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2. Association of HLA-DRB1 amino acid residues with giant cell arteritis: genetic association study, meta-analysis and geo-epidemiological investigation

Author

Mackie, SL, Taylor, JC, Haroon-Rashid, L, Martin, S, Dasgupta, B, Gough, A, Green, M, Hordon, L, Jarrett, S, Pease, CT, Barrett, JH, Watts, R, Morgan, AW, UK GCA Consortium, and UKRAG Consortium

Subjects
musculoskeletal diseases, immune system diseases, skin and connective tissue diseases
Abstract

Introduction: Giant cell arteritis (GCA) is an autoimmune disease commonest in Northern Europe and Scandinavia. Previous studies report various associations with HLA-DRB1*04 and HLA-DRB1*01; HLA-DRB1 alleles show a gradient in population prevalence within Europe. Our aims were (1) to determine which amino acid residues within HLA-DRB1 best explained HLA-DRB1 allele susceptibility and protective effects in GCA, seen in UK data combined in meta-analysis with previously published data, and (2) to determine whether the incidence of GCA in different countries is associated with the population prevalence of the HLA-DRB1 alleles that we identified in our meta-analysis. Methods: GCA patients from the UK GCA Consortium were genotyped by using single-strand oligonucleotide polymerization, allele-specific polymerase chain reaction, and direct sequencing. Meta-analysis was used to compare and combine our results with published data, and public databases were used to identify amino acid residues that may explain observed susceptibility/protective effects. Finally, we determined the relationship of HLA-DRB1*04 population carrier frequency and latitude to GCA incidence reported in different countries. Results: In our UK data (225 cases and 1378 controls), HLA-DRB1*04 carriage was associated with GCA susceptibility (odds ratio (OR) = 2.69, P = 1.5×10 −11 ), but HLA-DRB1*01 was protective (adjusted OR = 0.55, P = 0.0046). In meta-analysis combined with 14 published studies (an additional 691 cases and 4038 controls), protective effects were seen from HLA-DR2, which comprises HLA-DRB1*15 and HLA-DRB1*16 (OR = 0.65, P = 8.2×10 −6 ) and possibly from HLA-DRB1*01 (OR = 0.73, P = 0.037). GCA incidence (n = 17 countries) was associated with population HLA-DRB1*04 allele frequency (P = 0.008; adjusted R 2 = 0.51 on univariable analysis, adjusted R 2 = 0.62 after also including latitude); latitude also made an independent contribution. Conclusions: We confirm that HLA-DRB1*04 is a GCA susceptibility allele. The susceptibility data are best explained by amino acid risk residues V, H, and H at positions 11, 13, and 33, contrary to previous suggestions of amino acids in the second hypervariable region. Worldwide, GCA incidence was independently associated both with population frequency of HLA-DRB1*04 and with latitude itself. We conclude that variation in population HLA-DRB1*04 frequency may partly explain variations in GCA incidence and that HLA-DRB1*04 may warrant investigation as a potential prognostic or predictive biomarker.

Published
2015

3. Association of FCGR3A and FCGR3B haplotypes with rheumatoid arthritis and primary Sjögren's syndrome [POSTER PRESENTATION]\ud

Author

Mackie, S., Robinson, J.I., Barrett, J.H., Lawson, C.A., Martin, S., Haroon-Rashid, L., Cooper, D., Bowman, S.J., Pease, C.T., Conaghan, P.G., Green, M., Quinn, M., Isaacs, J.D., Emery, P., and Morgan, A.W.

