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Your search keyword '"Hibberd, M.L."' showing total 17 results
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17 results on '"Hibberd, M.L."'

1. Diagnosis of childhood febrile illness using a multi-class blood RNA molecular signature.

Author

Habgood-Coote, D., Wilson, C., Shimizu, C., Barendregt, A.M., Philipsen, R., Galassini, R., Calle, I.R., Workman, L., Agyeman, P.K.A., Ferwerda, G., Anderson, S.T., Berg, J.M. van den, Emonts, M., Carrol, E.D., Fink, C.G., Groot, R. de, Hibberd, M.L., Kanegaye, J., Nicol, M.P., Paulus, S., Pollard, A.J., Salas, A., Secka, F., Schlapbach, L.J., Tremoulet, A.H., Walther, M., Zenz, W., Flier, M. van der, Zar, H.J., Kuijpers, T., Burns, J.C., Martinón-Torres, F., Wright, V.J., Coin, L.J.M., Cunnington, A.J., Herberg, Jethro A., Levin, M., Kaforou, M., Habgood-Coote, D., Wilson, C., Shimizu, C., Barendregt, A.M., Philipsen, R., Galassini, R., Calle, I.R., Workman, L., Agyeman, P.K.A., Ferwerda, G., Anderson, S.T., Berg, J.M. van den, Emonts, M., Carrol, E.D., Fink, C.G., Groot, R. de, Hibberd, M.L., Kanegaye, J., Nicol, M.P., Paulus, S., Pollard, A.J., Salas, A., Secka, F., Schlapbach, L.J., Tremoulet, A.H., Walther, M., Zenz, W., Flier, M. van der, Zar, H.J., Kuijpers, T., Burns, J.C., Martinón-Torres, F., Wright, V.J., Coin, L.J.M., Cunnington, A.J., Herberg, Jethro A., Levin, M., and Kaforou, M.

Abstract

Contains fulltext : 296516.pdf (Publisher’s version ) (Open Access), BACKGROUND: Appropriate treatment and management of children presenting with fever depend on accurate and timely diagnosis, but current diagnostic tests lack sensitivity and specificity and are frequently too slow to inform initial treatment. As an alternative to pathogen detection, host gene expression signatures in blood have shown promise in discriminating several infectious and inflammatory diseases in a dichotomous manner. However, differential diagnosis requires simultaneous consideration of multiple diseases. Here, we show that diverse infectious and inflammatory diseases can be discriminated by the expression levels of a single panel of genes in blood. METHODS: A multi-class supervised machine-learning approach, incorporating clinical consequence of misdiagnosis as a "cost" weighting, was applied to a whole-blood transcriptomic microarray dataset, incorporating 12 publicly available datasets, including 1,212 children with 18 infectious or inflammatory diseases. The transcriptional panel identified was further validated in a new RNA sequencing dataset comprising 411 febrile children. FINDINGS: We identified 161 transcripts that classified patients into 18 disease categories, reflecting individual causative pathogen and specific disease, as well as reliable prediction of broad classes comprising bacterial infection, viral infection, malaria, tuberculosis, or inflammatory disease. The transcriptional panel was validated in an independent cohort and benchmarked against existing dichotomous RNA signatures. CONCLUSIONS: Our data suggest that classification of febrile illness can be achieved with a single blood sample and opens the way for a new approach for clinical diagnosis. FUNDING: European Union's Seventh Framework no. 279185; Horizon2020 no. 668303 PERFORM; Wellcome Trust (206508/Z/17/Z); Medical Research Foundation (MRF-160-0008-ELP-KAFO-C0801); NIHR Imperial BRC.

Published
2023

2. Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations

Author

Kumar, Vikrant, Pouw, R.B., Autio, M.I., Sagmeister, M.G., Phua, Z. Yang, Borghini, L., Wright, V.J., Hoggart, C., Pan, B., Tan, A., Binder, A., Brouwer, M.C.T., Pinnock, E., Groot, R. de, Hazelzet, J., Emonts, M., Flier, M. van der, Reiter, K., Nöthen, M.M., Hoffmann, P., consortium, E., Schlapbach, L.J., Bellos, E., Anderson, S., Secka, F., Martinón-Torres, F., Salas, A., Fink, C., Carrol, E.D., Pollard, A.J., Coin, L.J., Zenz, W., Wouters, D., Ang, L. Teng, Hibberd, M.L., Levin, M., Kuijpers, T.W., Davila, S., Kumar, Vikrant, Pouw, R.B., Autio, M.I., Sagmeister, M.G., Phua, Z. Yang, Borghini, L., Wright, V.J., Hoggart, C., Pan, B., Tan, A., Binder, A., Brouwer, M.C.T., Pinnock, E., Groot, R. de, Hazelzet, J., Emonts, M., Flier, M. van der, Reiter, K., Nöthen, M.M., Hoffmann, P., consortium, E., Schlapbach, L.J., Bellos, E., Anderson, S., Secka, F., Martinón-Torres, F., Salas, A., Fink, C., Carrol, E.D., Pollard, A.J., Coin, L.J., Zenz, W., Wouters, D., Ang, L. Teng, Hibberd, M.L., Levin, M., Kuijpers, T.W., and Davila, S.

