lung cancer biopsies failed to generate CRC cultures. In conclusion, patient-derived primary and metastatic lung cancer cells were negatively selected under CRC conditions, limiting the expansion to non-malignant lung epithelial stem cells either from tumor and non-tumor tissue sources. Thus, CRC approach cannot be applied for direct therapeutic testing of patient lung tumor cells, as the tumor- derived CRC cultures are composed of (non tumoral) airway basal cells.

Published
2018

36. Systems biology of the IMIDIA biobank from organ donors and pancreatectomised patients defines a novel transcriptomic signature of islets from individuals with type 2 diabetes

Author

Solimena, Michele, Schulte, A., Marselli, L., Ehehalt, F., Richter, D., Kleeberg, M., Mziaut, H., Knoch, K., Parnis, J., Bugliani, M., Siddiq, A., Jörns, A., Burdet, F., Liechti, R., Suleiman, M., Margerie, D., Syed, F., Distler, M., Grützmann, R., Petretto, E., Moreno-Moral, A., Wegbrod, C., Sönmez, A., Pfriem, K., Friedrich, A., Meinel, J., Wollheim, C., Baretton, G., Scharfmann, R., Nogoceke, E., Bonifacio, E., Sturm, D., Meyer-Puttlitz, B., Boggi, U., Saeger, H., Filipponi, F., Lesche, M., Meda, P., Dahl, A., Wigger, L., Xenarios, I., Falchi, M., Thorens, B., Weitz, J., Bokvist, K., Lenzen, S., Rutter, G., Froguel, P., von Bülow, M., Ibberson, M., Marchetti, P., Solimena, Michele, Schulte, A., Marselli, L., Ehehalt, F., Richter, D., Kleeberg, M., Mziaut, H., Knoch, K., Parnis, J., Bugliani, M., Siddiq, A., Jörns, A., Burdet, F., Liechti, R., Suleiman, M., Margerie, D., Syed, F., Distler, M., Grützmann, R., Petretto, E., Moreno-Moral, A., Wegbrod, C., Sönmez, A., Pfriem, K., Friedrich, A., Meinel, J., Wollheim, C., Baretton, G., Scharfmann, R., Nogoceke, E., Bonifacio, E., Sturm, D., Meyer-Puttlitz, B., Boggi, U., Saeger, H., Filipponi, F., Lesche, M., Meda, P., Dahl, A., Wigger, L., Xenarios, I., Falchi, M., Thorens, B., Weitz, J., Bokvist, K., Lenzen, S., Rutter, G., Froguel, P., von Bülow, M., Ibberson, M., and Marchetti, P.

Abstract

© 2017, The Author(s). Aims/hypothesis: Pancreatic islet beta cell failure causes type 2 diabetes in humans. To identify transcriptomic changes in type 2 diabetic islets, the Innovative Medicines Initiative for Diabetes: Improving beta-cell function and identification of diagnostic biomarkers for treatment monitoring in Diabetes (IMIDIA) consortium (www.imidia.org) established a comprehensive, unique multicentre biobank of human islets and pancreas tissues from organ donors and metabolically phenotyped pancreatectomised patients (PPP). Methods: Affymetrix microarrays were used to assess the islet transcriptome of islets isolated either by enzymatic digestion from 103 organ donors (OD), including 84 non-diabetic and 19 type 2 diabetic individuals, or by laser capture microdissection (LCM) from surgical specimens of 103 PPP, including 32 non-diabetic, 36 with type 2 diabetes, 15 with impaired glucose tolerance (IGT) and 20 with recent-onset diabetes (<1 year), conceivably secondary to the pancreatic disorder leading to surgery (type 3c diabetes). Bioinformatics tools were used to (1) compare the islet transcriptome of type 2 diabetic vs non-diabetic OD and PPP as well as vs IGT and type 3c diabetes within the PPP group; and (2) identify transcription factors driving gene co-expression modules correlated with insulin secretion ex vivo and glucose tolerance in vivo. Selected genes of interest were validated for their expression and function in beta cells. Results: Comparative transcriptomic analysis identified 19 genes differentially expressed (false discovery rate =0.05, fold change =1.5) in type 2 diabetic vs non-diabetic islets from OD and PPP. Nine out of these 19 dysregulated genes were not previously reported to be dysregulated in type 2 diabetic islets. Signature genes included TMEM37, which inhibited Ca2+-influx and insulin secretion in beta cells, and ARG2 and PPP1R1A, which promoted insulin secretion. Systems biology approaches identified HNF1A, PDX1 and RE

