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1. Selective IL-27 production by intestinal regulatory T cells permits gut-specific regulation of TH17 cell immunity

Author

Lin, Chia-Hao, Wu, Cheng-Jang, Cho, Sunglim, Patkar, Rasika, Huth, William J, Lin, Ling-Li, Chen, Mei-Chi, Israelsson, Elisabeth, Betts, Joanne, Niedzielska, Magdalena, Patel, Shefali A, Duong, Han G, Gerner, Romana R, Hsu, Chia-Yun, Catley, Matthew, Maciewicz, Rose A, Chu, Hiutung, Raffatellu, Manuela, Chang, John T, and Lu, Li-Fan

Subjects
Biomedical and Clinical Sciences, Immunology, Autoimmune Disease, Digestive Diseases, Inflammatory Bowel Disease, Aetiology, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Underpinning research, Inflammatory and immune system, Mice, Animals, T-Lymphocytes, Regulatory, Interleukin-27, T-Lymphocytes, Helper-Inducer, Immune Tolerance, Immunity, Cellular, Th17 Cells, Biochemistry and cell biology
Abstract

Regulatory T cells (Treg cells) are instrumental in establishing immunological tolerance. However, the precise effector mechanisms by which Treg cells control a specific type of immune response in a given tissue remains unresolved. By simultaneously studying Treg cells from different tissue origins under systemic autoimmunity, in the present study we show that interleukin (IL)-27 is specifically produced by intestinal Treg cells to regulate helper T17 cell (TH17 cell) immunity. Selectively increased intestinal TH17 cell responses in mice with Treg cell-specific IL-27 ablation led to exacerbated intestinal inflammation and colitis-associated cancer, but also helped protect against enteric bacterial infection. Furthermore, single-cell transcriptomic analysis has identified a CD83+CD62Llo Treg cell subset that is distinct from previously characterized intestinal Treg cell populations as the main IL-27 producers. Collectively, our study uncovers a new Treg cell suppression mechanism crucial for controlling a specific type of immune response in a particular tissue and provides further mechanistic insights into tissue-specific Treg cell-mediated immune regulation.

Published
2023

2. Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis.

Author

Castaño-Betancourt, Martha C, Evans, Dan S, Ramos, Yolande FM, Boer, Cindy G, Metrustry, Sarah, Liu, Youfang, den Hollander, Wouter, van Rooij, Jeroen, Kraus, Virginia B, Yau, Michelle S, Mitchell, Braxton D, Muir, Kenneth, Hofman, Albert, Doherty, Michael, Doherty, Sally, Zhang, Weiya, Kraaij, Robert, Rivadeneira, Fernando, Barrett-Connor, Elizabeth, Maciewicz, Rose A, Arden, Nigel, Nelissen, Rob GHH, Kloppenburg, Margreet, Jordan, Joanne M, Nevitt, Michael C, Slagboom, Eline P, Hart, Deborah J, Lafeber, Floris, Styrkarsdottir, Unnur, Zeggini, Eleftheria, Evangelou, Evangelos, Spector, Tim D, Uitterlinden, Andre G, Lane, Nancy E, Meulenbelt, Ingrid, Valdes, Ana M, and van Meurs, Joyce BJ

Subjects
Cartilage, Hip Joint, Humans, Osteoarthritis, Hip, Genetic Predisposition to Disease, Trehalase, Transforming Growth Factor alpha, Regulatory Sequences, Nucleic Acid, Genetic Heterogeneity, Polymorphism, Single Nucleotide, Aged, Aged, 80 and over, Middle Aged, Female, Male, Receptor, Fibroblast Growth Factor, Type 3, Genome-Wide Association Study, Phosphatidylinositol 3-Kinases, Class Ia Phosphatidylinositol 3-Kinase, Osteoarthritis, Hip, Regulatory Sequences, Nucleic Acid, Polymorphism, Single Nucleotide, and over, Receptor, Fibroblast Growth Factor, Type 3, Genetics, Developmental Biology
Abstract

Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10-8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies.

