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1. A de novo paradigm for male infertility

Author

Oud, M. S., Smits, R. M., Smith, H. E., Mastrorosa, F. K., Holt, G. S., Houston, B. J., de Vries, P. F., Alobaidi, B. K. S., Batty, L. E., Ismail, H., Greenwood, J., Sheth, H., Mikulasova, A., Astuti, G. D. N., Gilissen, C., McEleny, K., Turner, H., Coxhead, J., Cockell, S., Braat, D. D. M., Fleischer, K., D’Hauwers, K. W. M., Schaafsma, E., Nagirnaja, L., Conrad, D. F., Friedrich, C., Kliesch, S., Aston, K. I., Riera-Escamilla, A., Krausz, C., Gonzaga-Jauregui, C., Santibanez-Koref, M., Elliott, D. J., Vissers, L. E. L. M., Tüttelmann, F., O’Bryan, M. K., Ramos, L., Xavier, M. J., van der Heijden, G. W., and Veltman, J. A.

Published
2022
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2. Corrigendum to: “Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort☆” [J Hepatol (2020) 505–515, (S0168827820302130), (10.1016/j.jhep.2020.04.003)]

Author

Anstee Q. M., Anstee, Q, Darlay, R, Cockell, S, Meroni, M, Govaere, O, Tiniakos, D, Burt, A, Bedossa, P, Palmer, J, Liu, Y, Aithal, G, Allison, M, Yki-Jarvinen, H, Vacca, M, Dufour, J, Invernizzi, P, Prati, D, Ekstedt, M, Kechagias, S, Francque, S, Petta, S, Bugianesi, E, Clement, K, Ratziu, V, Schattenberg, J, Valenti, L, Day, C, Cordell, H, Daly, A, Anstee Q. M., Darlay R., Cockell S., Meroni M., Govaere O., Tiniakos D., Burt A. D., Bedossa P., Palmer J., Liu Y. -L., Aithal G. P., Allison M., Yki-Jarvinen H., Vacca M., Dufour J. -F., Invernizzi P., Prati D., Ekstedt M., Kechagias S., Francque S., Petta S., Bugianesi E., Clement K., Ratziu V., Schattenberg J. M., Valenti L., Day C. P., Cordell H. J., Daly A. K., Anstee Q. M., Anstee, Q, Darlay, R, Cockell, S, Meroni, M, Govaere, O, Tiniakos, D, Burt, A, Bedossa, P, Palmer, J, Liu, Y, Aithal, G, Allison, M, Yki-Jarvinen, H, Vacca, M, Dufour, J, Invernizzi, P, Prati, D, Ekstedt, M, Kechagias, S, Francque, S, Petta, S, Bugianesi, E, Clement, K, Ratziu, V, Schattenberg, J, Valenti, L, Day, C, Cordell, H, Daly, A, Anstee Q. M., Darlay R., Cockell S., Meroni M., Govaere O., Tiniakos D., Burt A. D., Bedossa P., Palmer J., Liu Y. -L., Aithal G. P., Allison M., Yki-Jarvinen H., Vacca M., Dufour J. -F., Invernizzi P., Prati D., Ekstedt M., Kechagias S., Francque S., Petta S., Bugianesi E., Clement K., Ratziu V., Schattenberg J. M., Valenti L., Day C. P., Cordell H. J., and Daly A. K.

Abstract

In this article we used data from the Understanding Society study as part of our control group. While we did explain that the data was provided by Understanding Society in the paper, we did not include the statement they required for use of these data which is the following: “Understanding Society: The UK Household Longitudinal Study is led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council. The survey was conducted by NatCen and the genome-wide scan data were analysed and deposited by the Wellcome Trust Sanger Institute. Information on how to access the data can be found on the Understanding Society website https://www.understandingsociety.ac.uk/.” We apologise for any inconvenience caused.

Published
2023

3. Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD : an individual patient data meta-analysis

Author

Mozes, F. E., Lee, J. A., Selvaraj, E. A., Jayaswal, A. N. A., Trauner, M., Boursier, J., Fournier, C., Staufer, K., Stauber, R. E., Bugianesi, E., Younes, R., Gaia, S., Lupsor-Platon, M., Petta, S., Shima, T., Okanoue, T., Mahadeva, S., Chan, W. -K., Eddowes, P. J., Newsome, P. N., Wong, V. W. -S., de Ledinghen, V., Fan, J., Shen, F., Cobbold, J. F., Sumida, Y., Okajima, A., Schattenberg, J. M., Labenz, C., Kim, W., Lee, M. S., Wiegand, J., Karlas, T., Yilmaz, Y., Aithal, G. P., Palaniyappan, N., Cassinotto, C., Aggarwal, S., Garg, H., Ooi, G. J., Nakajima, A., Yoneda, M., Ziol, M., Barget, N., Geier, A., Tuthill, T., Brosnan, M. J., Anstee, Q. M., Neubauer, S., Harrison, S. A., Bossuyt, P. M., Pavlides, M., Anstee, Q., Daly, A., Johnson, K., Govaere, O., Cockell, S., Tiniakos, D., Bedossa, P., Oakley, F., Cordell, H., Day, C., Wonders, K., Bossuyt, P., Zafarmand, H., Vali, Y., Lee, J., Ratziu, V., Clement, K., Pais, R., Schuppan, D., Schattenberg, J., Vidal-Puig, T., Vacca, M., Rodrigues-Cuenca, S., Allison, M., Kamzolas, I., Petsalaki, E., Oresic, M., Hyotylainen, T., Mcglinchey, A., Mato, J. M., Millet, O., Dufour, J. -F., Berzigotti, A., Harrison, S., Cobbold, J., Mozes, F., Akhtar, S., Banerjee, R., Kelly, M., Shumbayawonda, E., Dennis, A., Erpicum, C., Graham, M., Romero-Gomez, M., Gomez-Gonzalez, E., Ampuero, J., Castell, J., Gallego-Duran, R., Fernandez, I., Montero-Vallejo, R., Karsdal, M., Erhardtsen, E., Rasmussen, D., Leeming, D. J., Fisker, M. J., Sinisi, A., Musa, K., Betsou, F., Sandt, E., Tonini, M., Rosso, C., Armandi, A., Marra, F., Gastaldelli, A., Svegliati, G., Francque, S., Vonghia, L., Ekstedt, M., Kechagias, S., Yki-Jarvinen, H., Porthan, K., van Mil, S., Papatheodoridis, G., Cortez-Pinto, H., Valenti, L., Miele, L., Trautwein, C., Aithal, G., Hockings, P., Newsome, P., Wenn, D., Rodrigues, C. M. P., Chaumat, P., Hanf, R., Trylesinski, A., Ortiz, P., Duffin, K., Brosnan, J., Mcleod, E., Ertle, J., Ostroff, R., Alexander, L., Kjaer, M. S., Mikkelsen, L. F., Balp, M. -M., Brass, C., Jennings, L., Martic, M., Loeffler, J., Hanauer, G., Shankar, S., Pepin, K., Ehman, R., Myers, J., Ho, G., Torstenson, R., Myers, R., Doward, L., LITMUS Investigators, University of Denver, Medizinische Universität Wien = Medical University of Vienna, Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), SUACI Alpes du Nord, Medical University Graz, Mozes, Ferenc Emil, Lee, Jenny A., Selvaraj, Emmanuel Anandraj, Jayaswal, Arjun Narayan Ajmer, Trauner, Michael, Boursier, Jerome, Fournier, Celine, Staufer, Katharina, Stauber, Rudolf E., Bugianesi, Elisabetta, Younes, Ramy, Gaia, Silvia, Lupsor-Platon, Monica, Petta, Salvatore, Shima, Toshihide, Okanoue, Takeshi, Mahadeva, Sanjiv, Chan, Wah-Kheong, Eddowes, Peter J., Hirschfield, Gideon M., Newsome, Philip Noel, Wong, Vincent Wai-Sun, de Ledinghen, Victor, Fan, Jiangao, Shen, Feng, Cobbold, Jeremy F., Sumida, Yoshio, Okajima, Akira, Schattenberg, Joern M., Labenz, Christian, Kim, Won, Lee, Myoung Seok, Wiegand, Johannes, Karlas, Thomas, Yilmaz, Yusuf, Aithal, Guruprasad Padur, Palaniyappan, Naaventhan, Cassinotto, Christophe, Aggarwal, Sandeep, Garg, Harshit, Ooi, Geraldine J., Nakajima, Atsushi, Yoneda, Masato, Ziol, Marianne, Barget, Nathalie, Geier, Andreas, Tuthill, Theresa, Brosnan, M. Julia, Anstee, Quentin Mark, Neubauer, Stefan, Harrison, Stephen A., Bossuyt, Patrick M., Pavlides, Michael, Epidemiology and Data Science, APH - Methodology, APH - Personalized Medicine, ACS - Atherosclerosis & ischemic syndromes, APH - Aging & Later Life, ARD - Amsterdam Reproduction and Development, Graduate School, Mozes F.E., Lee J.A., Selvaraj E.A., Jayaswal A.N.A., Trauner M., Boursier J., Fournier C., Staufer K., Stauber R.E., Bugianesi E., Younes R., Gaia S., Lupsor-Platon M., Petta S., Shima T., Okanoue T., Mahadeva S., Chan W.-K., Eddowes P.J., Newsome P.N., Wong V.W.-S., de Ledinghen V., Fan J., Shen F., Cobbold J.F., Sumida Y., Okajima A., Schattenberg J.M., Labenz C., Kim W., Lee M.S., Wiegand J., Karlas T., Yilmaz Y., Aithal G.P., Palaniyappan N., Cassinotto C., Aggarwal S., Garg H., Ooi G.J., Nakajima A., Yoneda M., Ziol M., Barget N., Geier A., Tuthill T., Brosnan M.J., Anstee Q.M., Neubauer S., Harrison S.A., Bossuyt P.M., Pavlides M., Anstee Q., Daly A., Johnson K., Govaere O., Cockell S., Tiniakos D., Bedossa P., Oakley F., Cordell H., Day C., Wonders K., Bossuyt P., Zafarmand H., Vali Y., Lee J., Ratziu V., Clement K., Pais R., Schuppan D., Schattenberg J., Vidal-Puig T., Vacca M., Rodrigues-Cuenca S., Allison M., Kamzolas I., Petsalaki E., Oresic M., Hyotylainen T., McGlinchey A., Mato J.M., Millet O., Dufour J.-F., Berzigotti A., Harrison S., Cobbold J., Mozes F., Akhtar S., Banerjee R., Kelly M., Shumbayawonda E., Dennis A., Erpicum C., Graham M., Romero-Gomez M., Gomez-Gonzalez E., Ampuero J., Castell J., Gallego-Duran R., Fernandez I., Montero-Vallejo R., Karsdal M., Erhardtsen E., Rasmussen D., Leeming D.J., Fisker M.J., Sinisi A., Musa K., Betsou F., Sandt E., Tonini M., Rosso C., Armandi A., Marra F., Gastaldelli A., Svegliati G., Francque S., Vonghia L., Ekstedt M., Kechagias S., Yki-Jarvinen H., Porthan K., van Mil S., Papatheodoridis G., Cortez-Pinto H., Valenti L., Miele L., Trautwein C., Aithal G., Hockings P., Newsome P., Wenn D., Rodrigues C.M.P., Chaumat P., Hanf R., Trylesinski A., Ortiz P., Duffin K., Brosnan J., McLeod E., Ertle J., Ostroff R., Alexander L., Kjaer M.S., Mikkelsen L.F., Balp M.-M., Brass C., Jennings L., Martic M., Loeffler J., Hanauer G., Shankar S., Pepin K., Ehman R., Myers J., Ho G., Torstenson R., Myers R., and Doward L.