Published
2018

37. Decreased STARD10 expression is associated with defective insulin secretion in humans and mice

Author

Carrat, GR, Hu, M, Nguyen-Tu, M-S, Chabosseau, P, Gaulton, KJ, van de Bunt, M, Siddiq, A, Falchi, M, Thurner, M, Canouil, M, Pattou, F, Leclerc, I, Pullen, TJ, Cane, MC, Prabhala, P, Greenwald, W, Schulte, A, Marchetti, P, Ibberson, M, MacDonald, PE, Manning Fox, JE, Gloyn, AL, Froguel, P, Solimena, M, McCarthy, M, Rutter, GA, Commission of the European Communities, Medical Research Council (MRC), Société Francophone du Diabète, and Wellcome Trust

Subjects
endocrine system diseases, Medical and Health Sciences, Mice, Insulin-Secreting Cells, Insulin Secretion, RISK VARIANTS, 2.1 Biological and endogenous factors, Homeostasis, GWAS, Genetics(clinical), genetics, Aetiology, Cloning, Molecular, Genetics (clinical), IN-VIVO, Genetics & Heredity, diabetes, islet, GTPase-Activating Proteins, Adaptor Proteins, 11 Medical And Health Sciences, Biological Sciences, secretion, Liver, GTTT-REPEAT, Life Sciences & Biomedicine, Type 2, Proinsulin, ARAP1, insulin, mouse, STARD10, Adaptor Proteins, Signal Transducing, Alleles, Animals, Carrier Proteins, Diabetes Mellitus, Type 2, Gene Expression Regulation, Genetic Variation, Humans, Insulin, Phosphoproteins, Quantitative Trait Loci, Transcriptome, Genetics, Article, GENETIC ARCHITECTURE, TYPE-2, Diabetes Mellitus, GLYCEMIC TRAITS, ddc:610, GENOME-WIDE ASSOCIATION, Metabolic and endocrine, Science & Technology, TRANSFER PROTEIN, Human Genome, Signal Transducing, Molecular, 06 Biological Sciences, DIABETES SUSCEPTIBILITY LOCI, PANCREATIC BETA-CELL, Cloning
Abstract

Genetic variants near ARAP1 (CENTD2) and STARD10 influence type 2 diabetes (T2D) risk. The risk alleles impair glucose-induced insulin secretion and, paradoxically but characteristically, are associated with decreased proinsulin:insulin ratios, indicating improved proinsulin conversion. Neither the identity of the causal variants nor the gene(s) through which risk is conferred have been firmly established. Whereas ARAP1 encodes a GTPase activating protein, STARD10 is a member of the steroidogenic acute regulatory protein (StAR)-related lipid transfer protein family. By integrating genetic fine-mapping and epigenomic annotation data and performing promoter-reporter and chromatin conformational capture (3C) studies in β cell lines, we localize the causal variant(s) at this locus to a 5 kb region that overlaps a stretch-enhancer active in islets. This region contains several highly correlated T2D-risk variants, including the rs140130268 indel. Expression QTL analysis of islet transcriptomes from three independent subject groups demonstrated that T2D-risk allele carriers displayed reduced levels of STARD10 mRNA, with no concomitant change in ARAP1 mRNA levels. Correspondingly, β-cell-selective deletion of StarD10 in mice led to impaired glucose-stimulated Ca(2+) dynamics and insulin secretion and recapitulated the pattern of improved proinsulin processing observed at the human GWAS signal. Conversely, overexpression of StarD10 in the adult β cell improved glucose tolerance in high fat-fed animals. In contrast, manipulation of Arap1 in β cells had no impact on insulin secretion or proinsulin conversion in mice. This convergence of human and murine data provides compelling evidence that the T2D risk associated with variation at this locus is mediated through reduction in STARD10 expression in the β cell.

