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1. Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases

Author

Acosta-Herrera, Marialbert, Kerick, Martin, González-Serna, David, Wijmenga, Cisca, Franke, Andre, Gregersen, Peter K., Padyukov, Leonid, Worthington, J., Vyse, T. J., Alarcón-Riquelme, M. E., Mayes, M. D., Martín, J., Miller, Frederick W., Chen, Wei, O'Hanlon, Terrance P., Cooper, Robert G., Vencovsky, Jiri, Rider, Lisa G, Danko, Katalin, Wedderburn, Lucy R., Lundberg, Ingrid E., Pachman, Lauren M., Reed, Ann M., Ytterberg, Steven R, Selva-O'Callaghan, Alber, Radstake, Timothy R., Isenberg, David A, Chinoy, Hector, Ollier, William E. R, Scheet, Paul, Peng, Bo, Lee, Annette, Lamb, Janine A., Amos, Christopher I., Denton, Christopher, Hilton-Jones, David, Plotz, Paul H., Varsani, Hemlata, Radstake, Timothy R. D. J., Gorlova, Olga, Rueda, B., Martín, J. E., Alizadeh, B. Z., Palomino-Morales, Rogelio, Coenen, Marieke J. H., Vonk, Madelon C., Voskuyl, Alexandre E., Scheurwegh, Annemie J., Broen, Jasper C., van Riel, Piet L. C. M., van 't Slot, Rubén, Italiaander, Annet, Ophoff, Roel A., Riemekasten, Gabriela, Hunzelmann, Nicolas, Simeon, Carmen P., Ortego-Centeno, N., González-Gay, M. A., González-Escribano, María Francisca, Airó, Paolo, van Laar, Jaap, Herrick, Ariane L., Hesselstrand, Roger, Smith, Vanessa, de Keyser, Filip, Houssiau, Fredric, Chee, Meng May, Madhok, Rajan, Shiels, Paul, Westhovens, Rene, Kreuter, A., Kiener, Hans, de Baere, Elfride, Witte, Torsten, Klareskog, Lars, Beretta, Lorenzo, Scorza, Rafaella, Lie, Benedicte A., Hoffman-Vold, A. M., Carreira, P., Varga, John, Hinchcliff, Monique, Lee, Annette T., Ying, Jun, Han, Younghun, Weng, Shih-Feng, Wigley, Fredrick M., Hummers, L. K., Nelson, J. Lee, Agarwal, Sandeep K., Assassi, S., Gourh, Pravitt, Tan, Filemon K., Koeleman, B. P., Arnett, Frank C., Myositis Genetics Consortium, Scleroderma Genetics Consortium., Innovative Medicines Initiative, Ministerio de Economía, Industria y Competitividad (España), Junta de Andalucía, National Institute of Environmental Health Sciences (US), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Polymer Chemistry and Bioengineering, Life Course Epidemiology (LCE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Myositis Genetics Consortium, and Scleroderma Genetics Consortium

Subjects
0301 basic medicine, Male, Lydia Becker Institute, PATHOGENESIS, PROTEIN, Arthritis, VARIANTS, medicine.disease_cause, Myositis Genetics Consortium, Autoimmunity, Scleroderma, Arthritis, Rheumatoid, 0302 clinical medicine, Scleroderma Genetics Consortium, Rheumatoid, MULTIPLE, Lupus Erythematosus, Systemic, Immunology and Allergy, Medicine, 2.1 Biological and endogenous factors, Aetiology, Genetics, autoimmunity, Family aggregation, Lim Kinases, ASSOCIATION, Single Nucleotide, Public Health and Health Services, Female, ARTHRITIS, Life Sciences & Biomedicine, alpha Karyopherins, Adult, medicine.medical_specialty, GENETICS, gene polymorphism, Quantitative Trait Loci, Clinical Sciences, Immunology, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Autoimmune Disease, General Biochemistry, Genetics and Molecular Biology, White People, Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18], 03 medical and health sciences, Immune system, Rheumatology, Internal medicine, Rheumatic Diseases, ResearchInstitutes_Networks_Beacons/lydia_becker_institute_of_immunology_and_inflammation, Humans, Genetic Predisposition to Disease, autoimmune diseases, Polymorphism, SCLEROSIS, COMMON, 030203 arthritis & rheumatology, Science & Technology, Scleroderma, Systemic, COMPLEX, Myositis, Lupus Erythematosus, business.industry, Inflammatory and immune system, Systemic, Human Genome, Membrane Proteins, medicine.disease, Arthritis & Rheumatology, Repressor Proteins, 030104 developmental biology, Expression quantitative trait loci, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], Human medicine, Gene polymorphism, business, Genome-Wide Association Study
Abstract

