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15 results on '"Ochoa, Eguzkine"'

1. Germline pathogenic variants in HNRNPU are associated with alterations in blood methylome

Author

Lee, Sunwoo, Ochoa, Eguzkine, Badura-Stronka, Magdalena, Donnelly, Deirdre, Lederer, Damien, Lynch, Sally A., Gardham, Alice, Morton, Jenny, Stewart, Helen, Docquier, France, Rodger, Fay, Martin, Ezequiel, Toribio, Ana, Maher, Eamonn R., Balasubramanian, Meena, Lee, Sunwoo, Ochoa, Eguzkine, Badura-Stronka, Magdalena, Donnelly, Deirdre, Lederer, Damien, Lynch, Sally A., Gardham, Alice, Morton, Jenny, Stewart, Helen, Docquier, France, Rodger, Fay, Martin, Ezequiel, Toribio, Ana, Maher, Eamonn R., and Balasubramanian, Meena

Abstract

HNRNPU encodes a multifunctional RNA-binding protein that plays critical roles in regulating pre-mRNA splicing, mRNA stability, and translation. Aberrant expression and dysregulation of HNRNPU have been implicated in various human diseases, including cancers and neurological disorders. We applied a next generation sequencing based assay (EPIC-NGS) to investigate genome-wide methylation profiling for >2 M CpGs for 7 individuals with a neurodevelopmental disorder associated with HNRNPU germline pathogenic loss-of-function variants. Compared to healthy individuals, 227 HNRNPU-associated differentially methylated positions were detected. Both hyper- and hypomethylation alterations were identified but the former predominated. The identification of a methylation episignature for HNRNPU-associated neurodevelopmental disorder (NDD) implicates HNPRNPU-related chromatin alterations in the aetiopathogenesis of this disorder and suggests that episignature profiling should have clinical utility as a predictor for the pathogenicity of HNRNPU variants of uncertain significance. The detection of a methylation episignaure for HNRNPU-associated NDD is consistent with a recent report of a methylation episignature for HNRNPK-associated NDD.

Published
2023

2. Molecular characterisation of 36 multilocus imprinting disturbance (MLID) patients: a comprehensive approach

Author

Bilo, Larissa, Ochoa, Eguzkine, Lee, Sunwoo, Dey, Daniela, Kurth, Ingo, Kraft, Florian, Rodger, Fay, Docquier, France, Toribio, Ana, Bottolo, Leonardo, Binder, Gerhard, Fekete, György, Elbracht, Miriam, Maher, Eamonn R., Begemann, Matthias, Eggermann, Thomas, Bilo, Larissa, Ochoa, Eguzkine, Lee, Sunwoo, Dey, Daniela, Kurth, Ingo, Kraft, Florian, Rodger, Fay, Docquier, France, Toribio, Ana, Bottolo, Leonardo, Binder, Gerhard, Fekete, György, Elbracht, Miriam, Maher, Eamonn R., Begemann, Matthias, and Eggermann, Thomas

Abstract

BACKGROUND: Imprinting disorders (ImpDis) comprise diseases which are caused by aberrant regulation of monoallelically and parent-of-origin-dependent expressed genes. A characteristic molecular change in ImpDis patients is aberrant methylation signatures at disease-specific loci, without an obvious DNA change at the specific differentially methylated region (DMR). However, there is a growing number of reports on multilocus imprinting disturbances (MLIDs), i.e. aberrant methylation at different DMRs in the same patient. These MLIDs account for a significant number of patients with specific ImpDis, and several reports indicate a central role of pathogenic maternal effect variants in their aetiology by affecting the maturation of the oocyte and the early embryo. Though several studies on the prevalence and the molecular causes of MLID have been conducted, homogeneous datasets comprising both genomic and methylation data are still lacking. RESULTS: Based on a cohort of 36 MLID patients, we here present both methylation data obtained from next-generation sequencing (NGS, ImprintSeq) approaches and whole-exome sequencing (WES). The compilation of methylation data did not reveal a disease-specific MLID episignature, and a predisposition for the phenotypic modification was not obvious as well. In fact, this lack of epigenotype-phenotype correlation might be related to the mosaic distribution of imprinting defects and their functional relevance in specific tissues. CONCLUSIONS: Due to the higher sensitivity of NGS-based approaches, we suggest that ImprintSeq might be offered at reference centres in case of ImpDis patients with unusual phenotypes but MLID negative by conventional tests. By WES, additional MLID causes than the already known maternal effect variants could not be identified, neither in the patients nor in the maternal exomes. In cases with negative WES results, it is currently unclear to what extent either environmental factors or undetected genetic variants con