Published
2017
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39. Decreased STARD10 Expression Is Associated with Defective Insulin Secretion in Humans and Mice

Author

Carrat, G., Hu, M., Nguyen-Tu, M., Chabosseau, P., Gaulton, K., van de Bunt, M., Siddiq, A., Falchi, M., Thurner, M., Canouil, M., Pattou, F., Leclerc, I., Pullen, T., Cane, M., Prabhala, P., Greenwald, W., Schulte, A., Marchetti, P., Ibberson, M., MacDonald, P., Manning Fox, J., Gloyn, A., Froguel, P., Solimena, Michele, McCarthy, M., Rutter, G., Carrat, G., Hu, M., Nguyen-Tu, M., Chabosseau, P., Gaulton, K., van de Bunt, M., Siddiq, A., Falchi, M., Thurner, M., Canouil, M., Pattou, F., Leclerc, I., Pullen, T., Cane, M., Prabhala, P., Greenwald, W., Schulte, A., Marchetti, P., Ibberson, M., MacDonald, P., Manning Fox, J., Gloyn, A., Froguel, P., Solimena, Michele, McCarthy, M., and Rutter, G.

Abstract

© 2017 The Author(s) Genetic variants near ARAP1 (CENTD2) and STARD10 influence type 2 diabetes (T2D) risk. The risk alleles impair glucose-induced insulin secretion and, paradoxically but characteristically, are associated with decreased proinsulin:insulin ratios, indicating improved proinsulin conversion. Neither the identity of the causal variants nor the gene(s) through which risk is conferred have been firmly established. Whereas ARAP1 encodes a GTPase activating protein, STARD10 is a member of the steroidogenic acute regulatory protein (StAR)-related lipid transfer protein family. By integrating genetic fine-mapping and epigenomic annotation data and performing promoter-reporter and chromatin conformational capture (3C) studies in ß cell lines, we localize the causal variant(s) at this locus to a 5 kb region that overlaps a stretch-enhancer active in islets. This region contains several highly correlated T2D-risk variants, including the rs140130268 indel. Expression QTL analysis of islet transcriptomes from three independent subject groups demonstrated that T2D-risk allele carriers displayed reduced levels of STARD10 mRNA, with no concomitant change in ARAP1 mRNA levels. Correspondingly, ß-cell-selective deletion of StarD10 in mice led to impaired glucose-stimulated Ca2+dynamics and insulin secretion and recapitulated the pattern of improved proinsulin processing observed at the human GWAS signal. Conversely, overexpression of StarD10 in the adult ß cell improved glucose tolerance in high fat-fed animals. In contrast, manipulation of Arap1 in ß cells had no impact on insulin secretion or proinsulin conversion in mice. This convergence of human and murine data provides compelling evidence that the T2D risk associated with variation at this locus is mediated through reduction in STARD10 expression in the ß cell.

Published
2017

41. Multiple rare genetic variants co-segregating with familial IgA nephropathy all act within a single immune-related network

Author

Cox, S N, Pesce, F, El-Sayed Moustafa, J S, Sallustio, F, Serino, G, Kkoufou, C, Giampetruzzi, A, Ancona, N, Falchi, M, and Schena, F P

Subjects
kidney disease, genepolymorphism, genetics, familymedicine, glomerulonephritis
Abstract

BACKGROUND: IgA nephropathy (IgAN) is a common complex disease with a strong genetic involvement. We aimed to identify novel, rare, highly penetrant risk variants combining family-based linkage analysis with whole-exome sequencing (WES).METHODS: Linkage analysis of 16 kindreds of South Italian ancestry was performed using an 'affected-only' strategy. Eight most informative trios composed of two familial cases and an intrafamilial control were selected for WES. High-priority variants in linked regions were identified and validated using Sanger sequencing. Custom TaqMan assays were designed and carried out in the 16 kindreds and an independent cohort of 240 IgAN patients and 113 control subjects.RESULTS: We found suggestive linkage signals in 12 loci. After sequential filtering and validation of WES data, we identified 24 private or extremely rare (MAF CONCLUSION: Our findings suggest that disease susceptibility could be influenced by multiple rare variants acting in a common network that could provide the starting point for the identification of potential drug targets for personalized therapy.