Subjects
Liver Cirrhosis, Male, Cirrhosis, LIVER STIFFNESS MEASUREMENT, Biopsy, [SDV]Life Sciences [q-bio], biostatistics, Gastroenterology, DISEASE, clinical decision making, fatty liver, hepatic fibrosis, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Fibrosis, 2. Zero hunger, 0303 health sciences, medicine.diagnostic_test, NONALCOHOLIC STEATOHEPATITIS, TRANSIENT ELASTOGRAPHY, Fatty liver, CHRONIC HEPATITIS, Middle Aged, 3. Good health, Settore AGR/03 - Arboricoltura Generale E Coltivazioni Arboree, Liver, Liver biopsy, BIOPSY, Elasticity Imaging Techniques, Female, 030211 gastroenterology & hepatology, Median body, medicine.medical_specialty, CONTROLLED ATTENUATION PARAMETER, 610 Medicine & health, 03 medical and health sciences, Internal medicine, SCORE, medicine, Humans, biostatistics, clinical decision making, fatty liver, hepatic fibrosis, 030304 developmental biology, Receiver operating characteristic, business.industry, medicine.disease, Diabetes Mellitus, Type 2, XL PROBE, business, Hepatic fibrosis, Transient elastography, Biomarkers, PROSPECTIVE DERIVATION
Abstract

ObjectiveLiver biopsy is still needed for fibrosis staging in many patients with non-alcoholic fatty liver disease. The aims of this study were to evaluate the individual diagnostic performance of liver stiffness measurement by vibration controlled transient elastography (LSM-VCTE), Fibrosis-4 Index (FIB-4) and NAFLD (non-alcoholic fatty liver disease) Fibrosis Score (NFS) and to derive diagnostic strategies that could reduce the need for liver biopsies.DesignIndividual patient data meta-analysis of studies evaluating LSM-VCTE against liver histology was conducted. FIB-4 and NFS were computed where possible. Sensitivity, specificity and area under the receiver operating curve (AUROC) were calculated. Biomarkers were assessed individually and in sequential combinations.ResultsData were included from 37 primary studies (n=5735; 45% women; median age: 54 years; median body mass index: 30 kg/m2; 33% had type 2 diabetes; 30% had advanced fibrosis). AUROCs of individual LSM-VCTE, FIB-4 and NFS for advanced fibrosis were 0.85, 0.76 and 0.73. Sequential combination of FIB-4 cut-offs (ConclusionSequential combinations of markers with a lower cut-off to rule-out advanced fibrosis and a higher cut-off to rule-in cirrhosis can reduce the need for liver biopsies.

Published
2022

4. Corrigendum to: “Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort”☆ (J Hepatol [2020] 505–515) (Journal of Hepatology (2020) 73(3) (505–515), (S0168827820302130), (10.1016/j.jhep.2020.04.003))

Author

Anstee Q. M., Anstee, Q, Darlay, R, Cockell, S, Meroni, M, Govaere, O, Tiniakos, D, Burt, A, Bedossa, P, Palmer, J, Liu, Y, Aithal, G, Allison, M, Yki-Jarvinen, H, Vacca, M, Dufour, J, Invernizzi, P, Prati, D, Ekstedt, M, Kechagias, S, Francque, S, Petta, S, Bugianesi, E, Clement, K, Ratziu, V, Schattenberg, J, Valenti, L, Day, C, Cordell, H, Daly, A, Anstee Q. M., Darlay R., Cockell S., Meroni M., Govaere O., Tiniakos D., Burt A. D., Bedossa P., Palmer J., Liu Y. -L., Aithal G. P., Allison M., Yki-Jarvinen H., Vacca M., Dufour J. -F., Invernizzi P., Prati D., Ekstedt M., Kechagias S., Francque S., Petta S., Bugianesi E., Clement K., Ratziu V., Schattenberg J. M., Valenti L., Day C. P., Cordell H. J., Daly A. K., Anstee Q. M., Anstee, Q, Darlay, R, Cockell, S, Meroni, M, Govaere, O, Tiniakos, D, Burt, A, Bedossa, P, Palmer, J, Liu, Y, Aithal, G, Allison, M, Yki-Jarvinen, H, Vacca, M, Dufour, J, Invernizzi, P, Prati, D, Ekstedt, M, Kechagias, S, Francque, S, Petta, S, Bugianesi, E, Clement, K, Ratziu, V, Schattenberg, J, Valenti, L, Day, C, Cordell, H, Daly, A, Anstee Q. M., Darlay R., Cockell S., Meroni M., Govaere O., Tiniakos D., Burt A. D., Bedossa P., Palmer J., Liu Y. -L., Aithal G. P., Allison M., Yki-Jarvinen H., Vacca M., Dufour J. -F., Invernizzi P., Prati D., Ekstedt M., Kechagias S., Francque S., Petta S., Bugianesi E., Clement K., Ratziu V., Schattenberg J. M., Valenti L., Day C. P., Cordell H. J., and Daly A. K.

Abstract

It has come to our attention that there is a typographical error in Table 5 of our manuscript. In line 6 of column 2, “rs11852624” should read "rs11858624”. We apologise for any inconvenience caused.

Published
2021

6. Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort☆

Author

Anstee, Q, Darlay, R, Cockell, S, Meroni, M, Govaere, O, Tiniakos, D, Burt, A, Bedossa, P, Palmer, J, Liu, Y, Aithal, G, Allison, M, Yki-Jarvinen, H, Vacca, M, Dufour, J, Invernizzi, P, Prati, D, Ekstedt, M, Kechagias, S, Francque, S, Petta, S, Bugianesi, E, Clement, K, Ratziu, V, Schattenberg, J, Valenti, L, Day, C, Cordell, H, Daly, A, Anstee Q. M., Darlay R., Cockell S., Meroni M., Govaere O., Tiniakos D., Burt A. D., Bedossa P., Palmer J., Liu Y. -L., Aithal G. P., Allison M., Yki-Jarvinen H., Vacca M., Dufour J. -F., Invernizzi P., Prati D., Ekstedt M., Kechagias S., Francque S., Petta S., Bugianesi E., Clement K., Ratziu V., Schattenberg J. M., Valenti L., Day C. P., Cordell H. J., Daly A. K., Anstee, Q, Darlay, R, Cockell, S, Meroni, M, Govaere, O, Tiniakos, D, Burt, A, Bedossa, P, Palmer, J, Liu, Y, Aithal, G, Allison, M, Yki-Jarvinen, H, Vacca, M, Dufour, J, Invernizzi, P, Prati, D, Ekstedt, M, Kechagias, S, Francque, S, Petta, S, Bugianesi, E, Clement, K, Ratziu, V, Schattenberg, J, Valenti, L, Day, C, Cordell, H, Daly, A, Anstee Q. M., Darlay R., Cockell S., Meroni M., Govaere O., Tiniakos D., Burt A. D., Bedossa P., Palmer J., Liu Y. -L., Aithal G. P., Allison M., Yki-Jarvinen H., Vacca M., Dufour J. -F., Invernizzi P., Prati D., Ekstedt M., Kechagias S., Francque S., Petta S., Bugianesi E., Clement K., Ratziu V., Schattenberg J. M., Valenti L., Day C. P., Cordell H. J., and Daly A. K.

Abstract

Background & Aims: Genetic factors associated with non-alcoholic fatty liver disease (NAFLD) remain incompletely understood. To date, most genome-wide association studies (GWASs) have adopted radiologically assessed hepatic triglyceride content as the reference phenotype and so cannot address steatohepatitis or fibrosis. We describe a GWAS encompassing the full spectrum of histologically characterised NAFLD. Methods: The GWAS involved 1,483 European NAFLD cases and 17,781 genetically matched controls. A replication cohort of 559 NAFLD cases and 945 controls was genotyped to confirm signals showing genome-wide or close to genome-wide significance. Results: Case-control analysis identified signals showing p values ≤5 × 10−8 at 4 locations (chromosome [chr] 2 GCKR/C2ORF16; chr4 HSD17B13; chr19 TM6SF2; chr22 PNPLA3) together with 2 other signals with p <1 × 10−7 (chr1 near LEPR and chr8 near IDO2/TC1). Case-only analysis of quantitative traits showed that the PNPLA3 signal (rs738409) had genome-wide significance for steatosis, fibrosis and NAFLD activity score and a new signal (PYGO1 rs62021874) had close to genome-wide significance for steatosis (p = 8.2 × 10−8). Subgroup case-control analysis for NASH confirmed the PNPLA3 signal. The chr1 LEPR single nucleotide polymorphism also showed genome-wide significance for this phenotype. Considering the subgroup with advanced fibrosis (≥F3), the signals on chr2, chr19 and chr22 maintained their genome-wide significance. Except for GCKR/C2ORF16, the genome-wide significance signals were replicated. Conclusions: This study confirms PNPLA3 as a risk factor for the full histological spectrum of NAFLD at genome-wide significance levels, with important contributions from TM6SF2 and HSD17B13. PYGO1 is a novel steatosis modifier, suggesting that Wnt signalling pathways may be relevant in NAFLD pathogenesis. Lay summary: Non-alcoholic fatty liver disease is a common disease where excessive fat accumulates in the liver and may r

Published
2020

7. A de novo paradigm for male infertility

Author

Oud, M.S., Smits, R.M., Smith, H.E., Mastrorosa, F.K., Holt, G.S., Houston, B.J., Vries, P.F. de, Alobaidi, B.K.S., Batty, L.E., Ismail, H., Greenwood, J., Sheth, H., Mikulasova, A., Astuti, G.D.N, Gilissen, C., McEleny, K., Turner, H., Coxhead, J., Cockell, S., Braat, D.D.M., Fleischer, K., D'Hauwers, K.W.M., Schaafsma, E., Nagirnaja, L., Conrad, D.F., Friedrich, C., Kliesch, S., Aston, K.I., Riera-Escamilla, A., Krausz, C., Gonzaga-Jauregui, C., Santibanez-Koref, M., Elliott, D.J., Vissers, L.E.L.M., Tüttelmann, F., O'Bryan, M.K., Ramos, L., Xavier, M.J., Heijden, G.W. van der, Veltman, J.A., Oud, M.S., Smits, R.M., Smith, H.E., Mastrorosa, F.K., Holt, G.S., Houston, B.J., Vries, P.F. de, Alobaidi, B.K.S., Batty, L.E., Ismail, H., Greenwood, J., Sheth, H., Mikulasova, A., Astuti, G.D.N, Gilissen, C., McEleny, K., Turner, H., Coxhead, J., Cockell, S., Braat, D.D.M., Fleischer, K., D'Hauwers, K.W.M., Schaafsma, E., Nagirnaja, L., Conrad, D.F., Friedrich, C., Kliesch, S., Aston, K.I., Riera-Escamilla, A., Krausz, C., Gonzaga-Jauregui, C., Santibanez-Koref, M., Elliott, D.J., Vissers, L.E.L.M., Tüttelmann, F., O'Bryan, M.K., Ramos, L., Xavier, M.J., Heijden, G.W. van der, and Veltman, J.A.

Abstract

Item does not contain fulltext, De novo mutations are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that de novo mutations play an important role in severe male infertility and explain a portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome sequencing in a cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare (MAF < 0.1%) protein-altering de novo mutations are classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of loss-of-function de novo mutations in loss-of-function-intolerant genes (p-value = 1.00 × 10(-5)) in infertile men compared to controls. Additionally, we detected a significant increase in predicted pathogenic de novo missense mutations affecting missense-intolerant genes (p-value = 5.01 × 10(-4)) in contrast to predicted benign de novo mutations. One gene we identify, RBM5, is an essential regulator of male germ cell pre-mRNA splicing and has been previously implicated in male infertility in mice. In a follow-up study, 6 rare pathogenic missense mutations affecting this gene are observed in a cohort of 2,506 infertile patients, whilst we find no such mutations in a cohort of 5,784 fertile men (p-value = 0.03). Our results provide evidence for the role of de novo mutations in severe male infertility and point to new candidate genes affecting fertility.