Published
2023

3. Epigenotype-genotype-phenotype correlations in SETD1A and SETD2 chromatin disorders

Author

Lee, Sunwoo, Menzies, Lara, Hay, Eleanor, Ochoa, Eguzkine, Docquier, France, Rodger, Fay, Deshpande, Charu, Foulds, Nicola C., Jacquemont, Sébastien, Jizi, Khadije, Kiep, Henriette, Kraus, Alison, Löhner, Katharina, Morrison, Patrick J., Popp, Bernt, Richardson, Ruth, van Haeringen, Arie, Martin, Ezequiel, Toribio, Ana, Li, Fudong, Jones, Wendy D., Sansbury, Francis H., Maher, Eamonn R., Lee, Sunwoo, Menzies, Lara, Hay, Eleanor, Ochoa, Eguzkine, Docquier, France, Rodger, Fay, Deshpande, Charu, Foulds, Nicola C., Jacquemont, Sébastien, Jizi, Khadije, Kiep, Henriette, Kraus, Alison, Löhner, Katharina, Morrison, Patrick J., Popp, Bernt, Richardson, Ruth, van Haeringen, Arie, Martin, Ezequiel, Toribio, Ana, Li, Fudong, Jones, Wendy D., Sansbury, Francis H., and Maher, Eamonn R.

Abstract

Germline pathogenic variants in two genes encoding the lysine-specific histone methyltransferase genes SETD1A and SETD2 are associated with neurodevelopmental disorders (NDDs) characterized by developmental delay and congenital anomalies. The SETD1A and SETD2 gene products play a critical role in chromatin-mediated regulation of gene expression. Specific methylation episignatures have been detected for a range of chromatin gene-related NDDs and have impacted clinical practice by improving the interpretation of variant pathogenicity. To investigate if SETD1A and/or SETD2-related NDDs are associated with a detectable episignature, we undertook targeted genome-wide methylation profiling of > 2 M CpGs using a next-generation sequencing-based assay. A comparison of methylation profiles in patients with SETD1A variants (n = 6) did not reveal evidence of a strong methylation episignature. A review of the clinical and genetic features of the SETD2 patient group revealed that, as reported previously, there were phenotypic differences between patients with truncating mutations (n = 4, Luscan-Lumish syndrome; MIM:616831) and those with missense codon 1740 variants [p.Arg1740Trp (n = 4) and p.Arg1740Gln (n = 2)]. Both SETD2 subgroups demonstrated a methylation episignature, which was characterized by hypomethylation and hypermethylation events, respectively. Within the codon 1740 subgroup, both the methylation changes and clinical phenotype were more severe in those with p.Arg1740Trp variants. We also noted that two of 10 cases with a SETD2-NDD had developed a neoplasm. These findings reveal novel epigenotype-genotype-phenotype correlations in SETD2-NDDs and predict a gain-of-function mechanism for SETD2 codon 1740 pathogenic variants.

Published
2023

4. Molecular characterisation of 36 multilocus imprinting disturbance (MLID) patients: a comprehensive approach

Author

Bilo, Larissa, Ochoa, Eguzkine, Lee, Sunwoo, Dey, Daniela, Kurth, Ingo, Kraft, Florian, Rodger, Fay, Docquier, France, Toribio, Ana, Bottolo, Leonardo, Binder, Gerhard, Fekete, György, Elbracht, Miriam, Maher, Eamonn R., Begemann, Matthias, Eggermann, Thomas, Bilo, Larissa, Ochoa, Eguzkine, Lee, Sunwoo, Dey, Daniela, Kurth, Ingo, Kraft, Florian, Rodger, Fay, Docquier, France, Toribio, Ana, Bottolo, Leonardo, Binder, Gerhard, Fekete, György, Elbracht, Miriam, Maher, Eamonn R., Begemann, Matthias, and Eggermann, Thomas

Abstract

BACKGROUND: Imprinting disorders (ImpDis) comprise diseases which are caused by aberrant regulation of monoallelically and parent-of-origin-dependent expressed genes. A characteristic molecular change in ImpDis patients is aberrant methylation signatures at disease-specific loci, without an obvious DNA change at the specific differentially methylated region (DMR). However, there is a growing number of reports on multilocus imprinting disturbances (MLIDs), i.e. aberrant methylation at different DMRs in the same patient. These MLIDs account for a significant number of patients with specific ImpDis, and several reports indicate a central role of pathogenic maternal effect variants in their aetiology by affecting the maturation of the oocyte and the early embryo. Though several studies on the prevalence and the molecular causes of MLID have been conducted, homogeneous datasets comprising both genomic and methylation data are still lacking. RESULTS: Based on a cohort of 36 MLID patients, we here present both methylation data obtained from next-generation sequencing (NGS, ImprintSeq) approaches and whole-exome sequencing (WES). The compilation of methylation data did not reveal a disease-specific MLID episignature, and a predisposition for the phenotypic modification was not obvious as well. In fact, this lack of epigenotype-phenotype correlation might be related to the mosaic distribution of imprinting defects and their functional relevance in specific tissues. CONCLUSIONS: Due to the higher sensitivity of NGS-based approaches, we suggest that ImprintSeq might be offered at reference centres in case of ImpDis patients with unusual phenotypes but MLID negative by conventional tests. By WES, additional MLID causes than the already known maternal effect variants could not be identified, neither in the patients nor in the maternal exomes. In cases with negative WES results, it is currently unclear to what extent either environmental factors or undetected genetic variants con