Abstract

Background \ud \ud \ud Rheumatoid arthritis (RA) is an autoimmune disease that is thought to arise from a complex interaction between multiple genetic factors and environmental triggers. We have previously demonstrated an association between a Fc gamma receptor (FcγR) haplotype and RA in a cross-sectional cohort of RA patients. We have sought to confirm this association in an inception cohort of RA patients and matched controls. We also extended our study to investigate a second autoanti-body associated rheumatic disease, primary Sjögren's syndrome (PSS).\ud \ud Methods \ud \ud The FCGR3A-158F/V and FCGR3B-NA1/NA2 functional polymorphisms were examined for association in an inception cohort of RA patients (n = 448), and a well-characterised PSS cohort (n = 83) from the United Kingdom. Pairwise disequilibrium coefficients (D') were calculated in 267 Blood Service healthy controls. The EHPlus program was used to estimate haplotype frequencies for patients and controls and to determine whether significant linkage disequilibrium was present. A likelihood ratio test is performed to test for differences between the haplotype frequencies in cases and controls. A permutation procedure implemented in this program enabled 1000 permutations to be performed on all haplotype associations to assess significance.\ud \ud \ud Results \ud \ud There was significant linkage disequilibrium between FCGR3A and FCGR3B (D' = -0.445, P = 0.001). There was no significant difference in the FCGR3A or FCGR3B allele or genotype frequencies in the RA or PSS patients compared with controls. However, there was a significant difference in the FCGR3A-FCGR3B haplotype distributions with increased homozygosity for the FCGR3A-FCGR3B 158V-NA2 haplotype in both our inception RA cohort (odds ratio = 2.15, 95% confidence interval = 1.1–4.2 P = 0.027) and PSS (odds ratio = 2.83, 95% confidence interval = 1.0–8.2, P = 0.047) compared with controls. The reference group for these analyses comprised individuals who did not possess a copy of the FCGR3A-FCGR3B 158V-NA2 haplotype.\ud \ud \ud Conclusions \ud \ud We have confirmed our original findings of association between the FCGR3A-FCGR3B 158V-NA2 haplotype and RA in a new inception cohort of RA patients. This suggests that there may be an RA-susceptibility gene at this locus. The significant increased frequency of an identical haplotype in PSS suggests the FcγR genetic locus may contribute to the pathogenesis of diverse autoantibody-mediated rheumatic diseases.\ud \ud

Published
2005

4. Basic Science * 208. Stem Cell Factor Expression is Increased in the Skin of Patients with Systemic Sclerosis and Promotes Proliferation and Migration of Fibroblasts in vitro

