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6. Array-based DNA methylation profiling in follicular lymphoma

Author

O'Riain, C, O'Shea, D M, Yang, Y, Le Dieu, R, Gribben, J G, Summers, K, Yeboah-Afari, J, Bhaw-Rosun, L, Fleischmann, C, Mein, C A, Crook, T, Smith, P, Kelly, G, Rosenwald, A, Ott, G, Campo, E, Rimsza, L M, Smeland, E B, Chan, W C, Johnson, N, Gascoyne, R D, Reimer, S, Braziel, R M, Wright, G W, Staudt, L M, Lister, T A, and Fitzgibbon, J

Published
2009
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9. Array-based DNA methylation profiling in follicular lymphoma

Author

OʼRiain, C, OʼShea, D M, Yang, Y, Le Dieu, R, Gribben, J G, Summers, K, Yeboah-Afari, J, Bhaw-Rosun, L, Fleischmann, C, Mein, C A, Crook, T, Smith, P, Kelly, G, Rosenwald, A, Ott, G, Campo, E, Rimsza, L M, Smeland, E B, Chan, W C, Johnson, N, Gascoyne, R D, Reimer, S, Braziel, R M, Wright, G W, Staudt, L M, Lister, T A, and Fitzgibbon, J

Published
2009

17. Clinical and molecular features of harlequin ichthyosis: O-13

Author

KELSELL, D. P., NORGETT, E. E., UNSWORTH, H., TEH, M. T., CULLUP, T., MEIN, C. A., DOPPING-HEPENSTAL, P. J., KENNEDY, C. T., TAYLOR, A. E.M., ILCHYSHYN, A., MOSS, C., PAIGE, H. D., GOODYEAR, H., DALE, B. A., TADINI, G., HARPER, J. I., YOUNG, UK B.D., LEIGH, I. M., EADY, R. A., and OʼTOOLE, E. A.

Published
2005

24. Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease

Author

Trynka, G, Hunt, K, Bockett, N, Romanos, J, Mistry, V, Szperl, A, Bakker, S, Bardella, M, Bhaw Rosun, L, Castillejo, G, De la Concha, E, De Almeida, R, Dias, K, Van Diemen, C, Dubois, P, Duerr, R, Edkins, S, Franke, L, Fransen, K, Gutierrez, J, Heap, G, Hrdlickova, B, Hunt, S, Izurieta, L, Izzo, V, Joosten, L, Langford, C, Mazzilli, M, Mein, C, Midah, V, Mitrovic, M, Mora, B, Morelli, M, Nutland, S, Núñez, C, Onengut Gumuscu, S, Pearce, K, Platteel, M, Polanco, I, Potter, S, Ribes Koninckx, C, Ricaño Ponce, I, Rich, S, Rybak, A, Santiago, J, Senapati, S, Sood, A, Szajewska, H, Troncone, R, Varadé, J, Wallace, C, Wolters, V, Zhernakova, A, Spanish Consortium on the Genetics of Coeliac, D, PreventCD Study, G, Wellcome Trust Case Control, C, Thelma, B, Cukrowska, B, Urcelay, E, Bilbao, J, Mearin, M, Barisani, D, Barrett, J, Plagnol, V, Deloukas, P, Wijmenga, C, Van Heel, D, Hunt, KA, Bockett, NA, Bakker, SF, Bardella, MT, De la Concha, EG, De Almeida, RC, Dias, KR, Van Diemen, CC, Dubois, PC, Duerr, RH, Heap, GA, Izurieta, LP, Joosten, LA, Mazzilli, MC, Mein, CA, Rich, SS, Santiago, JL, Wolters, VM, Spanish Consortium on the Genetics of Coeliac Disease, PreventCD Study Group, Wellcome Trust Case Control Consortium, Thelma, BK, Bilbao, JR, Mearin, ML, Barrett, JC, Van Heel,DA, BARISANI, DONATELLA, Trynka, G, Hunt, K, Bockett, N, Romanos, J, Mistry, V, Szperl, A, Bakker, S, Bardella, M, Bhaw Rosun, L, Castillejo, G, De la Concha, E, De Almeida, R, Dias, K, Van Diemen, C, Dubois, P, Duerr, R, Edkins, S, Franke, L, Fransen, K, Gutierrez, J, Heap, G, Hrdlickova, B, Hunt, S, Izurieta, L, Izzo, V, Joosten, L, Langford, C, Mazzilli, M, Mein, C, Midah, V, Mitrovic, M, Mora, B, Morelli, M, Nutland, S, Núñez, C, Onengut Gumuscu, S, Pearce, K, Platteel, M, Polanco, I, Potter, S, Ribes Koninckx, C, Ricaño Ponce, I, Rich, S, Rybak, A, Santiago, J, Senapati, S, Sood, A, Szajewska, H, Troncone, R, Varadé, J, Wallace, C, Wolters, V, Zhernakova, A, Spanish Consortium on the Genetics of Coeliac, D, PreventCD Study, G, Wellcome Trust Case Control, C, Thelma, B, Cukrowska, B, Urcelay, E, Bilbao, J, Mearin, M, Barisani, D, Barrett, J, Plagnol, V, Deloukas, P, Wijmenga, C, Van Heel, D, Hunt, KA, Bockett, NA, Bakker, SF, Bardella, MT, De la Concha, EG, De Almeida, RC, Dias, KR, Van Diemen, CC, Dubois, PC, Duerr, RH, Heap, GA, Izurieta, LP, Joosten, LA, Mazzilli, MC, Mein, CA, Rich, SS, Santiago, JL, Wolters, VM, Spanish Consortium on the Genetics of Coeliac Disease, PreventCD Study Group, Wellcome Trust Case Control Consortium, Thelma, BK, Bilbao, JR, Mearin, ML, Barrett, JC, Van Heel,DA, and BARISANI, DONATELLA

