Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis

Carmen Pilar Simeón-Aznar; Martin Kerick; Marialbert Acosta-Herrera; Jose Luis Callejas Rubio; Shervin Assassi; Patricia E. Carreira-Delgado; Ivan Castellvi; Raquel Ríos; Rosa García-Portales; Antonio Fernández-Nebro; Francisco Jose García-Hernández; Mª Angeles Aguirre; Benjamín Fernández-Gutiérrez; Luis Rodríguez-Rodríguez; Paloma García de la Peña-Lefebvre; Esther Francisca Vicente-Rabaneda; José Luis Andréu; Mónica Fernández de Castro; Francisco Javier López-Longo; Vicente Fonollosa; Alfredo Guillén-Del-Castillo; Gerard Espinosa; Carlos Tolosa; Anna Pros; Emma Beltrán; Mónica Rodríguez-Carballeira; Francisco Javier Narváez; Manuel Rubio Rivas; Vera Ortiz-Santamaría; Ana Belén Madroñero; MA Gonzalez-Gay; Bernardino Díaz; Luis Trapiella; María Victoria Egurbide; Patricia Fanlo-Mateo; Luis Sáez-Comet; F. Díaz; José Andrés Román-Ivorra; Juan José Alegre-Sancho; Mercedes Freire; Francisco J.B. Garcia; Natividad Oreiro; Torsten Witte; Alexander Kreuter; Gabriela Riemekasten; Paolo Airò; César Magro-Checa; A.E. Voskuyl; Madelon C. Vonk; Roger Hesselstrand; Annika Nordin; Claudio Lunardi; Armando Gabrielli; A. Hoffmann-Vold; J.H.W. Distler; Leonid Padyukov; B.P.C. Koeleman; Susanna M. Proudman; Mandana Nikpour; W. Stevens; J. Zochling; J. Sahhar; J. Roddy; P. Nash; K. Tymms; Maureen Rischmueller; Susan Elizabeth Lester; Barbara Vigone; Jacques-Olivier Pers; Alain Saraux; Valérie Devauchelle-Pensec; Divi Cornec; Sandrine Jousse-Joulin; Bernard Lauwerys; Julie Ducreux; Anne-Lise Maudoux; Carlos Vasconcelos; Ana Tavares; Esmeralda Neves; Raquel Faria; Mariana Brandão; Ana Campar; António Marinho; Fátima Farinha; Isabel Almeida; MA Gonzalez-Gay; Ricardo Blanco; Universidad de Cantabria. Epidemiology. Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases. DIVAL Corrales Martínez; Ricard Cervera; Ignasi Rodríguez-Pintó; Gerard Espinosa; Rik Lories; Ellen De Langhe; Doreen Belz; Torsten Witte; Niklas Baerlecken; Georg Stummvoll; Michael Zauner; Michaela Lehner; Eduardo Collantes Estevéz; Rafaela Ortega Castro; Alejandro Escudero Contreras; Ma Carmen Castro-Villegas; María Concepción Fernández Roldán; Norberto Ortego; Enrique Raya; Inmaculada Jiménez Moleón; Enrique de Ramon; Isabel Díaz Quintero; Pier Luigi Meroni; Maria Gerosa; Tommaso Schioppo; Carolina Artusi; Carlo Chizzolini; Aleksandra Zuber; Donatirnne Wynar; Laszló Kovács; Attila Balog; Magdolna Deák; Márta Bocskai; Sonja Dulic; Gabriella Kádár; Falk Hiepe; Velia Gerl; Silvia Thiel; Manuel rodriguez Maresca; Antonio López-Berrio; Rocío Aguilar-Quesada; Héctor Navarro-Linares; Nicolas Hunzelmann; Gianluca Moroncini; Jeska K. de Vries-Bouwstra; Gisela Orozco; Anne Barton; Ariane Herrick; Chikashi Terao; Yannick Allanore; Carmen Fonseca; Marta E Alarcón-Riquelme; Timothy R.D.J. Radstake; Lorenzo Beretta; Christopher P. Denton; Maureen D. Mayes; Javier Martín