Author

Karrar, S., primary, Shiwen, X., additional, Nikotorowicz-Buniak, J., additional, Abraham, D. J., additional, Denton, C., additional, Stratton, R., additional, Bayley, R., additional, Kite, K. A., additional, Clay, E., additional, Smith, J. P., additional, Kitas, G. D., additional, Buckley, C., additional, Young, S. P., additional, Ye, L., additional, Zhang, L., additional, Goodall, J., additional, Gaston, H., additional, Xu, H., additional, Lutalo, P. M., additional, Zhao, Y., additional, Meng Choong, L., additional, Sangle, S., additional, Spencer, J., additional, D'Cruz, D., additional, Rysnik, O. J., additional, McHugh, K., additional, Bowness, P., additional, Rump-Goodrich, L., additional, Mattey, D., additional, Kehoe, O., additional, Middleton, J., additional, Cartwright, A., additional, Schmutz, C., additional, Askari, A., additional, Gardner, D. H., additional, Jeffery, L. E., additional, Raza, K., additional, Sansom, D. M., additional, Fitzpatrick, M., additional, Wallace, G., additional, Young, S., additional, Shaw, J., additional, Hatano, H., additional, Cauli, A., additional, Giles, J. L., additional, Mathieu, A., additional, Kollnberger, S., additional, Webster, S., additional, Ellis, L., additional, O'Brien, L. M., additional, Fitzmaurice, T. J., additional, Nazeer Moideen, A., additional, Evans, L., additional, Osgood, L., additional, Williams, A., additional, Jones, S., additional, Thomas, C., additional, O'Donnell, V., additional, Nowell, M., additional, Ouboussad, L., additional, Savic, S., additional, Dickie, L. J., additional, Hintze, J., additional, Wong, C. H., additional, Cook, G. P., additional, Buch, M., additional, Emery, P., additional, McDermott, M. F., additional, Hardcastle, S. A., additional, Gregson, C. L., additional, Deere, K., additional, Davey Smith, G., additional, Dieppe, P., additional, Tobias, J. H., additional, Dennison, E., additional, Edwards, M., additional, Bennett, J., additional, Coggon, D., additional, Palmer, K., additional, Cooper, C., additional, McWilliams, D., additional, Young, A., additional, Kiely, P. D., additional, Walsh, D., additional, Taylor, H. J., additional, Harding, I., additional, Hutchinson, J., additional, Nelson, I., additional, Blom, A., additional, Tobias, J., additional, Clark, E., additional, Parker, J., additional, Bukhari, M., additional, Jayakumar, K., additional, Kiely, P., additional, Diffin, J., additional, Lunt, M., additional, Marshall, T., additional, Chipping, J., additional, Symmons, D., additional, Verstappen, S., additional, Bluett, J., additional, Bowes, J., additional, Ho, P., additional, McHugh, N., additional, Buden, D., additional, Fitzgerald, O., additional, Barton, A., additional, Glossop, J. R., additional, Nixon, N. B., additional, Emes, R. D., additional, Dawes, P. T., additional, Farrell, W. E., additional, Mattey, D. L., additional, Scott, I. C., additional, Steer, S., additional, Seegobin, S., additional, Hinks, A. M., additional, Eyre, S., additional, Morgan, A., additional, Wilson, A. G., additional, Hocking, L., additional, Wordsworth, P., additional, Worthington, J., additional, Cope, A., additional, Lewis, C. M., additional, Guerra, S., additional, Ahmed, B. A., additional, Abraham, D., additional, Fonseca, C., additional, Robinson, J., additional, Taylor, J., additional, Haroon Rashid, L., additional, Flynn, E., additional, Isaacs, J., additional, Barrett, J. H., additional, Kingston, B., additional, Ahmed, M., additional, Kirwan, J. R., additional, Marshall, R., additional, Chapman, K., additional, Pearson, R., additional, Heycock, C., additional, Kelly, C., additional, Rynne, M., additional, Saravanan, V., additional, Hamilton, J., additional, Saeed, A., additional, Coughlan, R., additional, Carey, J. J., additional, Farah, Z., additional, Matthews, W., additional, Bell, C., additional, Petford, S., additional, Tibbetts, L.