Published
2016
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42. A GWAS sequence variant for platelet volume marks an alternative DNM3 promoter in megakaryocytes near a MEIS1 binding site

Author

Nürnberg ST, Rendon A, Smethurst PA, Paul DS, Voss K, Thon JN, Lloyd Jones H, Sambrook JG, Tijssen MR, Gieger C, Radhakrishnan A, Cvejic A, Tang W, Porcu E, Pistis G, Serbanovic Canic J, Elling U, Goodall AH, Labrune Y, Lopez LM, Mägi R, Meacham S, Okada Y, Sorice R, Teumer A, Zhang W, Ramirez Solis R, Bis JC, Ellinghaus D, Gögele M, Hottenga JJ, Langenberg C, Kovacs P, F. P, Shin SY, Esko T, Hartiala J, Kanoni S, Murgia F, Parsa A, Stephens J, van der Harst P, van der Schoot C, Allayee H, Attwood A, Balkau B, Bastardot F, Basu S, Baumeister SE, Biino G, Bomba L, Bonnefond A, Cambien F, Chambers JC, Cucca F, Davies G, de Geus EJ, de Boer RA, Döring A, Elliott P, Erdmann J, Feng W, Evans DM, Falchi M, Folsom AR, Frazer IH, Gibson QD, Glazer NL, Hammond C, Hartikainen AL, Heckbert SR, Hengstenberg C, Hersch M, Illig T, Loos RJ, Jolley J, Khaw KT, Kühnel B, Kyrtsonis MC, Lagou V, Lumley T, Mangino M, Maschio A, Mateo Leach I, McKnight B, Memari Y, Mitchell BD, Montgomery GW, Nöthlings U, Nakamura Y, Nauck M, Navis G, Nolte IM, Porteous DJ, Pouta A, Pramstaller PP, Pullat J, Ring SM, Rotter JI, Ruggiero D, Ruokonen A, Sala C, Samani NJ, Sambrook J, Schlessinger D, Schreiber S, Schunkert H, Scott J, Smith NL, Snieder H, Starr JM, Stumvoll M, Takahashi A, Taylor K, Tenesa A, Thein SL, Tönjes A, Uda M, Ulivi S, Wichmann HE, Yang TP, van Veldhuisen DJ, Visscher PM, Völker U, Wiggins KL, Willemsen G, Zhao JH, Zitting P, Bradley JR, Dedoussis GV, Hazen SL, Metspalu A, Pirastu M, Shuldiner AR, van Pelt L, Zwaginga JJ, Boomsma DI, Deary IJ, Franke A, Froguel P, Ganesh SK, Jarvelin MR, Martin NG, Meisinger C, Psaty BM, Spector TD, Wareham NJ, Akkerman JW, Ciullo M, Deloukas P, Greinacher A, Jupe S, Kamatani N, Khadake J, Kooner JS, Penninger J, Prokopenko I, Stemple D, Toniolo D, Wernisch L, Sanna S, Hicks AA, Ferreira MA, Italiano JE Jr, Gottgens B, Soranzo N, Ouwehand WH, PIRASTU, Nicola, D'ADAMO, ADAMO PIO, GASPARINI, PAOLO, Nürnberg, St, Rendon, A, Smethurst, Pa, Paul, D, Voss, K, Thon, Jn, Lloyd Jones, H, Sambrook, Jg, Tijssen, Mr, Gieger, C, Radhakrishnan, A, Cvejic, A, Tang, W, Porcu, E, Pistis, G, Serbanovic Canic, J, Elling, U, Goodall, Ah, Labrune, Y, Lopez, Lm, Mägi, R, Meacham, S, Okada, Y, Pirastu, Nicola, Sorice, R, Teumer, A, Zhang, W, Ramirez Solis, R, Bis, Jc, Ellinghaus, D, Gögele, M, Hottenga, Jj, Langenberg, C, Kovacs, P, F., P, Shin, Sy, Esko, T, Hartiala, J, Kanoni, S, Murgia, F, Parsa, A, Stephens, J, van der Harst, P, van der Schoot, C, Allayee, H, Attwood, A, Balkau, B, Bastardot, F, Basu, S, Baumeister, Se, Biino, G, Bomba, L, Bonnefond, A, Cambien, F, Chambers, Jc, Cucca, F, D'Adamo, ADAMO PIO, Davies, G, de Geus, Ej, de Boer, Ra, Döring, A, Elliott, P, Erdmann, J, Feng, W, Evans, Dm, Falchi, M, Folsom, Ar, Frazer, Ih, Gibson, Qd, Glazer, Nl, Hammond, C, Hartikainen, Al, Heckbert, Sr, Hengstenberg, C, Hersch, M, Illig, T, Loos, Rj, Jolley, J, Khaw, Kt, Kühnel, B, Kyrtsonis, Mc, Lagou, V, Lumley, T, Mangino, M, Maschio, A, Mateo Leach, I, Mcknight, B, Memari, Y, Mitchell, Bd, Montgomery, Gw, Nöthlings, U, Nakamura, Y, Nauck, M, Navis, G, Nolte, Im, Porteous, Dj, Pouta, A, Pramstaller, Pp, Pullat, J, Ring, Sm, Rotter, Ji, Ruggiero, D, Ruokonen, A, Sala, C, Samani, Nj, Sambrook, J, Schlessinger, D, Schreiber, S, Schunkert, H, Scott, J, Smith, Nl, Snieder, H, Starr, Jm, Stumvoll, M, Takahashi, A, Taylor, K, Tenesa, A, Thein, Sl, Tönjes, A, Uda, M, Ulivi, S, Wichmann, He, Yang, Tp, van Veldhuisen, Dj, Visscher, Pm, Völker, U, Wiggins, Kl, Willemsen, G, Zhao, Jh, Zitting, P, Bradley, Jr, Dedoussis, Gv, Gasparini, Paolo, Hazen, Sl, Metspalu, A, Pirastu, M, Shuldiner, Ar, van Pelt, L, Zwaginga, Jj, Boomsma, Di, Deary, Ij, Franke, A, Froguel, P, Ganesh, Sk, Jarvelin, Mr, Martin, Ng, Meisinger, C, Psaty, Bm, Spector, Td, Wareham, Nj, Akkerman, Jw, Ciullo, M, Deloukas, P, Greinacher, A, Jupe, S, Kamatani, N, Khadake, J, Kooner, J, Penninger, J, Prokopenko, I, Stemple, D, Toniolo, D, Wernisch, L, Sanna, S, Hicks, Aa, Ferreira, Ma, Italiano JE, Jr, Gottgens, B, Soranzo, N, Ouwehand, Wh, Biological Psychology, and EMGO+ - Mental Health