Published
2016

6. Genome-wide association and functional studies identify the DOT1L gene to be involved in cartilage thickness and hip osteoarthritis

Author

Betancourt, Martha C. Castaño, Cailotto, Frederic, Kerkhof, Hanneke J., Cornelis, Frederique M. F., Doherty, Sally A., Hart, Deborah J., Hofman, Albert, Luyten, Frank P., Maciewicz, Rose A., Mangino, Massimo, Metrustry, Sarah, Muir, Kenneth, Peters, Marjolein J., Rivadeneira, Fernando, Wheeler, Maggie, Zhang, Weiya, Arden, Nigel, Spector, Tim D., Uitterlinden, Andre G., Doherty, Michael, Lories, Rik J. U., Valdes, Ana M., and van Meurs, Joyce B. J.

Published
2012

8. Intestinal-derived ILCs migrating in lymph increase IFNγ production in response to Salmonella Typhimurium infection

Author

Kästele, Verena, primary, Mayer, Johannes, additional, Lee, Edward S., additional, Papazian, Natalie, additional, Cole, John J., additional, Cerovic, Vuk, additional, Belz, Gabrielle, additional, Tomura, Michio, additional, Eberl, Gerard, additional, Goodyear, Carl, additional, Maciewicz, Rose A., additional, Wall, Daniel, additional, Cupedo, Tom, additional, Withers, David R., additional, and Milling, Simon, additional

Published
2021
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9. Large-scale plasma proteomics can reveal distinct endotypes in chronic obstructive pulmonary disease and severe asthma

Author

1000010374290, Suzuki, Masaru, Cole, John J., 1000020399835, Konno, Satoshi, 1000070533537, Makita, Hironi, 1000060773314, Kimura, Hiroki, 1000000208224, Nishimura, Masaharu, Maciewicz, Rose A., 1000010374290, Suzuki, Masaru, Cole, John J., 1000020399835, Konno, Satoshi, 1000070533537, Makita, Hironi, 1000060773314, Kimura, Hiroki, 1000000208224, Nishimura, Masaharu, and Maciewicz, Rose A.

Abstract

Background Chronic airway diseases including chronic obstructive pulmonary disease (COPD) and asthma are heterogenous in nature and endotypes within are underpinned by complex biology. This study aimed to investigate the utility of proteomic profiling of plasma combined with bioinformatic mining, and to define molecular endotypes and expand our knowledge of the underlying biology in chronic respiratory diseases. Methods The plasma proteome was evaluated using an aptamer-based affinity proteomics platform (SOMAscan (R)), representing 1238 proteins in 34 subjects with stable COPD and 51 subjects with stable but severe asthma. For each disease, we evaluated a range of clinical/demographic characteristics including bronchodilator reversibility, blood eosinophilia levels, and smoking history. We applied modified bioinformatic approaches used in the evaluation of RNA transcriptomics. Results Subjects with COPD and severe asthma were distinguished from each other by 365 different protein abundancies, with differential pathway networks and upstream modulators. Furthermore, molecular endotypes within each disease could be defined. The protein groups that defined these endotypes had both known and novel biology including groups significantly enriched in exosomal markers derived from immune/inflammatory cells. Finally, we observed associations to clinical characteristics that previously have been under-explored. Conclusion This investigational study evaluating the plasma proteome in clinically-phenotyped subjects with chronic airway diseases provides support that such a method can be used to define molecular endotypes and pathobiological mechanisms that underpins these endotypes. It provided new concepts about the complexity of molecular pathways that define these diseases. In the longer term, such information will help to refine treatment options for defined groups.

Published
2021

10. Large-scale plasma proteomics can reveal distinct endotypes in chronic obstructive pulmonary disease and severe asthma

Author

Suzuki, Masaru, Cole, John J., Konno, Satoshi, Makita, Hironi, Kimura, Hiroki, Nishimura, Masaharu, Maciewicz, Rose A., Suzuki, Masaru, Cole, John J., Konno, Satoshi, Makita, Hironi, Kimura, Hiroki, Nishimura, Masaharu, and Maciewicz, Rose A.