-M., additional, Douglas, K. M. J., additional, Holden, W., additional, Ledingham, J., additional, Fletcher, M., additional, Winfield, R., additional, Price, Z., additional, Mackay, K., additional, Dixon, C., additional, Oppong, R., additional, Jowett, S., additional, Nicholls, E., additional, Whitehurst, D., additional, Hill, S., additional, Hammond, A., additional, Hay, E., additional, Dziedzic, K., additional, Righetti, C., additional, Lebmeier, M., additional, Manning, V. L., additional, Hurley, M., additional, Scott, D. L., additional, Choy, E., additional, Bearne, L., additional, Nikiphorou, E., additional, Morris, S., additional, James, D., additional, Wong, E. C., additional, Long, J., additional, Fletcher, A., additional, Holmes, S., additional, Hockey, P., additional, Abbas, M., additional, Chattopadhyay, C., additional, Flint, J., additional, Gayed, M., additional, Schreiber, K., additional, Arthanari, S., additional, Nisar, M., additional, Khamashta, M., additional, Gordon, C., additional, Giles, I., additional, Robson, J., additional, Kiran, A., additional, Maskell, J., additional, Arden, N., additional, Hutchings, A., additional, Emin, A., additional, Culliford, D., additional, Dasgupta, B., additional, Hamilton, W., additional, Luqmani, R., additional, Jethwa, H., additional, Rowczenio, D., additional, Trojer, H., additional, Russell, T., additional, Loeffler, J., additional, Hawkins, P., additional, Lachmann, H., additional, Verma, I., additional, Syngle, A., additional, Krishan, P., additional, Garg, N., additional, McGowan, S. P., additional, Gerrard, D. T., additional, Chinoy, H., additional, Ollier, W. E., additional, Cooper, R. G., additional, Lamb, J. A., additional, Taborda, L., additional, Correia Azevedo, P., additional, Isenberg, D., additional, Leyland, K. M., additional, Judge, A., additional, Hunter, D., additional, Hart, D., additional, Javaid, M. K., additional, Edwards, M. H., additional, Litwic, A. E., additional, Jameson, K. A., additional, Deeg, D., additional, Cushnaghan, J., additional, Aihie Sayer, A., additional, Jagannath, D., additional, Parsons, C., additional, Stoppiello, L., additional, Mapp, P., additional, Ashraf, S., additional, Wilson, D., additional, Hill, R., additional, Scammell, B., additional, Wenham, C., additional, Shore, P., additional, Hodgson, R., additional, Grainger, A., additional, Aaron, J., additional, Hordon, L., additional, Conaghan, P., additional, Bar-Ziv, Y., additional, Beer, Y., additional, Ran, Y., additional, Benedict, S., additional, Halperin, N., additional, Drexler, M., additional, Mor, A., additional, Segal, G., additional, Lahad, A., additional, Haim, A., additional, Rath, U., additional, Morgensteren, D. M., additional, Salai, M., additional, Elbaz, A., additional, Vasishta, V. G., additional, Derrett-Smith, E., additional, Hoyles, R., additional, Khan, K., additional, Ezeonyeji, A., additional, Takhar, G., additional, Ong, V., additional, Loughrey, L., additional, Bissell, L.-A., additional, Hensor, E., additional, Abignano, G., additional, Redmond, A., additional, Del Galdo, F., additional, Hall, F. C., additional, Malaviya, A., additional, Baker, S., additional, Furlong, A., additional, Mitchell, A., additional, Godfrey, A. L., additional, Ruddlesden, M., additional, Hadjinicolaou, A., additional, Hughes, M., additional, Moore, T., additional, O'Leary, N., additional, Tracey, A., additional, Ennis, H., additional, Dinsdale, G., additional, Roberts, C., additional, Herrick, A., additional, Denton, C. P., additional, Guillevin, L., additional, Hunsche, E., additional, Rosenberg, D., additional, Schwierin, B., additional, Scott, M., additional, Krieg, T., additional, Anderson, M., additional, Matucci-Cerinic, M., additional, Alade, R., additional, Xu, S., additional, Nihtyanova, S., additional, Clark, K. E., additional, Tam, F. W. K., additional, Unwin, R., additional, Stratton, R. J., additional, Schreiber, B., additional, Seng