Published
2022

8. A de novo paradigm for male infertility

Author

Oud, MS, Smits, RM, Smith, HE, Mastrorosa, FK, Holt, GS, Houston, BJ, de Vries, PF, Alobaidi, BKS, Batty, LE, Ismail, H, Greenwood, J, Sheth, H, Mikulasova, A, Astuti, GDN, Gilissen, C, McEleny, K, Turner, H, Coxhead, J, Cockell, S, Braat, DDM, Fleischer, K, D'Hauwers, KWM, Schaafsma, E, Nagirnaja, L, Conrad, DF, Friedrich, C, Kliesch, S, Aston, KI, Riera-Escamilla, A, Krausz, C, Gonzaga-Jauregui, C, Santibanez-Koref, M, Elliott, DJ, Vissers, LELM, Tuettelmann, F, O'Bryan, MK, Ramos, L, Xavier, MJ, van der Heijden, GW, Veltman, JA, Oud, MS, Smits, RM, Smith, HE, Mastrorosa, FK, Holt, GS, Houston, BJ, de Vries, PF, Alobaidi, BKS, Batty, LE, Ismail, H, Greenwood, J, Sheth, H, Mikulasova, A, Astuti, GDN, Gilissen, C, McEleny, K, Turner, H, Coxhead, J, Cockell, S, Braat, DDM, Fleischer, K, D'Hauwers, KWM, Schaafsma, E, Nagirnaja, L, Conrad, DF, Friedrich, C, Kliesch, S, Aston, KI, Riera-Escamilla, A, Krausz, C, Gonzaga-Jauregui, C, Santibanez-Koref, M, Elliott, DJ, Vissers, LELM, Tuettelmann, F, O'Bryan, MK, Ramos, L, Xavier, MJ, van der Heijden, GW, and Veltman, JA

Abstract

De novo mutations are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that de novo mutations play an important role in severe male infertility and explain a portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome sequencing in a cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare (MAF < 0.1%) protein-altering de novo mutations are classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of loss-of-function de novo mutations in loss-of-function-intolerant genes (p-value = 1.00 × 10-5) in infertile men compared to controls. Additionally, we detected a significant increase in predicted pathogenic de novo missense mutations affecting missense-intolerant genes (p-value = 5.01 × 10-4) in contrast to predicted benign de novo mutations. One gene we identify, RBM5, is an essential regulator of male germ cell pre-mRNA splicing and has been previously implicated in male infertility in mice. In a follow-up study, 6 rare pathogenic missense mutations affecting this gene are observed in a cohort of 2,506 infertile patients, whilst we find no such mutations in a cohort of 5,784 fertile men (p-value = 0.03). Our results provide evidence for the role of de novo mutations in severe male infertility and point to new candidate genes affecting fertility.

Published
2022

10. Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD: An individual patient data meta-analysis

Author

Mózes, F.E. Lee, J.A. Selvaraj, E.A. Jayaswal, A.N.A. Trauner, M. Boursier, J. Fournier, C. Staufer, K. Stauber, R.E. Bugianesi, E. Younes, R. Gaia, S. Lupșor-Platon, M. Petta, S. Shima, T. Okanoue, T. Mahadeva, S. Chan, W.-K. Eddowes, P.J. Newsome, P.N. Wong, V.W.-S. de Ledinghen, V. Fan, J. Shen, F. Cobbold, J.F. Sumida, Y. Okajima, A. Schattenberg, J.M. Labenz, C. Kim, W. Lee, M.S. Wiegand, J. Karlas, T. Yılmaz, Y. Aithal, G.P. Palaniyappan, N. Cassinotto, C. Aggarwal, S. Garg, H. Ooi, G.J. Nakajima, A. Yoneda, M. Ziol, M. Barget, N. Geier, A. Tuthill, T. Brosnan, M.J. Anstee, Q.M. Neubauer, S. Harrison, S.A. Bossuyt, P.M. Pavlides, M. Anstee, Q. Daly, A. Johnson, K. Govaere, O. Cockell, S. Tiniakos, D. Bedossa, P. Oakley, F. Cordell, H. Day, C. Wonders, K. Bossuyt, P. Zafarmand, H. Vali, Y. Lee, J. Ratziu, V. Clement, K. Pais, R. Schuppan, D. Schattenberg, J. Schuppan, D. Schattenberg, J. Vidal-Puig, T. Vacca, M. Rodrigues-Cuenca, S. Allison, M. Kamzolas, I. Petsalaki, E. Oresic, M. Hyötyläinen, T. McGlinchey, A. Mato, J.M. Millet, O. Dufour, J.-F. Berzigotti, A. Pavlides, M. Harrison, S. Neubauer, S. Cobbold, J. Mozes, F. Akhtar, S. Banerjee, R. Kelly, M. Shumbayawonda, E. Dennis, A. Erpicum, C. Graham, M. Romero-Gómez, M. Gómez-González, E. Ampuero, J. Castell, J. Gallego-Durán, R. Fernández, I. Montero-Vallejo, R. Karsdal, M. Erhardtsen, E. Rasmussen, D. Leeming, D.J. Fisker, M.J. Sinisi, A. Musa, K. Betsou, F. Sandt, E. Tonini, M. Bugianesi, E. Rosso, C. Armandi, A. Marra, F. Gastaldelli, A. Svegliati, G. Boursier, J. Francque, S. Vonghia, L. Ekstedt, M. Kechagias, S. Yki-Jarvinen, H. Porthan, K. van Mil, S. Papatheodoridis, G. Cortez-Pinto, H. Valenti, L. Petta, S. Miele, L. Geier, A. Trautwein, C. Aithal, G. Hockings, P. Newsome, P. Wenn, D. Rodrigues, C.M.P. Chaumat, P. Hanf, R. Trylesinski, A. Ortiz, P. Duffin, K. Brosnan, J. Tuthill, T. McLeod, E. Ertle, J. Younes, R. Ostroff, R. Alexander, L. Kjær, M.S. Mikkelsen, L.F. Balp, M.-M. Brass, C. Jennings, L. Martic, M. Loeffler, J. Hanauer, G. Shankar, S. Fournier, C. Pepin, K. Ehman, R. Myers, J. Ho, G. Torstenson, R. Myers, R. Doward, L. LITMUS Investigators

Abstract

Objective Liver biopsy is still needed for fibrosis staging in many patients with non-alcoholic fatty liver disease. The aims of this study were to evaluate the individual diagnostic performance of liver stiffness measurement by vibration controlled transient elastography (LSM-VCTE), Fibrosis-4 Index (FIB-4) and NAFLD (non-alcoholic fatty liver disease) Fibrosis Score (NFS) and to derive diagnostic strategies that could reduce the need for liver biopsies. Design Individual patient data meta-analysis of studies evaluating LSM-VCTE against liver histology was conducted. FIB-4 and NFS were computed where possible. Sensitivity, specificity and area under the receiver operating curve (AUROC) were calculated. Biomarkers were assessed individually and in sequential combinations. Results Data were included from 37 primary studies (n=5735; 45% women; median age: 54 years; median body mass index: 30 kg/m2; 33% had type 2 diabetes; 30% had advanced fibrosis). AUROCs of individual LSM-VCTE, FIB-4 and NFS for advanced fibrosis were 0.85, 0.76 and 0.73. Sequential combination of FIB-4 cut-offs (

Published
2021

11. Diagnostic accuracy of elastography and magnetic resonance imaging in patients with NAFLD: A systematic review and meta-analysis

Author

Selvaraj, E.A. Mózes, F.E. Jayaswal, A.N.A. Zafarmand, M.H. Vali, Y. Lee, J.A. Levick, C.K. Young, L.A.J. Palaniyappan, N. Liu, C.-H. Aithal, G.P. Romero-Gómez, M. Brosnan, M.J. Tuthill, T.A. Anstee, Q.M. Neubauer, S. Harrison, S.A. Bossuyt, P.M. Pavlides, M. Daly, A. Johnson, K. Govaere, O. Cockell, S. Tiniakos, D. Bedossa, P. Oakley, F. Cordell, H. Day, C. Wonders, K. Bossuyt, P. Zafarmand, H. Lee, J. Ratziu, V. Clement, K. Pais, R. Schuppan, D. Schattenberg, J. Vidal-Puig, T. Vacca, M. Rodrigues-Cuenca, S. Allison, M. Kamzolas, I. Petsalaki, E. Oresic, M. Hyötyläinen, T. McGlinchey, A. Mato, J.M. Millet, O. Dufour, J.-F. Berzigotti, A. Harrison, S. Cobbold, J. Mozes, F. Akhtar, S. Banerjee, R. Kelly, M. Shumbayawonda, E. Dennis, A. Erpicum, C. Gómez-González, E. Ampuero, J. Castell, J. Gallego-Durán, R. Fernández, I. Montero-Vallejo, R. Karsdal, M. Erhardtsen, E. Rasmussen, D. Leeming, D.J. Fisker, M.J. Sinisi, A. Musa, K. Betsou, F. Sandt, E. Tonini, M. Bugianesi, E. Rosso, C. Armandi, A. Marra, F. Gastaldelli, A. Svegliati, G. Boursier, J. Francque, S. Vonghia, L. Ekstedt, M. Kechagias, S. Yki-Jarvinen, H. Luukkonen, P. van Mil, S. Papatheodoridis, G. Cortez-Pinto, H. Valenti, L. Petta, S. Miele, L. Geier, A. Trautwein, C. Aithal, G. Hockings, P. Newsome, P. Wenn, D. Pereira Rodrigues, C.M. Chaumat, P. Hanf, R. Trylesinski, A. Ortiz, P. Duffin, K. Brosnan, J. Tuthill, T. McLeod, E. Ertle, J. Younes, R. Ostroff, R. Alexander, L. Kjær, M.S. Mikkelsen, L.F. Balp, M.-M. Brass, C. Jennings, L. Martic, M. Loeffler, J. Hanauer, G. Shankar, S. Fournier, C. Pepin, K. Ehman, R. Myers, J. Ho, G. Torstenson, R. Myers, R. Doward, L. LITMUS Investigators

Abstract

Background and Aims: Vibration-controlled transient elastography (VCTE), point shear wave elastography (pSWE), 2-dimensional shear wave elastography (2DSWE), magnetic resonance elastography (MRE), and magnetic resonance imaging (MRI) have been proposed as non-invasive tests for patients with non-alcoholic fatty liver disease (NAFLD). This study evaluated their diagnostic accuracy for liver fibrosis and non-alcoholic steatohepatitis (NASH). Methods: PubMED/MEDLINE, EMBASE and the Cochrane Library were searched for studies examining the diagnostic accuracy of these index tests, against histology as the reference standard, in adult patients with NAFLD. Two authors independently screened and assessed methodological quality of studies and extracted data. Summary estimates of sensitivity, specificity and area under the curve (sAUC) were calculated for fibrosis stages and NASH, using a random effects bivariate logit-normal model. Results: We included 82 studies (14,609 patients). Meta-analysis for diagnosing fibrosis stages was possible in 53 VCTE, 11 MRE, 12 pSWE and 4 2DSWE studies, and for diagnosing NASH in 4 MRE studies. sAUC for diagnosis of significant fibrosis were: 0.83 for VCTE, 0.91 for MRE, 0.86 for pSWE and 0.75 for 2DSWE. sAUC for diagnosis of advanced fibrosis were: 0.85 for VCTE, 0.92 for MRE, 0.89 for pSWE and 0.72 for 2DSWE. sAUC for diagnosis of cirrhosis were: 0.89 for VCTE, 0.90 for MRE, 0.90 for pSWE and 0.88 for 2DSWE. MRE had sAUC of 0.83 for diagnosis of NASH. Three (4%) studies reported intention-to-diagnose analyses and 15 (18%) studies reported diagnostic accuracy against pre-specified cut-offs. Conclusions: When elastography index tests are acquired successfully, they have acceptable diagnostic accuracy for advanced fibrosis and cirrhosis. The potential clinical impact of these index tests cannot be assessed fully as intention-to-diagnose analyses and validation of pre-specified thresholds are lacking. Lay summary: Non-invasive tests that measure liver stiffness or use magnetic resonance imaging (MRI) have been suggested as alternatives to liver biopsy for assessing the severity of liver scarring (fibrosis) and fatty inflammation (steatohepatitis) in patients with non-alcoholic fatty liver disease (NAFLD). In this study, we summarise the results of previously published studies on how accurately these non-invasive tests can diagnose liver fibrosis and inflammation, using liver biopsy as the reference. We found that some techniques that measure liver stiffness had a good performance for the diagnosis of severe liver scarring. © 2021 The Author(s)

Published
2021

12. Corrigendum to: 'Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort'☆ (J Hepatol [2020] 505–515) (Journal of Hepatology (2020) 73(3) (505–515), (S0168827820302130), (10.1016/j.jhep.2020.04.003))

Author

Anstee, Q.M. Darlay, R. Cockell, S. Meroni, M. Govaere, O. Tiniakos, D. Burt, A.D. Bedossa, P. Palmer, J. Liu, Y.-L. Aithal, G.P. Allison, M. Yki-Järvinen, H. Vacca, M. Dufour, J.-F. Invernizzi, P. Prati, D. Ekstedt, M. Kechagias, S. Francque, S. Petta, S. Bugianesi, E. Clement, K. Ratziu, V. Schattenberg, J.M. Valenti, L. Day, C.P. Cordell, H.J. Daly, A.K. EPoS Consortium Investigators

Abstract

It has come to our attention that there is a typographical error in Table 5 of our manuscript. In line 6 of column 2, “rs11852624” should read "rs11858624”. We apologise for any inconvenience caused. © 2020 European Association for the Study of the Liver

Published
2021

13. Network medicine for disease module identification and drug repurposing with the NeDRex platform

Author

Sadegh, S., Sadegh, S., Skelton, J., Anastasi, E., Bernett, J., Blumenthal, D.B., Galindez, G., Salgado-Albarran, M., Lazareva, O., Flanagan, K., Cockell, S., Nogales, C., Casas, A.I., Schmidt, H.H.H.W., Baumbach, J., Wipat, A., Kacprowski, T., Sadegh, S., Sadegh, S., Skelton, J., Anastasi, E., Bernett, J., Blumenthal, D.B., Galindez, G., Salgado-Albarran, M., Lazareva, O., Flanagan, K., Cockell, S., Nogales, C., Casas, A.I., Schmidt, H.H.H.W., Baumbach, J., Wipat, A., and Kacprowski, T.