Subjects
Netherlands Twin Register (NTR), Transcription, Genetic, Gene Expression, Biochemistry, megakaryocyte, Mice, DNM3 promoter, Transcription (biology), GWAS, Platelet, Thrombopoiesis, Myeloid Ecotropic Viral Integration Site 1 Protein, Promoter Regions, Genetic, Cells, Cultured, Reverse Transcriptase Polymerase Chain Reaction, Hematology, Neoplasm Proteins, Haematopoiesis, Transcription Initiation Site, Megakaryocytes, platelet volume, DNM3, megakaryocytes, MEIS1, Blood Platelets, Chromatin Immunoprecipitation, Immunology, Biology, Polymorphism, Single Nucleotide, MEIS1 binding site, SDG 3 - Good Health and Well-being, Cell Line, Tumor, Animals, Humans, Cell Lineage, Binding site, Gene, Transcription factor, Homeodomain Proteins, Binding Sites, Genome, Human, Platelet Count, Hydrazones, Genetic Variation, Cell Biology, Sequence Analysis, DNA, Platelets and Thrombopoiesis, Molecular biology, Dynamin III
Abstract

We recently identified 68 genomic loci where common sequence variants are associated with platelet count and volume. Platelets are formed in the bone marrow by megakaryocytes, which are derived from hematopoietic stem cells by a process mainly controlled by transcription factors. The homeobox transcription factor MEIS1 is uniquely transcribed in megakaryocytes and not in the other lineage-committed blood cells. By ChIP-seq, we show that 5 of the 68 loci pinpoint a MEIS1 binding event within a group of 252 MK-overexpressed genes. In one such locus in DNM3, regulating platelet volume, the MEIS1 binding site falls within a region acting as an alternative promoter that is solely used in megakaryocytes, where allelic variation dictates different levels of a shorter transcript. The importance of dynamin activity to the latter stages of thrombopoiesis was confirmed by the observation that the inhibitor Dynasore reduced murine proplatelet for-mation in vitro.

