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3. Discovery of new myositis genetic associations through leveraging other immune-mediated diseases

Author

Reales, Guillermo, Amos, Christopher I., Benveniste, Olivier, Chinoy, Hector, De Bleecker, Jan, De Paepe, Boel, Doria, Andrea, Gregersen, Peter K., Lamb, Janine A., Limaye, Vidya, Lundberg, Ingrid E., Machado, Pedro M., Maurer, Britta, Miller, Frederick W., Molberg, Øyvind, Pachman, Lauren M., Padyukov, Leonid, Radstake, Timothy R., Reed, Ann M., Rider, Lisa G., Rothwell, Simon, Selva-O'Callaghan, Albert, Vencovský, Jiri, Wedderburn, Lucy R., and Wallace, Chris

Published
2024
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4. Identification of connective tissue disease autoantibodies and a novel autoantibody anti-annexin A11 in patients with “idiopathic” interstitial lung disease

Author

Tansley, Sarah L., McMorrow, Fionnuala, Cotton, Caroline V., Adamali, Huzaifa, Barratt, Shaney L., Betteridge, Zoe E., Perurena-Prieto, Janire, Gibbons, Michael A., Kular, Raman, Loganathan, Aravinthan, Lamb, Janine A., Lu, Hui, New, Robert P., Pratt, Diane, Rivera-Ortega, Pilar, Sayers, Ross, Steward, Matthew, Stranks, Lachlan, Vital, Edward, Spencer, Lisa G., McHugh, Neil J., and Cooper, Robert G.

Published
2024
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5. Distinct HLA associations with autoantibody-defined subgroups in idiopathic inflammatory myopathies

Author

Bianchi, Matteo, Kozyrev, Sergey V., Sandling, Johanna K., Rönnblom, Lars, Eloranta, Maija-Leena, Syvänen, Ann-Christine, Leonard, Dag, Dahlqvist, Johanna, Lidén, Maria, Mathioudaki, Argyri, Meadows, Jennifer RS., Nordin, Jessika, Nordmark, Gunnel, Lundberg, Ingrid E., Notarnicola, Antonella, Padyukov, Leonid, Tjärnlund, Anna, Dastmalchi, Maryam, Eriksson, Daniel, Molberg, Øyvind, Andersson, Helena, Lindblad-Toh, Kerstin, Farias, Fabiana H.G., Wahren-Herlenius, Marie, Jalal, Awat, Hanna, Balsam, Hellström, Helena, Husmark, Tomas, Häggström, Åsa, Svärd, Anna, Skogh, Thomas, Diederichsen, Louise Pyndt, Lamb, Janine A., Rothwell, Simon, Chinoy, Hector, Cooper, Robert G., Pielberg, Gerli Rosengren, Lobell, Anna, Karlsson, Åsa, Murén, Eva, Ahlgren, Kerstin M., Andersson, Göran, Landegren, Nils, Kämpe, Olle, Söderkvis, Peter, Leclair, Valérie, Galindo-Feria, Angeles S., Kryštůfková, Olga, Zargar, Sepehr Sarrafzadeh, Mann, Herman, Klein, Martin, Tansley, Sarah, McHugh, Neil, Vencovský, Jiri, Holmqvist, Marie, and Diaz-Gallo, Lina-Marcela

Published
2023
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6. Comparison of clinical features between patients with anti-synthetase syndrome and dermatomyositis: results from the MYONET registry.

Author

Hum, Ryan Malcolm, Lilleker, James B, Lamb, Janine A, Oldroyd, Alexander G S, Wang, Guochun, Wedderburn, Lucy R, Diederichsen, Louise P, Schmidt, Jens, Danieli, Maria Giovanna, Oakley, Paula, Griger, Zoltan, Phuong, Thuy Nguyen Thi, Kodishala, Chanakya, Mercado, Monica Vazquez-Del, Andersson, Helena, Paepe, Boel De, Bleecker, Jan L De, Maurer, Britta, McCann, Liza, and Pipitone, Nicolo

Subjects
DERMATOMYOSITIS, DIFFERENTIAL diagnosis, RESEARCH funding, RAYNAUD'S disease, SKIN diseases, MYOSITIS, EXFOLIATIVE dermatitis, AUTOANTIBODIES, EXANTHEMA, INTERSTITIAL lung diseases, ANTISYNTHETASE syndrome, ARTHRITIS, COMPARATIVE studies, TUMORS, DISEASE complications, SYMPTOMS, ADULTS
Abstract

Objectives To compare clinical characteristics, including the frequency of cutaneous, extramuscular manifestations and malignancy, between adults with anti-synthetase syndrome (ASyS) and DM. Methods Using data regarding adults from the MYONET registry, a cohort of DM patients with anti-Mi2/-TIF1γ/-NXP2/-SAE/-MDA5 autoantibodies, and a cohort of ASyS patients with anti-tRNA synthetase autoantibodies (anti-Jo1/-PL7/-PL12/-OJ/-EJ/-Zo/-KS) were identified. Patients with DM sine dermatitis or with discordant dual autoantibody specificities were excluded. Sub-cohorts of patients with ASyS with or without skin involvement were defined based on presence of DM-type rashes (heliotrope rash, Gottron's papules/sign, violaceous rash, shawl sign, V-sign, erythroderma, and/or periorbital rash). Results In total 1054 patients were included (DM, n  = 405; ASyS, n  = 649). In the ASyS cohort, 31% (n  = 203) had DM-type skin involvement (ASyS-DMskin). A higher frequency of extramuscular manifestations, including Mechanic's hands, Raynaud's phenomenon, arthritis, interstitial lung disease and cardiac involvement differentiated ASyS-DMskin from DM (all P  < 0.001), whereas higher frequency of any of four DM-type rashes—heliotrope rash (n  = 248, 61% vs n  = 90, 44%), violaceous rash (n  = 166, 41% vs n  = 57, 9%), V-sign (n  = 124, 31% vs n  = 28, 4%), and shawl sign (n  = 133, 33% vs n  = 18, 3%)—differentiated DM from ASyS-DMskin (all P  < 0.005). Cancer-associated myositis (CAM) was more frequent in DM (n  = 67, 17%) compared with ASyS (n  = 21, 3%) and ASyS-DMskin (n  = 7, 3%) cohorts (both P  < 0.001). Conclusion DM-type rashes are frequent in patients with ASyS; however, distinct clinical manifestations differentiate these patients from classical DM. Skin involvement in ASyS does not necessitate increased malignancy surveillance. These findings will inform future ASyS classification criteria and patient management. [ABSTRACT FROM AUTHOR]