Abstract

Traditional drug discovery faces a severe efficacy crisis. Repurposing of registered drugs provides an alternative with lower costs and faster drug development timelines. However, the data necessary for the identification of disease modules, i.e. pathways and sub-networks describing the mechanisms of complex diseases which contain potential drug targets, are scattered across independent databases. Moreover, existing studies are limited to predictions for specific diseases or non-translational algorithmic approaches. There is an unmet need for adaptable tools allowing biomedical researchers to employ network-based drug repurposing approaches for their individual use cases. We close this gap with NeDRex, an integrative and interactive platform for network-based drug repurposing and disease module discovery. NeDRex integrates ten different data sources covering genes, drugs, drug targets, disease annotations, and their relationships. NeDRex allows for constructing heterogeneous biological networks, mining them for disease modules, prioritizing drugs targeting disease mechanisms, and statistical validation. We demonstrate the utility of NeDRex in five specific use-cases.There is an unmet need for adaptable tools allowing biomedical researchers to employ network-based drug repurposing approaches for their individual use cases. Here, the authors close this gap with NeDRex, an integrative and interactive platform.

Published
2021

14. Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis

Author

Govaere, O. Cockell, S. Tiniakos, D. Queen, R. Younes, R. Vacca, M. Alexander, L. Ravaioli, F. Palmer, J. Petta, S. Boursier, J. Rosso, C. Johnson, K. Wonders, K. Day, C.P. Ekstedt, M. Orešič, M. Darlay, R. Cordell, H.J. Marra, F. Vidal-Puig, A. Bedossa, P. Schattenberg, J.M. Clément, K. Allison, M. Bugianesi, E. Ratziu, V. Daly, A.K. Anstee, Q.M.

Abstract

The mechanisms that drive nonalcoholic fatty liver disease (NAFLD) remain incompletely understood. This large multicenter study characterized the transcriptional changes that occur in liver tissue across the NAFLD spectrum as disease progresses to cirrhosis to identify potential circulating markers. We performed high-throughput RNA sequencing on a discovery cohort comprising histologically characterized NAFLD samples from 206 patients. Unsupervised clustering stratified NAFLD on the basis of disease activity and fibrosis stage with differences in age, aspartate aminotransferase (AST), type 2 diabetes mellitus, and carriage of PNPLA3 rs738409, a genetic variant associated with NAFLD. Relative to early disease, we consistently identified 25 differentially expressed genes as fibrosing steatohepatitis progressed through stages F2 to F4. This 25-gene signature was independently validated by logistic modeling in a separate replication cohort (n = 175), and an integrative analysis with publicly available single-cell RNA sequencing data elucidated the likely relative contribution of specific intrahepatic cell populations. Translating these findings to the protein level, SomaScan analysis in more than 300 NAFLD serum samples confirmed that circulating concentrations of proteins AKR1B10 and GDF15 were strongly associated with disease activity and fibrosis stage. Supporting the biological plausibility of these data, in vitro functional studies determined that endoplasmic reticulum stress up-regulated expression of AKR1B10, GDF15, and PDGFA, whereas GDF15 supplementation tempered the inflammatory response in macrophages upon lipid loading and lipopolysaccharide stimulation. This study provides insights into the pathophysiology of progressive fibrosing steatohepatitis, and proof of principle that transcriptomic changes represent potentially tractable and clinically relevant markers of disease progression. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Published
2020

16. Deconstructing Retinal Organoids: Single Cell RNA-Seq Reveals the Cellular Components of Human Pluripotent Stem Cell-Derived Retina

Author

Collin, J., Queen, R., Zerti, D., Dorgau, B., Hussain, R., Coxhead, J., Cockell, S., and Lako, M.

Subjects
Pluripotent Stem Cells, Retinal Ganglion Cells, Ependymoglial Cells, Human Embryonic Stem Cells, Single cell RNA‐Seq, Retinal organoids, Cell Differentiation, Retinal Pigment Epithelium, Pluripotent stem cells, Single cell RNA-Seq, Extracellular Matrix, Humans, Organoids, RNA-Seq, Retina, Retinal Cone Photoreceptor Cells, Retinal Rod Photoreceptor Cells, Single-Cell Analysis, Embryonic Stem Cells/Induced Pluripotent Stem Cells, sense organs
Abstract

The rapid improvements in single cell sequencing technologies and analyses afford greater scope for dissecting organoid cultures composed of multiple cell types and create an opportunity to interrogate these models to understand tissue biology, cellular behavior and interactions. To this end, retinal organoids generated from human embryonic stem cells (hESCs) were analyzed by single cell RNA‐sequencing (scRNA‐Seq) at three time points of differentiation. Combinatorial data from all time points revealed the presence of nine clusters, five of which corresponded to key retinal cell types: retinal pigment epithelium (RPE), retinal ganglion cells (RGCs), cone and rod photoreceptors, and Müller glia. The remaining four clusters expressed genes typical of mitotic cells, extracellular matrix components and those involved in homeostasis. The cell clustering analysis revealed the decreasing presence of mitotic cells and RGCs, formation of a distinct RPE cluster, the emergence of cone and rod photoreceptors from photoreceptor precursors, and an increasing number of Müller glia cells over time. Pseudo‐time analysis resembled the order of cell birth during retinal development, with the mitotic cluster commencing the trajectory and the large majority of Müller glia completing the time line. Together, these data demonstrate the feasibility and potential of scRNA‐Seq to dissect the inherent complexity of retinal organoids and the orderly birth of key retinal cell types. Stem Cells 2019;37:593–598

Published
2018

22. Transcriptomics and proteomics show that selenium affects inflammation, ctoskeleton, and cancer pathways in human rectal biopsies

Author

Meplan, C., Johnson, I. T., Polley, A. C. J., Cockell, S., Bradburn, D. M., Commane, Danny M., Arasaradnam, R. P., Mulholland, F., Zupanic, A., Mathers, J. C., and Hesketh, J.

Abstract

Epidemiologic studies highlight the potential role of dietary selenium (Se) in colorectal cancer prevention. Our goal was to elucidate whether expression of factors crucial for colorectal homoeostasis is affected by physiologic differences in Se status. Using transcriptomics and proteomics followed by pathway analysis, we identified pathways affected by Se status in rectal biopsies from 22 healthy adults, including 11 controls with optimal status (mean plasma Se = 1.43 μM) and 11 subjects with suboptimal status (mean plasma Se = 0.86 μM). We observed that 254 genes and 26 proteins implicated in cancer (80%), immune function and inflammatory response (40%), cell growth and proliferation (70%), cellular movement, and cell death (50%) were differentially expressed between the 2 groups. Expression of 69 genes, including selenoproteins W1 and K, which are genes involved in cytoskeleton remodelling and transcription factor NFκB signaling, correlated significantly with Se status. Integrating proteomics and transcriptomics datasets revealed reduced inflammatory and immune responses and cytoskeleton remodelling in the suboptimal Se status group. This is the first study combining omics technologies to describe the impact of differences in Se status on colorectal expression patterns, revealing that suboptimal Se status could alter inflammatory signaling and cytoskeleton in human rectal mucosa and so influence cancer risk.

Published
2016

29. An integrated dataset for in silico drug discovery

Author

Cockell, S. J., Weile, J., Lord, P., Wipat, C., Andriychenko, D., Pocock, M., Darren James Wilkinson, Young, M., and Wipat, A.

Subjects
ComputingMethodologies_PATTERNRECOGNITION, Databases as Topic, Chlorpromazine, Drug Discovery, Computational Biology, Data processing, computer science, computer systems, General Medicine, TP248.13-248.65, Biotechnology, Semantics
Abstract

SummaryDrug development is expensive and prone to failure. It is potentially much less risky and expensive to reuse a drug developed for one condition for treating a second disease, than it is to develop an entirely new compound. Systematic approaches to drug repositioning are needed to increase throughput and find candidates more reliably. Here we address this need with an integrated systems biology dataset, developed using the Ondex data integration platform, for the in silico discovery of new drug repositioning candidates. We demonstrate that the information in this dataset allows known repositioning examples to be discovered. We also propose a means of automating the search for new treatment indications of existing compounds.

Published
2010
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34. The NF-κB subunit c-Rel regulates Bach2 tumour suppressor expression in B-cell lymphoma

Author

Hunter, J E, Butterworth, J A, Zhao, B, Sellier, H, Campbell, K J, Thomas, H D, Bacon, C M, Cockell, S J, Gewurz, B E, and Perkins, N D

Abstract

The REL gene, encoding the NF-κB subunit c-Rel, is frequently amplified in B-cell lymphoma and functions as a tumour-promoting transcription factor. Here we report the surprising result that c-rel–/– mice display significantly earlier lymphomagenesis in the c-Myc driven, Eμ-Myc model of B-cell lymphoma. c-Rel loss also led to earlier onset of disease in a separate TCL1-Tg-driven lymphoma model. Tumour reimplantation experiments indicated that this is an effect intrinsic to the Eμ-Myc lymphoma cells but, counterintuitively, c-rel–/– Eμ-Myc lymphoma cells were more sensitive to apoptotic stimuli. To learn more about why loss of c-Rel led to earlier onset of disease, microarray gene expression analysis was performed on B cells from 4-week-old, wild-type and c-rel–/– Eμ-Myc mice. Extensive changes in gene expression were not seen at this age, but among those transcripts significantly downregulated by the loss of c-Rel was the B-cell tumour suppressor BTB and CNC homology 2 (Bach2). Quantitative PCR and western blot analysis confirmed loss of Bach2 in c-Rel mutant Eμ-Myc tumours at both 4 weeks and the terminal stages of disease. Moreover, Bach2 expression was also downregulated in c-rel–/– TCL1-Tg mice and RelA Thr505Ala mutant Eμ-Myc mice. Analysis of wild-type Eμ-Myc mice demonstrated that the population expressing low levels of Bach2 exhibited the earlier onset of lymphoma seen in c-rel–/– mice. Confirming the relevance of these findings to human disease, analysis of chromatin immunoprecipitation sequencing data revealed that Bach2 is a c-Rel and NF-κB target gene in transformed human B cells, whereas treatment of Burkitt's lymphoma cells with inhibitors of the NF-κB/IκB kinase pathway or deletion of c-Rel or RelA resulted in loss of Bach2 expression. These data reveal a surprising tumour suppressor role for c-Rel in lymphoma development explained by regulation of Bach2 expression, underlining the context-dependent complexity of NF-κB signalling in cancer.