Abstract

Contains fulltext : 282924.pdf (Publisher’s version ) (Open Access)

Published
2022

3. Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

Author

Borghini, L., Png, E., Binder, A., Wright, V.J., Pinnock, E., Groot, R. de, Hazelzet, J., Emonts, M., Flier, M. van der, Philipsen, H.L.A., Schlapbach, L.J., Anderson, S., Secka, F., Salas, A., Fink, C., Carrol, E.D., Pollard, A.J., Coin, L.J., Kuijpers, T.W., Martinon-Torres, F., Zenz, W., Levin, M., Hibberd, M.L., Davila, S., Neeleman, C., Deuren, M. van, Kunze, W., Schermann, P., Borghini, L., Png, E., Binder, A., Wright, V.J., Pinnock, E., Groot, R. de, Hazelzet, J., Emonts, M., Flier, M. van der, Philipsen, H.L.A., Schlapbach, L.J., Anderson, S., Secka, F., Salas, A., Fink, C., Carrol, E.D., Pollard, A.J., Coin, L.J., Kuijpers, T.W., Martinon-Torres, F., Zenz, W., Levin, M., Hibberd, M.L., Davila, S., Neeleman, C., Deuren, M. van, Kunze, W., and Schermann, P.

Abstract

Contains fulltext : 204148.pdf (publisher's version ) (Open Access), Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes.

Published
2019

4. ISL1 is a major susceptibility gene for classic bladder exstrophy and a regulator of urinary tract development

Author

Zhang, R., Knapp, M., Suzuki, K., Kajioka, D., Schmidt, J.M., Winkler, J., Yilmaz, O., Pleschka, M., Cao, J., Kockum, C.C., Barker, G., Holmdahl, G., Beaman, G., Keene, D., Woolf, A.S., Cervellione, R.M., Cheng, W., Wilkins, S., Gearhart, J.P., Sirchia, F., Grazia, M. Di, Ebert, A.K., Rosch, W., Ellinger, J., Jenetzky, E., Zwink, N., Feitz, W.F.J., Marcelis, C.L., Schumacher, J., Martinon-Torres, F., Hibberd, M.L., Khor, C.C., Heilmann-Heimbach, S., Barth, S., Boyadjiev, S.A., Brusco, A., Ludwig, M., Newman, W., Nordenskjold, A., Yamada, G., Odermatt, B., Reutter, H., Zhang, R., Knapp, M., Suzuki, K., Kajioka, D., Schmidt, J.M., Winkler, J., Yilmaz, O., Pleschka, M., Cao, J., Kockum, C.C., Barker, G., Holmdahl, G., Beaman, G., Keene, D., Woolf, A.S., Cervellione, R.M., Cheng, W., Wilkins, S., Gearhart, J.P., Sirchia, F., Grazia, M. Di, Ebert, A.K., Rosch, W., Ellinger, J., Jenetzky, E., Zwink, N., Feitz, W.F.J., Marcelis, C.L., Schumacher, J., Martinon-Torres, F., Hibberd, M.L., Khor, C.C., Heilmann-Heimbach, S., Barth, S., Boyadjiev, S.A., Brusco, A., Ludwig, M., Newman, W., Nordenskjold, A., Yamada, G., Odermatt, B., and Reutter, H.

Abstract

Contains fulltext : 173200.pdf (publisher's version ) (Open Access), Previously genome-wide association methods in patients with classic bladder exstrophy (CBE) found association with ISL1, a master control gene expressed in pericloacal mesenchyme. This study sought to further explore the genetics in a larger set of patients following-up on the most promising genomic regions previously reported. Genotypes of 12 markers obtained from 268 CBE patients of Australian, British, German Italian, Spanish and Swedish origin and 1,354 ethnically matched controls and from 92 CBE case-parent trios from North America were analysed. Only marker rs6874700 at the ISL1 locus showed association (p = 2.22 x 10-08). A meta-analysis of rs6874700 of our previous and present study showed a p value of 9.2 x 10-19. Developmental biology models were used to clarify the location of ISL1 activity in the forming urinary tract. Genetic lineage analysis of Isl1-expressing cells by the lineage tracer mouse model showed Isl1-expressing cells in the urinary tract of mouse embryos at E10.5 and distributed in the bladder at E15.5. Expression of isl1 in zebrafish larvae staged 48 hpf was detected in a small region of the developing pronephros. Our study supports ISL1 as a major susceptibility gene for CBE and as a regulator of urinary tract development.