Published
2024
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9. Distinct HLA associations with autoantibody-defined subgroups in idiopathic inflammatory myopathies

Author

Leclair, Valérie, primary, Galindo-Feria, Angeles S., additional, Rothwell, Simon, additional, Kryštůfková, Olga, additional, Zargar, Sepehr Sarrafzadeh, additional, Mann, Herman, additional, Diederichsen, Louise Pyndt, additional, Andersson, Helena, additional, Klein, Martin, additional, Tansley, Sarah, additional, Rönnblom, Lars, additional, Lindblad-Toh, Kerstin, additional, Syvänen, Ann-Christine, additional, Wahren-Herlenius, Marie, additional, Sandling, Johanna K., additional, McHugh, Neil, additional, Lamb, Janine A., additional, Vencovský, Jiri, additional, Chinoy, Hector, additional, Holmqvist, Marie, additional, Bianchi, Matteo, additional, Padyukov, Leonid, additional, Lundberg, Ingrid E., additional, Diaz-Gallo, Lina-Marcela, additional, Kozyrev, Sergey V., additional, Eloranta, Maija-Leena, additional, Leonard, Dag, additional, Dahlqvist, Johanna, additional, Lidén, Maria, additional, Mathioudaki, Argyri, additional, Meadows, Jennifer RS., additional, Nordin, Jessika, additional, Nordmark, Gunnel, additional, Notarnicola, Antonella, additional, Tjärnlund, Anna, additional, Dastmalchi, Maryam, additional, Eriksson, Daniel, additional, Molberg, Øyvind, additional, Farias, Fabiana H.G., additional, Jalal, Awat, additional, Hanna, Balsam, additional, Hellström, Helena, additional, Husmark, Tomas, additional, Häggström, Åsa, additional, Svärd, Anna, additional, Skogh, Thomas, additional, Cooper, Robert G., additional, Pielberg, Gerli Rosengren, additional, Lobell, Anna, additional, Karlsson, Åsa, additional, Murén, Eva, additional, Ahlgren, Kerstin M., additional, Andersson, Göran, additional, Landegren, Nils, additional, Kämpe, Olle, additional, and Söderkvis, Peter, additional

Published
2023
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10. 130 Low Gene Copy Numbers (GCN) of complement C4 and C4A deficiency are highly significant genetic risk factors for idiopathic inflammatory myopathies and its major subgroups

Author

Zhou, Danlei, primary, King, Emily, additional, Rothwell, Simon, additional, Kryštůfková, Olga, additional, Notarnicola, Antonella, additional, Coss, Samantha, additional, Aziz, Rabheh, additional, Miller, Katherine, additional, Dang, Amanda, additional, Yu, Richard, additional, Drew, Joanne, additional, Lundstrom, Emeli, additional, Pachman, Lauren, additional, Mamyrova, Gulnara, additional, Curiel, Rodolfo, additional, De Paepe, Boel, additional, De Bleecker, Jan, additional, Payton, Antony, additional, Ollier, William, additional, O'Hanlon, Terrance, additional, Targoff, Ira, additional, Flegel, Willy, additional, Sivaraman, Vidya, additional, Obele, Edward, additional, Akoghlanian, Shoghik, additional, Driest, Kyla, additional, Spencer, Charles, additional, Ling Wu, Yee, additional, Nagaraja, Haikady, additional, Ardoin, Stacy, additional, Chinoy, Hector, additional, Rider, Lisa, additional, Miller, Frederick, additional, Lundberg, Ingrid, additional, Padyukov, Leonid, additional, Vencovský, Jiří, additional, Lamb, Janine, additional, and Yu, Chack-Yung, additional

Published
2023
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12. Individual common variants exert weak effects on the risk for autism spectrum disorders

Author

Anney, Richard, Klei, Lambertus, Pinto, Dalila, Almeida, Joana, Bacchelli, Elena, Baird, Gillian, Bolshakova, Nadia, Bölte, Sven, Bolton, Patrick F, Bourgeron, Thomas, Brennan, Sean, Brian, Jessica, Casey, Jillian, Conroy, Judith, Correia, Catarina, Corsello, Christina, Crawford, Emily L, de Jonge, Maretha, Delorme, Richard, Duketis, Eftichia, Duque, Frederico, Estes, Annette, Farrar, Penny, Fernandez, Bridget A, Folstein, Susan E, Fombonne, Eric, Gilbert, John, Gillberg, Christopher, Glessner, Joseph T, Green, Andrew, Green, Jonathan, Guter, Stephen J, Heron, Elizabeth A, Holt, Richard, Howe, Jennifer L, Hughes, Gillian, Hus, Vanessa, Igliozzi, Roberta, Jacob, Suma, Kenny, Graham P, Kim, Cecilia, Kolevzon, Alexander, Kustanovich, Vlad, Lajonchere, Clara M, Lamb, Janine A, Law-Smith, Miriam, Leboyer, Marion, Le Couteur, Ann, Leventhal, Bennett L, Liu, Xiao-Qing, Lombard, Frances, Lord, Catherine, Lotspeich, Linda, Lund, Sabata C, Magalhaes, Tiago R, Mantoulan, Carine, McDougle, Christopher J, Melhem, Nadine M, Merikangas, Alison, Minshew, Nancy J, Mirza, Ghazala K, Munson, Jeff, Noakes, Carolyn, Nygren, Gudrun, Papanikolaou, Katerina, Pagnamenta, Alistair T, Parrini, Barbara, Paton, Tara, Pickles, Andrew, Posey, David J, Poustka, Fritz, Ragoussis, Jiannis, Regan, Regina, Roberts, Wendy, Roeder, Kathryn, Roge, Bernadette, Rutter, Michael L, Schlitt, Sabine, Shah, Naisha, Sheffield, Val C, Soorya, Latha, Sousa, Inês, Stoppioni, Vera, Sykes, Nuala, Tancredi, Raffaella, Thompson, Ann P, Thomson, Susanne, Tryfon, Ana, Tsiantis, John, Van Engeland, Herman, Vincent, John B, Volkmar, Fred, Vorstman, JAS, Wallace, Simon, Wing, Kirsty, Wittemeyer, Kerstin, Wood, Shawn, Zurawiecki, Danielle, Zwaigenbaum, Lonnie, and Bailey, Anthony J

Subjects
Behavioral and Social Science, Clinical Research, Human Genome, Mental Health, Genetics, Brain Disorders, Pediatric, Intellectual and Developmental Disabilities (IDD), Autism, Prevention, Aetiology, 2.1 Biological and endogenous factors, Alleles, Child, Child Development Disorders, Pervasive, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Language Development, Male, Membrane Proteins, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Risk Factors, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.