Abstract

Using variants from the 1000 Genomes Project pilot European CEU dataset and data from additional resequencing studies, we densely genotyped 183 non-HLA risk loci previously associated with immune-mediated diseases in 12,041 individuals with celiac disease (cases) and 12,228 controls. We identified 13 new celiac disease risk loci reaching genome-wide significance, bringing the number of known loci (including the HLA locus) to 40. We found multiple independent association signals at over one-third of these loci, a finding that is attributable to a combination of common, low-frequency and rare genetic variants. Compared to previously available data such as those from HapMap3, our dense genotyping in a large sample collection provided a higher resolution of the pattern of linkage disequilibrium and suggested localization of many signals to finer scale regions. In particular, 29 of the 54 fine-mapped signals seemed to be localized to single genes and, in some instances, to gene regulatory elements. Altogether, we define the complex genetic architecture of the risk regions of and refine the risk signals for celiac disease, providing the next step toward uncovering the causal mechanisms of the disease. © 2011 Nature America, Inc. All rights reserved.

Published
2011

25. Multiple common variants for celiac disease influencing immune gene expression

Author

Dubois, P, Trynka, G, Franke, L, Hunt, K, Romanos, J, Curtotti, A, Zhernakova, A, Heap, G, Adány, R, Aromaa, A, Bardella, M, van den Berg, L, Bockett, N, de la Concha, E, Dema, B, Fehrmann, R, Fernández Arquero, M, Fiatal, S, Grandone, E, Green, P, Groen, H, Gwilliam, R, Houwen, R, Hunt, S, Kaukinen, K, Kelleher, D, Korponay Szabo, I, Kurppa, K, Macmathuna, P, Mäki, M, Mazzilli, M, Mccann, O, Mearin, M, Mein, C, Mirza, M, Mistry, V, Mora, B, Morley, K, Mulder, C, Murray, J, Núñez, C, Oosterom, E, Ophoff, R, Polanco, I, Peltonen, L, Platteel, M, Rybak, A, Salomaa, V, Schweizer, J, Sperandeo, M, Tack, G, Turner, G, Veldink, J, Verbeek, W, Weersma, R, Wolters, V, Urcelay, E, Cukrowska, B, Greco, L, Neuhausen, S, Mcmanus, R, Barisani, D, Deloukas, P, Barrett, J, Saavalainen, P, Wijmenga, C, van Heel, D, Dubois, PCA, Hunt, KA, Heap, GAR, Bardella, MT, van den Berg, LH, Bockett, NA, de la Concha, EG, Fehrmann, RSN, Green, PM, Groen, HJM, Houwen, RHJ, Hunt, SE, MacMathuna, P, Mazzilli, MC, McCann, OT, Mearin, ML, Mein, CA, Mirza, MM, Morley, KI, Mulder, CJ, Murray, JA, Ophoff, RA, Schweizer, JJ, Sperandeo, MP, Tack, GJ, Veldink, JH, Verbeek, WHM, Weersma, RK, Wolters, VM, Neuhausen, SL, McManus, R, Barrett, JC, van Heel, DA, BARISANI, DONATELLA, Dubois, P, Trynka, G, Franke, L, Hunt, K, Romanos, J, Curtotti, A, Zhernakova, A, Heap, G, Adány, R, Aromaa, A, Bardella, M, van den Berg, L, Bockett, N, de la Concha, E, Dema, B, Fehrmann, R, Fernández Arquero, M, Fiatal, S, Grandone, E, Green, P, Groen, H, Gwilliam, R, Houwen, R, Hunt, S, Kaukinen, K, Kelleher, D, Korponay Szabo, I, Kurppa, K, Macmathuna, P, Mäki, M, Mazzilli, M, Mccann, O, Mearin, M, Mein, C, Mirza, M, Mistry, V, Mora, B, Morley, K, Mulder, C, Murray, J, Núñez, C, Oosterom, E, Ophoff, R, Polanco, I, Peltonen, L, Platteel, M, Rybak, A, Salomaa, V, Schweizer, J, Sperandeo, M, Tack, G, Turner, G, Veldink, J, Verbeek, W, Weersma, R, Wolters, V, Urcelay, E, Cukrowska, B, Greco, L, Neuhausen, S, Mcmanus, R, Barisani, D, Deloukas, P, Barrett, J, Saavalainen, P, Wijmenga, C, van Heel, D, Dubois, PCA, Hunt, KA, Heap, GAR, Bardella, MT, van den Berg, LH, Bockett, NA, de la Concha, EG, Fehrmann, RSN, Green, PM, Groen, HJM, Houwen, RHJ, Hunt, SE, MacMathuna, P, Mazzilli, MC, McCann, OT, Mearin, ML, Mein, CA, Mirza, MM, Morley, KI, Mulder, CJ, Murray, JA, Ophoff, RA, Schweizer, JJ, Sperandeo, MP, Tack, GJ, Veldink, JH, Verbeek, WHM, Weersma, RK, Wolters, VM, Neuhausen, SL, McManus, R, Barrett, JC, van Heel, DA, and BARISANI, DONATELLA

Abstract

We performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects. We genotyped 113 selected SNPs with P(GWAS) < 10(-4) and 18 SNPs from 14 known loci in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome-wide significance (P(combined) < 5 x 10(-8)); most contain genes with immune functions (BACH2, CCR4, CD80, CIITA-SOCS1-CLEC16A, ICOSLG and ZMIZ1), with ETS1, RUNX3, THEMIS and TNFRSF14 having key roles in thymic T-cell selection. There was evidence to suggest associations for a further 13 regions. In an expression quantitative trait meta-analysis of 1,469 whole blood samples, 20 of 38 (52.6%) tested loci had celiac risk variants correlated (P < 0.0028, FDR 5%) with cis gene expression.