Published
2016
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35. A distributed computational search strategy for the identification of diagnostics targets: Application to finding aptamer targets for methicillin-resistant staphylococci

Author

Flanagan Keith, Cockell Simon, Harwood Colin, Hallinan Jennifer, Nakjang Sirintra, Lawry Beth, and Wipat Anil

Subjects
Biotechnology, TP248.13-248.65
Abstract

The rapid and cost-effective identification of bacterial species is crucial, especially for clinical diagnosis and treatment. Peptide aptamers have been shown to be valuable for use as a component of novel, direct detection methods. These small peptides have a number of advantages over antibodies, including greater specificity and longer shelf life. These properties facilitate their use as the detector components of biosensor devices. However, the identification of suitable aptamer targets for particular groups of organisms is challenging. We present a semi-automated processing pipeline for the identification of candidate aptamer targets from whole bacterial genome sequences. The pipeline can be configured to search for protein sequence fragments that uniquely identify a set of strains of interest. The system is also capable of identifying additional organisms that may be of interest due to their possession of protein fragments in common with the initial set. Through the use of Cloud computing technology and distributed databases, our system is capable of scaling with the rapidly growing genome repositories, and consequently of keeping the resulting data sets up-to-date. The system described is also more generically applicable to the discovery of specific targets for other diagnostic approaches such as DNA probes, PCR primers and antibodies.

Published
2014
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36. An integrated dataset for in silico drug discovery

Author

Cockell Simon J, Weile Jochen, Lord Phillip, Wipat Claire, Andriychenko Dmytro, Pocock Matthew, Wilkinson Darren, Young Malcolm, and Wipat Anil

Subjects
Biotechnology, TP248.13-248.65
Abstract

Drug development is expensive and prone to failure. It is potentially much less risky and expensive to reuse a drug developed for one condition for treating a second disease, than it is to develop an entirely new compound. Systematic approaches to drug repositioning are needed to increase throughput and find candidates more reliably. Here we address this need with an integrated systems biology dataset, developed using the Ondex data integration platform, for the in silico discovery of new drug repositioning candidates. We demonstrate that the information in this dataset allows known repositioning examples to be discovered. We also propose a means of automating the search for new treatment indications of existing compounds.

Published
2010
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37. Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort☆

Author

Jeremy M. Palmer, Michael Allison, Guruprasad P. Aithal, Simon Cockell, Vlad Ratziu, Alastair D. Burt, Yang-Lin Liu, Christopher P. Day, Jörn M. Schattenberg, Michele Vacca, Quentin M. Anstee, Pietro Invernizzi, Heather J. Cordell, Olivier Govaere, Stergios Kechagias, Sven Francque, Ann K. Daly, Dina Tiniakos, Jean-François Dufour, Rebecca Darlay, Salvatore Petta, Karine Clément, Luca Valenti, Daniele Prati, Pierre Bedossa, Mattias Ekstedt, Hannele Yki-Järvinen, Marica Meroni, Elisabetta Bugianesi, Anstee, Q, Darlay, R, Cockell, S, Meroni, M, Govaere, O, Tiniakos, D, Burt, A, Bedossa, P, Palmer, J, Liu, Y, Aithal, G, Allison, M, Yki-Jarvinen, H, Vacca, M, Dufour, J, Invernizzi, P, Prati, D, Ekstedt, M, Kechagias, S, Francque, S, Petta, S, Bugianesi, E, Clement, K, Ratziu, V, Schattenberg, J, Valenti, L, Day, C, Cordell, H, Daly, A, EPoS Consortium Investigators, Department of Medicine, HUS Internal Medicine and Rehabilitation, University of Helsinki, Helsinki University Hospital Area, Anstee Q.M., Darlay R., Cockell S., Meroni M., Govaere O., Tiniakos D., Burt A.D., Bedossa P., Palmer J., Liu Y.-L., Aithal G.P., Allison M., Yki-Jarvinen H., Vacca M., Dufour J.-F., Invernizzi P., Prati D., Ekstedt M., Kechagias S., Francque S., Petta S., Bugianesi E., Clement K., Ratziu V., Schattenberg J.M., Valenti L., Day C.P., Cordell H.J., and Daly A.K.

Subjects
0301 basic medicine, Male, Cirrhosis, 17-Hydroxysteroid Dehydrogenases, Fibrosi, VARIANT, LOCI, PROGRESSION, Genome-wide association study, Disease, Bioinformatics, DISEASE, Cohort Studies, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Risk Factors, GWAS, INCREASED RISK, CONFERS SUSCEPTIBILITY, education.field_of_study, Fatty liver, NASH, Middle Aged, 3. Good health, NAFLD, Fibrosis, PNPLA3, TM6SF2, GCKR, HSD17B13, SNP, Phenotype, Liver, 030211 gastroenterology & hepatology, Female, Life Sciences & Biomedicine, Adult, Population, 610 Medicine & health, Gastroenterology and Hepatology, Polymorphism, Single Nucleotide, 03 medical and health sciences, medicine, Gastroenterologi, Humans, Genetic Predisposition to Disease, education, Adaptor Proteins, Signal Transducing, Science & Technology, Gastroenterology & Hepatology, Hepatology, business.industry, nutritional and metabolic diseases, Membrane Proteins, Lipase, medicine.disease, POLYMORPHISM, LEPTIN RECEPTOR GENE, 030104 developmental biology, 3121 General medicine, internal medicine and other clinical medicine, Case-Control Studies, Human medicine, Steatosis, Steatohepatitis, business, Genome-Wide Association Study
Abstract

Background & Aims: Genetic factors associated with nonalcoholic fatty liver disease (NAFLD) remain incompletely understood. To date, most genome-wide association studies (GWASs) have adopted radiologically assessed hepatic triglyceride content as the reference phenotype and so cannot address steatohepatitis or fibrosis. We describe a GWAS encompassing the full spectrum of histologically characterised NAFLD. Methods: The GWAS involved 1,483 European NAFLD cases and 17,781 genetically matched controls. A replication cohort of 559 NAFLD cases and 945 controls was genotyped to confirm signals showing genome-wide or close to genome-wide significance. Results: Case-control analysis identified signals showing p values = F3), the signals on chr2, chr19 and chr22 maintained their genome-wide significance. Except for GCKR/C2ORF16, the genome-wide significance signals were replicated. Conclusions: This study confirms PNPLA3 as a risk factor for the full histological spectrum of NAFLD at genome-wide significance levels, with important contributions from TM6SF2 and HSD17B13. PYGO1 is a novel steatosis modifier, suggesting that Wnt signalling pathways may be relevant in NAFLD pathogenesis. Lay summary: Non-alcoholic fatty liver disease is a common disease where excessive fat accumulates in the liver and may result in cirrhosis. To understand who is at risk of developing this disease and suffering liver damage, we undertook a genetic study to compare the genetic profiles of people suffering from fatty liver disease with genetic profiles seen in the general population. We found that particular sequences in 4 different areas of the human genome were seen at different frequencies in the fatty liver disease cases. These sequences may help predict an individuals risk of developing advanced disease. Some genes where these sequences are located may also be good targets for future drug treatments. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V. Funding Agencies|EPoS (Elucidating Pathways of Steatohepatitis) consortium - Horizon 2020 Framework Program of the European Union [634413]; FLIP consortium(EuropeanUnion FP7 grant) [241762]; Newcastle NIHR Biomedical Research Centre

Published
2020
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38. Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis

Author

Matej Orešič, Fabio Marra, Christopher P. Day, Federico Ravaioli, Katherine Johnson, Elisabetta Bugianesi, Jérôme Boursier, Pierre Bedossa, Olivier Govaere, Rebecca Darlay, Salvatore Petta, Jeremy M. Palmer, Quentin M. Anstee, Ramy Younes, Heather J. Cordell, Rachel Queen, Jörn M. Schattenberg, Ann K. Daly, Mattias Ekstedt, Dina Tiniakos, Leigh Alexander, Michele Vacca, Antonio Vidal-Puig, Chiara Rosso, Karine Clément, Michael Allison, Vlad Ratziu, Kristy Wonders, Simon Cockell, Bioinformatics Support Unit, Newcastle University [Newcastle], Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Govaere O., Cockell S., Tiniakos D., Queen R., Younes R., Vacca M., Alexander L., Ravaioli F., Palmer J., Petta S., Boursier J., Rosso C., Johnson K., Wonders K., Day C.P., Ekstedt M., Oresic M., Darlay R., Cordell H.J., Marra F., Vidal-Puig A., Bedossa P., Schattenberg J.M., Clement K., Allison M., Bugianesi E., Ratziu V., Daly A.K., and Anstee Q.M.

Subjects
0301 basic medicine, Liver Cirrhosis, Cirrhosis, [SDV]Life Sciences [q-bio], Disease, Biology, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Fibrosis, nash, Non-alcoholic Fatty Liver Disease, Diabetes mellitus, Nonalcoholic fatty liver disease, medicine, Diabetes Mellitus, Humans, General Medicine, medicine.disease, 3. Good health, 030104 developmental biology, Diabetes Mellitus, Type 2, Liver, Immunology, 030211 gastroenterology & hepatology, GDF15, Steatohepatitis, Type 2
Abstract

International audience; The mechanisms that drive nonalcoholic fatty liver disease (NAFLD) remain incompletely understood. This large multicenter study characterized the transcriptional changes that occur in liver tissue across the NAFLD spectrum as disease progresses to cirrhosis to identify potential circulating markers. We performed high-throughput RNA sequencing on a discovery cohort comprising histologically characterized NAFLD samples from 206 patients. Unsupervised clustering stratified NAFLD on the basis of disease activity and fibrosis stage with differences in age, aspartate aminotransferase (AST), type 2 diabetes mellitus, and carriage of PNPLA3 rs738409 , a genetic variant associated with NAFLD. Relative to early disease, we consistently identified 25 differentially expressed genes as fibrosing steatohepatitis progressed through stages F2 to F4. This 25-gene signature was independently validated by logistic modeling in a separate replication cohort ( n = 175), and an integrative analysis with publicly available single-cell RNA sequencing data elucidated the likely relative contribution of specific intrahepatic cell populations. Translating these findings to the protein level, SomaScan analysis in more than 300 NAFLD serum samples confirmed that circulating concentrations of proteins AKR1B10 and GDF15 were strongly associated with disease activity and fibrosis stage. Supporting the biological plausibility of these data, in vitro functional studies determined that endoplasmic reticulum stress up-regulated expression of AKR1B10 , GDF15 , and PDGFA , whereas GDF15 supplementation tempered the inflammatory response in macrophages upon lipid loading and lipopolysaccharide stimulation. This study provides insights into the pathophysiology of progressive fibrosing steatohepatitis, and proof of principle that transcriptomic changes represent potentially tractable and clinically relevant markers of disease progression.