Published
2023

5. Epigenotype-genotype-phenotype correlations in SETD1A and SETD2 chromatin disorders

Author

Lee, Sunwoo, Menzies, Lara, Hay, Eleanor, Ochoa, Eguzkine, Docquier, France, Rodger, Fay, Deshpande, Charu, Foulds, Nicola C., Jacquemont, Sébastien, Jizi, Khadije, Kiep, Henriette, Kraus, Alison, Löhner, Katharina, Morrison, Patrick J., Popp, Bernt, Richardson, Ruth, van Haeringen, Arie, Martin, Ezequiel, Toribio, Ana, Li, Fudong, Jones, Wendy D., Sansbury, Francis H., Maher, Eamonn R., Lee, Sunwoo, Menzies, Lara, Hay, Eleanor, Ochoa, Eguzkine, Docquier, France, Rodger, Fay, Deshpande, Charu, Foulds, Nicola C., Jacquemont, Sébastien, Jizi, Khadije, Kiep, Henriette, Kraus, Alison, Löhner, Katharina, Morrison, Patrick J., Popp, Bernt, Richardson, Ruth, van Haeringen, Arie, Martin, Ezequiel, Toribio, Ana, Li, Fudong, Jones, Wendy D., Sansbury, Francis H., and Maher, Eamonn R.

Abstract

Germline pathogenic variants in two genes encoding the lysine-specific histone methyltransferase genes SETD1A and SETD2 are associated with neurodevelopmental disorders (NDDs) characterized by developmental delay and congenital anomalies. The SETD1A and SETD2 gene products play a critical role in chromatin-mediated regulation of gene expression. Specific methylation episignatures have been detected for a range of chromatin gene-related NDDs and have impacted clinical practice by improving the interpretation of variant pathogenicity. To investigate if SETD1A and/or SETD2-related NDDs are associated with a detectable episignature, we undertook targeted genome-wide methylation profiling of > 2 M CpGs using a next-generation sequencing-based assay. A comparison of methylation profiles in patients with SETD1A variants (n = 6) did not reveal evidence of a strong methylation episignature. A review of the clinical and genetic features of the SETD2 patient group revealed that, as reported previously, there were phenotypic differences between patients with truncating mutations (n = 4, Luscan-Lumish syndrome; MIM:616831) and those with missense codon 1740 variants [p.Arg1740Trp (n = 4) and p.Arg1740Gln (n = 2)]. Both SETD2 subgroups demonstrated a methylation episignature, which was characterized by hypomethylation and hypermethylation events, respectively. Within the codon 1740 subgroup, both the methylation changes and clinical phenotype were more severe in those with p.Arg1740Trp variants. We also noted that two of 10 cases with a SETD2-NDD had developed a neoplasm. These findings reveal novel epigenotype-genotype-phenotype correlations in SETD2-NDDs and predict a gain-of-function mechanism for SETD2 codon 1740 pathogenic variants.

Published
2023

6. Germline pathogenic variants in HNRNPU are associated with alterations in blood methylome

Author

Lee, Sunwoo, Ochoa, Eguzkine, Badura-Stronka, Magdalena, Donnelly, Deirdre, Lederer, Damien, Lynch, Sally A., Gardham, Alice, Morton, Jenny, Stewart, Helen, Docquier, France, Rodger, Fay, Martin, Ezequiel, Toribio, Ana, Maher, Eamonn R., Balasubramanian, Meena, Lee, Sunwoo, Ochoa, Eguzkine, Badura-Stronka, Magdalena, Donnelly, Deirdre, Lederer, Damien, Lynch, Sally A., Gardham, Alice, Morton, Jenny, Stewart, Helen, Docquier, France, Rodger, Fay, Martin, Ezequiel, Toribio, Ana, Maher, Eamonn R., and Balasubramanian, Meena