Abstract

Background Chronic airway diseases including chronic obstructive pulmonary disease (COPD) and asthma are heterogenous in nature and endotypes within are underpinned by complex biology. This study aimed to investigate the utility of proteomic profiling of plasma combined with bioinformatic mining, and to define molecular endotypes and expand our knowledge of the underlying biology in chronic respiratory diseases. Methods The plasma proteome was evaluated using an aptamer-based affinity proteomics platform (SOMAscan (R)), representing 1238 proteins in 34 subjects with stable COPD and 51 subjects with stable but severe asthma. For each disease, we evaluated a range of clinical/demographic characteristics including bronchodilator reversibility, blood eosinophilia levels, and smoking history. We applied modified bioinformatic approaches used in the evaluation of RNA transcriptomics. Results Subjects with COPD and severe asthma were distinguished from each other by 365 different protein abundancies, with differential pathway networks and upstream modulators. Furthermore, molecular endotypes within each disease could be defined. The protein groups that defined these endotypes had both known and novel biology including groups significantly enriched in exosomal markers derived from immune/inflammatory cells. Finally, we observed associations to clinical characteristics that previously have been under-explored. Conclusion This investigational study evaluating the plasma proteome in clinically-phenotyped subjects with chronic airway diseases provides support that such a method can be used to define molecular endotypes and pathobiological mechanisms that underpins these endotypes. It provided new concepts about the complexity of molecular pathways that define these diseases. In the longer term, such information will help to refine treatment options for defined groups.

Published
2021

17. Additional file 1: of MEK inhibition drives anti-viral defence in RV but not RSV challenged human airway epithelial cells through AKT/p70S6K/4E-BP1 signalling

Author

Baturcam, Engin, Vollmer, Stefan, Schlüter, Holger, Maciewicz, Rose, Kurian, Nisha, Vaarala, Outi, Ludwig, Stephan, and Danen Cunoosamy

Abstract

Figure S1. MEK inhibitor works to reduce pERK1/2 and enhances IFN-β release. Figure S2. Challenge with poly(I:C) is similar but not identical to challenge with RV2. Figure S3. PI3Ki does not cause cytotoxicity. Figure S4. Enhanced IFN-β response due to MEKi is not associated with increased IRF7 protein expression. Figure S5. Challenge with poly(I:C) is similar but not identical to challenge with RV2 or RSVA2. Figure S6. Induction of ISG15 mRNA by poly(I:C) is similar to that of RV2. Figure S7. MEKi reduces phosphorylation of STAT3 at S727. Table S1. NHBE donors. Table S2. Structure of small molecules and PROTACs. Table S3. List of antibodies used for immunoblotting. Table S4. Target sequence of short interfering RNA (siRNA). Table S5. List of Taqman primer/probe. (DOCX 1110 kb)

Published
2019
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20. Sensing of apoptotic cells through Axl causes lung basal cell proliferation in inflammatory diseases

Author

Fujino, Naoya, primary, Brand, Oliver J., additional, Morgan, David J., additional, Fujimori, Toshifumi, additional, Grabiec, Aleksander M., additional, Jagger, Christopher P., additional, Maciewicz, Rose A., additional, Yamada, Mitsuhiro, additional, Itakura, Koji, additional, Sugiura, Hisatoshi, additional, Ichinose, Masakazu, additional, and Hussell, Tracy, additional

Published
2019
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26. Intestinal-derived ILCs migrating in lymph increase IFNγ production in response to SalmonellaTyphimurium infection

Author

Kästele, Verena, Mayer, Johannes, Lee, Edward S., Papazian, Natalie, Cole, John J., Cerovic, Vuk, Belz, Gabrielle, Tomura, Michio, Eberl, Gerard, Goodyear, Carl, Maciewicz, Rose A., Wall, Daniel, Cupedo, Tom, Withers, David R., and Milling, Simon

Abstract

Innate lymphoid cells (ILCs) are enriched in mucosae and have been described as tissue-resident. Interestingly, ILCs are also present within lymph nodes (LNs), in the interfollicular regions, the destination for lymph-migratory cells. We have previously shown that LN ILCs are supplemented by peripheral tissue-derived ILCs. Using thoracic duct cannulations, we here enumerate the intestinal lymph ILCs that traffic from the intestine to the mesenteric LNs (MLNs). We provide, for the first time, a detailed characterisation of these lymph-migratory ILCs. We show that all ILC subsets migrate in lymph, and while global transcriptional analysis reveals a shared signature with tissue-resident ILCs, lymph ILCs express migration-associated genes including S1PRs, SELL(CD62L) and CCR7. Interestingly, we discovered that while SalmonellaTyphimurium infections do not increase the numbers of migrating ILCs, infection changes their composition and cytokine profile. Infection increases the proportions of RORyt+T-bet+ILCs, levels of IFNγ, and IFNγ/GM-CSF co-expression. Infection-induced changes in migratory ILCs are reflected in colon-draining MLN ILCs, where RORyt+T-bet+ILCs accumulate and display corresponding increased cytokine expression. Thus, we reveal that ILCs respond rapidly to intestinal infection and can migrate to the MLN where they produce cytokines.