Published
2012

13. A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder

Author

Casey, Jillian P, Magalhaes, Tiago, Conroy, Judith M, Regan, Regina, Shah, Naisha, Anney, Richard, Shields, Denis C, Abrahams, Brett S, Almeida, Joana, Bacchelli, Elena, Bailey, Anthony J, Baird, Gillian, Battaglia, Agatino, Berney, Tom, Bolshakova, Nadia, Bolton, Patrick F, Bourgeron, Thomas, Brennan, Sean, Cali, Phil, Correia, Catarina, Corsello, Christina, Coutanche, Marc, Dawson, Geraldine, de Jonge, Maretha, Delorme, Richard, Duketis, Eftichia, Duque, Frederico, Estes, Annette, Farrar, Penny, Fernandez, Bridget A, Folstein, Susan E, Foley, Suzanne, Fombonne, Eric, Freitag, Christine M, Gilbert, John, Gillberg, Christopher, Glessner, Joseph T, Green, Jonathan, Guter, Stephen J, Hakonarson, Hakon, Holt, Richard, Hughes, Gillian, Hus, Vanessa, Igliozzi, Roberta, Kim, Cecilia, Klauck, Sabine M, Kolevzon, Alexander, Lamb, Janine A, Leboyer, Marion, Le Couteur, Ann, Leventhal, Bennett L, Lord, Catherine, Lund, Sabata C, Maestrini, Elena, Mantoulan, Carine, Marshall, Christian R, McConachie, Helen, McDougle, Christopher J, McGrath, Jane, McMahon, William M, Merikangas, Alison, Miller, Judith, Minopoli, Fiorella, Mirza, Ghazala K, Munson, Jeff, Nelson, Stanley F, Nygren, Gudrun, Oliveira, Guiomar, Pagnamenta, Alistair T, Papanikolaou, Katerina, Parr, Jeremy R, Parrini, Barbara, Pickles, Andrew, Pinto, Dalila, Piven, Joseph, Posey, David J, Poustka, Annemarie, Poustka, Fritz, Ragoussis, Jiannis, Roge, Bernadette, Rutter, Michael L, Sequeira, Ana F, Soorya, Latha, Sousa, Inês, Sykes, Nuala, Stoppioni, Vera, Tancredi, Raffaella, Tauber, Maïté, Thompson, Ann P, Thomson, Susanne, Tsiantis, John, Van Engeland, Herman, Vincent, John B, Volkmar, Fred, Vorstman, Jacob AS, Wallace, Simon, Wang, Kai, Wassink, Thomas H, White, Kathy, and Wing, Kirsty

Subjects
Autism, Genetics, Mental Health, Intellectual and Developmental Disabilities (IDD), Brain Disorders, Biotechnology, Pediatric, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Mental health, Adult, Child, Child Development Disorders, Pervasive, Cluster Analysis, Cohort Studies, DNA Copy Number Variations, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Haplotypes, Homozygote, Humans, Linkage Disequilibrium, Male, Middle Aged, Nuclear Family, Polymorphism, Single Nucleotide, Complementary and Alternative Medicine, Paediatrics and Reproductive Medicine, Genetics & Heredity
Abstract

Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.

Published
2012

14. A genome-wide scan for common alleles affecting risk for autism

Author

Anney, Richard, Klei, Lambertus, Pinto, Dalila, Regan, Regina, Conroy, Judith, Magalhaes, Tiago R, Correia, Catarina, Abrahams, Brett S, Sykes, Nuala, Pagnamenta, Alistair T, Almeida, Joana, Bacchelli, Elena, Bailey, Anthony J, Baird, Gillian, Battaglia, Agatino, Berney, Tom, Bolshakova, Nadia, Bölte, Sven, Bolton, Patrick F, Bourgeron, Thomas, Brennan, Sean, Brian, Jessica, Carson, Andrew R, Casallo, Guillermo, Casey, Jillian, Chu, Su H, Cochrane, Lynne, Corsello, Christina, Crawford, Emily L, Crossett, Andrew, Dawson, Geraldine, de Jonge, Maretha, Delorme, Richard, Drmic, Irene, Duketis, Eftichia, Duque, Frederico, Estes, Annette, Farrar, Penny, Fernandez, Bridget A, Folstein, Susan E, Fombonne, Eric, Freitag, Christine M, Gilbert, John, Gillberg, Christopher, Glessner, Joseph T, Goldberg, Jeremy, Green, Jonathan, Guter, Stephen J, Hakonarson, Hakon, Heron, Elizabeth A, Hill, Matthew, Holt, Richard, Howe, Jennifer L, Hughes, Gillian, Hus, Vanessa, Igliozzi, Roberta, Kim, Cecilia, Klauck, Sabine M, Kolevzon, Alexander, Korvatska, Olena, Kustanovich, Vlad, Lajonchere, Clara M, Lamb, Janine A, Laskawiec, Magdalena, Leboyer, Marion, Le Couteur, Ann, Leventhal, Bennett L, Lionel, Anath C, Liu, Xiao-Qing, Lord, Catherine, Lotspeich, Linda, Lund, Sabata C, Maestrini, Elena, Mahoney, William, Mantoulan, Carine, Marshall, Christian R, McConachie, Helen, McDougle, Christopher J, McGrath, Jane, McMahon, William M, Melhem, Nadine M, Merikangas, Alison, Migita, Ohsuke, Minshew, Nancy J, Mirza, Ghazala K, Munson, Jeff, Nelson, Stanley F, Noakes, Carolyn, Noor, Abdul, Nygren, Gudrun, Oliveira, Guiomar, Papanikolaou, Katerina, Parr, Jeremy R, Parrini, Barbara, Paton, Tara, Pickles, Andrew, Piven, Joseph, Posey, David J, Poustka, Annemarie, and Poustka, Fritz

Subjects
Clinical Research, Human Genome, Mental Health, Genetics, Brain Disorders, Pediatric, Biotechnology, Intellectual and Developmental Disabilities (IDD), Autism, Prevention, Aetiology, 2.1 Biological and endogenous factors, Alleles, Autistic Disorder, DNA Copy Number Variations, Databases, Genetic, Genetic Predisposition to Disease, Genetic Variation, Genome, Human, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide, Risk Factors, White People, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.