Abstract

HNRNPU encodes a multifunctional RNA-binding protein that plays critical roles in regulating pre-mRNA splicing, mRNA stability, and translation. Aberrant expression and dysregulation of HNRNPU have been implicated in various human diseases, including cancers and neurological disorders. We applied a next generation sequencing based assay (EPIC-NGS) to investigate genome-wide methylation profiling for >2 M CpGs for 7 individuals with a neurodevelopmental disorder associated with HNRNPU germline pathogenic loss-of-function variants. Compared to healthy individuals, 227 HNRNPU-associated differentially methylated positions were detected. Both hyper- and hypomethylation alterations were identified but the former predominated. The identification of a methylation episignature for HNRNPU-associated neurodevelopmental disorder (NDD) implicates HNPRNPU-related chromatin alterations in the aetiopathogenesis of this disorder and suggests that episignature profiling should have clinical utility as a predictor for the pathogenicity of HNRNPU variants of uncertain significance. The detection of a methylation episignaure for HNRNPU-associated NDD is consistent with a recent report of a methylation episignature for HNRNPK-associated NDD.

Published
2023

7. Comparison of methylation episignatures in KMT2B- and KMT2D-related human disorders

Author

Lee, Sunwoo, Ochoa, Eguzkine, Barwick, Katy, Cif, Laura, Rodger, Fay, Docquier, France, Pérez-Dueñas, Bélen, Clark, Graeme, Martin, Ezequiel, Banka, Siddharth, Kurian, Manju A., Maher, Eamonn R., Lee, Sunwoo, Ochoa, Eguzkine, Barwick, Katy, Cif, Laura, Rodger, Fay, Docquier, France, Pérez-Dueñas, Bélen, Clark, Graeme, Martin, Ezequiel, Banka, Siddharth, Kurian, Manju A., and Maher, Eamonn R.

Abstract

Aim & methods: To investigate peripheral blood methylation episignatures in KMT2B-related dystonia (DYT-KMT2B), the authors undertook genome-wide methylation profiling of ∼2 M CpGs using a next-generation sequencing-based assay and compared the findings with those in controls and patients with KMT2D-related Kabuki syndrome type 1 (KS1). Results: A total of 1812 significantly differentially methylated CpG positions (false discovery rate < 0.05) were detected in DYT-KMT2B samples compared with controls. Multi-dimensional scaling analysis showed that the 10 DYT-KMT2B samples clustered together and separately from 29 controls and 10 with pathogenic variants in KMT2D. The authors found that most differentially methylated CpG positions were specific to one disorder and that all (DYT-KMT2B) and most (Kabuki syndrome type 1) methylation alterations in CpG islands were gain of methylation events. Conclusion: Using sensitive methylation profiling methodology, the authors replicated recent reports of a methylation episignature for DYT-KMT2B. These findings will facilitate the development of episignature-based assays to improve diagnostic accuracy.

Published
2022

8. Comparison of methylation episignatures in KMT2B- and KMT2D-related human disorders

Author

Lee, Sunwoo, Ochoa, Eguzkine, Barwick, Katy, Cif, Laura, Rodger, Fay, Docquier, France, Pérez-Dueñas, Bélen, Clark, Graeme, Martin, Ezequiel, Banka, Siddharth, Kurian, Manju A., Maher, Eamonn R., Lee, Sunwoo, Ochoa, Eguzkine, Barwick, Katy, Cif, Laura, Rodger, Fay, Docquier, France, Pérez-Dueñas, Bélen, Clark, Graeme, Martin, Ezequiel, Banka, Siddharth, Kurian, Manju A., and Maher, Eamonn R.

Abstract

Aim & methods: To investigate peripheral blood methylation episignatures in KMT2B-related dystonia (DYT-KMT2B), the authors undertook genome-wide methylation profiling of ∼2 M CpGs using a next-generation sequencing-based assay and compared the findings with those in controls and patients with KMT2D-related Kabuki syndrome type 1 (KS1). Results: A total of 1812 significantly differentially methylated CpG positions (false discovery rate < 0.05) were detected in DYT-KMT2B samples compared with controls. Multi-dimensional scaling analysis showed that the 10 DYT-KMT2B samples clustered together and separately from 29 controls and 10 with pathogenic variants in KMT2D. The authors found that most differentially methylated CpG positions were specific to one disorder and that all (DYT-KMT2B) and most (Kabuki syndrome type 1) methylation alterations in CpG islands were gain of methylation events. Conclusion: Using sensitive methylation profiling methodology, the authors replicated recent reports of a methylation episignature for DYT-KMT2B. These findings will facilitate the development of episignature-based assays to improve diagnostic accuracy.

Published
2022

9. A cross-disease meta-GWAS identifies four new susceptibility loci shared between systemic sclerosis and Crohn's disease.