Published
2021
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28. Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis

Author

Castaño-Betancourt, Martha C., Evans, Dan S., Ramos, Yolande F M, Boer, Cindy G., Metrustry, Sarah, Liu, Youfang, den Hollander, Wouter, van Rooij, Jeroen, Kraus, Virginia B., Yau, Michelle S., Mitchell, Braxton D., Muir, Kenneth, Hofman, Albert, Doherty, Michael, Doherty, Sally, Zhang, Weiya, Kraaij, Robert, Rivadeneira, Fernando, Barrett-Connor, Elizabeth, Maciewicz, Rose A., Arden, Nigel, Nelissen, Rob G H H, Kloppenburg, Margreet, Jordan, Joanne M., Nevitt, Michael C., Slagboom, Eline P., Hart, Deborah J., Lafeber, Floris, Styrkarsdottir, Unnur, Zeggini, Eleftheria, Evangelou, Evangelos, Spector, Tim D., Uitterlinden, Andre G., Lane, Nancy E., Meulenbelt, Ingrid, Valdes, Ana M., van Meurs, Joyce B J, Castaño-Betancourt, Martha C., Evans, Dan S., Ramos, Yolande F M, Boer, Cindy G., Metrustry, Sarah, Liu, Youfang, den Hollander, Wouter, van Rooij, Jeroen, Kraus, Virginia B., Yau, Michelle S., Mitchell, Braxton D., Muir, Kenneth, Hofman, Albert, Doherty, Michael, Doherty, Sally, Zhang, Weiya, Kraaij, Robert, Rivadeneira, Fernando, Barrett-Connor, Elizabeth, Maciewicz, Rose A., Arden, Nigel, Nelissen, Rob G H H, Kloppenburg, Margreet, Jordan, Joanne M., Nevitt, Michael C., Slagboom, Eline P., Hart, Deborah J., Lafeber, Floris, Styrkarsdottir, Unnur, Zeggini, Eleftheria, Evangelou, Evangelos, Spector, Tim D., Uitterlinden, Andre G., Lane, Nancy E., Meulenbelt, Ingrid, Valdes, Ana M., and van Meurs, Joyce B J

Published
2016

29. Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis

Author

Lab Reumatologie/Klinische Immunologie, Regenerative Medicine and Stem Cells, Infection & Immunity, dLAB Biobank, Castaño-Betancourt, Martha C., Evans, Dan S., Ramos, Yolande F M, Boer, Cindy G., Metrustry, Sarah, Liu, Youfang, den Hollander, Wouter, van Rooij, Jeroen, Kraus, Virginia B., Yau, Michelle S., Mitchell, Braxton D., Muir, Kenneth, Hofman, Albert, Doherty, Michael, Doherty, Sally, Zhang, Weiya, Kraaij, Robert, Rivadeneira, Fernando, Barrett-Connor, Elizabeth, Maciewicz, Rose A., Arden, Nigel, Nelissen, Rob G H H, Kloppenburg, Margreet, Jordan, Joanne M., Nevitt, Michael C., Slagboom, Eline P., Hart, Deborah J., Lafeber, Floris, Styrkarsdottir, Unnur, Zeggini, Eleftheria, Evangelou, Evangelos, Spector, Tim D., Uitterlinden, Andre G., Lane, Nancy E., Meulenbelt, Ingrid, Valdes, Ana M., van Meurs, Joyce B J, Lab Reumatologie/Klinische Immunologie, Regenerative Medicine and Stem Cells, Infection & Immunity, dLAB Biobank, Castaño-Betancourt, Martha C., Evans, Dan S., Ramos, Yolande F M, Boer, Cindy G., Metrustry, Sarah, Liu, Youfang, den Hollander, Wouter, van Rooij, Jeroen, Kraus, Virginia B., Yau, Michelle S., Mitchell, Braxton D., Muir, Kenneth, Hofman, Albert, Doherty, Michael, Doherty, Sally, Zhang, Weiya, Kraaij, Robert, Rivadeneira, Fernando, Barrett-Connor, Elizabeth, Maciewicz, Rose A., Arden, Nigel, Nelissen, Rob G H H, Kloppenburg, Margreet, Jordan, Joanne M., Nevitt, Michael C., Slagboom, Eline P., Hart, Deborah J., Lafeber, Floris, Styrkarsdottir, Unnur, Zeggini, Eleftheria, Evangelou, Evangelos, Spector, Tim D., Uitterlinden, Andre G., Lane, Nancy E., Meulenbelt, Ingrid, Valdes, Ana M., and van Meurs, Joyce B J