Published
2010

26. A novel protective prion protein variant that colocalizes with Kuru exposure

Author

Mead, S., Whitfield, Jerome, Poulter, M., Shah, P., Uphill, J., Campbell, T., Al-Dujaily, H., Hummerich, H., Beck, J., Mein, C., Verzilli, C., Whittaker, J., Alpers, Michael Philip, Collinge, J., Mead, S., Whitfield, Jerome, Poulter, M., Shah, P., Uphill, J., Campbell, T., Al-Dujaily, H., Hummerich, H., Beck, J., Mein, C., Verzilli, C., Whittaker, J., Alpers, Michael Philip, and Collinge, J.

Published
2009

27. Novel and recurring ABCA12 mutations associated with harlequin ichthyosis : implications for prenatal diagnosis

Author

Thomas, A C, Sinclair, C, Mahmud, N, Cullup, T, Mellerio, J E, Harper, J, Dale, B A, Turc-Carel, C, Hohl, D, McGrath, J A, Vahlquist, Anders, Hellström-Pigg, Maritta, Ganemo, A, Metcalfe, K, Mein, C A, O'Toole, E A, Kelsell, D P, Thomas, A C, Sinclair, C, Mahmud, N, Cullup, T, Mellerio, J E, Harper, J, Dale, B A, Turc-Carel, C, Hohl, D, McGrath, J A, Vahlquist, Anders, Hellström-Pigg, Maritta, Ganemo, A, Metcalfe, K, Mein, C A, O'Toole, E A, and Kelsell, D P

Published
2008
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30. Yes-associated protein (YAP) functions as a tumor suppressor in breast

Author

Yuan, M, primary, Tomlinson, V, additional, Lara, R, additional, Holliday, D, additional, Chelala, C, additional, Harada, T, additional, Gangeswaran, R, additional, Manson-Bishop, C, additional, Smith, P, additional, Danovi, S A, additional, Pardo, O, additional, Crook, T, additional, Mein, C A, additional, Lemoine, N R, additional, Jones, L J, additional, and Basu, S, additional

Published
2008
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33. NO ASSOCIATION OF THE WNK1 GENE WITH ESSENTIAL HYPERTENSION IN THE MRC BRIGHT STUDY

Author

Newhouse, S., primary, Dobson, R., additional, Wallace, C., additional, Pembroke, J., additional, Garcia, E., additional, Mein, C., additional, Clayton, D., additional, Samani, N., additional, Dominiczak, A., additional, Brown, M., additional, Webster, J., additional, Lathrop, G., additional, Farrall, M., additional, Connell, J., additional, Caulfield, M., additional, and Munroe, P., additional

Published
2004
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35. A new variation in the promoter region, the −604 C>T, and the Leu72Met polymorphism of the ghrelin gene are associated with protection to insulin resistance.

Author

Zavarella, S., Petrone, A., Zampetti, S., Gueorguiev, M., Spoletini, M., Mein, C. A., Leto, G., Korbonits, M., and Buzzetti, R.

Subjects
GENETIC polymorphisms, INSULIN resistance, NUCLEOTIDES, OBESITY, NUTRITION disorders
Abstract

Objective:Previous studies suggested that polymorphisms in the coding region of the preproghrelin were involved in the etiology of obesity and might modulate glucose-induced insulin secretion. We evaluated the association of a new variation, −604C>T, in the promoter region of the ghrelin gene, of Leu72Met (247C>A) and of Gln90Leu (265A>T), all haplotype-tagging single nucleotide polymorphisms (SNPs), with measures of insulin sensitivity in 1420 adult individuals.Research methods:The three SNPs were genotyped using ABI PRISM 7900 HT Sequence Detection System. We used multiple linear regression analysis for quantitative traits and THESIAS software for haplotype analysis.Results:We observed a protective effect exerted by Met72 variant of Leu72Met SNP on insulin resistance parameters; a significant decreasing trend from Leu/Leu to Leu/Met and to Met/Met homozygous subjects in triglycerides, fasting insulin levels and HOMA-IR index (P=0.02, 0.01 and 0.003, respectively), and, consistently, an increase in ghrelin levels (P=0.003) was found. A significant decrease from CC to TC and to TT genotypes in insulin levels and HOMA-IR index was also detected (P=0.00l for both), but only in subjects homozygous for Leu72, where the protective effect of Met72 was not present. The haplotype analysis results supported the data obtained by the evaluation of each single SNP, showing the highest value of insulin levels and HOMA-IR index in the −604c247c haplotype intermediate value in −604T247C and lowest value in −604C247A.Conclusion:Our observations suggest a protective role of the Met72 variant and of −604 T allele in modulating insulin resistance. These SNPs or an unknown functional variant in linkage disequilibrium could increase ghrelin levels and probably insulin sensitivity.International Journal of Obesity (2008) 32, 663–668; doi:10.1038/sj.ijo.0803766; published online 11 December 2007 [ABSTRACT FROM AUTHOR]

Published
2008
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36. Evaluation of single nucleotide polymorphism typing with invader on PCR amplicons and its automation.