doi:10.1038/s41525-022-00327-8

Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis

Carmen Pilar Simeón-Aznar, Martin Kerick, Marialbert Acosta-Herrera, Jose Luis Callejas Rubio, Shervin Assassi, Patricia E. Carreira-Delgado, Ivan Castellvi, Raquel Ríos, Rosa García-Portales, Antonio Fernández-Nebro, Francisco Jose García-Hernández, Mª Angeles Aguirre, Benjamín Fernández-Gutiérrez, Luis Rodríguez-Rodríguez, Paloma García de la Peña-Lefebvre, Esther Francisca Vicente-Rabaneda, José Luis Andréu, Mónica Fernández de Castro, Francisco Javier López-Longo, Vicente FonollosaAlfredo Guillén-Del-Castillo, Gerard Espinosa, Carlos Tolosa, Anna Pros, Emma Beltrán, Mónica Rodríguez-Carballeira, Francisco Javier Narváez, Manuel Rubio Rivas, Vera Ortiz-Santamaría, Ana Belén Madroñero, MA Gonzalez-Gay, Bernardino Díaz, Luis Trapiella, María Victoria Egurbide, Patricia Fanlo-Mateo, Luis Sáez-Comet, F. Díaz, José Andrés Román-Ivorra, Juan José Alegre-Sancho, Mercedes Freire, Francisco J.B. Garcia, Natividad Oreiro, Torsten Witte, Alexander Kreuter, Gabriela Riemekasten, Paolo Airò, César Magro-Checa, A.E. Voskuyl, Madelon C. Vonk, Roger Hesselstrand, Annika Nordin, Claudio Lunardi, Armando Gabrielli, A. Hoffmann-Vold, J.H.W. Distler, Leonid Padyukov, B.P.C. Koeleman, Susanna M. Proudman, Mandana Nikpour, W. Stevens, J. Zochling, J. Sahhar, J. Roddy, P. Nash, K. Tymms, Maureen Rischmueller, Susan Elizabeth Lester, Barbara Vigone, Jacques-Olivier Pers, Alain Saraux, Valérie Devauchelle-Pensec, Divi Cornec, Sandrine Jousse-Joulin, Bernard Lauwerys, Julie Ducreux, Anne-Lise Maudoux, Carlos Vasconcelos, Ana Tavares, Esmeralda Neves, Raquel Faria, Mariana Brandão, Ana Campar, António Marinho, Fátima Farinha, Isabel Almeida, MA Gonzalez-Gay, Ricardo Blanco, Universidad de Cantabria. Epidemiology. Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases. DIVAL Corrales Martínez, Ricard Cervera, Ignasi Rodríguez-Pintó, Gerard Espinosa, Rik Lories, Ellen De Langhe, Doreen Belz, Torsten Witte, Niklas Baerlecken, Georg Stummvoll, Michael Zauner, Michaela Lehner, Eduardo Collantes Estevéz, Rafaela Ortega Castro, Alejandro Escudero Contreras, Ma Carmen Castro-Villegas, María Concepción Fernández Roldán, Norberto Ortego, Enrique Raya, Inmaculada Jiménez Moleón, Enrique de Ramon, Isabel Díaz Quintero, Pier Luigi Meroni, Maria Gerosa, Tommaso Schioppo, Carolina Artusi, Carlo Chizzolini, Aleksandra Zuber, Donatirnne Wynar, Laszló Kovács, Attila Balog, Magdolna Deák, Márta Bocskai, Sonja Dulic, Gabriella Kádár, Falk Hiepe, Velia Gerl, Silvia Thiel, Manuel rodriguez Maresca, Antonio López-Berrio, Rocío Aguilar-Quesada, Héctor Navarro-Linares, Nicolas Hunzelmann, Gianluca Moroncini, Jeska K. de Vries-Bouwstra, Gisela Orozco, Anne Barton, Ariane Herrick, Chikashi Terao, Yannick Allanore, Carmen Fonseca, Marta E Alarcón-Riquelme, Timothy R.D.J. Radstake, Lorenzo Beretta, Christopher P. Denton, Maureen D. Mayes, Javier Martín

Departament de Medicina

Producció científica: Contribució a revista › Article › Recerca › Avaluat per experts

10 Cites (Scopus)

Resum

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.