Author

Universidad de Salamanca, Junta de Andalucía, Instituto de Salud Carlos III, Ministerio de Economía, Industria y Competitividad (España), Ministerio de Economía y Competitividad (España), González-Serna, David, Ochoa, Eguzkine, López-Isac, Elena, Julià, Antonio, Degenhardt, Frauke, Ortego-Centeno, N., Radstake, Timothy R. D. J., Franke, Andre, Marsal, Sara, Mayes, Maureen D., Martín, J., Márquez, Ana, Universidad de Salamanca, Junta de Andalucía, Instituto de Salud Carlos III, Ministerio de Economía, Industria y Competitividad (España), Ministerio de Economía y Competitividad (España), González-Serna, David, Ochoa, Eguzkine, López-Isac, Elena, Julià, Antonio, Degenhardt, Frauke, Ortego-Centeno, N., Radstake, Timothy R. D. J., Franke, Andre, Marsal, Sara, Mayes, Maureen D., Martín, J., and Márquez, Ana

Abstract

Genome-wide association studies (GWASs) have identified a number of genetic risk loci associated with systemic sclerosis (SSc) and Crohn’s disease (CD), some of which confer susceptibility to both diseases. In order to identify new risk loci shared between these two immune-mediated disorders, we performed a cross-disease meta-analysis including GWAS data from 5,734 SSc patients, 4,588 CD patients and 14,568 controls of European origin. We identified 4 new loci shared between SSc and CD, IL12RB2, IRF1/SLC22A5, STAT3 and an intergenic locus at 6p21.31. Pleiotropic variants within these loci showed opposite allelic effects in the two analysed diseases and all of them showed a significant effect on gene expression. In addition, an enrichment in the IL-12 family and type I interferon signaling pathways was observed among the set of SSc-CD common genetic risk loci. In conclusion, through the first cross-disease meta-analysis of SSc and CD, we identified genetic variants with pleiotropic effects on two clinically distinct immune-mediated disorders. The fact that all these pleiotropic SNPs have opposite allelic effects in SSc and CD reveals the complexity of the molecular mechanisms by which polymorphisms affect diseases.

Published
2020

10. IDENTIFICATION OF FOUR NEW SHARED SUSCEPTIBILITY GENES IN SYSTEMIC SCLEROSIS AND CROHN¿S DISEASE THROUGH A CROSS-DISEASE META-GWAS

Author

González-Serna, David, Ochoa, Eguzkine, López-Isac, Elena, Julià, A., Degenhardt, Frauke, van Beelen Granlund, A, Carreira, PE, Simeón, Carmen P., Ortego-Centeno, N., González-Gay, M. A., Vicente, Esther, Beltrán, E., Alegre-Sancho, Juan-José, Spanish Scleroderma Group, Beretta, L., Santaniello, A, Lunardi, C., Hunzelmann, Nicolas, Riemekasten, G, Witte, T, Distler, J.H.W., Kreuter, A., Airó, P, Koeleman, B. P., Voskuyl, AE, de Vries-Bouwstra, Jeska, Radstake, Timothy R. D. J., Wijmenga, C, Assassi, S., Franke, Andre, Marsal, Sara, Mayes, Maureen D., Martín, J., Márquez A, González-Serna, David, Ochoa, Eguzkine, López-Isac, Elena, Julià, A., Degenhardt, Frauke, van Beelen Granlund, A, Carreira, PE, Simeón, Carmen P., Ortego-Centeno, N., González-Gay, M. A., Vicente, Esther, Beltrán, E., Alegre-Sancho, Juan-José, Spanish Scleroderma Group, Beretta, L., Santaniello, A, Lunardi, C., Hunzelmann, Nicolas, Riemekasten, G, Witte, T, Distler, J.H.W., Kreuter, A., Airó, P, Koeleman, B. P., Voskuyl, AE, de Vries-Bouwstra, Jeska, Radstake, Timothy R. D. J., Wijmenga, C, Assassi, S., Franke, Andre, Marsal, Sara, Mayes, Maureen D., Martín, J., and Márquez A

Published
2019

11. A CROSS-DISEASE META-GWAS IDENTIFIES IRF1, STAT3 AND ZBTB9-BAK1 AS NEW SHARED SUSCEPTIBILITY LOCI IN SYSTEMIC SCLEROSIS AND CROHN¿S DISEASE