Author

Mein, C A, Barratt, B J, Dunn, M G, Siegmund, T, Smith, A N, Esposito, L, Nutland, S, Stevens, H E, Wilson, A J, Phillips, M S, Jarvis, N, Law, S, de Arruda, M, and Todd, J A

Abstract

Large-scale pharmacogenetics and complex disease association studies will require typing of thousands of single-nucleotide polymorphisms (SNPs) in thousands of individuals. Such projects would benefit from a genotyping system with accuracy >99% and a failure rate <5% on a simple, reliable, and flexible platform. However, such a system is not yet available for routine laboratory use. We have evaluated a modification of the previously reported Invader SNP-typing chemistry for use in a genotyping laboratory and tested its automation. The Invader technology uses a Flap Endonuclease for allele discrimination and a universal fluorescence resonance energy transfer (FRET) reporter system. Three hundred and eighty-four individuals were genotyped across a panel of 36 SNPs and one insertion/deletion polymorphism with Invader assays using PCR product as template, a total of 14,208 genotypes. An average failure rate of 2.3% was recorded, mostly associated with PCR failure, and the typing was 99.2% accurate when compared with genotypes generated with established techniques. An average signal-to-noise ratio (9:1) was obtained. The high degree of discrimination for single base changes, coupled with homogeneous format, has allowed us to deploy liquid handling robots in a 384-well microtitre plate format and an automated end-point capture of fluorescent signal. Simple semiautomated data interpretation allows the generation of approximately 25,000 genotypes per person per week, which is 10-fold greater than gel-based SNP typing and microsatellite typing in our laboratory. Savings on labor costs are considerable. We conclude that Invader chemistry using PCR products as template represents a useful technology for typing large numbers of SNPs rapidly and efficiently.

Published
2000

40. Breast and ovarian carcinoma in the same patient, metastasis or dual primaries?

Author

Baykal, C., Tulunay, G., Özfuttu, A., Jacobs, I., Mein, C. A., Küçükali, T., Ayse AYHAN, Baykal, C., Tulunay, G., Özfuttu, A., Jacobs, I., Mein, C.A., Küçükali, T., Ayhan, A., and Yeditepe Üniversitesi

Subjects
Breast carcinoma, skin and connective tissue diseases, Ovarian carcinoma, Clonality, Metastasis
Abstract

Metastases to breast from extramammary primaries are very rare events. These lesions differ from primary breast carcinomas and they are known to have poor prognosis. Discrimination between metastatic tumors and primary breast carcinomas are usually done by clinical and pathological evaluation including immunohistochemistry. Here we report an unusual case of ovarian epithelial carcinoma which was initially diagnosed as to give metastasis to breast 17 months later than the first diagnosis of ovarian carcinoma. Clonality evaluation revealed that breast and ovarian tumors were metachronous dual primaries.

43. Negligible impact of rare autoimmune-locus coding-region variants on missing heritability

Author

Hunt, K. A., Mistry, V., Bockett, N. A., Ahmad, T., Ban, M., Barker, J. N., Barrett, J. C., Blackburn, H., Brand, O. J., Burren, O., Capon, F., Compston, A., Gough, S. C. L., Jostins, L., Kong, Y., Lee, J. C., Lek, M., MacArthur, D. G., Mansfield, J. C., Mathew, C. G., Mein, C. A., Mirza, M., Nutland, S., Onengut-Gumuscu, S., Papouli, E., Parkes, M., Rich, S. S., Sawcer, S., Satsangi, J., Simmonds, M. J., Trembath, R. C., Walker, N. M., Wozniak, E., Todd, J. A., Simpson, M. A., Plagnol, V., van Heel, D. A., Hunt, K. A., Mistry, V., Bockett, N. A., Ahmad, T., Ban, M., Barker, J. N., Barrett, J. C., Blackburn, H., Brand, O. J., Burren, O., Capon, F., Compston, A., Gough, S. C. L., Jostins, L., Kong, Y., Lee, J. C., Lek, M., MacArthur, D. G., Mansfield, J. C., Mathew, C. G., Mein, C. A., Mirza, M., Nutland, S., Onengut-Gumuscu, S., Papouli, E., Parkes, M., Rich, S. S., Sawcer, S., Satsangi, J., Simmonds, M. J., Trembath, R. C., Walker, N. M., Wozniak, E., Todd, J. A., Simpson, M. A., Plagnol, V., and van Heel, D. A.

Abstract

Genome-wide association studies (GWAS) have identified common variants of modest-effect size at hundreds of loci for common autoimmune diseases; however, a substantial fraction of heritability remains unexplained, to which rare variants may contribute. To discover rare variants and test them for association with a phenotype, most studies re-sequence a small initial sample size and then genotype the discovered variants in a larger sample set. This approach fails to analyse a large fraction of the rare variants present in the entire sample set. Here we perform simultaneous amplicon-sequencing-based variant discovery and genotyping for coding exons of 25 GWAS risk genes in 41,911 UK residents of white European origin, comprising 24,892 subjects with six autoimmune disease phenotypes and 17,019 controls, and show that rare coding-region variants at known loci have a negligible role in common autoimmune disease susceptibility. These results do not support the rare-variant synthetic genome-wide-association hypothesis (in which unobserved rare causal variants lead to association detected at common tag variants). Many known autoimmune disease risk loci contain multiple, independently associated, common and low-frequency variants, and so genes at these loci are a priori stronger candidates for harbouring rare coding-region variants than other genes. Our data indicate that the missing heritability for common autoimmune diseases may not be attributable to the rare coding-region variant portion of the allelic spectrum, but perhaps, as others have proposed, may be a result of many common-variant loci of weak effect. © 2013 Macmillan Publishers Limited. All rights reserved.