ObjectiveImmune-mediated inflammatory diseases (IMIDs) are heterogeneous and complex conditions with overlapping clinical symptoms and elevated familial aggregation, which suggests the existence of a shared genetic component. In order to identify this genetic background in a systematic fashion, we performed the first cross-disease genome-wide meta-analysis in systemic seropositive rheumatic diseases, namely, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and idiopathic inflammatory myopathies.MethodsWe meta-analysed ~6.5 million single nucleotide polymorphisms in 11 678 cases and 19 704 non-affected controls of European descent populations. The functional roles of the associated variants were interrogated using publicly available databases.ResultsOur analysis revealed five shared genome-wide significant independent loci that had not been previously associated with these diseases: NAB1, KPNA4-ARL14, DGQK, LIMK1 and PRR12. All of these loci are related with immune processes such as interferon and epidermal growth factor signalling, response to methotrexate, cytoskeleton dynamics and coagulation cascade. Remarkably, several of the associated loci are known key players in autoimmunity, which supports the validity of our results. All the associated variants showed significant functional enrichment in DNase hypersensitivity sites, chromatin states and histone marks in relevant immune cells, including shared expression quantitative trait loci. Additionally, our results were significantly enriched in drugs that are being tested for the treatment of the diseases under study.ConclusionsWe have identified shared new risk loci with functional value across diseases and pinpoint new potential candidate loci that could be further investigated. Our results highlight the potential of drug repositioning among related systemic seropositive rheumatic IMIDs.