Published
2017

5. Association between telomere length and risk of cancer and non-neoplastic diseases a mendelian randomization study

Author

Haycock, P. (Philip), Burgess, S. (Stephen), Nounu, A. (Aayah), Zheng, J. (Jie), Okoli, G.N. (George N.), Bowden, J., Wade, K.H. (Kaitlin Hazel), Timpson, N.J. (Nicholas J.), Evans, D.M. (David M.), Willeit, P. (Peter), Aviv, A. (Abraham), Gaunt, T.R. (Tom), Hemani, G., Mangino, M. (Massimo), Ellis, H.P. (Hayley Patricia), Kurian, K.M. (Kathreena M.), Pooley, K.A. (Karen A.), Eeles, R. (Rosalind), Lee, J.E. (Jeffrey E.), Fang, S. (Shenying), Chen, W.V. (Wei V.), Law, M.H. (Matthew H.), Bowdler, L.M. (Lisa M.), Iles, M.M. (Mark M.), Yang, Q. (Qiong Fang), Worrall, B.B. (Bradford B.), Markus, H.S. (Hugh), Hung, R.J. (Rayjean J.), Amos, W., Spurdle, A.B. (Amanda), Thompson, D. (Deborah), O'Mara, T.A. (Tracy A.), Wolpin, B. (Brian), Amundadottir, L. (Laufey), Stolzenberg-Solomon, R. (Rachael), Trichopoulou, A. (Antonia), Onland-Moret, N.C. (Charlotte), Lund, E. (Eiliv), Duell, E.J. (Eric), Canzian, F. (Federico), Severi, G. (Gianluca), Overvad, K. (Kim), Gunter, M.J. (Marc J.), Tumino, R. (Rosario), Svenson, U. (Ulrika), Rij, A.M. (Andre) van, Baas, A.F. (Annette), Bown, N., Samani, N.J. (Nilesh), Van t'Hof, F.N.G. (Femke N.G.), Tromp, G. (Gerard), Jones, G.T. (Gregory T.), Kuivaniemi, H. (Helena), Elmore, J.R. (James R.), Johansson, M. (Mattias), Mckay, J. (James), Scelo, G. (Ghislaine), Carreras-Torres, R. (Robert), Gaborieau, V. (Valerie), Brennan, P. (Paul), Bracci, P.M. (Paige M.), Neale, R.E. (Rachel E.), Olson, S.H. (Sara H.), Gallinger, S. (Steve), Li, D. (Donghui), Olson, S.H. (Sara), Risch, H. (Harvey), Klein, A.P. (Alison P.), Han, J., Abnet, C.C. (Christian C.), Freedman, N.D. (Neal D.), Taylor, P.R. (Phil R.), Maris, J.M. (John), Aben, K.K.H. (Katja), Kiemeney, L.A.L.M. (Bart), Vermeulen, S.H.H.M. (Sita), Wiencke, J.K. (John K.), Walsh, K.M. (Kyle M.), Wrensch, M. (Margaret), Rice, T. (Terri), Turnbull, C. (Clare), Litchfield, K. (Kevin), Paternoster, L. (Lavinia), Standl, M. (Marie), Abecasis, G.R. (Gonçalo), SanGiovanni, J.P. (John Paul), Li, Y. (Yong), Mijatovic, V. (Vladan), Sapkota, Y. (Yadav), Low, S.-K. (Siew-Kee), Zondervan, K.T. (Krina), Montgomery, G.W. (Grant W.), Nyholt, D.R. (Dale), Heel, D.A. (David) van, Hunt, K. (Karen), Arking, D.E. (Dan), Ashar, F.N. (Foram N.), Sotoodehnia, N. (Nona), Woo, D. (Daniel), Rosand, J. (Jonathan), Comeau, M.E. (Mary E.), Brown, W.M. (W. Mark), Silverman, E. (Edwin), Hokanson, J.E. (John E.), Cho, M.H. (Michael), Hui, J. (Jennie), Ferreira, M.A. (Manuel A.), Thompson, P.J. (Philip J.), Morrison, A.C. (Alanna), Felix, J.F. (Janine F.), Smith, N.L. (Nicholas L.), Christiano, A.M. (Angela), Petukhova, L. (Lynn), Betz, R.C. (Regina), Fan, X. (Xing), Zhang, X. (Xuejun), Zhu, C. (Caihong), Langefeld, C.D. (Carl), Thompson, S.D. (Susan D.), Wang, F. (Feijie), Lin, X. (Xu), Schwartz, D.A. (David A.), Fingerlin, T.E. (Tasha E.), Rotter, J.I. (Jerome I.), Cotch, M.F. (Mary Frances), Jensen, R.A. (Richard A.), Munz, M. (Matthias), Dommisch, H. (Henrik), Schaefer, A. (Antje), Han, F. (Fang), Ollila, H.M., Hillary, R.P. (Ryan P.), Albagha, O.M.E. (Omar M.), Ralston, S.H. (Stuart), Zeng, C. (Chenjie), Zheng, W. (Wei), Shu, X.-O. (Xiao-Ou), Reis, A. (André), Uebe, S. (Steffen), Hüffmeier, U. (Ulrike), Kawamura, Y. (Yoshiya), Otowa, T. (Takeshi), Sasaki, T. (Tsukasa), Hibberd, M.L. (Martin), Davila, S. (Sonia), Xie, G. (Gang), Siminovitch, K.A. (Katherine), Bei, J.-X. (Jin-Xin), Zeng, Y.X., Försti, A. (Asta), Chen, B. (Bowang), Landi, S. (Stefano), Franke, A. (Andre), Fischer, A. (Annegret), Ellinghaus, D. (David), Flores, C. (Carlos), Noth, I. (Imre), Ma, S.-F. (Shwu-Fan), Foo, J.-N. (Jia-Nee), Liu, J. (Jianjun), Kim, J.-W. (Jong-Won), Cox, D.G. (David), Delattre, O. (Olivier), Mirabeau, O. (Olivier), Skibola, C.F. (Christine F.), Tang, C.S. (Clara S.), Garcia-Barcelo, M., Chang, K.-P. (Kai-Ping), Su, W.-H. (Wen-Hui), Chang, Y.-S. (Yu-Sun), Martin, N.G. (Nicholas G.), Gordon, S.D. (Scott D.), Wade, T.D. (Tracey D.), Lee, C. (Chaeyoung), Kubo, M. (Michiaki), Cha, P.-C. (Pei-Chieng), Nakamura, Y. (Yusuke), Levy, D. (Daniel), Kimura, M. (Masayuki), Hwang, S.