44. Negligible impact of rare autoimmune-locus coding-region variants on missing heritability

Author

Hunt, K. A., Mistry, V., Bockett, N. A., Ahmad, T., Ban, M., Barker, J. N., Barrett, J. C., Blackburn, H., Brand, O. J., Burren, O., Capon, F., Compston, A., Gough, S. C. L., Jostins, L., Kong, Y., Lee, J. C., Lek, M., MacArthur, D. G., Mansfield, J. C., Mathew, C. G., Mein, C. A., Mirza, M., Nutland, S., Onengut-Gumuscu, S., Papouli, E., Parkes, M., Rich, S. S., Sawcer, S., Satsangi, J., Simmonds, M. J., Trembath, R. C., Walker, N. M., Wozniak, E., Todd, J. A., Simpson, M. A., Plagnol, V., van Heel, D. A., Hunt, K. A., Mistry, V., Bockett, N. A., Ahmad, T., Ban, M., Barker, J. N., Barrett, J. C., Blackburn, H., Brand, O. J., Burren, O., Capon, F., Compston, A., Gough, S. C. L., Jostins, L., Kong, Y., Lee, J. C., Lek, M., MacArthur, D. G., Mansfield, J. C., Mathew, C. G., Mein, C. A., Mirza, M., Nutland, S., Onengut-Gumuscu, S., Papouli, E., Parkes, M., Rich, S. S., Sawcer, S., Satsangi, J., Simmonds, M. J., Trembath, R. C., Walker, N. M., Wozniak, E., Todd, J. A., Simpson, M. A., Plagnol, V., and van Heel, D. A.

Abstract

Genome-wide association studies (GWAS) have identified common variants of modest-effect size at hundreds of loci for common autoimmune diseases; however, a substantial fraction of heritability remains unexplained, to which rare variants may contribute. To discover rare variants and test them for association with a phenotype, most studies re-sequence a small initial sample size and then genotype the discovered variants in a larger sample set. This approach fails to analyse a large fraction of the rare variants present in the entire sample set. Here we perform simultaneous amplicon-sequencing-based variant discovery and genotyping for coding exons of 25 GWAS risk genes in 41,911 UK residents of white European origin, comprising 24,892 subjects with six autoimmune disease phenotypes and 17,019 controls, and show that rare coding-region variants at known loci have a negligible role in common autoimmune disease susceptibility. These results do not support the rare-variant synthetic genome-wide-association hypothesis (in which unobserved rare causal variants lead to association detected at common tag variants). Many known autoimmune disease risk loci contain multiple, independently associated, common and low-frequency variants, and so genes at these loci are a priori stronger candidates for harbouring rare coding-region variants than other genes. Our data indicate that the missing heritability for common autoimmune diseases may not be attributable to the rare coding-region variant portion of the allelic spectrum, but perhaps, as others have proposed, may be a result of many common-variant loci of weak effect. © 2013 Macmillan Publishers Limited. All rights reserved.

46. Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study

Author

Rautanen, Anna, Mills, Tara C., Gordon, Anthony C., Hutton, Paula, Steffens, Michael, Nuamah, Rosamond, Chiche, Jean-Daniel, Parks, Tom, Chapman, Stephen J., Davenport, Emma E., Elliott, Katherine S., Bion, Julian, Lichtner, Peter, Meitinger, Thomas, Wienker, Thomas F., Caulfield, Mark, Mein, Charles, Bloos, Frank, Bobek, Ilona, Cotogni, Paolo, Sramek, Vladimir, Sarapuu, Silver, Kobilay, Makbule, Ranieri, V Marco, Rello, Jordi, Sirgo, Gonzalo, Weiss, Yoram G., Russwurm, Stefan, Schneider, E. Marion, Reinhart, Konrad, Holloway, Paul A. H., Knight, Julian C., Garrard, Chris S., Russell, James A., Walley, Keith R., Stüber, Frank, Hill, Adrian V S., Hinds, Charles J., Universitat Autònoma de Barcelona, National Institute for Health Research, Rautanen A, Mills TC, Gordon AC, Hutton P, Steffens M, Nuamah R, Chiche JD, Parks T, Chapman SJ, Davenport EE, Elliott KS, Bion J, Lichtner P, Meitinger T, Wienker TF, Caulfield MJ, Mein C, Bloos F, Bobek I, Cotogni P, Sramek V, Sarapuu S, Kobilay M, RANIERI, VITO MARCO, Rello J, Sirgo G, Weiss YG, Russwurm S, Schneider EM, Reinhart K, Holloway PA, Knight JC, Garrard CS, Russell JA, Walley KR, Stüber F, Hill AV, Hinds CJ, and ESICM/ECCRN GenOSept Investigators