Published
2010

16. Genome-wide imputation identifies novel associations and localises signals in idiopathic inflammatory myopathies

Author

Rothwell, Simon, Amos, Christopher I, Miller, Frederick W, Rider, Lisa G, Lundberg, Ingrid E, Gregersen, Peter K, Vencovsky, Jiri, McHugh, Neil, Limaye, Vidya, Selva-O'Callaghan, Albert, Hanna, Michael G, Machado, Pedro M, Pachman, Lauren M, Reed, Ann M, Molberg, Øyvind, Benveniste, Olivier, Mathiesen, Pernille, Radstake, Timothy, Doria, Andrea, De Bleecker, Jan L, De Paepe, Boel, Maurer, Britta, Ollier, William E, Padyukov, Leonid, O'Hanlon, Terrance P, Lee, Annette, Wedderburn, Lucy R, Chinoy, Hector, and Lamb, Janine A

Subjects
610 Medicine & health
Abstract

OBJECTIVES The idiopathic inflammatory myopathies (IIM) are heterogeneous diseases, thought to be initiated by immune activation in genetically predisposed individuals. In this study we imputed variants from the Immunochip array using a large reference panel to fine-map associations and identify novel associations in IIM. METHODS We analysed 2,565 Caucasian IIM samples collected through the Myositis Genetics Consortium (MYOGEN) and 10,260 ethnically-matched controls. We imputed 1,648,116 variants from the Immunochip array using the Haplotype Reference Consortium panel and conducted association analysis on IIM, and clinical and serological subgroups. RESULTS The human leukocyte antigen (HLA) locus was consistently the most significantly associated region. Four non-HLA regions reached genome-wide significance, three in the whole IIM cohort (SDK2 and LINC00924 - both novel, and STAT4), with evidence of independent variants in STAT4, and NAB1 in the polymyositis (PM) subgroup. We also found suggestive evidence of association with loci previously associated with other autoimmune rheumatic diseases (TEC and LTBR). We identified more significant associations than those previously reported in IIM, for STAT4 and DGKQ in the total cohort, for NAB1 and FAM167A-BLK loci in PM, and CCR5 in inclusion body myositis. We found enrichment of variants among DNase I hypersensitivity sites and histone marks associated with active transcription within blood cells. CONCLUSIONS We report novel and strong associations in IIM and PM, and localise signals to single genes and immune cell types. This article is protected by copyright. All rights reserved.

Published
2023

19. Distinct HLA associations with autoantibody-defined subgroups in idiopathic inflammatory myopathies

Author

Leclair, Valerie, Galindo-Feria, Angeles S., Rothwell, Simon, Krystufkova, Olga, Zargar, Sepehr Sarrafzadeh, Mann, Herman, Diederichsen, Louise Pyndt, Andersson, Helena, Klein, Martin, Tansley, Sarah, Rönnblom, Lars, Lindblad-Toh, Kerstin, Syvänen, Ann-Christine, Wahren-Herlenius, Marie, Sandling, Johanna K., McHugh, Neil, Lamb, Janine A., Vencovsky, Jiri, Chinoy, Hector, Holmqvist, Marie, Bianchi, Matteo, Padyukov, Leonid, Lundberg, Ingrid E., Diaz-Galloc, Lina-Marcela, Leclair, Valerie, Galindo-Feria, Angeles S., Rothwell, Simon, Krystufkova, Olga, Zargar, Sepehr Sarrafzadeh, Mann, Herman, Diederichsen, Louise Pyndt, Andersson, Helena, Klein, Martin, Tansley, Sarah, Rönnblom, Lars, Lindblad-Toh, Kerstin, Syvänen, Ann-Christine, Wahren-Herlenius, Marie, Sandling, Johanna K., McHugh, Neil, Lamb, Janine A., Vencovsky, Jiri, Chinoy, Hector, Holmqvist, Marie, Bianchi, Matteo, Padyukov, Leonid, Lundberg, Ingrid E., and Diaz-Galloc, Lina-Marcela

Abstract

Background In patients with idiopathic inflammatory myopathies (IIM), autoantibodies are associated with specific clinical phenotypes suggesting a pathogenic role of adaptive immunity. We explored if autoantibody profiles are associated with specific HLA genetic variants and clinical manifestations in IIM. Methods We included 1348 IIM patients and determined the occurrence of 14 myositis-specific or-associated autoantibodies. We used unsupervised cluster analysis to identify autoantibody-defined subgroups and logistic regression to estimate associations with clinical manifestations, HLA-DRB1, HLA-DQA1, HLA-DQB1 alleles, and amino acids imputed from genetic information of HLA class II and I molecules. Findings We identified eight subgroups with the following dominant autoantibodies: anti-Ro52, -U1RNP, -PM/Scl,-Mi2,-Jo1,-Jo1/Ro52,-TIF1 gamma or negative for all analysed autoantibodies. Associations with HLA-DRB1*11, HLA-DRB1*15, HLA-DQA1*03, and HLA-DQB1*03 were present in the anti-U1RNP-dominated subgroup. HLA-DRB1*03, HLA-DQA1*05, and HLA-DQB1*02 alleles were overrepresented in the anti-PM/Scl and anti-Jo1/ Ro52-dominated subgroups. HLA-DRB1*16, HLA-DRB1*07 alleles were most frequent in anti-Mi2 and HLA- DRB1*01 and HLA-DRB1*07 alleles in the anti-TIF1 gamma subgroup. The HLA-DRB1*13, HLA-DQA1*01 and HLA-DQB1*06 alleles were overrepresented in the negative subgroup. Significant signals from variations in class I molecules were detected in the subgroups dominated by anti-Mi2, anti-Jo1/Ro52, anti-TIF1 gamma, and the negative subgroup. Interpretation Distinct HLA class II and I associations were observed for almost all autoantibody-defined subgroups. The associations support autoantibody profiles use for classifying IIM which would likely reflect underlying pathogenic mechanisms better than classifications based on clinical symptoms and/or histopathological features. Funding See a detailed list of funding bodies in the Acknowledgements section at the end of the manuscr

Published
2023
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21. Genome-wide imputation identifies novel associations and localises signals in idiopathic inflammatory myopathies

Author

Rothwell, Simon, Chinoy, Hector, and Lamb, Janine A.