Published
2019

2. Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases

Author

Innovative Medicines Initiative, Ministerio de Economía, Industria y Competitividad (España), Junta de Andalucía, National Institute of Environmental Health Sciences (US), Acosta-Herrera, Marialbert, Kerick, Martin, González-Serna, David, Wijmenga, Cisca, Franke, Andre, Gregersen, Peter K., Padyukov, Leonid, Worthington, J., Vyse, T. J., Alarcón-Riquelme, M. E., Mayes, Maureen D., Martín, J., Miller, Frederick W., Chen, Wei, O'Hanlon, Terrance P., Cooper, Robert G., Vencovsky, Jiri, Rider, Lisa G, Danko, Katalin, Wedderburn, Lucy R., Lundberg, Ingrid E., Pachman, Lauren M., Reed, Ann M., Ytterberg, Steven R, Selva-O'Callaghan, Alber, Radstake, Timothy R., Isenberg, David A, Chinoy, Hector, Ollier, William E. R, Scheet, Paul, Peng, Bo, Lee, Annette T., Lamb, Janine A., Amos, Christopher I., Denton, Christopher, Hilton-Jones, David, Plotz, Paul H., Varsani, Hemlata, Radstake, Timothy R. D. J., Gorlova, Olga, Rueda, B., Martín, J. E., Alizadeh, B. Z., Palomino-Morales, Rogelio, Coenen, Marieke J. H., Vonk, Madelon C., Voskuyl, Alexandre E., Scheurwegh, Annemie J., Broen, Jasper C., van Riel, Piet L. C. M., van 't Slot, Rubén, Italiaander, Annet, Ophoff, Roel A., Riemekasten, Gabriela, Hunzelmann, Nicolas, Simeón, Carmen P., Ortego-Centeno, N., González-Gay, M. A., González-Escribano, María Francisca, Airó, Paolo, van Laar, Jaap, Herrick, Ariane L., Hesselstrand, Roger, Smith, Vanessa, de Keyser, Filip, Houssiau, Fredric, Chee, Meng May, Madhok, Rajan, Shiels, Paul, Westhovens, Rene, Kreuter, A., Kiener, Hans, de Baere, Elfride, Witte, Torsten, Klareskog, Lars, Beretta, Lorenzo, Scorza, Rafaella, Lie, Benedicte A., Hoffman-Vold, A. M., Carreira, P., Varga, John, Hinchcliff, Monique, Ying, Jun, Han, Younghun, Weng, Shih-Feng, Wigley, Fredrick M., Hummers, L. K., Nelson, J. Lee, Agarwal, Sandeep K., Assassi, S., Gourh, Pravitt, Tan, Filemon K., Koeleman, B. P., Arnett, Frank C., Myositis Genetics Consortium, Scleroderma Genetics Consortium., Innovative Medicines Initiative, Ministerio de Economía, Industria y Competitividad (España), Junta de Andalucía, National Institute of Environmental Health Sciences (US), Acosta-Herrera, Marialbert, Kerick, Martin, González-Serna, David, Wijmenga, Cisca, Franke, Andre, Gregersen, Peter K., Padyukov, Leonid, Worthington, J., Vyse, T. J., Alarcón-Riquelme, M. E., Mayes, Maureen D., Martín, J., Miller, Frederick W., Chen, Wei, O'Hanlon, Terrance P., Cooper, Robert G., Vencovsky, Jiri, Rider, Lisa G, Danko, Katalin, Wedderburn, Lucy R., Lundberg, Ingrid E., Pachman, Lauren M., Reed, Ann M., Ytterberg, Steven R, Selva-O'Callaghan, Alber, Radstake, Timothy R., Isenberg, David A, Chinoy, Hector, Ollier, William E. R, Scheet, Paul, Peng, Bo, Lee, Annette T., Lamb, Janine A., Amos, Christopher I., Denton, Christopher, Hilton-Jones, David, Plotz, Paul H., Varsani, Hemlata, Radstake, Timothy R. D. J., Gorlova, Olga, Rueda, B., Martín, J. E., Alizadeh, B. Z., Palomino-Morales, Rogelio, Coenen, Marieke J. H., Vonk, Madelon C., Voskuyl, Alexandre E., Scheurwegh, Annemie J., Broen, Jasper C., van Riel, Piet L. C. M., van 't Slot, Rubén, Italiaander, Annet, Ophoff, Roel A., Riemekasten, Gabriela, Hunzelmann, Nicolas, Simeón, Carmen P., Ortego-Centeno, N., González-Gay, M. A., González-Escribano, María Francisca, Airó, Paolo, van Laar, Jaap, Herrick, Ariane L., Hesselstrand, Roger, Smith, Vanessa, de Keyser, Filip, Houssiau, Fredric, Chee, Meng May, Madhok, Rajan, Shiels, Paul, Westhovens, Rene, Kreuter, A., Kiener, Hans, de Baere, Elfride, Witte, Torsten, Klareskog, Lars, Beretta, Lorenzo, Scorza, Rafaella, Lie, Benedicte A., Hoffman-Vold, A. M., Carreira, P., Varga, John, Hinchcliff, Monique, Ying, Jun, Han, Younghun, Weng, Shih-Feng, Wigley, Fredrick M., Hummers, L. K., Nelson, J. Lee, Agarwal, Sandeep K., Assassi, S., Gourh, Pravitt, Tan, Filemon K., Koeleman, B. P., Arnett, Frank C., Myositis Genetics Consortium, and Scleroderma Genetics Consortium.