Subjects
Male, INFECTIOUS-DISEASE, Respiratory System, Genome-wide association study, SUSCEPTIBILITY, Cohort Studies, ESICM/ECCRN GenOSept Investigators, EPIDEMIOLOGY, PHOSPHORYLATION, Hazard ratio, Middle Aged, Protein-Tyrosine Kinases, 3. Good health, Sepsis continues to be a major cause of death, disability, and health-care expenditure worldwide. Despite evidence suggesting that host genetics can influence sepsis outcomes, no specific loci have y, Cohort, Female, Life Sciences & Biomedicine, Cohort study, Genetic Markers, Pulmonary and Respiratory Medicine, medicine.medical_specialty, UNITED-STATES, 610 Medicine & health, 1117 Public Health and Health Services, Sepsis, Critical Care Medicine, General & Internal Medicine, Internal medicine, Intensive care, MANNOSE-BINDING LECTIN, medicine, Humans, Genetic Predisposition to Disease, POLYMORPHISMS, Science & Technology, business.industry, Septic shock, MORTALITY, SEPTIC SHOCK, 1103 Clinical Sciences, Pneumonia, Odds ratio, medicine.disease, Survival Analysis, TYROSINE-KINASE FER, Immunology, business, Genome-Wide Association Study, 1199 Other Medical and Health Sciences
Abstract

Background: Sepsis continues to be a major cause of death, disability, and health-care expenditure worldwide. Despite evidence suggesting that host genetics can influence sepsis outcomes, no specific loci have yet been convincingly replicated. The aim of this study was to identify genetic variants that influence sepsis survival. Methods: We did a genome-wide association study in three independent cohorts of white adult patients admitted to intensive care units with sepsis, severe sepsis, or septic shock (as defined by the International Consensus Criteria) due to pneumonia or intra-abdominal infection (cohorts 1-3, n=2534 patients). The primary outcome was 28 day survival. Results for the cohort of patients with sepsis due to pneumonia were combined in a meta-analysis of 1553 patients from all three cohorts, of whom 359 died within 28 days of admission to the intensive-care unit. The most significantly associated single nucleotide polymorphisms (SNPs) were genotyped in a further 538 white patients with sepsis due to pneumonia (cohort 4), of whom 106 died. Findings: In the genome-wide meta-analysis of three independent pneumonia cohorts (cohorts 1-3), common variants in the FER gene were strongly associated with survival (p=9·7 × 10-8). Further genotyping of the top associated SNP (rs4957796) in the additional cohort (cohort 4) resulted in a combined p value of 5·6 × 10-8 (odds ratio 0·56, 95% CI 0·45-0·69). In a time-to-event analysis, each allele reduced the mortality over 28 days by 44% (hazard ratio for death 0·56, 95% CI 0·45-0·69; likelihood ratio test p=3·4 × 10-9, after adjustment for age and stratification by cohort). Mortality was 9·5% in patients carrying the CC genotype, 15·2% in those carrying the TC genotype, and 25·3% in those carrying the TT genotype. No significant genetic associations were identified when patients with sepsis due to pneumonia and intra-abdominal infection were combined. Interpretation: We have identified common variants in the FER gene that associate with a reduced risk of death from sepsis due to pneumonia. The FER gene and associated molecular pathways are potential novel targets for therapy or prevention and candidates for the development of biomarkers for risk stratification. Funding: European Commission and the Wellcome Trust.

Published
2015
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47. Multiple common variants for celiac disease influencing immune gene expression

Author

Anna Rybak, Luigi Greco, Joseph A. Murray, Graham A. Heap, Katherine I. Morley, Maria Teresa Bardella, Päivi Saavalainen, Graham Turner, Jeffrey C. Barrett, Alexandra Zhernakova, Veikko Salomaa, Bárbara Dema, Róza Ádány, Lude Franke, Charles A. Mein, Owen T. McCann, Sarah E. Hunt, Roel A. Ophoff, Susan L. Neuhausen, Rudolf S N Fehrmann, Karen A. Hunt, Patrick Dubois, Kalle Kurppa, Roderick H. J. Houwen, Bożena Cukrowska, Nicholas A. Bockett, M. Luisa Mearin, Leena Peltonen, Elena Urcelay, Emilio G. de la Concha, Maria Cristina Mazzilli, Vanisha Mistry, Rinse K. Weersma, Concepción Núñez, Ross McManus, Harry J.M. Groen, Joachim J. Schweizer, Cisca Wijmenga, Gosia Trynka, Greetje J. Tack, Markku Mäki, Alessandra Curtotti, Rhian Gwilliam, Padraic MacMathuna, Maria Pia Sperandeo, Peter M. Green, David A. van Heel, Jihane Romanos, Dermot Kelleher, Ilma Rita Korponay-Szabó, Victorien M. Wolters, Isabel Polanco, Katri Kaukinen, Szilvia Fiatal, Elvira Grandone, Wieke H. M. Verbeek, Arpo Aromaa, Panos Deloukas, Leonard H. van den Berg, Elvira Oosterom, Barbara Mora, Donatella Barisani, Muddassar M. Mirza, Jan H. Veldink, Mathieu Platteel, Chris J. J. Mulder, Miguel Fernández-Arquero, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Stem Cell Aging Leukemia and Lymphoma (SALL), Gastroenterology and hepatology, CCA - Immuno-pathogenesis, Dubois, P, Trynka, G, Franke, L, Hunt, K, Romanos, J, Curtotti, A, Zhernakova, A, Heap, G, Adány, R, Aromaa, A, Bardella, M, van den Berg, L, Bockett, N, de la Concha, E, Dema, B, Fehrmann, R, Fernández Arquero, M, Fiatal, S, Grandone, E, Green, P, Groen, H, Gwilliam, R, Houwen, R, Hunt, S, Kaukinen, K, Kelleher, D, Korponay Szabo, I, Kurppa, K, Macmathuna, P, Mäki, M, Mazzilli, M, Mccann, O, Mearin, M, Mein, C, Mirza, M, Mistry, V, Mora, B, Morley, K, Mulder, C, Murray, J, Núñez, C, Oosterom, E, Ophoff, R, Polanco, I, Peltonen, L, Platteel, M, Rybak, A, Salomaa, V, Schweizer, J, Sperandeo, M, Tack, G, Turner, G, Veldink, J, Verbeek, W, Weersma, R, Wolters, V, Urcelay, E, Cukrowska, B, Greco, L, Neuhausen, S, Mcmanus, R, Barisani, D, Deloukas, P, Barrett, J, Saavalainen, P, Wijmenga, C, and van Heel, D