Abstract

Objectives: The idiopathic inflammatory myopathies (IIM) are heterogeneous diseases, thought to be initiated by immune activation in genetically predisposed individuals. In this study we imputed variants from the Immunochip array using a large reference panel to fine-map associations and identify novel associations in IIM. Methods: We analysed 2,565 Caucasian IIM samples collected through the Myositis Genetics Consortium (MYOGEN) and 10,260 ethnically-matched controls. We imputed 1,648,116 variants from the Immunochip array using the Haplotype Reference Consortium panel and conducted association analysis on IIM, and clinical and serological subgroups. Results: The human leukocyte antigen (HLA) locus was consistently the most significantly associated region. Four non-HLA regions reached genome-wide significance, three in the whole IIM cohort (SDK2 and LINC00924 - both novel, and STAT4), with evidence of independent variants in STAT4, and NAB1 in the polymyositis (PM) subgroup. We also found suggestive evidence of association with loci previously associated with other autoimmune rheumatic diseases (TEC and LTBR). We identified more significant associations than those previously reported in IIM, for STAT4 and DGKQ in the total cohort, for NAB1 and FAM167A-BLK loci in PM, and CCR5 in inclusion body myositis. We found enrichment of variants among DNase I hypersensitivity sites and histone marks associated with active transcription within blood cells.Conclusions: We report novel and strong associations in IIM and PM, and localise signals to single genes and immune cell types.

Published
2022

22. Anti-transcription intermediary factor 1-gamma IgG2 isotype is associated with cancer in adult dermatomyositis: an ENMC multinational study

Author

Cordel, Nadège, primary, Dechelotte, Benoît, additional, Jouen, Fabienne, additional, Lamb, Janine A, additional, Chinoy, Hector, additional, New, Paul, additional, Vencovsky, Jiri, additional, Mann, Herman, additional, Galindo-Feria, Angeles S, additional, Dani, Lara, additional, Selva-O’Callaghan, Albert, additional, Werth, Victoria P, additional, Ravishankar, Adarsh, additional, Landon-Cardinal, Océane, additional, Tressières, Benoit, additional, and Boyer, Olivier, additional

Published
2022
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23. Low copy numbers of complementC4andC4Adeficiency are risk factors for myositis, its subgroups and autoantibodies

Author

Zhou, Danlei, primary, King, Emily H, additional, Rothwell, Simon, additional, Krystufkova, Olga, additional, Notarnicola, Antonella, additional, Coss, Samantha, additional, Abdul-Aziz, Rabheh, additional, Miller, Katherine E, additional, Dang, Amanda, additional, Yu, G Richard, additional, Drew, Joanne, additional, Lundström, Emeli, additional, Pachman, Lauren M, additional, Mamyrova, Gulnara, additional, Curiel, Rodolfo V, additional, De Paepe, Boel, additional, De Bleecker, Jan L, additional, Payton, Antony, additional, Ollier, William, additional, O'Hanlon, Terrance P, additional, Targoff, Ira N, additional, Flegel, Willy A, additional, Sivaraman, Vidya, additional, Oberle, Edward, additional, Akoghlanian, Shoghik, additional, Driest, Kyla, additional, Spencer, Charles H, additional, Wu, Yee Ling, additional, Nagaraja, Haikady N, additional, Ardoin, Stacy P, additional, Chinoy, Hector, additional, Rider, Lisa G, additional, Miller, Frederick W, additional, Lundberg, Ingrid E, additional, Padyukov, Leonid, additional, Vencovský, Jiří, additional, Lamb, Janine A, additional, and Yu, Chack-Yung, additional

Published
2022
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25. The EuroMyositis registry: an international collaborative tool to facilitate myositis research