Published
2019

3. A genome-wide association study of rheumatoid arthritis without antibodies against citrullinated peptides

Author

Bossini-Castillo, L., de Kovel, C., Kallberg, H., van 't Slot, R., Italiaander, A., Coenen, M., Tak, P. P., Posthumus, M. D., Wijmenga, C., Huizinga, T., van der Helm-van Mil, A. H. M., Stoeken-Rijsbergen, G., Rodriguez-Rodriguez, Luis, Balsa, Alejandro, Gonzalez-Alvaro, Isidoro, Angel Gonzalez-Gay, Miguel, Gomez-Vaquero, Carmen, Franke, B., Vermeulen, S., van der Horst-Bruinsma, I. E., Dijkmans, B. A. C., Wolbink, G. J., Ophoff, R. A., Maehlen, M. T., van Riel, P., Merriman, M., Klareskog, L., Lie, B. A., Merriman, T., Crusius, J. B. A., Brouwer, E., Martin, J., de Vries, N., Toes, R., Padyukov, L., Koeleman, B. P. C., LifeLines Cohort Study, Bossini-Castillo, L., de Kovel, C., Kallberg, H., van 't Slot, R., Italiaander, A., Coenen, M., Tak, P. P., Posthumus, M. D., Wijmenga, C., Huizinga, T., van der Helm-van Mil, A. H. M., Stoeken-Rijsbergen, G., Rodriguez-Rodriguez, Luis, Balsa, Alejandro, Gonzalez-Alvaro, Isidoro, Angel Gonzalez-Gay, Miguel, Gomez-Vaquero, Carmen, Franke, B., Vermeulen, S., van der Horst-Bruinsma, I. E., Dijkmans, B. A. C., Wolbink, G. J., Ophoff, R. A., Maehlen, M. T., van Riel, P., Merriman, M., Klareskog, L., Lie, B. A., Merriman, T., Crusius, J. B. A., Brouwer, E., Martin, J., de Vries, N., Toes, R., Padyukov, L., Koeleman, B. P. C., and LifeLines Cohort Study

Published
2015

4. Evaluation of genetic risk loci for intracranial aneurysms in sporadic arteriovenous malformations of the brain

Author

Kremer, P. H C, Koeleman, B. P C, Pawlikowska, L., Weinsheimer, S., Bendjilali, N., Sidney, S., Zaroff, J. G., Rinkel, G. J E, Van Den Berg, L. H., Ruigrok, Y. M., De Kort, G. A P, Veldink, J. H., Kim, H., Klijn, C. J M, Kremer, P. H C, Koeleman, B. P C, Pawlikowska, L., Weinsheimer, S., Bendjilali, N., Sidney, S., Zaroff, J. G., Rinkel, G. J E, Van Den Berg, L. H., Ruigrok, Y. M., De Kort, G. A P, Veldink, J. H., Kim, H., and Klijn, C. J M

Published
2015

5. Evaluation of genetic risk loci for intracranial aneurysms in sporadic arteriovenous malformations of the brain

Author

Genetica Groep Koeleman, Brain, Child Health, Neurologie, Projectafdeling ALS, ZL Cerebrovasculaire Ziekten Medisch, MS Radiologie, Neurogenetica, Kremer, P. H C, Koeleman, B. P C, Pawlikowska, L., Weinsheimer, S., Bendjilali, N., Sidney, S., Zaroff, J. G., Rinkel, G. J E, Van Den Berg, L. H., Ruigrok, Y. M., De Kort, G. A P, Veldink, J. H., Kim, H., Klijn, C. J M, Genetica Groep Koeleman, Brain, Child Health, Neurologie, Projectafdeling ALS, ZL Cerebrovasculaire Ziekten Medisch, MS Radiologie, Neurogenetica, Kremer, P. H C, Koeleman, B. P C, Pawlikowska, L., Weinsheimer, S., Bendjilali, N., Sidney, S., Zaroff, J. G., Rinkel, G. J E, Van Den Berg, L. H., Ruigrok, Y. M., De Kort, G. A P, Veldink, J. H., Kim, H., and Klijn, C. J M