Idioma original	Anglès
Revista	npj Genomic Medicine
Volum	7
Número	1
DOIs	https://doi.org/10.1038/s41525-022-00327-8
Estat de la publicació	Publicada - 2022

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10.1038/s41525-022-00327-8

https://ddd.uab.cat/record/282313

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https://www.scopus.com/pages/publications/85139419835

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Simeón-Aznar, C. P., Kerick, M., Acosta-Herrera, M., Callejas Rubio, J. L., Assassi, S., Carreira-Delgado, P. E., Castellvi, I., Ríos, R., García-Portales, R., Fernández-Nebro, A., García-Hernández, F. J., Aguirre, M. A., Fernández-Gutiérrez, B., Rodríguez-Rodríguez, L., de la Peña-Lefebvre, P. G., Vicente-Rabaneda, E. F., Andréu, J. L., Fernández de Castro, M., López-Longo, F. J., ... Martín, J. (2022). Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis. npj Genomic Medicine, 7(1). https://doi.org/10.1038/s41525-022-00327-8

@article{e14404982523450fa70bb16fa3473984,

title = "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 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.",

author = "Sime{\'o}n-Aznar, \{Carmen Pilar\} and Martin Kerick and Marialbert Acosta-Herrera and \{Callejas Rubio\}, \{Jose Luis\} and Shervin Assassi and Carreira-Delgado, \{Patricia E.\} and Ivan Castellvi and Raquel R{\'i}os and Rosa Garc{\'i}a-Portales and Antonio Fern{\'a}ndez-Nebro and Garc{\'i}a-Hern{\'a}ndez, \{Francisco Jose\} and Aguirre, \{Mª Angeles\} and Benjam{\'i}n Fern{\'a}ndez-Guti{\'e}rrez and Luis Rodr{\'i}guez-Rodr{\'i}guez and \{de la Pe{\~n}a-Lefebvre\}, \{Paloma Garc{\'i}a\} and Vicente-Rabaneda, \{Esther Francisca\} and Andr{\'e}u, \{Jos{\'e} Luis\} and \{Fern{\'a}ndez de Castro\}, M{\'o}nica and L{\'o}pez-Longo, \{Francisco Javier\} and Vicente Fonollosa and Alfredo Guill{\'e}n-Del-Castillo and Gerard Espinosa and Carlos Tolosa and Anna Pros and Emma Beltr{\'a}n and M{\'o}nica Rodr{\'i}guez-Carballeira and Narv{\'a}ez, \{Francisco Javier\} and \{Rubio Rivas\}, Manuel and Vera Ortiz-Santamar{\'i}a and Madro{\~n}ero, \{Ana Bel{\'e}n\} and MA Gonzalez-Gay and Bernardino D{\'i}az and Luis Trapiella and Egurbide, \{Mar{\'i}a Victoria\} and Patricia Fanlo-Mateo and Luis S{\'a}ez-Comet and F. D{\'i}az and Rom{\'a}n-Ivorra, \{Jos{\'e} Andr{\'e}s\} and Alegre-Sancho, \{Juan Jos{\'e}\} and Mercedes Freire and Garcia, \{Francisco J.B.\} and Natividad Oreiro and Torsten Witte and Alexander Kreuter and Gabriela Riemekasten and Paolo Air{\`o} and C{\'e}sar Magro-Checa and A.E. Voskuyl and Vonk, \{Madelon C.\} and Roger Hesselstrand and Annika Nordin and Claudio Lunardi and Armando Gabrielli and A. Hoffmann-Vold and J.H.W. Distler and Leonid Padyukov and B.P.C. Koeleman and Proudman, \{Susanna M.\} and Mandana Nikpour and W. Stevens and J. Zochling and J. Sahhar and J. Roddy and P. Nash and K. Tymms and Maureen Rischmueller and Lester, \{Susan Elizabeth\} and Barbara Vigone and Jacques-Olivier Pers and Alain Saraux and Val{\'e}rie Devauchelle-Pensec and Divi Cornec and Sandrine Jousse-Joulin and Bernard Lauwerys and Julie Ducreux and Anne-Lise Maudoux and Carlos Vasconcelos and Ana Tavares and Esmeralda Neves and Raquel Faria and Mariana Brand{\~a}o and Ana Campar and Ant{\'o}nio Marinho and F{\'a}tima Farinha and Isabel Almeida and MA Gonzalez-Gay and Ricardo Blanco and \{Corrales Mart{\'i}nez\}, \{Universidad de Cantabria. Epidemiology. Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases. DIVAL\} and Ricard Cervera and Ignasi Rodr{\'i}guez-Pint{\'o} and Gerard Espinosa and Rik Lories and \{De Langhe\}, Ellen and Doreen Belz and Torsten Witte and Niklas Baerlecken and Georg Stummvoll and Michael Zauner and Michaela Lehner and \{Collantes Estev{\'e}z\}, Eduardo and \{Ortega Castro\}, Rafaela and \{Escudero Contreras\}, Alejandro and Castro-Villegas, \{Ma Carmen\} and \{Fern{\'a}ndez Rold{\'a}n\}, \{Mar{\'i}a Concepci{\'o}n\} and Norberto Ortego and Enrique Raya and \{Jim{\'e}nez Mole{\'o}n\}, Inmaculada and \{de Ramon\}, Enrique and \{D{\'i}az Quintero\}, Isabel and Meroni, \{Pier Luigi\} and Maria Gerosa and Tommaso Schioppo and Carolina Artusi and Carlo Chizzolini and Aleksandra Zuber and Donatirnne Wynar and Laszl{\'o} Kov{\'a}cs and Attila Balog and Magdolna De{\'a}k and M{\'a}rta Bocskai and Sonja Dulic and Gabriella K{\'a}d{\'a}r and Falk Hiepe and Velia Gerl and Silvia Thiel and \{rodriguez Maresca\}, Manuel and Antonio L{\'o}pez-Berrio and Roc{\'i}o Aguilar-Quesada and H{\'e}ctor Navarro-Linares and Nicolas Hunzelmann and Gianluca Moroncini and \{de Vries-Bouwstra\}, \{Jeska K.\} and Gisela Orozco and Anne Barton and Ariane Herrick and Chikashi Terao and Yannick Allanore and Carmen Fonseca and Alarc{\'o}n-Riquelme, \{Marta E\} and Radstake, \{Timothy R.D.J.\} and Lorenzo Beretta and Denton, \{Christopher P.\} and Mayes, \{Maureen D.\} and Javier Mart{\'i}n",