-J. (Shih-Jen), Hunt, S.C. (Steven), Spector, T.D. (Timothy), Soranzo, N. (Nicole), Manichaikul, A.W. (Ani W.), Barr, R.G. (Graham), Kahali, B. (Bratati), Speliotes, E.K. (Elizabeth), Yerges-Armstrong, L.M. (Laura), Cheng, C-Y. (Ching-Yu), Jonas, J.B. (Jost B.), Wong, T.Y. (Tien Yin), Fogh, I. (Isabella), Lin, K. (Kuang), Powell, J. (John), Rice, K. (Kenneth), Relton, C.L. (Caroline), Martin, R.M. (Richard M.), Smith, A.V. (Davey), Haycock, P. (Philip), Burgess, S. (Stephen), Nounu, A. (Aayah), Zheng, J. (Jie), Okoli, G.N. (George N.), Bowden, J., Wade, K.H. (Kaitlin Hazel), Timpson, N.J. (Nicholas J.), Evans, D.M. (David M.), Willeit, P. (Peter), Aviv, A. (Abraham), Gaunt, T.R. (Tom), Hemani, G., Mangino, M. (Massimo), Ellis, H.P. (Hayley Patricia), Kurian, K.M. (Kathreena M.), Pooley, K.A. (Karen A.), Eeles, R. (Rosalind), Lee, J.E. (Jeffrey E.), Fang, S. (Shenying), Chen, W.V. (Wei V.), Law, M.H. (Matthew H.), Bowdler, L.M. (Lisa M.), Iles, M.M. (Mark M.), Yang, Q. (Qiong Fang), Worrall, B.B. (Bradford B.), Markus, H.S. (Hugh), Hung, R.J. (Rayjean J.), Amos, W., Spurdle, A.B. (Amanda), Thompson, D. (Deborah), O'Mara, T.A. (Tracy A.), Wolpin, B. (Brian), Amundadottir, L. (Laufey), Stolzenberg-Solomon, R. (Rachael), Trichopoulou, A. (Antonia), Onland-Moret, N.C. (Charlotte), Lund, E. (Eiliv), Duell, E.J. (Eric), Canzian, F. (Federico), Severi, G. (Gianluca), Overvad, K. (Kim), Gunter, M.J. (Marc J.), Tumino, R. (Rosario), Svenson, U. (Ulrika), Rij, A.M. (Andre) van, Baas, A.F. (Annette), Bown, N., Samani, N.J. (Nilesh), Van t'Hof, F.N.G. (Femke N.G.), Tromp, G. (Gerard), Jones, G.T. (Gregory T.), Kuivaniemi, H. (Helena), Elmore, J.R. (James R.), Johansson, M. (Mattias), Mckay, J. (James), Scelo, G. (Ghislaine), Carreras-Torres, R. (Robert), Gaborieau, V. (Valerie), Brennan, P. (Paul), Bracci, P.M. (Paige M.), Neale, R.E. (Rachel E.), Olson, S.H. (Sara H.), Gallinger, S. (Steve), Li, D. (Donghui), Olson, S.H. (Sara), Risch, H. (Harvey), Klein, A.P. (Alison P.), Han, J., Abnet, C.C. (Christian C.), Freedman, N.D. (Neal D.), Taylor, P.R. (Phil R.), Maris, J.M. (John), Aben, K.K.H. (Katja), Kiemeney, L.A.L.M. (Bart), Vermeulen, S.H.H.M. (Sita), Wiencke, J.K. (John K.), Walsh, K.M. (Kyle M.), Wrensch, M. (Margaret), Rice, T. (Terri), Turnbull, C. (Clare), Litchfield, K. (Kevin), Paternoster, L. (Lavinia), Standl, M. (Marie), Abecasis, G.R. (Gonçalo), SanGiovanni, J.P. (John Paul), Li, Y. (Yong), Mijatovic, V. (Vladan), Sapkota, Y. (Yadav), Low, S.-K. (Siew-Kee), Zondervan, K.T. (Krina), Montgomery, G.W. (Grant W.), Nyholt, D.R. (Dale), Heel, D.A. (David) van, Hunt, K. (Karen), Arking, D.E. (Dan), Ashar, F.N. (Foram N.), Sotoodehnia, N. (Nona), Woo, D. (Daniel), Rosand, J. (Jonathan), Comeau, M.E. (Mary E.), Brown, W.M. (W. Mark), Silverman, E. (Edwin), Hokanson, J.E. (John E.), Cho, M.H. (Michael), Hui, J. (Jennie), Ferreira, M.A. (Manuel A.), Thompson, P.J. (Philip J.), Morrison, A.C. (Alanna), Felix, J.F. (Janine F.), Smith, N.L. (Nicholas L.), Christiano, A.M. (Angela), Petukhova, L. (Lynn), Betz, R.C. (Regina), Fan, X. (Xing), Zhang, X. (Xuejun), Zhu, C. (Caihong), Langefeld, C.D. (Carl), Thompson, S.D. (Susan D.), Wang, F. (Feijie), Lin, X. (Xu), Schwartz, D.A. (David A.), Fingerlin, T.E. (Tasha E.), Rotter, J.I. (Jerome I.), Cotch, M.F. (Mary Frances), Jensen, R.A. (Richard A.), Munz, M. (Matthias), Dommisch, H. (Henrik), Schaefer, A. (Antje), Han, F. (Fang), Ollila, H.M., Hillary, R.P. (Ryan P.), Albagha, O.M.E. (Omar M.), Ralston, S.H. (Stuart), Zeng, C. (Chenjie), Zheng, W. (Wei), Shu, X.-O. (Xiao-Ou), Reis, A. (André), Uebe, S. (Steffen), Hüffmeier, U. (Ulrike), Kawamura, Y. (Yoshiya), Otowa, T. (Takeshi), Sasaki, T. (Tsukasa), Hibberd, M.L. (Martin), Davila, S. (Sonia), Xie, G. (Gang), Siminovitch, K.A. (Katherine), Bei, J.-X. (Jin-Xin), Zeng, Y.X., Försti, A. (Asta), Chen, B. (Bowang), Landi, S. (Stefano), Franke, A. (Andre), Fischer, A. (Annegret), Ellinghaus, D. (David), Flores, C. (Carlos), Noth, I. (Imre), Ma, S.-F. (Shwu-Fan), Foo, J.-N. (Jia-Nee), Liu, J. (Jianjun), Kim, J.-W. (Jong-Won), Cox, D.G. (David), Delattre, O. (Olivier), Mirabeau, O. (Olivier), Skibola, C.F. (Christine F.), Tang, C.S. (Clara S.), Garcia-Barcelo, M., Chang, K.-P. (Kai-Ping), Su, W.-H. (Wen-Hui), Chang, Y.-S. (Yu-Sun), Martin, N.G. (Nicholas G.), Gordon, S.D. (Scott D.), Wade, T.D. (Tracey D.), Lee, C. (Chaeyoung), Kubo, M. (Michiaki), Cha, P.-C. (Pei-Chieng), Nakamura, Y. (Yusuke), Levy, D. (Daniel), Kimura, M. (Masayuki), Hwang, S.-J. (Shih-Jen), Hunt, S.C. (Steven), Spector, T.D. (Timothy), Soranzo, N. (Nicole), Manichaikul, A.W. (Ani W.), Barr, R.G. (Graham), Kahali, B. (Bratati), Speliotes, E.K. (Elizabeth), Yerges-Armstrong, L.M. (Laura), Cheng, C-Y. (Ching-Yu), Jonas, J.B. (Jost B.), Wong, T.Y. (Tien Yin), Fogh, I. (Isabella), Lin, K. (Kuang), Powell, J. (John), Rice, K. (Kenneth), Relton, C.L. (Caroline), Martin, R.M. (Richard M.), and Smith, A.V. (Davey)