Subjects
POSITIVE SELECTION, HETERODIMER, Genes, MHC Class I, Gene Expression, Genome-wide association study, Medical and Health Sciences, MHC Class I, 0302 clinical medicine, Immunopathology, RISK VARIANTS, 2.1 Biological and endogenous factors, Aetiology, POPULATION, Genetics, 0303 health sciences, education.field_of_study, THYMUS, Orvostudományok, Single Nucleotide, THYMOCYTES, Biological Sciences, 3. Good health, 030220 oncology & carcinogenesis, Egészségtudományok, Human, Biotechnology, Risk, SUSCEPTIBILITY LOCI, Population, Single-nucleotide polymorphism, CLEC16A, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Meta-Analysis as Topic, Humans, Allele, GENOME-WIDE ASSOCIATION, Polymorphism, education, 030304 developmental biology, Gene Expression Profiling, Human Genome, BIO/13 - BIOLOGIA APPLICATA, ALLELES, RHEUMATOID-ARTHRITIS, Gene expression profiling, Celiac Disease, Genes, Case-Control Studies, genome-wide association rheumatoid-arthritis susceptibility loci positive selection risk variants population alleles thymus heterodimer thymocytes, Digestive Diseases, Genome-Wide Association Study, Developmental Biology
Abstract

We performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects. We genotyped 113 selected SNPs with P(GWAS)

Published
2010
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48. Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease

Author

Trynka, G., Hunt, K.A., Bockett, N.A., Romanos, J., Mistry, V., Szperl, A., Bakker, S.F., Bardella, M.T., Bhaw-Rosun, L., Castillejo, G., Concha, E.G. de la, Almeida, R.C. de, Dias, K.R.M., Diemen, C.C. van, Dubois, P.C.A., Duerr, R.H., Edkins, S., Franke, L., Fransen, K., Gutierrez, J., Heap, G.A.R., Hrdlickova, B., Hunt, S., Izurieta, L.P., Izzo, V., Joosten, L.A.B., Langford, C., Mazzilli, M.C., Mein, C.A., Midah, V., Mitrovic, M., Mora, B., Morelli, M., Nutland, S., Nunez, C., Onengut-Gumuscu, S., Pearce, K., Platteel, M., Polanco, I., Potter, S., Ribes-Koninckx, C., Ricano-Ponce, I., Rich, S.S., Rybak, A., Santiago, J.L., Senapati, S., Sood, A., Szajewska, H., Troncone, R., Varade, J., Wallace, C., Wolters, V.M., Zhernakova, A., Thelma, B.K., Cukrowska, B., Urcelay, E., Bilbao, J.R., Mearin, M.L., Barisani, D., Barrett, J.C., Plagnol, V., Deloukas, P., Wijmenga, C., Heel, D.A. van, Spanish Consortium Genetics Coelia, PreventCD Study Grp, WTCCC, Trynka, G, Hunt, K, Bockett, N, Romanos, J, Mistry, V, Szperl, A, Bakker, S, Bardella, M, Bhaw Rosun, L, Castillejo, G, De la Concha, E, De Almeida, R, Dias, K, Van Diemen, C, Dubois, P, Duerr, R, Edkins, S, Franke, L, Fransen, K, Gutierrez, J, Heap, G, Hrdlickova, B, Hunt, S, Izurieta, L, Izzo, V, Joosten, L, Langford, C, Mazzilli, M, Mein, C, Midah, V, Mitrovic, M, Mora, B, Morelli, M, Nutland, S, Núñez, C, Onengut Gumuscu, S, Pearce, K, Platteel, M, Polanco, I, Potter, S, Ribes Koninckx, C, Ricaño Ponce, I, Rich, S, Rybak, A, Santiago, J, Senapati, S, Sood, A, Szajewska, H, Troncone, R, Varadé, J, Wallace, C, Wolters, V, Zhernakova, A, Spanish Consortium on the Genetics of Coeliac, D, PreventCD Study, G, Wellcome Trust Case Control, C, Thelma, B, Cukrowska, B, Urcelay, E, Bilbao, J, Mearin, M, Barisani, D, Barrett, J, Plagnol, V, Deloukas, P, Wijmenga, C, Van Heel, D, Gastroenterology and hepatology, CCA - Disease profiling, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), and Translational Immunology Groningen (TRIGR)

Subjects
EXPRESSION, Linkage disequilibrium, Population, LOCI, Genome-wide association study, Locus (genetics), Human leukocyte antigen, Biology, PHENOTYPE, Polymorphism, Single Nucleotide, Linkage Disequilibrium, REGION, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Risk Factors, Genetics, RISK VARIANTS, Humans, 1000 Genomes Project, GENOME-WIDE ASSOCIATION, education, Genotyping, POPULATION, 030304 developmental biology, 0303 health sciences, education.field_of_study, celiac disease, GWAS, LARGE-SCALE, BIO/13 - BIOLOGIA APPLICATA, Chromosome Mapping, Pathogenesis and modulation of inflammation Infection and autoimmunity [N4i 1], GENE, Genetic architecture, Celiac Disease, Haplotypes, Genetic Loci, 030220 oncology & carcinogenesis, Case-Control Studies, MAP, Genome-Wide Association Study
Abstract