Edwin Lim, C., additional, Corsiero, E., additional, Sutcliffe, N., additional, Wardemann, H., additional, Pitzalis, C., additional, Bombardieri, M., additional, Tahir, H., additional, Donnelly, S., additional, Greenwood, M., additional, Smith, T. O., additional, Easton, V., additional, Bacon, H., additional, Jerman, E., additional, Armon, K., additional, Poland, F., additional, Macgregor, A., additional, van der Heijde, D., additional, Sieper, J., additional, Elewaut, D., additional, Pangan, A. L., additional, Nguyen, D., additional, Badenhorst, C., additional, Kirby, S., additional, White, D., additional, Harrison, A., additional, Garcia, J. A., additional, Stebbings, S., additional, MacKay, J. W., additional, Aboelmagd, S., additional, Gaffney, K., additional, Deodhar, A., additional, Braun, J., additional, Mack, M., additional, Hsu, B., additional, Gathany, T., additional, Han, C., additional, Inman, R. D., additional, Cooper-Moss, N., additional, Packham, J., additional, Strauss, V., additional, Freeston, J. E., additional, Coates, L., additional, Nam, J., additional, Moverley, A. R., additional, Helliwell, P., additional, Wakefield, R., additional, Mease, P., additional, Fleischmann, R., additional, Wollenhaupt, J., additional, Kielar, D., additional, Woltering, F., additional, Stach, C., additional, Hoepken, B., additional, Arledge, T., additional, Gladman, D., additional, Coteur, G., additional, Kavanaugh, A., additional, Purcaru, O., additional, McInnes, I., additional, Gottlieb, A. B., additional, Puig, L., additional, Rahman, P., additional, Ritchlin, C., additional, Li, S., additional, Wang, Y., additional, Mendelsohn, A., additional, Doyle, M., additional, Tillett, W., additional, Jadon, D., additional, Shaddick, G., additional, Cavill, C., additional, Robinson, G., additional, Sengupta, R., additional, Korendowych, E., additional, de Vries, C., additional, Thomas, R. C., additional, Shuto, T., additional, Busquets-Perez, N., additional, Marzo-Ortega, H., additional, McGonagle, D., additional, Richards, G., additional, Bingham, S., additional, John Hamlin, P., additional, Adshead, R., additional, Cambridge, S., additional, Suppiah, P., additional, Cullinan, M., additional, Nolan, A., additional, Thompson, W. M., additional, Mathieson, H. R., additional, Mackie, S. L., additional, Bryer, D., additional, Krutikov, M., additional, Gray, L., additional, Bruce, E., additional, Keat, A., additional, Innes, W., additional, Pandit, R., additional, Kay, L., additional, Lapshina, S., additional, Myasoutova, L., additional, Erdes, S., additional, Wallis, D., additional, Waldron, N., additional, Thorne, I., additional, Harris, C., additional, Vohra, K., additional, Khinchi, D., additional, Kaur, L., additional, Jones, A., additional, Harrison, N., additional, Harris, D., additional, Jones, T., additional, Rees, J., additional, Bennett, A., additional, Fazal, S., additional, Tugnet, N., additional, Barkham, N., additional, Basu, N., additional, McClean, A., additional, Harper, L., additional, Amft, E. N., additional, Dhaun, N., additional, Luqmani, R. A., additional, Little, M. A., additional, Jayne, D. R., additional, Flossmann, O., additional, McLaren, J., additional, Kumar, V., additional, Reid, D. M., additional, Macfarlane, G. J., additional, Jones, G., additional, Yates, M., additional, Watts, R. A., additional, Igali, L., additional, Mukhtyar, C., additional, Doll, H., additional, Yew, S., additional, Suppiah, R., additional, Hoglund, P., additional, Jayne, D., additional, Westman, K., additional, Win Maw, W., additional, Patil, P., additional, Williams, M., additional, Adizie, T., additional, Christidis, D., additional, Borg, F., additional, Robertson, A., additional, Croft, A. P., additional, Smith, S., additional, Carr, S., additional, Youssouf, S., additional, Salama, A., additional, Pusey, C., additional, and Morgan, M., additional