Abstract

IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer ca

Published
2017
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6. Diagnosis of Childhood Tuberculosis and Host RNA Expression in Africa

Author

Anderson, S.T., Kaforou, M., Brent, A.J., Wright, V.J., Banwell, C.M., Chagaluka, G., Crampin, A.C., Dockrell, H.M., French, N., Hamilton, M.S., Hibberd, M.L., Kern, F., Langford, P.R., Ling, L., Mlotha, R., Ottenhoff, T.H.M., Pienaar, S., Pillay, V., Scott, J.A.G., Twahir, H., Wilkinson, R.J., Coin, L.J., Heyderman, R.S., Levin, M., Eley, B., ILULU Consortium, and KIDS TB Study Grp

Subjects
Tuberculosis, biology, Latent tuberculosis, business.industry, Host (biology), 1. No poverty, wa_395, General Medicine, Disease, biology.organism_classification, medicine.disease, Article, 3. Good health, Mycobacterium tuberculosis, qu_58.7, Tuberculosis diagnosis, Immunology, wf_220, ws_280, Medicine, Population study, wf_200, Differential diagnosis, business
Abstract

Background\ud \ud Improved diagnostic tests for tuberculosis in children are needed. We hypothesized that transcriptional signatures of host blood could be used to distinguish tuberculosis from other diseases in African children who either were or were not infected with the human immunodeficiency virus (HIV).\ud \ud Methods\ud \ud The study population comprised prospective cohorts of children who were undergoing evaluation for suspected tuberculosis in South Africa (655 children), Malawi (701 children), and Kenya (1599 children). Patients were assigned to groups according to whether the diagnosis was culture-confirmed tuberculosis, culture-negative tuberculosis, diseases other than tuberculosis, or latent tuberculosis infection. Diagnostic signatures distinguishing tuberculosis from other diseases and from latent tuberculosis infection were identified from genomewide analysis of RNA expression in host blood.\ud \ud Results\ud \ud We identified a 51-transcript signature distinguishing tuberculosis from other diseases in the South African and Malawian children (the discovery cohort). In the Kenyan children (the validation cohort), a risk score based on the signature for tuberculosis and for diseases other than tuberculosis showed a sensitivity of 82.9% (95% confidence interval [CI], 68.6 to 94.3) and a specificity of 83.6% (95% CI, 74.6 to 92.7) for the diagnosis of culture-confirmed tuberculosis. Among patients with cultures negative for Mycobacterium tuberculosis who were treated for tuberculosis (those with highly probable, probable, or possible cases of tuberculosis), the estimated sensitivity was 62.5 to 82.3%, 42.1 to 80.8%, and 35.3 to 79.6%, respectively, for different estimates of actual tuberculosis in the groups. In comparison, the sensitivity of the Xpert MTB/RIF assay for molecular detection of M. tuberculosis DNA in cases of culture-confirmed tuberculosis was 54.3% (95% CI, 37.1 to 68.6), and the sensitivity in highly probable, probable, or possible cases was an estimated 25.0 to 35.7%, 5.3 to 13.3%, and 0%, respectively; the specificity of the assay was 100%.\ud \ud Conclusions\ud \ud RNA expression signatures provided data that helped distinguish tuberculosis from other diseases in African children with and those without HIV infection. (Funded by the European Union Action for Diseases of Poverty Program and others).