Published
2013
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43. Investigating the effects of copy number variants on reading and language performance

Author

Gialluisi, A., Visconti, A., Willcutt, E.G., Smith, S.D., Pennington, B.F., Falchi, M., DeFries, J.C., Olson, R.K., Francks, C., Fisher, S.E., Gialluisi, A., Visconti, A., Willcutt, E.G., Smith, S.D., Pennington, B.F., Falchi, M., DeFries, J.C., Olson, R.K., Francks, C., and Fisher, S.E.

Abstract

Contains fulltext : 162007.pdf (publisher's version ) (Open Access)

Published
2016

44. y New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

Author

Lu, YC, Day, FR, Gustafsson, S, Buchkovich, ML, Na, JB, Bataille, V, Cousminer, DL, Dastani, Z, Drong, AW, Esko, T, Evans, DM, Falchi, M, Feitosa, MF, Ferreira, T, Hedman, AK, Haring, R, Hysi, PG, Iles, MM, Justice, AE, Kanoni, S, Lagou, V, Li, R, Li, X, Locke, A, Lu, C, Magi, R, Perry, JRB, Pers, TH, Qi, QB, Sanna, M, Schmidt, EM, Scott, WR, Shungin, D, Teumer, A, Vinkhuyzen, AAE, Walker, RW, Westra, HJ, Zhang, MF, Zhang, WH, Zhao, JH, Zhu, ZH, Afzal, U, Ahluwalia, TS, Bakker, SJL, Bellis, C, Bonnefond, A, Borodulin, K, Buchman, AS, Cederholm, T, Choh, AC, Choi, HJ, Curran, JE, de Groot, LCPGM (Lisette), De Jager, PL, Dhonukshe-Rutten, RAM, Enneman, Anke, Eury, E, Evans, DS, Forsen, T, Friedrich, N, Fumeron, F, Garcia, ME, Gartner, S, Han, BG, Havulinna, AS, Hayward, C, Hernandez, D, Hillege, H, Ittermann, T, Kent, JW, Kolcic, I, Laatikainen, T, Lahti, J, Leach, IM, Lee, CG, Lee, JY, Liu, T, Liu, YF, Lobbens, S, Loh, M, Lyytikainen, LP, Medina-Gomez, C, Michaelsson, K, Nalls, MA, Nielson, CM, Oozageer, L, Pascoe, L, Paternoster, L, Polasek, O, Ripatti, S, Sarzynski, MA, Shin, CS, Narancic, NS, Spira, D, Srikanth, P, Steinhagen-Thiessen, E, Sung, YJ, Swart, KMA, Taittonen, L, Tanaka, T, Tikkanen, E, van der Velde, Nathalie, Schoor, NM, Verweij, N (Niek), Wright, AF, Yu, L, Zmuda, JM, Eklund, N, Forrester, T, Grarup, N, Jackson, AU, Kristiansson, K, Kuulasmaa, T, Kuusisto, J, Lichtner, P, Luan, JA, Mahajan, A, Mannisto, S, Palmer, CD, Ried, JS, Scott, RA, Stancakova, A, Wagner, PJ, Demirkan, Ayse, Doring, A, Gudnason, V, Kiel, DP, Kuhnel, B, Mangino, M, McKnight, B, Menni, C, O'Connell, JR, Oostra, Ben, Shuldiner, AR, Song, KJ, Vandenput, L, Duijn, Cornelia, Vollenweider, P, White, CC, Boehnke, M, Boettcher, Y, Cooper, RS, Forouhi, NG, Gieger, C, Grallert, H, Hingorani, A, Jorgensen, T, Jousilahti, P, Kivimaki, M, Kumari, M, Laakso, M, Langenberg, C, Linneberg, A, Luke, A, McKenzie, CA, Palotie, A, Pedersen, O, Peters, A, Strauch, K, Tayo, BO, Wareham, NJ, Bennett, DA, Bertram, L, Blangero, J, Bluher, M, Bouchard, C, Campbell, H, Cho, NH, Cummings, SR, Czerwinski, SA, Demuth, I, Eckardt, R, Eriksson, JG, Ferrucci, L, Franco Duran, OH, Froguel, P, Gansevoort, RT, Hansen, T, Harris, TB, Hastie, N, Heliovaara, M, Hofman, Bert, Jordan, JM, Jula, A, Kahonen, M, Kajantie, E, Knekt, PB, Koskinen, S, Kovacs, P, Lehtimaki, T, Lind, L, Liu, YM, Orwoll, ES, Osmond, C, Perola, M, Perusse, L, Raitakari, OT, Rankinen, T, Rao, DC, Rice, TK, Rivadeneira, Fernando, Rudan, I, Salomaa, V, Sorensen, TIA, Stumvoll, M, Tonjes, A, Towne, B, Tranah, GJ, Tremblay, A, Uitterlinden, André, van der