Author

Lilleker, James B, Vencovsky, Jiri, Wang, Guochun, Wedderburn, Lucy R, Diederichsen, Louise Pyndt, Schmidt, Jens, Oakley, Paula, Benveniste, Olivier, Danieli, Maria Giovanna, Danko, Katalin, Thuy, Nguyen Thi Phuong, Vazquez-Del Mercado, Monica, Andersson, Helena, De Paepe, Boel, deBleecker, Jan L, Maurer, Britta, McCann, Liza J, Pipitone, Nicolo, McHugh, Neil, Betteridge, Zoe E, New, Paul, Cooper, Robert G, Ollier, William E, Lamb, Janine A, Krogh, Niels Steen, Lundberg, Ingrid E, Chinoy, Hector, D’hose, Sophie, Tian, Xin Lu,xiaolan, Mann, Herman, Kryštufková, Olga, Pleštilová, Lenka, Barochová,katerina kubínová, Martin Klein,tereza, Gelardi, Chiara, Pedini, Veronica, Cardinaletti, Paolo, Jara, Luis J, Saavedra, Miguel A, Cruz-reyes, Claudia V, Vera-lastra, Olga, Andrade-ortega, Lilia, Medrano-ramírez, Gabriel, Satoh, Minoru, Salazar-páramo, Mario, Gomez-bañuelos, Eduardo, Aguilar-arreola, Jorge, Durán-barragán, Sergio, Navarro-hernandez, Rosa Elena, Petri, Marcelo H, Molberg, Øyvind, Dastmalchi, Maryam, Notarnicola, Antonella, Gheorghe, Karina, Rönnelid, Johan, Liden, Maria, Hanna, Balsam, Jalal, Awat, Hellström, Helena, Martineus, Jehns Christian, Ngoc lan, Nguyen Thi, Padyukov, Leonid, New, Paul, Platt, Hazel, Rothwell, Simon, Ahmed, Yasmeen, Armstrong, Raymond, Bernstein, Robert, Black, Carol, Bowman, Simon, Bruce, Ian, Butler, Robin, Carty, John, Chattopadhyay, Chandra, Chelliah, Easwaradhas, Clarke, Fiona, Dawes, Peter, Denton, Christopher, Devlin, Joseph, Edwards, Christopher, Emery, Paul, Fordham, John, Fraser, Alexander, Gaston, Hill, Gordon, Patrick, Griffiths, Bridget, Gunawardena, Harsha, Hall, Frances, Hanna, Michael, Harrison, Beverley, Hay, Elaine, Hilton-jones, David, Horden, Lesley, Isaacs, John, Isenberg, David, Jones, Adrian, Kamath, Sanjeet, Kennedy, Thomas, Kitas, George, Klimiuk, Peter, Knights, Sally, Lambert, John, Lanyon, Peter, Laxminarayan, Ramasharan, Lecky, Bryan, Luqmani, Raashid, Machado, Pedro, Marks, Jeffrey, Martin, Michael, Mcgonagle, Dennis, Mchugh, Neil, Mckenna, Francis, Mclaren, John, Mcmahon, Michael, Mcrorie, Euan, Merry, Peter, Miles, Sarah, Miller, James, Nicholls, Anne, Nixon, Jennifer, Ong, Voon, Over, Katherine, Packham, John, Pipitone, Nicolo, Plant, Michael, Pountain, Gillian, Pullar, Thomas, Roberts, Mark, Sanders, Paul, Scott, David, Scott, David, Shadforth, Michael, Sheeran, Thomas, Srinivasan, Arul, Swinson, David, Teh, Lee-suan, Webley, Michael, Williams, Brian, and Winer, Jonathan

Published
2018
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31. Contribution of rare genetic variation to disease susceptibility in a large Scandinavian myositis cohort

Author

Bianchi, Matteo, Kozyrev, Sergey V., Notarnicola, Antonella, Hultin-Rosenberg, Lina, Karlsson, Åsa, Pucholt, Pascal, Rothwell, Simon, Alexsson, Andrei, Sandling, Johanna K., Andersson, Helena, Cooper, Robert G., Padyukov, Leonid, Tjärnlund, Anna, Dastmalchi, Maryam, Meadows, Jennifer, Pyndt Diederichsen, Louise, Molberg, Øyvind, Chinoy, Hector, Lamb, Janine, Rönnblom, Lars, Lindblad-Toh, Kerstin, Lundberg, Ingrid E., Bianchi, Matteo, Kozyrev, Sergey V., Notarnicola, Antonella, Hultin-Rosenberg, Lina, Karlsson, Åsa, Pucholt, Pascal, Rothwell, Simon, Alexsson, Andrei, Sandling, Johanna K., Andersson, Helena, Cooper, Robert G., Padyukov, Leonid, Tjärnlund, Anna, Dastmalchi, Maryam, Meadows, Jennifer, Pyndt Diederichsen, Louise, Molberg, Øyvind, Chinoy, Hector, Lamb, Janine, Rönnblom, Lars, Lindblad-Toh, Kerstin, and Lundberg, Ingrid E.

Abstract

Objective Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of complex autoimmune conditions characterized by inflammation in skeletal muscle and extramuscular compartments, and interferon (IFN) system activation. We undertook this study to examine the contribution of genetic variation to disease susceptibility and to identify novel avenues for research in IIMs. Methods Targeted DNA sequencing was used to mine coding and potentially regulatory single nucleotide variants from ~1,900 immune-related genes in a Scandinavian case–control cohort of 454 IIM patients and 1,024 healthy controls. Gene-based aggregate testing, together with rare variant– and gene-level enrichment analyses, was implemented to explore genotype–phenotype relations. Results Gene-based aggregate tests of all variants, including rare variants, identified IFI35 as a potential genetic risk locus for IIMs, suggesting a genetic signature of type I IFN pathway activation. Functional annotation of the IFI35 locus highlighted a regulatory network linked to the skeletal muscle–specific gene PTGES3L, as a potential candidate for IIM pathogenesis. Aggregate genetic associations with AGER and PSMB8 in the major histocompatibility complex locus were detected in the antisynthetase syndrome subgroup, which also showed a less marked genetic signature of the type I IFN pathway. Enrichment analyses indicated a burden of synonymous and noncoding rare variants in IIM patients, suggesting increased disease predisposition associated with these classes of rare variants. Conclusion Our study suggests the contribution of rare genetic variation to disease susceptibility in IIM and specific patient subgroups, and pinpoints genetic associations consistent with previous findings by gene expression profiling. These features highlight genetic profiles that are potentially relevant to disease pathogenesis.

Published
2022
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32. Anti-transcription intermediary factor 1-gamma IgG2 isotype is associated with cancer in adult dermatomyositis: an ENMC multinational study.

Author

Cordel, Nadège, Dechelotte, Benoît, Jouen, Fabienne, Lamb, Janine A, Chinoy, Hector, New, Paul, Vencovsky, Jiri, Mann, Herman, Galindo-Feria, Angeles S, Dani, Lara, Selva-O'Callaghan, Albert, Werth, Victoria P, Ravishankar, Adarsh, Landon-Cardinal, Océane, Tressières, Benoit, and Boyer, Olivier

Subjects
TUMOR risk factors, AUTOANTIBODIES, DERMATOMYOSITIS, RETROSPECTIVE studies, GAMMA globulins, RISK assessment, IMMUNOASSAY, CANCER patients, ENZYME-linked immunosorbent assay, DESCRIPTIVE statistics, TRANSCRIPTION factors, TUMOR markers, CRYOPRESERVATION of organs, tissues, etc., CHEMICAL inhibitors, ADULTS
Abstract