Published
2014

7. A genome wide association study of pulmonary tuberculosis susceptibility in Indonesians.

Author

Png, E., Alisjahbana, B., Sahiratmadja, E., Marzuki, S., Nelwan, R., Balabanova, Y., Nikolayevskyy, V., Drobniewski, F., Nejentsev, S., Adnan, I., Vosse, E. van de, Hibberd, M.L., Crevel, R. van, Ottenhoff, T.H., Seielstad, M., Png, E., Alisjahbana, B., Sahiratmadja, E., Marzuki, S., Nelwan, R., Balabanova, Y., Nikolayevskyy, V., Drobniewski, F., Nejentsev, S., Adnan, I., Vosse, E. van de, Hibberd, M.L., Crevel, R. van, Ottenhoff, T.H., and Seielstad, M.

Abstract

Contains fulltext : 110652.pdf (publisher's version ) (Open Access), BACKGROUND: There is reason to expect strong genetic influences on the risk of developing active pulmonary tuberculosis (TB) among latently infected individuals. Many of the genome wide linkage and association studies (GWAS) to date have been conducted on African populations. In order to identify additional targets in genetically dissimilar populations, and to enhance our understanding of this disease, we performed a multi-stage GWAS in a Southeast Asian cohort from Indonesia. METHODS: In stage 1, we used the Affymetrix 100 K SNP GeneChip marker set to genotype 259 Indonesian samples. After quality control filtering, 108 cases and 115 controls were analyzed for association of 95,207 SNPs. In stage 2, we attempted validation of 2,453 SNPs with promising associations from the first stage, in 1,189 individuals from the same Indonesian cohort, and finally in stage 3 we selected 251 SNPs from this stage to test TB association in an independent Caucasian cohort (n = 3,760) from Russia. RESULTS: Our study suggests evidence of association (P = 0.0004-0.0067) for 8 independent loci (nominal significance P < 0.05), which are located within or near the following genes involved in immune signaling: JAG1, DYNLRB2, EBF1, TMEFF2, CCL17, HAUS6, PENK and TXNDC4. CONCLUSIONS: Mechanisms of immune defense suggested by some of the identified genes exhibit biological plausibility and may suggest novel pathways involved in the host containment of infection with TB.

Published
2012

8. Genome-wide expression profiling identifies type 1 interferon response pathways in active tuberculosis

Author

Ottenhoff, T.H., Dass, R.H., Yang, N., Zhang, M.M., Wong, H.E., Sahiratmadja, E., Khor, C.C., Alisjahbana, B., van Crevel, R., Marzuki, S., Seielstad, M., van de Vosse, E., Hibberd, M.L., Ottenhoff, T.H., Dass, R.H., Yang, N., Zhang, M.M., Wong, H.E., Sahiratmadja, E., Khor, C.C., Alisjahbana, B., van Crevel, R., Marzuki, S., Seielstad, M., van de Vosse, E., and Hibberd, M.L.

Abstract

Contains fulltext : 108027.pdf (publisher's version ) (Open Access), Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), remains the leading cause of mortality from a single infectious agent. Each year around 9 million individuals newly develop active TB disease, and over 2 billion individuals are latently infected with M.tb worldwide, thus being at risk of developing TB reactivation disease later in life. The underlying mechanisms and pathways of protection against TB in humans, as well as the dynamics of the host response to M.tb infection, are incompletely understood. We carried out whole-genome expression profiling on a cohort of TB patients longitudinally sampled along 3 time-points: during active infection, during treatment, and after completion of curative treatment. We identified molecular signatures involving the upregulation of type-1 interferon (alpha/beta) mediated signaling and chronic inflammation during active TB disease in an Indonesian population, in line with results from two recent studies in ethnically and epidemiologically different populations in Europe and South Africa. Expression profiles were captured in neutrophil-depleted blood samples, indicating a major contribution of lymphocytes and myeloid cells. Expression of type-1 interferon (alpha/beta) genes mediated was also upregulated in the lungs of M.tb infected mice and in infected human macrophages. In patients, the regulated gene expression-signature normalized during treatment, including the type-1 interferon mediated signaling and a concurrent opposite regulation of interferon-gamma. Further analysis revealed IL15RA, UBE2L6 and GBP4 as molecules involved in the type-I interferon response in all three experimental models. Our data is highly suggestive that the innate immune type-I interferon signaling cascade could be used as a quantitative tool for monitoring active TB disease, and provide evidence that components of the patient's blood gene expression signature bear similarities to the pulmonary and macrophage response to mycobacterial infec

Published
2012

9. Genome-wide association studies in Asians confirm the involvement of ATOH7 and TGFBR3, and further identify CARD10 as a novel locus influencing optic discarea