Harst, P, Vartiainen, E, Viikari, JS, Vitart, V, Vohl, MC, Volzke, H, Walker, M, Wallaschofski, H, Wild, S, Wilson, JF, Yengo, L, Bishop, DT, Borecki, IB, Chambers, JC, Cupples, LA, Dehghan, Abbas, Deloukas, P, Fatemifar, G, Fox, C, Furey, TS, Franke, L, Han, JL, Hunter, DJ, Karjalainen, J, Karpe, F, Kaplan, RC, Kooner, JS, McCarthy, MI, Murabito, JM, Morris, AP, Bishop, JAN, North, KE, Ohlsson, C, Ong, KK, Prokopenko, I, Richards, JB, Schadt, EE, Spector, TD, Widen, E, Willer, CJ, Yang, Jiaqi, Ingelsson, E, Mohlke, KL, Hirschhorn, JN, Pospisilik, JA, Zillikens, M.C., Lindgren, C, Kilpelainen, TO, Loos, RJF, Lu, YC, Day, FR, Gustafsson, S, Buchkovich, ML, Na, JB, Bataille, V, Cousminer, DL, Dastani, Z, Drong, AW, Esko, T, Evans, DM, Falchi, M, Feitosa, MF, Ferreira, T, Hedman, AK, Haring, R, Hysi, PG, Iles, MM, Justice, AE, Kanoni, S, Lagou, V, Li, R, Li, X, Locke, A, Lu, C, Magi, R, Perry, JRB, Pers, TH, Qi, QB, Sanna, M, Schmidt, EM, Scott, WR, Shungin, D, Teumer, A, Vinkhuyzen, AAE, Walker, RW, Westra, HJ, Zhang, MF, Zhang, WH, Zhao, JH, Zhu, ZH, Afzal, U, Ahluwalia, TS, Bakker, SJL, Bellis, C, Bonnefond, A, Borodulin, K, Buchman, AS, Cederholm, T, Choh, AC, Choi, HJ, Curran, JE, de Groot, LCPGM (Lisette), De Jager, PL, Dhonukshe-Rutten, RAM, Enneman, Anke, Eury, E, Evans, DS, Forsen, T, Friedrich, N, Fumeron, F, Garcia, ME, Gartner, S, Han, BG, Havulinna, AS, Hayward, C, Hernandez, D, Hillege, H, Ittermann, T, Kent, JW, Kolcic, I, Laatikainen, T, Lahti, J, Leach, IM, Lee, CG, Lee, JY, Liu, T, Liu, YF, Lobbens, S, Loh, M, Lyytikainen, LP, Medina-Gomez, C, Michaelsson, K, Nalls, MA, Nielson, CM, Oozageer, L, Pascoe, L, Paternoster, L, Polasek, O, Ripatti, S, Sarzynski, MA, Shin, CS, Narancic, NS, Spira, D, Srikanth, P, Steinhagen-Thiessen, E, Sung, YJ, Swart, KMA, Taittonen, L, Tanaka, T, Tikkanen, E, van der Velde, Nathalie, Schoor, NM, Verweij, N (Niek), Wright, AF, Yu, L, Zmuda, JM, Eklund, N, Forrester, T, Grarup, N, Jackson, AU, Kristiansson, K, Kuulasmaa, T, Kuusisto, J, Lichtner, P, Luan, JA, Mahajan, A, Mannisto, S, Palmer, CD, Ried, JS, Scott, RA, Stancakova, A, Wagner, PJ, Demirkan, Ayse, Doring, A, Gudnason, V, Kiel, DP, Kuhnel, B, Mangino, M, McKnight, B, Menni, C, O'Connell, JR, Oostra, Ben, Shuldiner, AR, Song, KJ, Vandenput, L, Duijn, Cornelia, Vollenweider, P, White, CC, Boehnke, M, Boettcher, Y, Cooper, RS, Forouhi, NG, Gieger, C, Grallert, H, Hingorani, A, Jorgensen, T, Jousilahti, P, Kivimaki, M, Kumari, M, Laakso, M, Langenberg, C, Linneberg, A, Luke, A, McKenzie, CA, Palotie, A, Pedersen, O, Peters, A, Strauch, K, Tayo, BO, Wareham, NJ, Bennett, DA, Bertram, L, Blangero, J, Bluher, M, Bouchard, C, Campbell, H, Cho, NH, Cummings, SR, Czerwinski, SA, Demuth, I, Eckardt, R, Eriksson, JG, Ferrucci, L, Franco Duran, OH, Froguel, P, Gansevoort, RT, Hansen, T, Harris, TB, Hastie, N, Heliovaara, M, Hofman, Bert, Jordan, JM, Jula, A, Kahonen, M, Kajantie, E, Knekt, PB, Koskinen, S, Kovacs, P, Lehtimaki, T, Lind, L, Liu, YM, Orwoll, ES, Osmond, C, Perola, M, Perusse, L, Raitakari, OT, Rankinen, T, Rao, DC, Rice, TK, Rivadeneira, Fernando, Rudan, I, Salomaa, V, Sorensen, TIA, Stumvoll, M, Tonjes, A, Towne, B, Tranah, GJ, Tremblay, A, Uitterlinden, André, van der Harst, P, Vartiainen, E, Viikari, JS, Vitart, V, Vohl, MC, Volzke, H, Walker, M, Wallaschofski, H, Wild, S, Wilson, JF, Yengo, L, Bishop, DT, Borecki, IB, Chambers, JC, Cupples, LA, Dehghan, Abbas, Deloukas, P, Fatemifar, G, Fox, C, Furey, TS, Franke, L, Han, JL, Hunter, DJ, Karjalainen, J, Karpe, F, Kaplan, RC, Kooner, JS, McCarthy, MI, Murabito, JM, Morris, AP, Bishop, JAN, North, KE, Ohlsson, C, Ong, KK, Prokopenko, I, Richards, JB, Schadt, EE, Spector, TD, Widen, E, Willer, CJ, Yang, Jiaqi, Ingelsson, E, Mohlke, KL, Hirschhorn, JN, Pospisilik, JA, Zillikens, M.C., Lindgren, C, Kilpelainen, TO, and Loos, RJF