Author

González-Serna, David, Ochoa, Eguzkine, López-Isac, Elena, Julià, A., Degenhardt, Frauke, van Beelen Granlund,, A., Carreira, P.E., Simeón, Carmen P., Ortego-Centeno, N., González-Gay, M. A., Vicente, Esther, Beltrán, E., Alegre-Sancho, Juan-José, Beretta, L., Santaniello, A., Lunardi, C., Hunzelmann, Nicolas, Riemekasten, .G, Witte, T., Distler, J.H.W., Kreuter, A., Airó, P., Koeleman, BPC, Voskuyl, T..A.E., de Vries-Bouwstra, Jeska, Radstake, Timothy R. D. J., Wijmenga, C., Assassi, S.., Franke, Andre, Marsal, Sara, Mayes, Maureen D., Martín, J., Márquez, A., González-Serna, David, Ochoa, Eguzkine, López-Isac, Elena, Julià, A., Degenhardt, Frauke, van Beelen Granlund,, A., Carreira, P.E., Simeón, Carmen P., Ortego-Centeno, N., González-Gay, M. A., Vicente, Esther, Beltrán, E., Alegre-Sancho, Juan-José, Beretta, L., Santaniello, A., Lunardi, C., Hunzelmann, Nicolas, Riemekasten, .G, Witte, T., Distler, J.H.W., Kreuter, A., Airó, P., Koeleman, BPC, Voskuyl, T..A.E., de Vries-Bouwstra, Jeska, Radstake, Timothy R. D. J., Wijmenga, C., Assassi, S.., Franke, Andre, Marsal, Sara, Mayes, Maureen D., Martín, J., and Márquez, A.

Published
2019

12. Immunochip Analysis Identifies Multiple Susceptibility Loci for Systemic Sclerosis

Author

Mayes, Maureen D., Bossini-Castillo, Lara, Gorlova, Olga, Martin, Jose Ezequiel, Zhou, Xiaodong, Chen, Wei V., Assassi, Shervin, Ying, Jun, Tan, Filemon K., Arnett, Frank C., Reveille, John D., Guerra, Sandra, Terue, Maria, Carmona, Francisco David, Gregersen, Peter K., Lee, Annette T., Lopez-Isac, Elena, Ochoa, Eguzkine, Carreira, Patricia, Simeon, Carmen Pilar, Castellvi, Ivan, Angel Gonzalez-Gay, Miguel, Zhernakova, Alexandra, Padyukov, Leonid, Aarcon-Riquelme, Marta, Wijmenga, Cisca, Brown, Matthew, Beretta, Lorenzo, Riemekasten, Gabriela, Witte, Torsten, Hunzelmann, Nicolas, Kreuter, Alexander, Distler, Jorg H. W., Voskuy, Alexandre E., Schuerwegh, Annemie J., Hesselstrand, Roger, Nordin, Annika, Airo, Paolo, Lunardi, Claudio, Shiels, Paul, van Laar, Jacob M., Herrick, Ariane, Worthington, Jane, Denton, Christopher, Wigley, Fredrick M., Hummers, Laura K., Varga, John, Hinchcliff, Monique E., Baron, Murray, Hudson, Marie, Pope, Janet E., Furst, Daniel E., Khanna, Dinesh, Phillips, Kristin, Schiopu, Elena, Segal, Barbara M., Molitor, Jerry A., Silver, Richard M., Steen, Virginia D., Simms, Robert W., Lafyatis, Robert A., Fessler, Barn I. J., Frech, Tracy M., AlKassab, Firas, Docherty, Peter, Kaminska, Elzbieta, Khalidi, Nader, Jones, Henry Niall, Markland, Janet, Robinson, David, Broen, Jasper, Radstake, Timothy R. D. J., Fonseca, Carmen, Koeleman, Bobby P., Martin, Javier, Mayes, Maureen D., Bossini-Castillo, Lara, Gorlova, Olga, Martin, Jose Ezequiel, Zhou, Xiaodong, Chen, Wei V., Assassi, Shervin, Ying, Jun, Tan, Filemon K., Arnett, Frank C., Reveille, John D., Guerra, Sandra, Terue, Maria, Carmona, Francisco David, Gregersen, Peter K., Lee, Annette T., Lopez-Isac, Elena, Ochoa, Eguzkine, Carreira, Patricia, Simeon, Carmen Pilar, Castellvi, Ivan, Angel Gonzalez-Gay, Miguel, Zhernakova, Alexandra, Padyukov, Leonid, Aarcon-Riquelme, Marta, Wijmenga, Cisca, Brown, Matthew, Beretta, Lorenzo, Riemekasten, Gabriela, Witte, Torsten, Hunzelmann, Nicolas, Kreuter, Alexander, Distler, Jorg H. W., Voskuy, Alexandre E., Schuerwegh, Annemie J., Hesselstrand, Roger, Nordin, Annika, Airo, Paolo, Lunardi, Claudio, Shiels, Paul, van Laar, Jacob M., Herrick, Ariane, Worthington, Jane, Denton, Christopher, Wigley, Fredrick M., Hummers, Laura K., Varga, John, Hinchcliff, Monique E., Baron, Murray, Hudson, Marie, Pope, Janet E., Furst, Daniel E., Khanna, Dinesh, Phillips, Kristin, Schiopu, Elena, Segal, Barbara M., Molitor, Jerry A., Silver, Richard M., Steen, Virginia D., Simms, Robert W., Lafyatis, Robert A., Fessler, Barn I. J., Frech, Tracy M., AlKassab, Firas, Docherty, Peter, Kaminska, Elzbieta, Khalidi, Nader, Jones, Henry Niall, Markland, Janet, Robinson, David, Broen, Jasper, Radstake, Timothy R. D. J., Fonseca, Carmen, Koeleman, Bobby P., and Martin, Javier

Abstract

In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.