Objective To assess the role of the anti-TIF1γ auto-antibody (aAb) IgG2 isotype as a biomarker of cancer in anti-TIF1γ aAb-positive adult DM. Methods International multicentre retrospective study with the following inclusion criteria: (i) diagnosis of DM according to ENMC criteria; (ii) presence of anti-TIF1γ IgG aAb determined using an in-house addressable laser bead immunoassay (ALBIA) from cryopreserved serums sampled at time of DM diagnosis and (iii) available baseline characteristics and follow-up data until the occurrence of cancer and/or a minimum follow-up of 1 year for patients without known cancer at diagnosis. Detection and quantification of anti-TIF1γ IgG2 aAb was done using the in-house ALBIA. In addition, a recent ELISA commercial kit was used for anti-TIF1γ IgG aAb quantification. Results A total of 132 patients (mean age 55±15 years) of whom 72 (54.5%) had an associated cancer were analysed. The association between the presence of cancer and the presence of anti-TIF1γ IgG2 aAb was statistically significant (P  = 0.026), with an OR of 2.26 (95% CI: 1.10, 4.76). Patients with cancer displayed significantly higher anti-TIF1γ IgG2 aAb ALBIA values with a median value of 1.15 AU/ml (IQR: 0.14–9.76) compared with 0.50 AU/ml (IQR: 0.14–1.46) for patients without cancer (P  = 0.042). In addition, patients with cancer displayed significantly higher anti-TIF1γ IgG aAb ELISA values with a median value of 127.5 AU/ml (IQR: 81.5–139.6) compared with 93.0 AU/ml (IQR: 54.0–132.9) for patients without cancer (P  = 0.004). Conclusion These results suggest considering anti-TIF1γ IgG2 ALBIA and IgG ELISA values as biomarkers of cancer in anti-TIF1 γ aAb-positive adult DM. [ABSTRACT FROM AUTHOR]

Published
2023
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33. Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations

Author

Seldin, Michael F., Alkhairy, Omar K., Lee, Annette T., Lamb, Janine A., Sussman, Jon, Pirskanen-Matell, Ritva, Piehl, Fredrik, Verschuuren, Jan J. G. M., Kostera-Pruszczyk, Anna, Szczudlik, Piotr, McKee, David, Maniaol, Angelina H., Harbo, Hanne F., Lie, Benedicte A., Melms, Arthur, Garchon, Henri-Jean, Willcox, Nicholas, Gregersen, Peter K., and Hammarstrom, Lennart

Published
2015
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34. P222 Clinical features of extra-muscular disease in dermatomyositis and anti-synthetase syndrome patients with skin involvement classified by presence of disease-specific autoantibodies: results from the EuroMyositis registry

Author

Hum, Ryan M, primary, Lilleker, James B, additional, Lamb, Janine A, additional, Ollier, William E, additional, Wang, Guochung, additional, Wedderburn, Lucy R, additional, Diederichsen, Louise P, additional, Schmidt, Jens, additional, Oakley, Paula, additional, Benveniste, Olivier, additional, Danieli, Maria G, additional, Danko, Katalin, additional, Thuy, Nguyen T. P, additional, Mercado, Monica V. D, additional, Andersson, Helena, additional, Paepe, Boel D, additional, Bleecker, Jan L. D, additional, Maurer, Britta, additional, McCann, Liza J, additional, Pipitone, Nicolo, additional, McHugh, Neil, additional, New, Paul, additional, Vencovsky, Jiri, additional, Lundberg, Ingrid E, additional, and Chinoy, Hector, additional

Published
2022
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36. Disease specificity of autoantibodies to cytosolic 5′-nucleotidase 1A in sporadic inclusion body myositis versus known autoimmune diseases

Author

Herbert, Megan K, Stammen-Vogelzangs, Judith, Verbeek, Marcel M, Rietveld, Anke, Lundberg, Ingrid E, Chinoy, Hector, Lamb, Janine A, Cooper, Robert G, Roberts, Mark, Badrising, Umesh A, De Bleecker, Jan L, Machado, Pedro M, Hanna, Michael G, Plestilova, Lenka, Vencovsky, Jiri, van Engelen, Baziel G, and Pruijn, Ger J M

Published
2016
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37. Rare variants in SQSTM1 and VCP genes and risk of sporadic inclusion body myositis

Author

Hanna, Michael G., Houlden, Henry, Machado, Pedro M., Gang, Qiang, Bettencourt, Conceicao, Healy, Estelle, Parton, Matthew, Holton, Janice L., Brady, Stefen, Hilton-Jones, David, Shieh, Perry B., Zanoteli, Edmar, de Camargo, Leonardo Valente, De Paepe, Boel, De Bleecker, Jan, Shaibani, Aziz, Ripolone, Michela, Violano, Raffaella, Moggio, Maurizio, Barohn, Richard J., Dimachkie, Mazen M., McVey, April L., Pasnoor, Mamatha, Glenn, Melanie, Jawdat, Omar, Statland, Jeffrey, Rico, Gabrielle, Mora, Marina, Mantegazza, Renato, Zanotti, Simona, Needham, Merrilee, Mastaglia, Frank, Liang, Christina, Dalakas, Marinos C., Biba, Angie, Chinoy, Hector, Lilleker, James B., Lamb, Janine, Platt, Hazel, Cooper, Robert G., Miller, James A.L., Roberts, Mark, Househam, Elizabeth, Hilton, David, Shivane, Aditya, Bartlett, Amy, Kissel, John T., Runk, Heidi, Wicklund, Matthew, Saperstein, David S., McKinney, Lynette R., Bettencourt, Conceição, Pittman, Alan M., Hughes, Deborah, and Singleton, Andrew B.

Published
2016
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38. A whole-genome scan and fine-mapping linkage study of auditory-visual synesthesia reveals evidence of linkage to chromosomes 2q24, 5q33, 6p12, and 12p12

Author

Asher, Julian E., Lamb, Janine A., Brocklebank, Denise, Cazier, Jean-Baptiste, Monaco, Anthony P., Maestrini, Elena, Addis, Laura, Sen, Mallika, and Baron-Cohen, Simon

Subjects
Microsatellites (Genetics) -- Usage, Neuroimaging -- Usage, Synesthesia -- Genetic aspects, X chromosome -- Research, Perception -- Analysis, Chromosome mapping -- Usage, Biological sciences
Abstract

The article discusses the results obtained from a whole-genome study and fine-mapping linkage study that is conducted to analyze the auditory-visual synesthesia, a neurological condition characterized by anomalous sensory perception. The results prove that the disorder is highly linked to various chromosomes, including 2q24, 5q33, 6p12, and 12p12.