Published
2016

30. Gene-environment interaction between body mass index and transforming growth factor beta 1 (TGF?1) gene in knee and hip osteoarthritis

Author

Muthuri, Stella G., Doherty, Sally, Zhang, Weiya, Maciewicz, Rose A., Muir, Kenneth R., and Doherty, Michael

Abstract

Introduction: The objective was to investigate potential gene-environment interaction between body mass index (BMI) and each of eight TGF?1 polymorphisms in knee and hip osteoarthritis (OA).Methods: We conducted a case-control study of Caucasian men and women aged 45 to 86 years from Nottingham, United Kingdom (Genetics of OA and Lifestyle (GOAL) study). Cases had clinically severe symptoms and radiographic knee or hip OA; controls had no symptoms and no radiographic knee/hip OA. We used logistic regression to investigate the association of TGF?1 polymorphisms and OA when stratifying by BMI. Knee and hip OA were analyzed separately with adjustment for potential confounders. Additive and multiplicative interactions were examined.Results: 2,048 cases (1,042 knee OA, 1,006 hip OA) and 967 controls were studied. For hip OA, the highest risk was in overweight (BMI ?25 kg/m2) individuals with the variant allele of single-nucleotide polymorphism (SNP)rs1800468 (odds ratio (OR) 2.21, 95% confidence interval (CI) 1.55, 3.15). Evaluation of gene-environment interaction indicated significant synergetic interaction (relative excess risk due to interaction (RERI) = 0.93, synergy index (SI) = 4.33) with an attributable proportion due to interaction (AP) of 42% (AP = 0.42; 95% CI 0.16, 0.68). Multiplicative interaction was also significant (OR for interaction (ORINT) = 2.27, P = 0.015). For knee OA, the highest risk was in overweight individuals with homozygous genotype 11 of SNP rs2278422 (OR = 6.95, P < 0.001). In contrast, the variant allele indicated slightly lower risks (OR = 4.72, P < 0.001), a significant antagonistic interaction (RERI = -2.66, SI = 0.59), AP = -0.56 (95%CI -0.94, -0.17) and a significant multiplicative interaction (ORINT = 0.47, P = 0.013).Conclusion: TGF?1 gene polymorphisms interact with being overweight to influence the risk of large joint OA.

Published
2013

35. Genome-wide association and functional studies identify theDOT1Lgene to be involved in cartilage thickness and hip osteoarthritis

Author

Castaño Betancourt, Martha C., primary, Cailotto, Frederic, additional, Kerkhof, Hanneke J., additional, Cornelis, Frederique M. F., additional, Doherty, Sally A., additional, Hart, Deborah J., additional, Hofman, Albert, additional, Luyten, Frank P., additional, Maciewicz, Rose A., additional, Mangino, Massimo, additional, Metrustry, Sarah, additional, Muir, Kenneth, additional, Peters, Marjolein J., additional, Rivadeneira, Fernando, additional, Wheeler, Maggie, additional, Zhang, Weiya, additional, Arden, Nigel, additional, Spector, Tim D., additional, Uitterlinden, Andre G., additional, Doherty, Michael, additional, Lories, Rik J. U., additional, Valdes, Ana M., additional, and Meurs, Joyce B. J. van, additional

Published
2012
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39. A Variant in MCF2L Is Associated with Osteoarthritis