Published
2014

13. Systemic Sclerosis Patients with Antitopoisomerase Antibodies Showed Significant Association with CCR6 Polymorphisms.

Author

Martin, Javier, Ochoa, Eguzkine, Ezequiel Martin, Jose, Assassi, Shervin, Beretta, Lorenzo, Caireira, Patricia, Pilar Simeon, Carmen, Koumakis, Eugenie, Dieude, Philippe, Allanore, Yannick, Garcia-Hernandez, Francisco J., Espinosa, Gerard, Castellvi Barranco, Ivan, Trapiella, Luis, Rodriguez Rodriguez, Luis, Gonzalez-Gay, Miguel A., Egurbide, Maria-Victoria, Saez, Luis, Luis Callejas, Jose, Vargas-Hitos, J. A., Hunzelmann, Nicolas, Riemekasten, Gabriela, Witte, Torsten, Distler, Joerg H. W., Kreuter, Alexander, Lunardi, Claudio, Santaniello, Alessandro, Tan, Filemon K., Arnett, Frank C., Shiels, Paul, Herrick, Ariane L., Worthington, Jane, Vonk, Madelon C., Koeleman, Bobby P. C., Radstake, T. R. D. J., Mayes, Maureen, Martin, Javier, Ochoa, Eguzkine, Ezequiel Martin, Jose, Assassi, Shervin, Beretta, Lorenzo, Caireira, Patricia, Pilar Simeon, Carmen, Koumakis, Eugenie, Dieude, Philippe, Allanore, Yannick, Garcia-Hernandez, Francisco J., Espinosa, Gerard, Castellvi Barranco, Ivan, Trapiella, Luis, Rodriguez Rodriguez, Luis, Gonzalez-Gay, Miguel A., Egurbide, Maria-Victoria, Saez, Luis, Luis Callejas, Jose, Vargas-Hitos, J. A., Hunzelmann, Nicolas, Riemekasten, Gabriela, Witte, Torsten, Distler, Joerg H. W., Kreuter, Alexander, Lunardi, Claudio, Santaniello, Alessandro, Tan, Filemon K., Arnett, Frank C., Shiels, Paul, Herrick, Ariane L., Worthington, Jane, Vonk, Madelon C., Koeleman, Bobby P. C., Radstake, T. R. D. J., and Mayes, Maureen