Abstract

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P < 5 x 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.

Published
2016

46. Low-frequency variants in HMGA1 are not associated with type 2 diabetes risk

Author

Marquez, M, Huyvaert, M, Perry, JRB, Pearson, RD, Falchi, M, Morris, AP, Vivequin, S, Lobbens, S, Yengo, L, Gaget, S, Pattou, F, Poulain-Godefroy, O, Charpentier, G, Carlsson, LMS, Jacobson, P, Sjöström, L, Lantieri, O, Heude, B, Walley, A, Balkau, B, Marre, M, Froguel, P, Cauchi, S, and DIAGRAM Consortium

Abstract

It has recently been suggested that the low-frequency c.136-14_136-13insC variant in high-mobility group A1 (HMGA1) may strongly contribute to insulin resistance and type 2 diabetes risk. In our study, we attempted to confirm that HMGA1 is a novel type 2 diabetes locus in French Caucasians. The gene was sequenced in 368 type 2 diabetic case subjects with a family history of type 2 diabetes and 372 normoglycemic control subjects without a family history of type 2 diabetes. None of the 41 genetic variations identified were associated with type 2 diabetes. The lack of association between the c.136-14_136-13insC variant and type 2 diabetes was confirmed in an independent French group of 4,538 case subjects and 4,015 control subjects and in a large meta-analysis of 16,605 case subjects and 46,179 control subjects. Finally, this variant had no effects on metabolic traits and was not involved in variations of HMGA1 and insulin receptor (INSR) expressions. The c.136-14_136-13insC variant was not associated with type 2 diabetes in individuals of European descent. Our study emphasizes the need to analyze a large number of subjects to reliably assess the association of low-frequency variants with the disease.

Published
2012

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