Using variants from the 1000 Genomes Project pilot European CEU dataset and data from additional resequencing studies, we densely genotyped 183 non-HLA risk loci previously associated with immune-mediated diseases in 12,041 individuals with celiac disease (cases) and 12,228 controls. We identified 13 new celiac disease risk loci reaching genome-wide significance, bringing the number of known loci (including the HLA locus) to 40. We found multiple independent association signals at over one-third of these loci, a finding that is attributable to a combination of common, low-frequency and rare genetic variants. Compared to previously available data such as those from HapMap3, our dense genotyping in a large sample collection provided a higher resolution of the pattern of linkage disequilibrium and suggested localization of many signals to finer scale regions. In particular, 29 of the 54 fine-mapped signals seemed to be localized to single genes and, in some instances, to gene regulatory elements. Altogether, we define the complex genetic architecture of the risk regions of and refine the risk signals for celiac disease, providing the next step toward uncovering the causal mechanisms of the disease. © 2011 Nature America, Inc. All rights reserved.

Published
2011
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49. Mapping chromatin remodelling in glioblastoma identifies epigenetic regulation of key molecular pathways and novel druggable targets.

Author

Vinel C, Boot J, Jin W, Pomella N, Hadaway A, Mein C, Zabet NR, and Marino S

Subjects
Humans, Brain Neoplasms genetics, Brain Neoplasms metabolism, Brain Neoplasms drug therapy, Gene Expression Regulation, Neoplastic, Signal Transduction drug effects, Animals, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells metabolism, Mice, Glioblastoma genetics, Glioblastoma metabolism, Glioblastoma drug therapy, Epigenesis, Genetic, Chromatin Assembly and Disassembly
Abstract

Background: Glioblastoma is the most common and aggressive malignant brain tumour in the adult population and its prognosis is dismal. The heterogeneous nature of the tumour, to which epigenetic dysregulation significantly contributes, is among the main therapeutic challenges of the disease., Results: We have leveraged SYNGN, an experimental pipeline enabling the syngeneic comparison of glioblastoma stem cells and expanded potential stem cell (EPSC)-derived neural stem cells to identify regulatory features driven by chromatin remodelling specifically in glioblastoma stem cells., Conclusions: We show epigenetic regulation of the expression of genes and related signalling pathways contributing to glioblastoma development. We also identify novel epigenetically regulated druggable target genes on a patient-specific level, including SMOX and GABBR2., Competing Interests: Declarations. Ethics approval and consent to participate: The use of human tissue samples was approved by the National Research Ethics Service (NRES), University College London Hospitals NRES Project ref 08/0077 (S Brandner); Amendment 1 17/10/2014. Consent for publication: All authors read and approved the final manuscript. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Published
2025
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50. Single cell sequencing data identify distinct B cell and fibroblast populations in stricturing Crohn's disease.

Author

Humphreys DT, Lewis A, Pan-Castillo B, Berti G, Mein C, Wozniak E, Gordon H, Gadhok R, Minicozzi A, ChinAleong J, Feakins R, Giannoulatou E, James LK, Stagg AJ, Lindsay JO, and Silver A

Subjects
Humans, Male, Female, Adult, Gene Expression Profiling, Crohn Disease genetics, Crohn Disease pathology, Crohn Disease metabolism, Fibroblasts metabolism, Fibroblasts pathology, Single-Cell Analysis methods, B-Lymphocytes metabolism, B-Lymphocytes immunology, B-Lymphocytes pathology
Abstract

Single cell RNA sequencing of human full thickness Crohn's disease (CD) small bowel resection specimens was used to identify potential therapeutic targets for stricturing (S) CD. Using an unbiased approach, 16 cell lineages were assigned within 14,539 sequenced cells from patient-matched SCD and non-stricturing (NSCD) preparations. SCD and NSCD contained identical cell types. Amongst immune cells, B cells and plasma cells were selectively increased in SCD samples. B cell subsets suggested formation of tertiary lymphoid tissue in SCD and compared with NSCD there was an increase in IgG, and a decrease in IgA plasma cells, consistent with their potential role in CD fibrosis. Two Lumican-positive fibroblast subtypes were identified and subclassified based on expression of selectively enriched genes as fibroblast clusters (C) 12 and C9. Cells within these clusters expressed the profibrotic genes Decorin (C12) and JUN (C9). C9 cells expressed ACTA2; ECM genes COL4A1, COL4A2, COL15A1, COL6A3, COL18A1 and ADAMDEC1; LAMB1 and GREM1. GO and KEGG Biological terms showed extracellular matrix and stricture organization associated with C12 and C9, and regulation of WNT pathway genes with C9. Trajectory and differential gene analysis of C12 and C9 identified four sub-clusters. Intra sub-cluster gene analysis detected 13 co-regulated gene modules that aligned along predicted pseudotime trajectories. CXCL14 and ADAMDEC1 were key markers in module 1. Our findings support further investigation of fibroblast heterogeneity and interactions with local and circulating immune cells at earlier time points in fibrosis progression. Breaking these interactions by targeting one or other population may improve therapeutic management for SCD., (© 2024 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Published
2024
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