Published
2020

39. Diagnostic accuracy of elastography and magnetic resonance imaging in patients with NAFLD: A systematic review and meta-analysis

Author

Emmanuel Anandraj Selvaraj, Ferenc Emil Mózes, Arjun Narayan Ajmer Jayaswal, Mohammad Hadi Zafarmand, Yasaman Vali, Jenny A. Lee, Christina Kim Levick, Liam Arnold Joseph Young, Naaventhan Palaniyappan, Chang-Hai Liu, Guruprasad Padur Aithal, Manuel Romero-Gómez, M. Julia Brosnan, Theresa A. Tuthill, Quentin M. Anstee, Stefan Neubauer, Stephen A. Harrison, Patrick M. Bossuyt, Michael Pavlides, Quentin Anstee, Ann Daly, Katherine Johnson, Olivier Govaere, Simon Cockell, Dina Tiniakos, Pierre Bedossa, Fiona Oakley, Heather Cordell, Chris Day, Kristy Wonders, Patrick Bossuyt, Hadi Zafarmand, Jenny Lee, Vlad Ratziu, Karine Clement, Raluca Pais, Detlef Schuppan, Jörn Schattenberg, Toni Vidal-Puig, Michele Vacca, Sergio Rodrigues-Cuenca, Mike Allison, Ioannis Kamzolas, Evangelia Petsalaki, Matej Oresic, Tuulia Hyötyläinen, Aiden McGlinchey, Jose M. Mato, Oscar Millet, Jean-François Dufour, Annalisa Berzigotti, Stephen Harrison, Jeremy Cobbold, Ferenc Mozes, Salma Akhtar, Rajarshi Banerjee, Matt Kelly, Elizabeth Shumbayawonda, Andrea Dennis, Charlotte Erpicum, Emilio Gómez-González, Javier Ampuero, Javier Castell, Rocío Gallego-Durán, Isabel Fernández, Rocío Montero-Vallejo, Morten Karsdal, Elisabeth Erhardtsen, Daniel Rasmussen, Diana Julie Leeming, Mette Juul Fisker, Antonia Sinisi, Kishwar Musa, Fay Betsou, Estelle Sandt, Manuela Tonini, Elisabetta Bugianesi, Chiara Rosso, Angelo Armandi, Fabio Marra, Amalia Gastaldelli, Gianluca Svegliati, Jérôme Boursier, Sven Francque, Luisa Vonghia, Mattias Ekstedt, Stergios Kechagias, Hannele Yki-Jarvinen, Panu Luukkonen, Saskia van Mil, George Papatheodoridis, Helena Cortez-Pinto, Luca Valenti, Salvatore Petta, Luca Miele, Andreas Geier, Christian Trautwein, Guru Aithal, Paul Hockings, Philip Newsome, David Wenn, Cecília Maria Pereira Rodrigues, Pierre Chaumat, Rémy Hanf, Aldo Trylesinski, Pablo Ortiz, Kevin Duffin, Julia Brosnan, Theresa Tuthill, Euan McLeod, Judith Ertle, Ramy Younes, Rachel Ostroff, Leigh Alexander, Mette Skalshøi Kjær, Lars Friis Mikkelsen, Maria-Magdalena Balp, Clifford Brass, Lori Jennings, Miljen Martic, Juergen Loeffler, Guido Hanauer, Sudha Shankar, Céline Fournier, Kay Pepin, Richard Ehman, Joel Myers, Gideon Ho, Richard Torstenson, Rob Myers, Lynda Doward, LITMUS Investigators, Innovative Medicines Initiative, European Commission, European Federation of Pharmaceutical Industries and Associations, Epidemiology and Data Science, APH - Aging & Later Life, APH - Methodology, ARD - Amsterdam Reproduction and Development, Graduate School, APH - Personalized Medicine, Selvaraj E.A., Mozes F.E., Jayaswal A.N.A., Zafarmand M.H., Vali Y., Lee J.A., Levick C.K., Young L.A.J., Palaniyappan N., Liu C.-H., Aithal G.P., Romero-Gomez M., Brosnan M.J., Tuthill T.A., Anstee Q.M., Neubauer S., Harrison S.A., Bossuyt P.M., Pavlides M., Daly A., Johnson K., Govaere O., Cockell S., Tiniakos D., Bedossa P., Oakley F., Cordell H., Day C., Wonders K., Bossuyt P., Zafarmand H., Lee J., Ratziu V., Clement K., Pais R., Schuppan D., Schattenberg J., Vidal-Puig T., Vacca M., Rodrigues-Cuenca S., Allison M., Kamzolas I., Petsalaki E., Oresic M., Hyotylainen T., McGlinchey A., Mato J.M., Millet O., Dufour J.-F., Berzigotti A., Harrison S., Cobbold J., Mozes F., Akhtar S., Banerjee R., Kelly M., Shumbayawonda E., Dennis A., Erpicum C., Gomez-Gonzalez E., Ampuero J., Castell J., Gallego-Duran R., Fernandez I., Montero-Vallejo R., Karsdal M., Erhardtsen E., Rasmussen D., Leeming D.J., Fisker M.J., Sinisi A., Musa K., Betsou F., Sandt E., Tonini M., Bugianesi E., Rosso C., Armandi A., Marra F., Gastaldelli A., Svegliati G., Boursier J., Francque S., Vonghia L., Ekstedt M., Kechagias S., Yki-Jarvinen H., Luukkonen P., van Mil S., Papatheodoridis G., Cortez-Pinto H., Valenti L., Petta S., Miele L., Geier A., Trautwein C., Aithal G., Hockings P., Newsome P., Wenn D., Pereira Rodrigues C.M., Chaumat P., Hanf R., Trylesinski A., Ortiz P., Duffin K., Brosnan J., Tuthill T., McLeod E., Ertle J., Younes R., Ostroff R., Alexander L., Kjaer M.S., Mikkelsen L.F., Balp M.-M., Brass C., Jennings L., Martic M., Loeffler J., Hanauer G., Shankar S., Fournier C., Pepin K., Ehman R., Myers J., Ho G., Torstenson R., Myers R., and Doward L.

Subjects
0301 basic medicine, FIBROSIS NONINVASIVE ASSESSMENT, Cirrhosis, Transient elastography, deMILI, 0302 clinical medicine, Medicine, BARIATRIC SURGERY CANDIDATES, Non-alcoholic steatohepatitis, medicine.diagnostic_test, NONALCOHOLIC STEATOHEPATITIS, Fatty liver, Magnetic Resonance Imaging, 3. Good health, Area Under Curve, Liver biopsy, Elasticity Imaging Techniques, NASH-MRI, 030211 gastroenterology & hepatology, Bio-markers, Radiology, Elastography, Diffusion-weighted imaging, Life Sciences & Biomedicine, Adult, PREDICTS ADVANCED FIBROSIS, medicine.medical_specialty, Biomarkers, deMILI, Diffusion-weighted imaging, Magnetic resonance elastography, NASH-MRI, Non-alcoholic fatty liver disease, Non-alcoholic steatohepatitis, Shear wave elastography, Transient elastography, Adult,Area Under Curve, Elasticity Imaging Techniques, Humans, Magnetic Resonance Imaging, Non-alcoholic Fatty Liver Disease, ROC Curve, fibro-MRI, Iron-corrected T1, Liver fibrosis, Liver fibrosis, CONTROLLED ATTENUATION PARAMETER, STIFFNESS MEASUREMENT, 03 medical and health sciences, Iron-corrected T1, Humans, FATTY LIVER-DISEASE, Science & Technology, Hepatology, Gastroenterology & Hepatology, business.industry, RADIATION FORCE IMPULSE, Magnetic resonance imaging, medicine.disease, CONTROLLED TRANSIENT ELASTOGRAPHY, Magnetic resonance elastography, 030104 developmental biology, ROC Curve, Shear wave elastography, XL PROBE, Human medicine, fibro-MRI, Steatohepatitis, business, Biomarkers, Non-alcoholic fatty liver disease
Abstract

[Background and Aims] Vibration-controlled transient elastography (VCTE), point shear wave elastography (pSWE), 2-dimensional shear wave elastography (2DSWE), magnetic resonance elastography (MRE), and magnetic resonance imaging (MRI) have been proposed as non-invasive tests for patients with non-alcoholic fatty liver disease (NAFLD). This study evaluated their diagnostic accuracy for liver fibrosis and non-alcoholic steatohepatitis (NASH)., [Methods] PubMED/MEDLINE, EMBASE and the Cochrane Library were searched for studies examining the diagnostic accuracy of these index tests, against histology as the reference standard, in adult patients with NAFLD. Two authors independently screened and assessed methodological quality of studies and extracted data. Summary estimates of sensitivity, specificity and area under the curve (sAUC) were calculated for fibrosis stages and NASH, using a random effects bivariate logit-normal model., [Results] We included 82 studies (14,609 patients). Meta-analysis for diagnosing fibrosis stages was possible in 53 VCTE, 11 MRE, 12 pSWE and 4 2DSWE studies, and for diagnosing NASH in 4 MRE studies. sAUC for diagnosis of significant fibrosis were: 0.83 for VCTE, 0.91 for MRE, 0.86 for pSWE and 0.75 for 2DSWE. sAUC for diagnosis of advanced fibrosis were: 0.85 for VCTE, 0.92 for MRE, 0.89 for pSWE and 0.72 for 2DSWE. sAUC for diagnosis of cirrhosis were: 0.89 for VCTE, 0.90 for MRE, 0.90 for pSWE and 0.88 for 2DSWE. MRE had sAUC of 0.83 for diagnosis of NASH. Three (4%) studies reported intention-to-diagnose analyses and 15 (18%) studies reported diagnostic accuracy against pre-specified cut-offs., [Conclusions] When elastography index tests are acquired successfully, they have acceptable diagnostic accuracy for advanced fibrosis and cirrhosis. The potential clinical impact of these index tests cannot be assessed fully as intention-to-diagnose analyses and validation of pre-specified thresholds are lacking., [Lay summary] Non-invasive tests that measure liver stiffness or use magnetic resonance imaging (MRI) have been suggested as alternatives to liver biopsy for assessing the severity of liver scarring (fibrosis) and fatty inflammation (steatohepatitis) in patients with non-alcoholic fatty liver disease (NAFLD). In this study, we summarise the results of previously published studies on how accurately these non-invasive tests can diagnose liver fibrosis and inflammation, using liver biopsy as the reference. We found that some techniques that measure liver stiffness had a good performance for the diagnosis of severe liver scarring., This work has been undertaken as part of the LITMUS (Liver Investigation: Testing Marker Utility in Steatohepatitis) project. The LITMUS project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 777377. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and Europen Federation of Pharmaceutical Industries and Associations (efpia.eu).

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40. Scientific Business Abstracts.

Author

Cooles F, Vidal-Pedrola G, Naamane N, Pratt A, Barron-Millar B, Anderson A, Hilkens C, Casement J, Bondet V, Duffy D, Zhang F, Shukla R, Isaacs J, Little M, Payne M, Coupe N, Fairfax B, Taylor CA, Mackay S, Milotay G, Bos S, Hunter B, Mcdonald D, Merces G, Sheldon G, Pradère P, Majo J, Pulle J, Vanstapel A, Vanaudenaerde BM, Vos R, Filby AJ, Fisher AJ, Collier J, Lambton J, Suomi F, Prigent M, Guissart C, Erskine D, Rozanska A, Mccorvie T, Trimouille A, Imam A, Hobson E, Mccullagh H, Frengen E, Misceo D, Bjerre A, Smeland M, Klingenberg C, Alkuraya F, Mcfarland R, Alston C, Yue W, Legouis R, Koenig M, Lako M, Mcwilliams T, Oláhová M, Taylor R, Newman W, Harkness R, McDermott J, Metcalfe K, Khan N, Macken W, Pitceathly R, Record C, Maroofian R, Sabir A, Santra S, Urquhart J, Demain L, Byers H, Beaman G, Yue W, Taylor R, Durmusalioglu E, Atik T, Isik E, Cogulu O, Reunert J, Marquardt T, Ryba L, Buchert-Lo R, Haack T, Lassuthova P, Polavarapu K, Lochmuller H, Horvath R, Jamieson P, Reilly M, O'Keefe R, Boggan R, Ng YS, Franklin I, Alston C, Blakely E, Büchner B, Bugiardini E, Colclough K, Feeney C, Hanna M, Hattersley A, Klopstock T, Kornblum C, Mancuso M, Patel K, Pitceathly R, Pizzamiglio C, Prokisch H, Schäfer J, Schaefer A, Shepherd M, Thaele A, Thomas R, Turnbull D, Gorman G, Woodward C, McFarland R, Taylor R, Cordell H, Pickett S, Tsilifis C, Pearce M, Gennery A, Daly A, Darlay R, Zatorska M, Worthington S, Anstee Q, Cordell H, Reeves H, Nizami S, Mauricio-Muir J, McCain M, Singh R, Wordsworth J, Kadharusman M, Watson R, Masson S, McPherson S, Burt A, Tiniakos D, Littler P, Nsengimana J, Zhang S, Mann D, Jamieson D, Leslie J, Shukla R, Wilson C, Betts J, Croall I, Hoggard N, Bennett J, Naamane N, Hollingsworth KG, Pratt AG, Egail M, Feeney C, Di Leo V, Taylor RW, Dodds R, Anderson AE, Sayer AA, Isaacs JD, McCracken C, Condurache DG, Szabo L, Elghazaly H, Walter F, Meade A, Chakraverty R, Harvey N, Manisty C, Petersen S, Neubauer S, Raisi-Estabragh Z, Allen L, Taylor P, Carlsson A, Hagopian W, Hedlund E, Hill A, Jones A, Ludvigsson J, Onengut-Gumuscu S, Redondo M, Rich S, Gillespie K, Dayan C, Oram R, Resteu A, Wonders K, Schattenberg J, Straub B, Ekstedt M, Berzigotti A, Geier A, Francque S, Driessen A, Boursier J, Yki-Jarvinen H, Arola J, Aithal G, Holleboom A, Verheij J, Yunis C, Trylesinski A, Papatheodoridis G, Petta S, Romero-Gomez M, Bugianesi E, Paradis V, Ratziu V, Tiniakos D, Anstee Q, Burton J, Ciminata G, Geue C, Quinn T, Glover E, Morais M, Reynolds G, Denby L, Ali S, Lennon R, Sheerin N, Yang F, Zounemat-Kermani N, Dixey P, Adcock IM, Bloom CI, Chung KF, Govaere O, Hasoon M, Alexander L, Cockell S, Tiniakos D, Ekstedt M, Schattenberg JM, Boursier J, Bugianesi E, Ratziu V, Daly AK, and Anstee QM

Published
2024
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41. Exposures and conditions prior to age 16 are associated with dementia status among adults in the United States Health and Retirement Study.