Published
2015

6. A genome-wide association study of rheumatoid arthritis without antibodies against citrullinated peptides

Author

Genetica Groep Koeleman, Hersenen-Bedrijfsvoering, MMB, Child Health, Bossini-Castillo, L., de Kovel, C., Kallberg, H., van 't Slot, R., Italiaander, A., Coenen, M., Tak, P. P., Posthumus, M. D., Wijmenga, C., Huizinga, T., van der Helm-van Mil, A. H. M., Stoeken-Rijsbergen, G., Rodriguez-Rodriguez, Luis, Balsa, Alejandro, Gonzalez-Alvaro, Isidoro, Angel Gonzalez-Gay, Miguel, Gomez-Vaquero, Carmen, Franke, B., Vermeulen, S., van der Horst-Bruinsma, I. E., Dijkmans, B. A. C., Wolbink, G. J., Ophoff, R. A., Maehlen, M. T., van Riel, P., Merriman, M., Klareskog, L., Lie, B. A., Merriman, T., Crusius, J. B. A., Brouwer, E., Martin, J., de Vries, N., Toes, R., Padyukov, L., Koeleman, B. P. C., LifeLines Cohort Study, Genetica Groep Koeleman, Hersenen-Bedrijfsvoering, MMB, Child Health, Bossini-Castillo, L., de Kovel, C., Kallberg, H., van 't Slot, R., Italiaander, A., Coenen, M., Tak, P. P., Posthumus, M. D., Wijmenga, C., Huizinga, T., van der Helm-van Mil, A. H. M., Stoeken-Rijsbergen, G., Rodriguez-Rodriguez, Luis, Balsa, Alejandro, Gonzalez-Alvaro, Isidoro, Angel Gonzalez-Gay, Miguel, Gomez-Vaquero, Carmen, Franke, B., Vermeulen, S., van der Horst-Bruinsma, I. E., Dijkmans, B. A. C., Wolbink, G. J., Ophoff, R. A., Maehlen, M. T., van Riel, P., Merriman, M., Klareskog, L., Lie, B. A., Merriman, T., Crusius, J. B. A., Brouwer, E., Martin, J., de Vries, N., Toes, R., Padyukov, L., Koeleman, B. P. C., and LifeLines Cohort Study

Published
2015

7. A replication study confirms the association of TNFSF4 (OX40L) polymorphisms with systemic sclerosis in a large European cohort.

Author

Bossini-Castillo, L., Broen, Jasper C., Simeón, Carmen P., Beretta, L., Vonk, Madelon C., Ortego-Centeno, N., Espinosa, Gerard, Carreira, P., Camps, M. T., Navarrete, N., González-Escribano, María Francisca, Vicente, Esther, Rodríguez-Rodríguez, Luis, Tolosa, Carlos, Román-Ivorra, J. A., Gómez-Gracía, I., García-Hernández, Francisco José, Castellví, I., Gallego, María, Fernández-Nebro, Antonio, García-Portales, Rosa, Egurbide, M. V., Fonollosa, V., García de la Peña, P., Pros, A., González-Gay, M. A., Hesselstrand, R., Riemekasten, G., Witte, Torsten, Coenen, M. J., Koeleman, B. P., Houssiau, F., Smith, V., Keyser, F. de, Westhovens, R., Langhe, E. de, Voskuyl, Alexandre E., Schuerwegh, A. J., Chee, M. M., Madhok, R., Shiels, Paul G., Fonseca, C., Denton, C., Claes, K., Padyukov, Leonid, Nordin, A., Palm, Øyvind, Lie, B. A., Airó, Paolo, Scorza, R., Laar, Jacob M. van, Hunzelmann, Nicolas, Kreuter, A., Herrick, A., Worthington, J., Radstake, T. R., Martín, J., Rueda, B., Bossini-Castillo, L., Broen, Jasper C., Simeón, Carmen P., Beretta, L., Vonk, Madelon C., Ortego-Centeno, N., Espinosa, Gerard, Carreira, P., Camps, M. T., Navarrete, N., González-Escribano, María Francisca, Vicente, Esther, Rodríguez-Rodríguez, Luis, Tolosa, Carlos, Román-Ivorra, J. A., Gómez-Gracía, I., García-Hernández, Francisco José, Castellví, I., Gallego, María, Fernández-Nebro, Antonio, García-Portales, Rosa, Egurbide, M. V., Fonollosa, V., García de la Peña, P., Pros, A., González-Gay, M. A., Hesselstrand, R., Riemekasten, G., Witte, Torsten, Coenen, M. J., Koeleman, B. P., Houssiau, F., Smith, V., Keyser, F. de, Westhovens, R., Langhe, E. de, Voskuyl, Alexandre E., Schuerwegh, A. J., Chee, M. M., Madhok, R., Shiels, Paul G., Fonseca, C., Denton, C., Claes, K., Padyukov, Leonid, Nordin, A., Palm, Øyvind, Lie, B. A., Airó, Paolo, Scorza, R., Laar, Jacob M. van, Hunzelmann, Nicolas, Kreuter, A., Herrick, A., Worthington, J., Radstake, T. R., Martín, J., and Rueda, B.