Author

Khor, C.C., Ramdas, W.D. (Wishal), Vithana, E.N. (Eranga), Cornes, B.K. (Belinda), Sim, X. (Xueling), Tay, W.-T., Saw, S-M. (Seang-Mei), Lavanya, Y.Z., Wu, R. (Renyi), Wang, J.J. (Jie Jin), Mitchell, P. (Paul), Uitterlinden, A.G. (André), Rivadeneira Ramirez, F. (Fernando), Teo, Y.-Y., Chia, K.-S., Seielstad, M. (Mark), Hibberd, M.L. (Martin), Vingerling, J.R. (Hans), Klaver, C.C.W. (Caroline), Jansonius, N.M. (Nomdo), Tai, E.S. (Shyong), Wong, T.Y. (Tien Yin), Tikka-Kleemola, P. (Päivi), Aung, T. (Tin), Khor, C.C., Ramdas, W.D. (Wishal), Vithana, E.N. (Eranga), Cornes, B.K. (Belinda), Sim, X. (Xueling), Tay, W.-T., Saw, S-M. (Seang-Mei), Lavanya, Y.Z., Wu, R. (Renyi), Wang, J.J. (Jie Jin), Mitchell, P. (Paul), Uitterlinden, A.G. (André), Rivadeneira Ramirez, F. (Fernando), Teo, Y.-Y., Chia, K.-S., Seielstad, M. (Mark), Hibberd, M.L. (Martin), Vingerling, J.R. (Hans), Klaver, C.C.W. (Caroline), Jansonius, N.M. (Nomdo), Tai, E.S. (Shyong), Wong, T.Y. (Tien Yin), Tikka-Kleemola, P. (Päivi), and Aung, T. (Tin)

Abstract

Damage to the optic nerve (e.g. from glaucoma) has an adverse and often irreversible impact on vision. Earlier studies have suggested that the size of the optic nerve head could be governed by hereditary factors. We conducted a genome-wide association study (GWAS) on 4445 Singaporean individuals (n 5 2132 of Indian and n 5 2313 of Malay ancestry, respectively), with replication in Rotterdam, the Netherlands (n 5 9326 individuals of Caucasian ancestry) using the most widely reported parameter for optic disc traits, the optic disc area. We identified a novel locus on chromosome 22q13.1, CARD10, which strongly associates with optic disc area in both Singaporean cohorts as well as in the Rotterdam Study (RS; rs9607469, perallele change in optic disc area 5 0.051 mm2; Pmeta5 2.73310-12) and confirmed the association between CDC7/TGFBR3 (lead single nucleotide polymorphism (SNP) rs1192415, Pmeta5 7.57310-17) and ATOH7 (lead SNP rs7916697, Pmeta5 2.00 3 10-15) and optic disc area in Asians. This is the first Asian-based GWAS on optic disc area, identifying a novel locus for the optic disc area, but also confirming the results found in Caucasian persons suggesting that there are general genetic determinants applicable to the size of the optic disc across different ethnicities.

Published
2011
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10. Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease.

Author

Davila, S., Wright, V.J., Khor, C.C., Sim, K.S., Binder, A., Breunis, W.B., Inwald, D., Nadel, S., Betts, H., Carrol, E.D., Groot, R. de, Hermans, P.W.M., Hazelzet, J., Emonts, M., Lim, C.C., Kuijpers, T.W., Martinon-Torres, F., Salas, A., Zenz, W., Levin, M., Hibberd, M.L., Davila, S., Wright, V.J., Khor, C.C., Sim, K.S., Binder, A., Breunis, W.B., Inwald, D., Nadel, S., Betts, H., Carrol, E.D., Groot, R. de, Hermans, P.W.M., Hazelzet, J., Emonts, M., Lim, C.C., Kuijpers, T.W., Martinon-Torres, F., Salas, A., Zenz, W., Levin, M., and Hibberd, M.L.

Abstract

1 september 2010, Contains fulltext : 88509.pdf (publisher's version ) (Closed access), Meningococcal disease is an infection caused by Neisseria meningitidis. Genetic factors contribute to host susceptibility and progression to disease, but the genes responsible for disease development are largely unknown. We report here a genome-wide association study for host susceptibility to meningococcal disease using 475 individuals with meningococcal disease (cases) and 4,703 population controls from the UK. We performed, in Western European and South European cohorts (consisting of 968 cases and 1,376 controls), two replication studies for the most significant SNPs. A cluster of complement factor SNPs replicated independently in both cohorts, including SNPs within complement factor H (CFH) (rs1065489 (p.936D

Published
2010

11. Genome-wide association identifies multiple ulcerative colitis susceptibility loci.

Author

McGovern, D.P., Gardet, A., Torkvist, L., Goyette, P., Essers, J., Taylor, K.D., Neale, B.M., Ong, R.T., Lagace, C., Li, C., Green, T., Stevens, C.R., Beauchamp, C., Fleshner, P.R., Carlson, M., D'Amato, M., Halfvarson, J., Hibberd, M.L., Lordal, M., Padyukov, L., Andriulli, A., Colombo, E., Latiano, A., Palmieri, O., Bernard, E.J., Deslandres, C., Hommes, D.W., Jong, D.J. de, Stokkers, P.C., Weersma, R.K., Sharma, Y., Silverberg, M.S., Cho, J.H., Wu, J., Roeder, K., Brant, S.R., Schumm, L.P., Duerr, R.H., Dubinsky, M.C., Glazer, N.L., Haritunians, T., Ippoliti, A., Melmed, G.Y., Siscovick, D.S., Vasiliauskas, E.A., Targan, S.R., Annese, V., Wijmenga, C., Pettersson, S., Rotter, J.I., Xavier, R.J., Daly, M.J., Rioux, J.D., Seielstad, M., McGovern, D.P., Gardet, A., Torkvist, L., Goyette, P., Essers, J., Taylor, K.D., Neale, B.M., Ong, R.T., Lagace, C., Li, C., Green, T., Stevens, C.R., Beauchamp, C., Fleshner, P.R., Carlson, M., D'Amato, M., Halfvarson, J., Hibberd, M.L., Lordal, M., Padyukov, L., Andriulli, A., Colombo, E., Latiano, A., Palmieri, O., Bernard, E.J., Deslandres, C., Hommes, D.W., Jong, D.J. de, Stokkers, P.C., Weersma, R.K., Sharma, Y., Silverberg, M.S., Cho, J.H., Wu, J., Roeder, K., Brant, S.R., Schumm, L.P., Duerr, R.H., Dubinsky, M.C., Glazer, N.L., Haritunians, T., Ippoliti, A., Melmed, G.Y., Siscovick, D.S., Vasiliauskas, E.A., Targan, S.R., Annese, V., Wijmenga, C., Pettersson, S., Rotter, J.I., Xavier, R.J., Daly, M.J., Rioux, J.D., and Seielstad, M.