Author

Cockell S, Wang H, Benke KS, Ware EB, and Bakulski KM

Abstract

Background: Dementia susceptibility likely begins years before symptoms. Early life has not been comprehensively tested for dementia associations., Method: In the US Health and Retirement Study (normal baseline cognition; n=16,509; 2008-2018 waves), 31 exposures before age 16 were retrospectively assessed with ten-year incident cognitive status (dementia, impaired, normal). Using parallel logistic models, each exposure was tested with incident cognition, adjusting for sex, baseline age, follow-up, race/ethnicity, personal/parental education., Result: 14.5% had incident impairment and 5.3% had dementia. Depression was associated with 1.71 (95%CI:1.28,2.26) times higher odds of incident impairment, relative to normal cognition. Headaches/migraines were associated with 1.63 (95%CI:1.18,2.22) times higher odds of incident impairment. Learning problems were associated with 1.75 (95%CI:1.05,2.79) times higher odds of incident impairment. Childhood self-rated health of fair (1.86, 95%CI:1.27,2.64) and poor (3.39, 95%CI:1.91,5.82) were associated with higher incident dementia odds, relative to excellent., Conclusion: Early life factors may be important for impairment or dementia, extending the relevant risk window.

Published
2024
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42. Exposome-wide association study of cognition among older adults in the National Health and Nutrition Examination Survey.

Author

Middleton LYM, Walker E, Cockell S, Dou J, Nguyen VK, Schrank M, Patel CJ, Ware EB, Colacino JA, Park SK, and Bakulski KM

Abstract

Cognitive impairment among older adults is a growing public health challenge and environmental chemicals may be modifiable risk factors. A wide array of chemicals has not yet been tested for association with cognition in an environment-wide association framework. In the US National Health and Nutrition Examination Survey (NHANES) 1999-2000 and 2011-2014 cross-sectional cycles, cognition was assessed using the Digit Symbol Substitution Test (DSST, scores 0-117) among participants aged 60 years and older. Concentrations of environmental chemicals measured in blood or urine were log 2 transformed and standardized. Chemicals with at least 50% of measures above the lower limit of detection were included (n chemicals =147, n classes =14). We tested for associations between chemical concentrations and cognition using parallel survey-weighted multivariable linear regression models adjusted for age, sex, race/ethnicity, education, smoking status, fish consumption, cycle year, urinary creatinine, and cotinine. Participants with at least one chemical measurement (n=4,982) were mean age 69.8 years, 55.0% female, 78.2% non-Hispanic White, and 77.0% at least high school educated. The mean DSST score was 50.4 (standard deviation (SD)=17.4). In adjusted analyses, 5 of 147 exposures were associated with DSST at p-value<0.01. Notably, a SD increase in log 2 -scaled cotinine concentration was associated with 2.71 points lower DSST score (95% CI -3.69, -1.73). A SD increase in log 2 -scaled urinary tungsten concentration was associated with 1.34 points lower DSST score (95% CI -2.11, -0.56). Exposure to environmental chemicals, particularly heavy metals and tobacco smoke, may be modifiable factors for cognition among older adults.

Published
2024
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43. An unbiased ranking of murine dietary models based on their proximity to human metabolic dysfunction-associated steatotic liver disease (MASLD).

Author

Vacca M, Kamzolas I, Harder LM, Oakley F, Trautwein C, Hatting M, Ross T, Bernardo B, Oldenburger A, Hjuler ST, Ksiazek I, Lindén D, Schuppan D, Rodriguez-Cuenca S, Tonini MM, Castañeda TR, Kannt A, Rodrigues CMP, Cockell S, Govaere O, Daly AK, Allison M, Honnens de Lichtenberg K, Kim YO, Lindblom A, Oldham S, Andréasson AC, Schlerman F, Marioneaux J, Sanyal A, Afonso MB, Younes R, Amano Y, Friedman SL, Wang S, Bhattacharya D, Simon E, Paradis V, Burt A, Grypari IM, Davies S, Driessen A, Yashiro H, Pors S, Worm Andersen M, Feigh M, Yunis C, Bedossa P, Stewart M, Cater HL, Wells S, Schattenberg JM, Anstee QM, Tiniakos D, Perfield JW, Petsalaki E, Davidsen P, and Vidal-Puig A

Subjects
Animals, Humans, Mice, Male, Liver metabolism, Liver pathology, Metabolic Diseases metabolism, Metabolic Diseases etiology, Diet, Western adverse effects, Retrospective Studies, Liver Cirrhosis metabolism, Liver Cirrhosis etiology, Disease Models, Animal, Non-alcoholic Fatty Liver Disease metabolism, Non-alcoholic Fatty Liver Disease etiology, Non-alcoholic Fatty Liver Disease pathology
Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease, encompasses steatosis and metabolic dysfunction-associated steatohepatitis (MASH), leading to cirrhosis and hepatocellular carcinoma. Preclinical MASLD research is mainly performed in rodents; however, the model that best recapitulates human disease is yet to be defined. We conducted a wide-ranging retrospective review (metabolic phenotype, liver histopathology, transcriptome benchmarked against humans) of murine models (mostly male) and ranked them using an unbiased MASLD 'human proximity score' to define their metabolic relevance and ability to induce MASH-fibrosis. Here, we show that Western diets align closely with human MASH; high cholesterol content, extended study duration and/or genetic manipulation of disease-promoting pathways are required to intensify liver damage and accelerate significant (F2+) fibrosis development. Choline-deficient models rapidly induce MASH-fibrosis while showing relatively poor translatability. Our ranking of commonly used MASLD models, based on their proximity to human MASLD, helps with the selection of appropriate in vivo models to accelerate preclinical research., (© 2024. The Author(s).)

Published
2024
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44. RNA Sequencing Demonstrates Ex Vivo Neocortical Transcriptomic Changes Induced by Epileptiform Activity in Male and Female Mice.

Author

Vaughan AJ, McMeekin LJ, Hine K, Stubbs IW, Codadu NK, Cockell S, Hill JT, Cowell R, Trevelyan AJ, and Parrish RR

Subjects
Animals, Female, Male, Mice, Seizures genetics, Seizures metabolism, Seizures physiopathology, Sequence Analysis, RNA methods, Epilepsy genetics, Epilepsy metabolism, Epilepsy physiopathology, Mice, Inbred C57BL, Neocortex metabolism, Neocortex drug effects, Transcriptome, 4-Aminopyridine pharmacology
Abstract

Seizures are generally associated with epilepsy but may also be a symptom of many other neurological conditions. A hallmark of a seizure is the intensity of the local neuronal activation, which can drive large-scale gene transcription changes. Such changes in the transcriptional profile likely alter neuronal function, thereby contributing to the pathological process. Therefore, there is a strong clinical imperative to characterize how gene expression is changed by seizure activity. To this end, we developed a simplified ex vivo technique for studying seizure-induced transcriptional changes. We compared the RNA sequencing profile in mouse neocortical tissue with up to 3 h of epileptiform activity induced by 4-aminopyridine (4AP) relative to control brain slices not exposed to the drug. We identified over 100 genes with significantly altered expression after 4AP treatment, including multiple genes involved in MAPK, TNF, and neuroinflammatory signaling pathways, all of which have been linked to epilepsy previously. Notably, the patterns in male and female brain slices were almost identical. Various immediate early genes were among those showing the largest upregulation. The set of down-regulated genes included ones that might be expected either to increase or to decrease neuronal excitability. In summary, we found the seizure-induced transcriptional profile complex, but the changes aligned well with an analysis of published epilepsy-associated genes. We discuss how simple models may provide new angles for investigating seizure-induced transcriptional changes., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Vaughan et al.)

Published
2024
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45. Intestinal B cells license metabolic T-cell activation in NASH microbiota/antigen-independently and contribute to fibrosis by IgA-FcR signalling.

Author

Kotsiliti E, Leone V, Schuehle S, Govaere O, Li H, Wolf MJ, Horvatic H, Bierwirth S, Hundertmark J, Inverso D, Zizmare L, Sarusi-Portuguez A, Gupta R, O'Connor T, Giannou AD, Shiri AM, Schlesinger Y, Beccaria MG, Rennert C, Pfister D, Öllinger R, Gadjalova I, Ramadori P, Rahbari M, Rahbari N, Healy ME, Fernández-Vaquero M, Yahoo N, Janzen J, Singh I, Fan C, Liu X, Rau M, Feuchtenberger M, Schwaneck E, Wallace SJ, Cockell S, Wilson-Kanamori J, Ramachandran P, Kho C, Kendall TJ, Leblond AL, Keppler SJ, Bielecki P, Steiger K, Hofmann M, Rippe K, Zitzelsberger H, Weber A, Malek N, Luedde T, Vucur M, Augustin HG, Flavell R, Parnas O, Rad R, Pabst O, Henderson NC, Huber S, Macpherson A, Knolle P, Claassen M, Geier A, Trautwein C, Unger K, Elinav E, Waisman A, Abdullah Z, Haller D, Tacke F, Anstee QM, and Heikenwalder M

Subjects
Humans, Mice, Animals, Mice, Inbred C57BL, Liver pathology, Fibrosis, Liver Cirrhosis complications, Mice, Transgenic, Immunoglobulin A metabolism, Immunoglobulin A pharmacology, Disease Models, Animal, Diet, High-Fat adverse effects, Non-alcoholic Fatty Liver Disease complications, Carcinoma, Hepatocellular pathology, Liver Neoplasms genetics, Microbiota
Abstract

Background & Aims: The progression of non-alcoholic steatohepatitis (NASH) to fibrosis and hepatocellular carcinoma (HCC) is aggravated by auto-aggressive T cells. The gut-liver axis contributes to NASH, but the mechanisms involved and the consequences for NASH-induced fibrosis and liver cancer remain unknown. We investigated the role of gastrointestinal B cells in the development of NASH, fibrosis and NASH-induced HCC., Methods: C57BL/6J wild-type (WT), B cell-deficient and different immunoglobulin-deficient or transgenic mice were fed distinct NASH-inducing diets or standard chow for 6 or 12 months, whereafter NASH, fibrosis, and NASH-induced HCC were assessed and analysed. Specific pathogen-free/germ-free WT and μMT mice (containing B cells only in the gastrointestinal tract) were fed a choline-deficient high-fat diet, and treated with an anti-CD20 antibody, whereafter NASH and fibrosis were assessed. Tissue biopsy samples from patients with simple steatosis, NASH and cirrhosis were analysed to correlate the secretion of immunoglobulins to clinicopathological features. Flow cytometry, immunohistochemistry and single-cell RNA-sequencing analysis were performed in liver and gastrointestinal tissue to characterise immune cells in mice and humans., Results: Activated intestinal B cells were increased in mouse and human NASH samples and licensed metabolic T-cell activation to induce NASH independently of antigen specificity and gut microbiota. Genetic or therapeutic depletion of systemic or gastrointestinal B cells prevented or reverted NASH and liver fibrosis. IgA secretion was necessary for fibrosis induction by activating CD11b+CCR2+F4/80+CD11c-FCGR1+ hepatic myeloid cells through an IgA-FcR signalling axis. Similarly, patients with NASH had increased numbers of activated intestinal B cells; additionally, we observed a positive correlation between IgA levels and activated FcRg+ hepatic myeloid cells, as well the extent of liver fibrosis., Conclusions: Intestinal B cells and the IgA-FcR signalling axis represent potential therapeutic targets for the treatment of NASH., Impact and Implications: There is currently no effective treatment for non-alcoholic steatohepatitis (NASH), which is associated with a substantial healthcare burden and is a growing risk factor for hepatocellular carcinoma (HCC). We have previously shown that NASH is an auto-aggressive condition aggravated, amongst others, by T cells. Therefore, we hypothesized that B cells might have a role in disease induction and progression. Our present work highlights that B cells have a dual role in NASH pathogenesis, being implicated in the activation of auto-aggressive T cells and the development of fibrosis via activation of monocyte-derived macrophages by secreted immunoglobulins (e.g., IgA). Furthermore, we show that the absence of B cells prevented HCC development. B cell-intrinsic signalling pathways, secreted immunoglobulins, and interactions of B cells with other immune cells are potential targets for combinatorial NASH therapies against inflammation and fibrosis., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Published
2023
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46. Corrigendum to: "Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort ☆ " [J Hepatol (2020) 505-515].