Author

Day-Williams, Aaron G., primary, Southam, Lorraine, additional, Panoutsopoulou, Kalliope, additional, Rayner, Nigel W., additional, Esko, Tonu, additional, Estrada, Karol, additional, Helgadottir, Hafdis T., additional, Hofman, Albert, additional, Ingvarsson, Throvaldur, additional, Jonsson, Helgi, additional, Keis, Aime, additional, Kerkhof, Hanneke J.M., additional, Thorleifsson, Gudmar, additional, Arden, Nigel K., additional, Carr, Andrew, additional, Chapman, Kay, additional, Deloukas, Panos, additional, Loughlin, John, additional, McCaskie, Andrew, additional, Ollier, William E.R., additional, Ralston, Stuart H., additional, Spector, Timothy D., additional, Wallis, Gillian A., additional, Wilkinson, J. Mark, additional, Aslam, Nadim, additional, Birell, Fraser, additional, Carluke, Ian, additional, Joseph, John, additional, Rai, Ashok, additional, Reed, Mike, additional, Walker, Kirsten, additional, Doherty, Sally A., additional, Jonsdottir, Ingileif, additional, Maciewicz, Rose A., additional, Muir, Kenneth R., additional, Metspalu, Andres, additional, Rivadeneira, Fernando, additional, Stefansson, Kari, additional, Styrkarsdottir, Unnur, additional, Uitterlinden, Andre G., additional, van Meurs, Joyce B.J., additional, Zhang, Weiya, additional, Valdes, Ana M., additional, Doherty, Michael, additional, and Zeggini, Eleftheria, additional

Published
2011
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40. Large Scale Replication Study of the Association between HLA Class II/BTNL2 Variants and Osteoarthritis of the Knee in European-Descent Populations

Author

Valdes, Ana M., primary, Styrkarsdottir, Unnur, additional, Doherty, Michael, additional, Morris, David L., additional, Mangino, Massimo, additional, Tamm, Agu, additional, Doherty, Sally A., additional, Kisand, Kalle, additional, Kerna, Irina, additional, Tamm, Ann, additional, Wheeler, Margaret, additional, Maciewicz, Rose A., additional, Zhang, Weiya, additional, Muir, Kenneth R., additional, Dennison, Elaine M., additional, Hart, Deborah J., additional, Metrustry, Sarah, additional, Jonsdottir, Ingileif, additional, Jonsson, Gudbjorn F., additional, Jonsson, Helgi, additional, Ingvarsson, Thorvaldur, additional, Cooper, Cyrus, additional, Vyse, Timothy J., additional, Spector, Tim D., additional, Stefansson, Kari, additional, and Arden, Nigel K., additional

Published
2011
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42. Role of the NaV1.7 R1150W amino acid change in susceptibility to symptomatic knee osteoarthritis and multiple regional pain

Author

Valdes, Ana M, primary, Arden, Nigel K, additional, Vaughn, Frances L, additional, Doherty, Sally A, additional, Leaverton, Paul E, additional, Zhang, Weiya, additional, Muir, Kenneth R, additional, Rampersaud, Evadnie, additional, Dennison, Elaine M, additional, Edwards, Mark H, additional, Jameson, Karen A, additional, Javaid, M Kassim, additional, Spector, Tim D, additional, Cooper, Cyrus, additional, Maciewicz, Rose A, additional, and Doherty, Michael, additional

Published
2010
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45. Catalytic activity of ADAM28

Author

Howard, Linda, primary, Zheng, Yufang, additional, Horrocks, Maureen, additional, Maciewicz, Rose A., additional, and Blobel, Carl, additional

Published
2001
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49. Role of the Nav1.7 R1150W amino acid change in susceptibility to symptomatic knee osteoarthritis and multiple regional pain.