year = "2022",

doi = "10.1038/s41525-022-00327-8",

language = "English",

volume = "7",

journal = "npj Genomic Medicine",

issn = "2056-7944",

publisher = "Nature Research",

number = "1",

}

Simeón-Aznar, CP, Kerick, M, Acosta-Herrera, M, Callejas Rubio, JL, Assassi, S, Carreira-Delgado, PE, Castellvi, I, Ríos, R, García-Portales, R, Fernández-Nebro, A, García-Hernández, FJ, Aguirre, MA, Fernández-Gutiérrez, B, Rodríguez-Rodríguez, L, de la Peña-Lefebvre, PG, Vicente-Rabaneda, EF, Andréu, JL, Fernández de Castro, M, López-Longo, FJ, Fonollosa, V, Guillén-Del-Castillo, A, Espinosa, G, Tolosa, C, Pros, A, Beltrán, E, Rodríguez-Carballeira, M, Narváez, FJ, Rubio Rivas, M, Ortiz-Santamaría, V, Madroñero, AB, Gonzalez-Gay, MA, Díaz, B, Trapiella, L, Egurbide, MV, Fanlo-Mateo, P, Sáez-Comet, L, Díaz, F, Román-Ivorra, JA, Alegre-Sancho, JJ, Freire, M, Garcia, FJB, Oreiro, N, Witte, T, Kreuter, A, Riemekasten, G, Airò, P, Magro-Checa, C, Voskuyl, AE, Vonk, MC, Hesselstrand, R, Nordin, A, Lunardi, C, Gabrielli, A, Hoffmann-Vold, A, Distler, JHW, Padyukov, L, Koeleman, BPC, Proudman, SM, Nikpour, M, Stevens, W, Zochling, J, Sahhar, J, Roddy, J, Nash, P, Tymms, K, Rischmueller, M, Lester, SE, Vigone, B, Pers, J-O, Saraux, A, Devauchelle-Pensec, V, Cornec, D, Jousse-Joulin, S, Lauwerys, B, Ducreux, J, Maudoux, A-L, Vasconcelos, C, Tavares, A, Neves, E, Faria, R, Brandão, M, Campar, A, Marinho, A, Farinha, F, Almeida, I, Gonzalez-Gay, MA, Blanco, R, Corrales Martínez, UDCEGAARGOSIDDIVAL, Cervera, R, Rodríguez-Pintó, I, Espinosa, G, Lories, R, De Langhe, E, Belz, D, Witte, T, Baerlecken, N, Stummvoll, G, Zauner, M, Lehner, M, Collantes Estevéz, E, Ortega Castro, R, Escudero Contreras, A, Castro-Villegas, MC, Fernández Roldán, MC, Ortego, N, Raya, E, Jiménez Moleón, I, de Ramon, E, Díaz Quintero, I, Meroni, PL, Gerosa, M, Schioppo, T, Artusi, C, Chizzolini, C, Zuber, A, Wynar, D, Kovács, L, Balog, A, Deák, M, Bocskai, M, Dulic, S, Kádár, G, Hiepe, F, Gerl, V, Thiel, S, rodriguez Maresca, M, López-Berrio, A, Aguilar-Quesada, R, Navarro-Linares, H, Hunzelmann, N, Moroncini, G, de Vries-Bouwstra, JK, Orozco, G, Barton, A, Herrick, A, Terao, C, Allanore, Y, Fonseca, C, Alarcón-Riquelme, ME, Radstake, TRDJ, Beretta, L, Denton, CP, Mayes, MD & Martín, J 2022, 'Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis', npj Genomic Medicine, vol. 7, núm. 1. https://doi.org/10.1038/s41525-022-00327-8