Author

Anstee QM, Darlay R, Cockell S, Meroni M, Govaere O, Tiniakos D, Burt AD, Bedossa P, Palmer J, Liu YL, Aithal GP, Allison M, Yki-Järvinen H, Vacca M, Dufour JF, Invernizzi P, Prati D, Ekstedt M, Kechagias S, Francque S, Petta S, Bugianesi E, Clement K, Ratziu V, Schattenberg JM, Valenti L, Day CP, Cordell HJ, and Daly AK

Published
2023
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47. A proteo-transcriptomic map of non-alcoholic fatty liver disease signatures.

Author

Govaere O, Hasoon M, Alexander L, Cockell S, Tiniakos D, Ekstedt M, Schattenberg JM, Boursier J, Bugianesi E, Ratziu V, Daly AK, and Anstee QM

Subjects
Adult, Aged, Female, Humans, Male, Middle Aged, Body Mass Index, Cohort Studies, Diabetes Mellitus, Type 2 complications, Disease Progression, Fatty Liver complications, Fatty Liver metabolism, Immunohistochemistry, Liver Cirrhosis complications, Liver Cirrhosis metabolism, Logistic Models, Registries, Single-Cell Gene Expression Analysis, Gene Expression Profiling, Non-alcoholic Fatty Liver Disease complications, Non-alcoholic Fatty Liver Disease diagnosis, Non-alcoholic Fatty Liver Disease genetics, Non-alcoholic Fatty Liver Disease metabolism, Proteomics
Abstract

Non-alcoholic fatty liver disease (NAFLD) is a common, progressive liver disease strongly associated with the metabolic syndrome. It is unclear how progression of NAFLD towards cirrhosis translates into systematic changes in circulating proteins. Here, we provide a detailed proteo-transcriptomic map of steatohepatitis and fibrosis during progressive NAFLD. In this multicentre proteomic study, we characterize 4,730 circulating proteins in 306 patients with histologically characterized NAFLD and integrate this with transcriptomic analysis in paired liver tissue. We identify circulating proteomic signatures for active steatohepatitis and advanced fibrosis, and correlate these with hepatic transcriptomics to develop a proteo-transcriptomic signature of 31 markers. Deconvolution of this signature by single-cell RNA sequencing reveals the hepatic cell types likely to contribute to proteomic changes with disease progression. As an exemplar of use as a non-invasive diagnostic, logistic regression establishes a composite model comprising four proteins (ADAMTSL2, AKR1B10, CFHR4 and TREM2), body mass index and type 2 diabetes mellitus status, to identify at-risk steatohepatitis., (© 2023. The Author(s).)

Published
2023
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48. Quantitative modeling of human liver reveals dysregulation of glycosphingolipid pathways in nonalcoholic fatty liver disease.

Author

Sen P, Govaere O, Sinioja T, McGlinchey A, Geng D, Ratziu V, Bugianesi E, Schattenberg JM, Vidal-Puig A, Allison M, Cockell S, Daly AK, Hyötyläinen T, Anstee QM, and Orešič M

Abstract

Nonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent disease that is associated with multiple metabolic disturbances, yet the metabolic pathways underlying its progression are poorly understood. Here, we studied metabolic pathways of the human liver across the full histological spectrum of NAFLD. We analyzed whole liver tissue transcriptomics and serum metabolomics data obtained from a large, prospectively enrolled cohort of 206 histologically characterized patients derived from the European NAFLD Registry and developed genome-scale metabolic models (GEMs) of human hepatocytes at different stages of NAFLD. We identified several metabolic signatures in the liver and blood of these patients, specifically highlighting the alteration of vitamins (A, E) and glycosphingolipids, and their link with complex glycosaminoglycans in advanced fibrosis. Furthermore, we derived GEMs and identified metabolic signatures of three common NAFLD-associated gene variants (PNPLA3 , TM6SF2 , and HSD17B13) . The study demonstrates dysregulated liver metabolic pathways which may contribute to the progression of NAFLD., Competing Interests: J.M.S. declares Consultancy: Boehringer Ingelheim, BMS, Genfit, Gilead Sciences, Intercept Pharmaceuticals, Madrigal, Novartis, Novo Nordisk, Nordic Bioscience, Pfizer, Roche, Sanofi, Siemens Healthcare GmbH. Research Funding: Gilead Sciences, Boehringer Ingelheim. Speakers Bureau: Falk Foundation MSD Sharp & Dohme GmbH. M.A. reports consultancy/advisory with MedImmune/Astra Zeneca and E3Bio, as well as honoraria from Intercept and grant support from GSK and Takeda. E.B. reports advisory/consulting for BMS, Genfit SA, Gilead, Intercept, and Novartis. Q.M.A. reports grants, personal fees and other from Allergan/Tobira, other from E3Bio, other from Eli Lilly & Company Ltd, other from Galmed, grants, personal fees and other from Genfit SA, personal fees and other from Gilead, other from Grunthal, other from Imperial Innovations, grants and other from Intercept Pharma Europe Ltd, other from Inventiva, other from Janssen, personal fees from Kenes, other from MedImmune, other from NewGene, grants, personal fees and other from Pfizer Ltd, other from Raptor Pharma, grants and other from Novartis Pharma AG, grants from Abbvie, personal fees and other from BMS, grants from GSK, other from NGMBio, other from Madrigal, other from Servier, other from EcoR1, other from 89Bio, other from Altimmune, grants and other from AstraZeneca, other from Axcella, other from Blade, other from BNN Cardio, other from Celgene, other from Cirius, other from CymaBay, other from Genentech, other from HistoIndex, other from Indalo, other from IQVIA, other from Metacrine, other from North Sea Therapeutics, personal fees and other from Novo Nordisk, other from Poxel, other from Terns, other from Viking Therapeutics, grants from Glympse Bio, other from PathAI, outside the submitted work. All other authors declare that they have no competing interests., (© 2022 The Author(s).)

Published
2022
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49. Network medicine for disease module identification and drug repurposing with the NeDRex platform.

Author

Sadegh S, Skelton J, Anastasi E, Bernett J, Blumenthal DB, Galindez G, Salgado-Albarrán M, Lazareva O, Flanagan K, Cockell S, Nogales C, Casas AI, Schmidt HHHW, Baumbach J, Wipat A, and Kacprowski T

Subjects
Algorithms, Computational Biology, Disease classification, Disease genetics, Humans, Knowledge Bases, Workflow, Databases, Factual, Drug Repositioning methods
Abstract

Traditional drug discovery faces a severe efficacy crisis. Repurposing of registered drugs provides an alternative with lower costs and faster drug development timelines. However, the data necessary for the identification of disease modules, i.e. pathways and sub-networks describing the mechanisms of complex diseases which contain potential drug targets, are scattered across independent databases. Moreover, existing studies are limited to predictions for specific diseases or non-translational algorithmic approaches. There is an unmet need for adaptable tools allowing biomedical researchers to employ network-based drug repurposing approaches for their individual use cases. We close this gap with NeDRex, an integrative and interactive platform for network-based drug repurposing and disease module discovery. NeDRex integrates ten different data sources covering genes, drugs, drug targets, disease annotations, and their relationships. NeDRex allows for constructing heterogeneous biological networks, mining them for disease modules, prioritizing drugs targeting disease mechanisms, and statistical validation. We demonstrate the utility of NeDRex in five specific use-cases., (© 2021. The Author(s).)

Published
2021
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50. Transcriptomics Identify Thrombospondin-2 as a Biomarker for NASH and Advanced Liver Fibrosis.

Author

Kozumi K, Kodama T, Murai H, Sakane S, Govaere O, Cockell S, Motooka D, Kakita N, Yamada Y, Kondo Y, Tahata Y, Yamada R, Hikita H, Sakamori R, Kamada Y, Daly AK, Anstee QM, Tatsumi T, Morii E, and Takehara T

Subjects
Adult, Aged, Area Under Curve, Aspartate Aminotransferases blood, Biomarkers blood, Biopsy, Female, Follow-Up Studies, Gene Expression Profiling methods, Humans, Hyaluronic Acid blood, Liver pathology, Liver Cirrhosis diagnosis, Liver Cirrhosis pathology, Male, Middle Aged, Non-alcoholic Fatty Liver Disease diagnosis, Non-alcoholic Fatty Liver Disease pathology, Platelet Count, Prognosis, ROC Curve, Retrospective Studies, Up-Regulation genetics, Liver Cirrhosis blood, Liver Cirrhosis genetics, Non-alcoholic Fatty Liver Disease blood, Non-alcoholic Fatty Liver Disease genetics, Thrombospondins blood, Thrombospondins genetics, Transcriptome genetics
Abstract

Background and Aims: NAFLD is the most common liver disease worldwide. NASH, the progressive form of NAFLD, and advanced fibrosis are associated with poor outcomes. We searched for their noninvasive biomarkers., Approach and Results: Global RNA sequencing of liver tissue from 98 patients with biopsy-proven NAFLD was performed. Unsupervised hierarchical clustering well distinguished NASH from nonalcoholic fatty liver (NAFL), and patients with NASH exhibited molecular abnormalities reflecting their pathological features. Transcriptomic analysis identified proteins up-regulated in NASH and/or advanced fibrosis (stage F3-F4), including matricellular glycoprotein thrombospondin-2 (TSP-2), encoded by the thrombospondin 2 (THBS2) gene. The intrahepatic THBS2 expression level showed the highest areas under the receiver operating characteristic curves (AUROCs) of 0.915 and 0.957 for diagnosing NASH and advanced fibrosis, respectively. THBS2 positively correlated with inflammation and ballooning according to NAFLD activity score, serum aspartate aminotransferase and hyaluronic acid (HA) levels, and NAFLD Fibrosis Score (NFS). THBS2 was associated with extracellular matrix and collagen biosynthesis, platelet activation, caspase-mediated cleavage of cytoskeletal proteins, and immune cell infiltration. Serum TSP-2 expression was measured in 213 patients with biopsy-proven NAFLD, was significantly higher in NASH than in NAFL, and increased parallel to fibrosis stage. The AUROCs for predicting NASH and advanced fibrosis were 0.776 and 0.856, respectively, which were comparable to Fibrosis-4 index, serum HA level, and NFS in advanced fibrosis diagnosis. Serum TSP-2 level and platelet count were independent predictors of NASH and advanced fibrosis. Serum TSP-2 levels could stratify patients with NAFLD according to the risk of hepatic complications, including liver cancer and decompensated cirrhotic events., Conclusions: TSP-2 may be a useful biomarker for NASH and advanced fibrosis diagnosis in patients with NAFLD., (© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Published
2021
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