Abstract

Objectives: The aim of this study was to confirm the influence of TNFSF4 polymorphisms on systemic sclerosis (SSc) susceptibility and phenotypic features. Methods: A total of 8 European populations of Caucasian ancestry were included, comprising 3014 patients with SSc and 3125 healthy controls. Four genetic variants of TNFSF4 gene promoter (rs1234314, rs844644, rs844648 and rs12039904) were selected as genetic markers. Results: A pooled analysis revealed the association of rs1234314 and rs12039904 polymorphisms with SSc (OR 1.15, 95% CI 1.02 to 1.31; OR 1.18, 95% CI 1.08 to 1.29, respectively). Significant association of the four tested variants with patients with limited cutaneous SSc (lcSSc) was revealed (rs1234314 OR 1.22, 95% CI 1.07 to 1.38; rs844644 OR 0.91, 95% CI 0.83 to 0.99; rs844648 OR 1.10, 95% CI 1.01 to 1.20 and rs12039904 OR 1.20, 95% CI 1.09 to 1.33). Association of rs1234314, rs844648 and rs12039904 minor alleles with patients positive for anti-centromere antibodies (ACA) remained significant (OR 1.23, 95% CI 1.10 to 1.37; OR 1.12, 95% CI 1.01 to 1.25; OR 1.22, 95% CI 1.07 to 1.38, respectively). Haplotype analysis confirmed a protective haplotype associated with SSc, lcSSc and ACA positive subgroups (OR 0.88, 95% CI 0.82 to 0.96; OR 0.88, 95% CI 0.80 to 0.96; OR 0.86, 95% CI 0.77 to 0.97, respectively) and revealed a new risk haplotype associated with the same groups of patients (OR 1.14, 95% CI 1.03 to 1.26; OR 1.20, 95% CI 1.08 to 1.35; OR 1.23, 95% CI 1.07 to 1.42, respectively). Conclusions: The data confirm the influence of TNFSF4 polymorphisms in SSc genetic susceptibility, especially in subsets of patients positive for lcSSc and ACA.

Published
2011

8. Susceptibility loci for sporadic brain arteriovenous malformation; a replication study and meta-analysis.

Author

Kremer, P. H. C., Koeleman, B. P. C., Rinkel, G. JE, Diekstra, F. P., van den Berg, L. H., Veldink, J. H., and Klijn, C. J. M.

Subjects
CEREBRAL arteriovenous malformations, SINGLE nucleotide polymorphisms, BRAIN blood-vessel abnormalities, PATHOLOGICAL physiology, META-analysis, GENETICS, CELL receptors, COMPARATIVE studies, DISEASE susceptibility, GENES, GENETIC polymorphisms, GENOMES, INTERLEUKIN-1, RESEARCH methodology, MEDICAL cooperation, PROTEINS, PROTEOLYTIC enzymes, RESEARCH, RESEARCH evaluation, EVALUATION research, VASCULAR endothelial growth factors, CASE-control method, ARTERIOVENOUS malformation, SEQUENCE analysis, GENOTYPES
Abstract