Author

Valdes, Ana M., Arden, Nigel K., Vaughn, Frances L., Doherty, Sally A., Leaverton, Paul E., Zhang, Weiya, Muir, Kenneth R., Rampersaud, Evadnie, Dennison, Elaine M., Edwards, Mark H., Jameson, Karen A., Javaid, M. Kassim, Spector, Tim D., Cooper, Cyrus, Maciewicz, Rose A., and Doherty, Michael

Abstract

Objective: To assess the genetic association of pain in patients with knee osteoarthritis (OA) and those with multiple regional pain with the R1150W variant in the α-subunit of the voltage-gated sodium channel Na(V)1.7.Methods: Knee OA patients from 2 UK cohorts (1,411 from the Genetics of Osteoarthritis and Lifestyle study and 267 from the Hertfordshire Cohort Study; 74% with symptomatic OA) with Western Ontario and McMaster Universities OA Index (WOMAC) pain scores were genotyped for rs6746030 (encoding the R1150W change). One hundred seventy-six knee OA patients (53% symptomatic) from the Clearwater Osteoarthritis Study were also tested. A total of 4,295 samples (both affected and unaffected OA) from all 3 studies with data on multiple regional pain were tested. Fixed-effects meta-analyses were carried out with the WOMAC, symptomatic OA (adjusting for radiographic severity), and multiple regional pain as outcomes.Results: No association with the WOMAC was seen in the UK cohorts. Overall, the meta-analysis of WOMAC yielded a summary statistic of β = 0.47 (95% confidence interval [95% CI] 0.04, 0.89; P = 0.030) for the variant allele. The meta-analysis of symptomatic versus asymptomatic OA did not demonstrate an association with rs6746030 (odds ratio [OR] 0.90 [95% CI 0.71, 1.15], P = 0.38). The meta-analysis of multiple regional pain resulted in a significant OR of 1.40 (95% CI 1.08, 1.80; P = 0.0085). No interstudy heterogeneity was seen for any of the analyses.Conclusion: We find evidence that the R1150W amino acid change in the Na(V)1.7 α-chain is associated with multiple regional pain. This variant is confirmed to be involved in genetic susceptibility to pain, but it does not appear to have a major role in OA-specific pain. [ABSTRACT FROM AUTHOR]

Published
2011
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50. Role of the Nav1.7 R1150W amino acid change in susceptibility to symptomatic knee osteoarthritis and multiple regional pain.

Author

Valdes, Ana M., Arden, Nigel K., Vaughn, Frances L., Doherty, Sally A., Leaverton, Paul E., Zhang, Weiya, Muir, Kenneth R., Rampersaud, Evadnie, Dennison, Elaine M., Edwards, Mark H., Jameson, Karen A., Javaid, M. Kassim, Spector, Tim D., Cooper, Cyrus, Maciewicz, Rose A., and Doherty, Michael

Abstract

Objective To assess the genetic association of pain in patients with knee osteoarthritis (OA) and those with multiple regional pain with the R1150W variant in the α-subunit of the voltage-gated sodium channel NaV1.7. Methods Knee OA patients from 2 UK cohorts (1,411 from the Genetics of Osteoarthritis and Lifestyle study and 267 from the Hertfordshire Cohort Study; 74% with symptomatic OA) with Western Ontario and McMaster Universities OA Index (WOMAC) pain scores were genotyped for rs6746030 (encoding the R1150W change). One hundred seventy-six knee OA patients (53% symptomatic) from the Clearwater Osteoarthritis Study were also tested. A total of 4,295 samples (both affected and unaffected OA) from all 3 studies with data on multiple regional pain were tested. Fixed-effects meta-analyses were carried out with the WOMAC, symptomatic OA (adjusting for radiographic severity), and multiple regional pain as outcomes. Results No association with the WOMAC was seen in the UK cohorts. Overall, the meta-analysis of WOMAC yielded a summary statistic of β = 0.47 (95% confidence interval [95% CI] 0.04, 0.89; P = 0.030) for the variant allele. The meta-analysis of symptomatic versus asymptomatic OA did not demonstrate an association with rs6746030 (odds ratio [OR] 0.90 [95% CI 0.71, 1.15], P = 0.38). The meta-analysis of multiple regional pain resulted in a significant OR of 1.40 (95% CI 1.08, 1.80; P = 0.0085). No interstudy heterogeneity was seen for any of the analyses. Conclusion We find evidence that the R1150W amino acid change in the NaV1.7 α-chain is associated with multiple regional pain. This variant is confirmed to be involved in genetic susceptibility to pain, but it does not appear to have a major role in OA-specific pain. [ABSTRACT FROM AUTHOR]

Published
2011
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