Abstract

01 april 2010, Contains fulltext : 88540.pdf (publisher's version ) (Closed access), Ulcerative colitis is a chronic, relapsing inflammatory condition of the gastrointestinal tract with a complex genetic and environmental etiology. In an effort to identify genetic variation underlying ulcerative colitis risk, we present two distinct genome-wide association studies of ulcerative colitis and their joint analysis with a previously published scan, comprising, in aggregate, 2,693 individuals with ulcerative colitis and 6,791 control subjects. Fifty-nine SNPs from 14 independent loci attained an association significance of P < 10(-5). Seven of these loci exceeded genome-wide significance (P < 5 x 10(-8)). After testing an independent cohort of 2,009 cases of ulcerative colitis and 1,580 controls, we identified 13 loci that were significantly associated with ulcerative colitis (P < 5 x 10(-8)), including the immunoglobulin receptor gene FCGR2A, 5p15, 2p16 and ORMDL3 (orosomucoid1-like 3). We confirmed association with 14 previously identified ulcerative colitis susceptibility loci, and an analysis of acknowledged Crohn's disease loci showed that roughly half of the known Crohn's disease associations are shared with ulcerative colitis. These data implicate approximately 30 loci in ulcerative colitis, thereby providing insight into disease pathogenesis.

Published
2010

12. Genetic association and expression studies indicate a role of toll-like receptor 8 in pulmonary tuberculosis.

Author

Davila, S., Hibberd, M.L., Hari Dass, R., Wong, H.E., Sahiratmadja, E., Bonnard, C., Alisjahbana, B., Szeszko, J.S., Balabanova, Y., Drobniewski, F., Crevel, R. van, Vosse, E. van de, Nejentsev, S., Ottenhoff, T.H., Seielstad, M., Davila, S., Hibberd, M.L., Hari Dass, R., Wong, H.E., Sahiratmadja, E., Bonnard, C., Alisjahbana, B., Szeszko, J.S., Balabanova, Y., Drobniewski, F., Crevel, R. van, Vosse, E. van de, Nejentsev, S., Ottenhoff, T.H., and Seielstad, M.

Abstract

Contains fulltext : 70181.pdf (publisher's version ) (Open Access), Despite high rates of exposure, only 5-10% of people infected with Mycobacterium tuberculosis will develop active tuberculosis (TB) disease, suggesting a significant role for genetic variation in the human immune response to this infection. Here, we studied TB association and expression of 18 genes involved in the Toll-like receptor (TLR) pathways. Initially, we genotyped 149 sequence polymorphisms in 375 pulmonary TB patients and 387 controls from Indonesia. We found that four polymorphisms in the TLR8 gene on chromosome X showed evidence of association with TB susceptibility in males, including a non-synonymous polymorphism rs3764880 (Met1Val; P = 0.007, odds ratio (OR) = 1.8, 95% c.i. = 1.2-2.7). We genotyped these four TLR8 polymorphisms in an independent collection of 1,837 pulmonary TB patients and 1,779 controls from Russia and again found evidence of association in males (for rs3764880 P = 0.03, OR = 1.2, 95% c.i. = 1.02-1.48). Combined evidence for association is P = 1.2x10(-3)-6x10(-4). In addition, a quantitative PCR analysis indicated that TLR8 transcript levels are significantly up-regulated in patients during the acute phase of disease (P = 9.36x10(-5)), relative to baseline levels following successful chemotherapy. A marked increase in TLR8 protein expression was also observed directly in differentiated macrophages upon infection with M. bovis bacille Calmette-Guerin (BCG). Taken together, our results provide evidence, for the first time, of a role for the TLR8 gene in susceptibility to pulmonary TB across different populations.

Published
2008

13. Analysis of association of the TIRAP (MAL) S180L variant and tuberculosis in three populations.

Author

Nejentsev, S., Thye, T., Szeszko, J.S., Stevens, H., Balabanova, Y., Chinbuah, A.M., Hibberd, M.L., Vosse, E. van de, Alisjahbana, B., Crevel, R. van, Ottenhoff, T.H., Png, E., Drobniewski, F., Todd, J.A., Seielstad, M., Horstmann, R.D., Nejentsev, S., Thye, T., Szeszko, J.S., Stevens, H., Balabanova, Y., Chinbuah, A.M., Hibberd, M.L., Vosse, E. van de, Alisjahbana, B., Crevel, R. van, Ottenhoff, T.H., Png, E., Drobniewski, F., Todd, J.A., Seielstad, M., and Horstmann, R.D.

Abstract

Contains fulltext : 69793.pdf (publisher's version ) (Closed access)

Published
2008

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