Background: Case-control studies have reported multiple genetic loci to be associated with sporadic brain arteriovenous malformations (AVMs) but most of these have not been replicated in independent populations. The aim of this study was to find additional evidence for these reported associations and perform a meta-analysis including all previously published results.Methods: We included 167 Dutch patients and 1038 Dutch controls. Case genotyping was performed by KASPar assays. Controls had been previously genotyped with a genome wide single nucleotide polymorphisms (SNP) array. Differences in genotype frequencies between cases and controls were estimated by χ(2) testing in Plink V.1.07. Meta-analysis was performed in RevMan V.5.3.Results: In our case-control study we found no significant association with brain AVM (BAVM) for previously discovered SNPs near ANGPTL4, IL-1β, GPR124, VEGFA and MMP-3. The meta-analysis revealed a statistically significant association with BAVMs for the polymorphism rs11672433 near ANGPTL4 (OR 1.39; 95% CI 1.10 to 1.75, p value 0.005).Conclusions: The results of this study support a role for the previously identified SNP near ANGPTL4 in the pathogenesis of AVMs. Previously found associations with SNPs near IL-1β, GPR124, VEGFA and MMP-3 genes could not be substantiated in our replication cohort or in the meta-analysis. [ABSTRACT FROM AUTHOR]

Published
2016
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9. Evaluation of genetic risk loci for intracranial aneurysms in sporadic arteriovenous malformations of the brain.

Author

Kremer, P. H. C., Koeleman, B. P. C., Pawlikowska, L., Weinsheimer, S., Bendjilali, N., Sidney, S., Zaroff, J. G., Rinkel, G. J. E., van den Berg, L. H., Ruigrok, Y. M., de Kort, G. A. P., Veldink, J. H., Kim, H., and Klijn, C. J. M.

Subjects
*ARTERIOVENOUS malformation, *INTRACRANIAL aneurysms, *LOCUS (Genetics), *SINGLE nucleotide polymorphisms, *SOX transcription factors, *BRAIN diseases, *GENOTYPES
Abstract

Background In genome-wide association studies (GWAS) five putative risk loci are associated with intracranial aneurysm. As brain arteriovenous malformations (AVM) and intracranial aneurysms are both intracranial vascular diseases and AVMs often have associated aneurysms, we investigated whether these loci are also associated with sporadic brain AVM. Methods: We included 506 patients (168 Dutch, 338 American) and 1548 controls, all Caucasians. Controls had been recruited as part of previous GWAS. Dutch patients were genotyped by KASPar assay and US patients by Affymetrix SNP 6.0 array. Associations in each cohort were tested by univariable logistic regression modelling, with subgroup analysis in 205 American cases with aneurysm data. Meta-analysis was performed by a Mantel-Haenszel fixed-effect method. Results: In the Dutch cohort none of the single nucleotide polymorphisms (SNPs) were associated with AVMs. In the American cohort, genotyped SNPs near SOX-17 (OR 0.74; 95% CI 0.56-0.98), RBBP8 (OR 0.76; 95% CI 0.62-0.94) and an imputed SNP near CDKN2B-AS1 (OR 0.79; 95% CI 0.64-0.98) were significantly associated with AVM. The association with SNPs near SOX-17 and CDKN2B-AS1 but not RBBP8 were strongest in patients with AVM with associated aneurysms. In the meta-analysis we found no significant associations between allele frequencies and AVM occurrence, but rs9298506, near SOX-17 approached statistical significance (OR 0.77; 95% CI 0.57-1.03, p=0.08). Conclusions: Our meta-analysis of two Caucasian cohorts did not showan association between five aneurysmassociated loci and sporadic brain AVM. Possible involvement of SOX-17 and RBBP8, genes involved in cell cycle progression, deserves further investigation. [ABSTRACT FROM AUTHOR]

Published
2015
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10. Genetic variants in IL15 associate with progression of joint destruction in rheumatoid arthritis: a multicohort study.

