Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis
Abstract Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validate...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-10-01
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| Series: | npj Genomic Medicine |
| Online Access: | https://doi.org/10.1038/s41525-022-00327-8 |
| _version_ | 1811194788124295168 |
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| author | Martin Kerick Marialbert Acosta-Herrera Carmen Pilar Simeón-Aznar José Luis Callejas Shervin Assassi International SSc Group Susanna M. Proudman Mandana Nikpour Australian Scleroderma Interest Group (ASIG) PRECISESADS Clinical Consortium Nicolas Hunzelmann Gianluca Moroncini Jeska K. de Vries-Bouwstra Gisela Orozco Anne Barton Ariane L. Herrick Chikashi Terao Yannick Allanore Carmen Fonseca Marta Eugenia Alarcón-Riquelme Timothy R. D. J. Radstake Lorenzo Beretta Christopher P. Denton Maureen D. Mayes Javier Martin |
| author_facet | Martin Kerick Marialbert Acosta-Herrera Carmen Pilar Simeón-Aznar José Luis Callejas Shervin Assassi International SSc Group Susanna M. Proudman Mandana Nikpour Australian Scleroderma Interest Group (ASIG) PRECISESADS Clinical Consortium Nicolas Hunzelmann Gianluca Moroncini Jeska K. de Vries-Bouwstra Gisela Orozco Anne Barton Ariane L. Herrick Chikashi Terao Yannick Allanore Carmen Fonseca Marta Eugenia Alarcón-Riquelme Timothy R. D. J. Radstake Lorenzo Beretta Christopher P. Denton Maureen D. Mayes Javier Martin |
| author_sort | Martin Kerick |
| collection | DOAJ |
| description | Abstract Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals. |
| first_indexed | 2024-04-12T00:32:24Z |
| format | Article |
| id | doaj.art-bc1f849f269a49ad8114bddf64958fc9 |
| institution | Directory Open Access Journal |
| issn | 2056-7944 |
| language | English |
| last_indexed | 2024-04-12T00:32:24Z |
| publishDate | 2022-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Genomic Medicine |
| spelling | doaj.art-bc1f849f269a49ad8114bddf64958fc92022-12-22T03:55:17ZengNature Portfolionpj Genomic Medicine2056-79442022-10-017111210.1038/s41525-022-00327-8Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosisMartin Kerick0Marialbert Acosta-Herrera1Carmen Pilar Simeón-Aznar2José Luis Callejas3Shervin Assassi4International SSc GroupSusanna M. Proudman5Mandana Nikpour6Australian Scleroderma Interest Group (ASIG)PRECISESADS Clinical ConsortiumNicolas Hunzelmann7Gianluca Moroncini8Jeska K. de Vries-Bouwstra9Gisela Orozco10Anne Barton11Ariane L. Herrick12Chikashi Terao13Yannick Allanore14Carmen Fonseca15Marta Eugenia Alarcón-Riquelme16Timothy R. D. J. Radstake17Lorenzo Beretta18Christopher P. Denton19Maureen D. Mayes20Javier Martin21Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine López-Neyra, CSICDepartment of Cell Biology and Immunology, Institute of Parasitology and Biomedicine López-Neyra, CSICDepartment of Internal Medicine, Valle de Hebrón HospitalDepartment of Internal Medicine, Hospital San CecilioDepartment of Rheumatology, The University of Texas Health Science Center at HoustonRheumatology Unit, Royal Adelaide Hospital and University of AdelaideThe University of Melbourne at St. Vincent’s HospitalDepartment of Dermatology, University of CologneDepartment of Clinical and Molecular Science, Università Politecnica delle Marche e Ospedali RiunitiDepartment of Rheumatology, Leiden University Medical CenterCenter for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterCenter for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterDivision of Musculoskeletal and Dermatological Sciences, The University of Manchester, Northern care Alliance NHS Foundation Trust, Manchester Academic Health Science CentreLaboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical SciencesDepartment of Rheumatology A, Hospital CochinCenter for Rheumatology, Royal Free and University College Medical SchoolCenter for Genomics and Oncological Research (GENYO), Pfizer-University of Granada-Andalusian Regional GovernmentDepartment of Rheumatology and Clinical Immunology, University Medical Center UtrechtReferral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di MilanoCenter for Rheumatology, Royal Free and University College Medical SchoolDepartment of Rheumatology, The University of Texas Health Science Center at HoustonDepartment of Cell Biology and Immunology, Institute of Parasitology and Biomedicine López-Neyra, CSICAbstract Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals.https://doi.org/10.1038/s41525-022-00327-8 |
| spellingShingle | Martin Kerick Marialbert Acosta-Herrera Carmen Pilar Simeón-Aznar José Luis Callejas Shervin Assassi International SSc Group Susanna M. Proudman Mandana Nikpour Australian Scleroderma Interest Group (ASIG) PRECISESADS Clinical Consortium Nicolas Hunzelmann Gianluca Moroncini Jeska K. de Vries-Bouwstra Gisela Orozco Anne Barton Ariane L. Herrick Chikashi Terao Yannick Allanore Carmen Fonseca Marta Eugenia Alarcón-Riquelme Timothy R. D. J. Radstake Lorenzo Beretta Christopher P. Denton Maureen D. Mayes Javier Martin Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis npj Genomic Medicine |
| title | Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis |
| title_full | Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis |
| title_fullStr | Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis |
| title_full_unstemmed | Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis |
| title_short | Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis |
| title_sort | complement component c4 structural variation and quantitative traits contribute to sex biased vulnerability in systemic sclerosis |
| url | https://doi.org/10.1038/s41525-022-00327-8 |
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