Published
2009

39. Genome-Wide Association Study of Dermatomyositis Reveals Genetic Overlap With Other Autoimmune Disorders

Author

Miller, Frederick W., Cooper, Robert G., Vencovský, Jiří, Rider, Lisa G., Danko, Katalin, Wedderburn, Lucy R., Lundberg, Ingrid E., Pachman, Lauren M., Reed, Ann M., Ytterberg, Steven R., Padyukov, Leonid, Selva-OʼCallaghan, Albert, Radstake, Timothy R. D. J., Isenberg, David A., Chinoy, Hector, Ollier, William E. R., OʼHanlon, Terrance P., Peng, Bo, Lee, Annette, Lamb, Janine A., Chen, Wei, Amos, Christopher I., and Gregersen, Peter K.

Published
2013
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40. Additional file 6 of MicroRNA and mRNA profiling in the idiopathic inflammatory myopathies

Author

Parkes, Joanna E., Thoma, Anastasia, Lightfoot, Adam P., Day, Philip J., Chinoy, Hector, and Lamb, Janine A.

Abstract

Additional file 6: Table S1. Assays used in RTqPCR experiments The assay IDs for the TaqMan® Advanced miRNA assays and gene expression assays used to assess reference genes (‘Reference selection’), for validation of microRNA (‘miRNA validation’) and targets (‘mRNA validation’) found to be dysregulated in RNA sequencing of whole blood from idiopathic inflammatory myopathy patients compared to controls and used to assess expression in human skeletal muscle cells transfected with miRNA mimic compared to cells transfected with negative control miRNA mimic (‘Transfection’). Table S2. RTqPCR to validate microRNA identified in RNA sequencing in idiopathic inflammatory myopathy patients versus controls PM Polymyositis, DM Dermatomyositis, IBM Inclusion body myositis, Anti-Jo1 Subset of PM and DM with anti-Jo1 autoantibodies, IIM Idiopathic inflammatory myopathy, DE Differentially expressed RTqPCR was performed on total RNA from 6 PM and 5 DM (including 5 anti-Jo-1), 4 IBM, and 4 control whole blood samples. The RTqPCR results are presented next to the RNA sequencing results for these microRNA for comparison. Expression fold change was calculated using the 2-∆∆Ct method and then converted to Log2 fold change values. P-values were calculated using an independent T-test on delta Ct values from each sample (Experimental Ct-Reference Ct) in the subgroups. Table S3. RTqPCR results for skeletal muscle cells transfected with miR-96-5p mimic compared to controls RTqPCR assays for the expression of predicted miR-96-5p mRNA targets were performed on total RNA extracted from human skeletal muscle cells transfected with miR-96-5p miRNA mimic (n = 5) and cells transfected with negative control miRNA mimic (n = 3). Expression fold change was calculated using the 2-∆∆Ct method and then converted to Log2 fold change values. P-values were calculated using an independent T-test on delta Ct values from each sample (Experimental Ct-Reference Ct).

Published
2020
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42. MicroRNA and mRNA profiling in the idiopathic inflammatory myopathies

Author

Parkes, Joanna E, Thoma, Anastasia, Lightfoot, Adam P, Day, Philip J, Chinoy, Hector, Lamb, Janine A, Parkes, Joanna E, Thoma, Anastasia, Lightfoot, Adam P, Day, Philip J, Chinoy, Hector, and Lamb, Janine A

Abstract

Background The idiopathic inflammatory myopathies (IIMs) are heterogeneous autoimmune conditions of skeletal muscle inflammation and weakness. MicroRNAs (miRNAs) are short, non-coding RNA which regulate gene expression of target mRNAs. The aim of this study was to profile miRNA and mRNA in IIM and identify miRNA-mRNA relationships which may be relevant to disease. Methods mRNA and miRNA in whole blood samples from 7 polymyositis (PM), 7 dermatomyositis (DM), 5 inclusion body myositis and 5 non-myositis controls was profiled using next generation RNA sequencing. Gene ontology and pathway analyses were performed using GOseq and Ingenuity Pathway Analysis. Dysregulation of miRNAs and opposite dysregulation of predicted target mRNAs in IIM subgroups was validated using RTqPCR and investigated by transfecting human skeletal muscle cells with miRNA mimic. Results Analysis of differentially expressed genes showed that interferon signalling, and anti-viral response pathways were upregulated in PM and DM compared to controls. An anti-Jo1 autoantibody positive subset of PM and DM (n = 5) had more significant upregulation and predicted activation of interferon signalling and highlighted T-helper (Th1 and Th2) cell pathways. In miRNA profiling miR-96-5p was significantly upregulated in PM, DM and the anti-Jo1 positive subset. RTqPCR replicated miR-96-5p upregulation and predicted mRNA target (ADK, CD28 and SLC4A10) downregulation. Transfection of a human skeletal muscle cell line with miR-96-5p mimic resulted in significant downregulation of ADK. Conclusion MiRNA and mRNA profiling identified dysregulation of interferon signalling, anti-viral response and T-helper cell pathways, and indicates a possible role for miR-96-5p regulation of ADK in pathogenesis of IIM.

Published
2020

46. Risk for myasthenia gravis maps to a 151Pro→Ala change in TNIP1 and to human leukocyte antigen-B*08

Author

Gregersen, Peter K., Kosoy, Roman, Lee, Annette T., Lamb, Janine, Sussman, Jon, McKee, David, Simpfendorfer, Kim R., Pirskanen-Matell, Ritva, Piehl, Frederik, Pan-Hammarstrom, Qiang, Verschuuren, Jan J. G. M., Titulaer, Maarten J., Niks, Erik H., Marx, Alexander, Ströbel, Philipp, Tackenberg, Björn, Pütz, Michael, Maniaol, Angelina, Elsais, Ahmed, Tallaksen, Chantal, Harbo, Hanne F., Lie, Benedicte A., Raychaudhuri, Soumya, de Bakker, Paul I. W., Melms, Arthur, Garchon, Henri-Jean, Willcox, Nicholas, Hammarstrom, Lennart, and Seldin, Michael F.

Published
2012
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