Published
2013
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8. Association of HLA-DRB1 amino acid residues with giant cell arteritis: genetic association study, meta-analysis and geo-epidemiological investigation.

Author

Mackie SL, Taylor JC, Haroon-Rashid L, Martin S, Dasgupta B, Gough A, Green M, Hordon L, Jarrett S, Pease CT, Barrett JH, Watts R, and Morgan AW

Subjects
Amino Acids, Gene Frequency genetics, Giant Cell Arteritis diagnosis, Humans, Prospective Studies, Retrospective Studies, United Kingdom epidemiology, Genetic Association Studies methods, Giant Cell Arteritis epidemiology, Giant Cell Arteritis genetics, HLA-DRB1 Chains genetics
Abstract

Introduction: Giant cell arteritis (GCA) is an autoimmune disease commonest in Northern Europe and Scandinavia. Previous studies report various associations with HLA-DRB1*04 and HLA-DRB1*01; HLA-DRB1 alleles show a gradient in population prevalence within Europe. Our aims were (1) to determine which amino acid residues within HLA-DRB1 best explained HLA-DRB1 allele susceptibility and protective effects in GCA, seen in UK data combined in meta-analysis with previously published data, and (2) to determine whether the incidence of GCA in different countries is associated with the population prevalence of the HLA-DRB1 alleles that we identified in our meta-analysis., Methods: GCA patients from the UK GCA Consortium were genotyped by using single-strand oligonucleotide polymerization, allele-specific polymerase chain reaction, and direct sequencing. Meta-analysis was used to compare and combine our results with published data, and public databases were used to identify amino acid residues that may explain observed susceptibility/protective effects. Finally, we determined the relationship of HLA-DRB1*04 population carrier frequency and latitude to GCA incidence reported in different countries., Results: In our UK data (225 cases and 1378 controls), HLA-DRB1*04 carriage was associated with GCA susceptibility (odds ratio (OR) = 2.69, P = 1.5×10(-11)), but HLA-DRB1*01 was protective (adjusted OR = 0.55, P = 0.0046). In meta-analysis combined with 14 published studies (an additional 691 cases and 4038 controls), protective effects were seen from HLA-DR2, which comprises HLA-DRB1*15 and HLA-DRB1*16 (OR = 0.65, P = 8.2×10(-6)) and possibly from HLA-DRB1*01 (OR = 0.73, P = 0.037). GCA incidence (n = 17 countries) was associated with population HLA-DRB1*04 allele frequency (P = 0.008; adjusted R(2) = 0.51 on univariable analysis, adjusted R(2) = 0.62 after also including latitude); latitude also made an independent contribution., Conclusions: We confirm that HLA-DRB1*04 is a GCA susceptibility allele. The susceptibility data are best explained by amino acid risk residues V, H, and H at positions 11, 13, and 33, contrary to previous suggestions of amino acids in the second hypervariable region. Worldwide, GCA incidence was independently associated both with population frequency of HLA-DRB1*04 and with latitude itself. We conclude that variation in population HLA-DRB1*04 frequency may partly explain variations in GCA incidence and that HLA-DRB1*04 may warrant investigation as a potential prognostic or predictive biomarker.

Published
2015
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9. The shared epitope hypothesis in rheumatoid arthritis: evaluation of alternative classification criteria in a large UK Caucasian cohort.

Author

Morgan AW, Haroon-Rashid L, Martin SG, Gooi HC, Worthington J, Thomson W, Barrett JH, and Emery P

Subjects
HLA-DR Antigens genetics, HLA-DRB1 Chains, Humans, United Kingdom, Arthritis, Rheumatoid classification, Arthritis, Rheumatoid genetics, Epitopes, White People
Abstract

Objective: Many classification systems for the HLA-DRB1 allelic association with rheumatoid arthritis (RA) have been reported, but few have been validated in additional populations. We sought to evaluate 3 different DRB1 allele classification systems in a large cohort of Caucasian RA patients and control subjects in the UK., Methods: HLA-DRB1 typing was undertaken in 1,325 Caucasian RA patients and 462 healthy Caucasian controls who were residents of the UK. Logistic regression analyses were performed to investigate the different classification systems., Results: We confirmed the association between the susceptibility alleles S2 and S3P, as proposed by Tezenas du Montcel, and the presence of RA in UK Caucasians. A significant hierarchy of risk was observed within the S3P allele group. There was no evidence of a significant association between DRB1*1001 and RA. Our data did not support the hypothesis that an isoleucine at position 67 conferred protection against RA, other than in contrast to the susceptibility alleles. However, the presence of an aspartic acid at amino acid 70 did appear to confer some degree of protection., Conclusion: We were unable to fully substantiate any of the 3 recent revisions of the shared epitope hypothesis in this large cohort of Caucasian RA patients and control subjects in the UK. This reinforces the importance of evaluating disease susceptibility alleles in different Caucasian populations as well as in other ethnic groups. In particular, it will be important to clarify the precise DRB1 association in a given population before DRB1 genotyping is incorporated into clinical diagnostic or treatment algorithms.

Published
2008
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