Published
2014

14. Immunochip Analysis Identifies Multiple Susceptibility Loci for Systemic Sclerosis

Author

Mayes, Maureen D., Bossini-Castillo, Lara, Gorlova, Olga, Martin, Jose Ezequiel, Zhou, Xiaodong, Chen, Wei V., Assassi, Shervin, Ying, Jun, Tan, Filemon K., Arnett, Frank C., Reveille, John D., Guerra, Sandra, Terue, Maria, Carmona, Francisco David, Gregersen, Peter K., Lee, Annette T., Lopez-Isac, Elena, Ochoa, Eguzkine, Carreira, Patricia, Simeon, Carmen Pilar, Castellvi, Ivan, Angel Gonzalez-Gay, Miguel, Zhernakova, Alexandra, Padyukov, Leonid, Aarcon-Riquelme, Marta, Wijmenga, Cisca, Brown, Matthew, Beretta, Lorenzo, Riemekasten, Gabriela, Witte, Torsten, Hunzelmann, Nicolas, Kreuter, Alexander, Distler, Jorg H. W., Voskuy, Alexandre E., Schuerwegh, Annemie J., Hesselstrand, Roger, Nordin, Annika, Airo, Paolo, Lunardi, Claudio, Shiels, Paul, van Laar, Jacob M., Herrick, Ariane, Worthington, Jane, Denton, Christopher, Wigley, Fredrick M., Hummers, Laura K., Varga, John, Hinchcliff, Monique E., Baron, Murray, Hudson, Marie, Pope, Janet E., Furst, Daniel E., Khanna, Dinesh, Phillips, Kristin, Schiopu, Elena, Segal, Barbara M., Molitor, Jerry A., Silver, Richard M., Steen, Virginia D., Simms, Robert W., Lafyatis, Robert A., Fessler, Barn I. J., Frech, Tracy M., AlKassab, Firas, Docherty, Peter, Kaminska, Elzbieta, Khalidi, Nader, Jones, Henry Niall, Markland, Janet, Robinson, David, Broen, Jasper, Radstake, Timothy R. D. J., Fonseca, Carmen, Koeleman, Bobby P., Martin, Javier, Mayes, Maureen D., Bossini-Castillo, Lara, Gorlova, Olga, Martin, Jose Ezequiel, Zhou, Xiaodong, Chen, Wei V., Assassi, Shervin, Ying, Jun, Tan, Filemon K., Arnett, Frank C., Reveille, John D., Guerra, Sandra, Terue, Maria, Carmona, Francisco David, Gregersen, Peter K., Lee, Annette T., Lopez-Isac, Elena, Ochoa, Eguzkine, Carreira, Patricia, Simeon, Carmen Pilar, Castellvi, Ivan, Angel Gonzalez-Gay, Miguel, Zhernakova, Alexandra, Padyukov, Leonid, Aarcon-Riquelme, Marta, Wijmenga, Cisca, Brown, Matthew, Beretta, Lorenzo, Riemekasten, Gabriela, Witte, Torsten, Hunzelmann, Nicolas, Kreuter, Alexander, Distler, Jorg H. W., Voskuy, Alexandre E., Schuerwegh, Annemie J., Hesselstrand, Roger, Nordin, Annika, Airo, Paolo, Lunardi, Claudio, Shiels, Paul, van Laar, Jacob M., Herrick, Ariane, Worthington, Jane, Denton, Christopher, Wigley, Fredrick M., Hummers, Laura K., Varga, John, Hinchcliff, Monique E., Baron, Murray, Hudson, Marie, Pope, Janet E., Furst, Daniel E., Khanna, Dinesh, Phillips, Kristin, Schiopu, Elena, Segal, Barbara M., Molitor, Jerry A., Silver, Richard M., Steen, Virginia D., Simms, Robert W., Lafyatis, Robert A., Fessler, Barn I. J., Frech, Tracy M., AlKassab, Firas, Docherty, Peter, Kaminska, Elzbieta, Khalidi, Nader, Jones, Henry Niall, Markland, Janet, Robinson, David, Broen, Jasper, Radstake, Timothy R. D. J., Fonseca, Carmen, Koeleman, Bobby P., and Martin, Javier

Abstract

In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.

Published
2014

15. Systemic Sclerosis Patients with Antitopoisomerase Antibodies Showed Significant Association with CCR6 Polymorphisms.

Author

Martin, Javier, Ochoa, Eguzkine, Ezequiel Martin, Jose, Assassi, Shervin, Beretta, Lorenzo, Caireira, Patricia, Pilar Simeon, Carmen, Koumakis, Eugenie, Dieude, Philippe, Allanore, Yannick, Garcia-Hernandez, Francisco J., Espinosa, Gerard, Castellvi Barranco, Ivan, Trapiella, Luis, Rodriguez Rodriguez, Luis, Gonzalez-Gay, Miguel A., Egurbide, Maria-Victoria, Saez, Luis, Luis Callejas, Jose, Vargas-Hitos, J. A., Hunzelmann, Nicolas, Riemekasten, Gabriela, Witte, Torsten, Distler, Joerg H. W., Kreuter, Alexander, Lunardi, Claudio, Santaniello, Alessandro, Tan, Filemon K., Arnett, Frank C., Shiels, Paul, Herrick, Ariane L., Worthington, Jane, Vonk, Madelon C., Koeleman, Bobby P. C., Radstake, T. R. D. J., Mayes, Maureen, Martin, Javier, Ochoa, Eguzkine, Ezequiel Martin, Jose, Assassi, Shervin, Beretta, Lorenzo, Caireira, Patricia, Pilar Simeon, Carmen, Koumakis, Eugenie, Dieude, Philippe, Allanore, Yannick, Garcia-Hernandez, Francisco J., Espinosa, Gerard, Castellvi Barranco, Ivan, Trapiella, Luis, Rodriguez Rodriguez, Luis, Gonzalez-Gay, Miguel A., Egurbide, Maria-Victoria, Saez, Luis, Luis Callejas, Jose, Vargas-Hitos, J. A., Hunzelmann, Nicolas, Riemekasten, Gabriela, Witte, Torsten, Distler, Joerg H. W., Kreuter, Alexander, Lunardi, Claudio, Santaniello, Alessandro, Tan, Filemon K., Arnett, Frank C., Shiels, Paul, Herrick, Ariane L., Worthington, Jane, Vonk, Madelon C., Koeleman, Bobby P. C., Radstake, T. R. D. J., and Mayes, Maureen

Published
2014

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