Author

Knevel, R., Krabben, A., Brouwer, E., Posthumus, M. D., Wilson, A. G., Lindqvist, E., Saxne, T., De Rooy, D., Daha, N., Van Der Linden, M. P. M., Stoeken, G., Van Toorn, L., Koeleman, B., Tsonaka, R., Zhernakoza, A., Houwing-Duistermaat, J. J., Toes, R., Huizinga, T. W. J., and Van Der Helm-Van Mil, A.

Abstract

Background Interleukin (IL)-15 levels are increased in serum, synovium and bone marrow of patients with rheumatoid arthritis (RA). IL-15 influences both the innate and the adaptive immune response; its major role is activation and proliferation of T cells. There are also emerging data that IL-15 affects osteoclastogenesis. The authors investigated the association of genetic variants in IL15 with the rate of joint destruction in RA. Method 1418 patients with 4885 x-ray sets of both hand and feet of four independent data sets were studied. First, explorative analyses were performed on 600 patients with early RA enrolled in the Leiden Early Arthritis Clinic. Twenty five single-nucleotide polymorphisms (SNPs) tagging IL-15 were tested. Second, SNPs with significant associations in the explorative phase were genotyped in data sets from Groningen, Sheffield and Lund. In each data set, the relative increase of the progression rate per year in the presence of a genotype was assessed. Subsequently, data were summarised in an inverse weighting meta-analysis. Results Five SNPs were significantly associated with rate of joint destruction in phase 1 and typed in the other data sets. Patients homozygous for rs7667746, rs7665842, rs2322182, rs6821171 and rs4371699 had respectively 0.94-, 1.04-, 1.09-, 1.09- and 1.09-fold rate of joint destruction compared to other patients (p=4.0x10-6, p=3.8x10-4, p=5.0x10-3, p=5.0x10-3 and p=9.4x10-3). Discussion Independent replication was not obtained, possibly due to insufficient power. Meta-analyses of all data sets combined resulted in significant results for four SNPs (rs7667746, p<0.001; rs7665842, p<0.001; rs4371699, p=0.01; rs6821171, p=0.01). These SNPs were also significant after correction for multiple testing. Conclusion Genetic variants in IL-15 are associated wit progression of joint destruction in RA. [ABSTRACT FROM AUTHOR]

Published
2012
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12. Genotype-phenotype relationship in hereditary haemorrhagic telangiectasia.

Author

Letteboer, T. G. W., Mager, J. J., Snijder, R. J., Koeleman, B. P. C., Lindhout, D., van Amstel, J. K. Ploos, and Westermann, C. J. J.

Subjects
TELANGIECTASIA, VASCULAR diseases, IMMUNOLOGICAL deficiency syndromes, GENETIC polymorphisms, GENOTYPE-environment interaction, HEMORRHAGIC diseases
Abstract

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterised by vascular malformations in multiple organ systems, resulting in mucocutaneous telangiectases and arteriovenous malformations predominantly in the lungs (pulmonary arteriovenous malformation; PAVM), brain (cerebral arteriovenous malformation; CAVM), and liver (hepatic arteriovenous malformation; HAVM). Mutations in the ENG and ALK-1 genes lead to HHT1 and HHT2 respectively. In this study, a genotype-phenotype analysis was performed. A uniform and well classified large group of HHT patients and their family members were screened for HHT manifestations. Groups of patients with a clinically confirmed diagnosis and/ or genetically established diagnosis (HHT1 or HHT2) were compared. The frequency of PAVM, CAVM, HAVM, and gastrointestinal telangiectases were determined to establish the genotype-phenotype relationship. The analysis revealed differences between HHT1 and HHT2 and within HHT1 and HHT2 between men and women. PAVMs and CAVMs occur more often in HHT1, whereas HAVMs are more frequent in HHT2. Furthermore, there is a higher prevalence of PAVM in women compared with men in HHT1. In HHT1 and HHT2, there is a higher frequency of HAVM in women. HHT1 has a distinct, more severe phenotype than HHT2. There is a difference in the presence of symptoms between men and women. With these data, genetic counselling can be given more accurately when the family mutation is known. [ABSTRACT FROM AUTHOR]

Published
2006
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