TY - JOUR

T1 - Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis

AU - Simeón-Aznar, Carmen Pilar

AU - Kerick, Martin

AU - Acosta-Herrera, Marialbert

AU - Callejas Rubio, Jose Luis

AU - Assassi, Shervin

AU - Carreira-Delgado, Patricia E.

AU - Castellvi, Ivan

AU - Ríos, Raquel

AU - García-Portales, Rosa

AU - Fernández-Nebro, Antonio

AU - García-Hernández, Francisco Jose

AU - Aguirre, Mª Angeles

AU - Fernández-Gutiérrez, Benjamín

AU - Rodríguez-Rodríguez, Luis

AU - de la Peña-Lefebvre, Paloma García

AU - Vicente-Rabaneda, Esther Francisca

AU - Andréu, José Luis

AU - Fernández de Castro, Mónica

AU - López-Longo, Francisco Javier

AU - Fonollosa, Vicente

AU - Guillén-Del-Castillo, Alfredo

AU - Espinosa, Gerard

AU - Tolosa, Carlos

AU - Pros, Anna

AU - Beltrán, Emma

AU - Rodríguez-Carballeira, Mónica

AU - Narváez, Francisco Javier

AU - Rubio Rivas, Manuel

AU - Ortiz-Santamaría, Vera

AU - Madroñero, Ana Belén

AU - Gonzalez-Gay, MA

AU - Díaz, Bernardino

AU - Trapiella, Luis

AU - Egurbide, María Victoria

AU - Fanlo-Mateo, Patricia

AU - Sáez-Comet, Luis

AU - Díaz, F.

AU - Román-Ivorra, José Andrés

AU - Alegre-Sancho, Juan José

AU - Freire, Mercedes

AU - Garcia, Francisco J.B.

AU - Oreiro, Natividad

AU - Witte, Torsten

AU - Kreuter, Alexander

AU - Riemekasten, Gabriela

AU - Airò, Paolo

AU - Magro-Checa, César

AU - Voskuyl, A.E.

AU - Vonk, Madelon C.

AU - Hesselstrand, Roger

AU - Nordin, Annika

AU - Lunardi, Claudio

AU - Gabrielli, Armando

AU - Hoffmann-Vold, A.

AU - Distler, J.H.W.

AU - Padyukov, Leonid

AU - Koeleman, B.P.C.

AU - Proudman, Susanna M.

AU - Nikpour, Mandana

AU - Stevens, W.

AU - Zochling, J.

AU - Sahhar, J.

AU - Roddy, J.

AU - Nash, P.

AU - Tymms, K.

AU - Rischmueller, Maureen

AU - Lester, Susan Elizabeth

AU - Vigone, Barbara

AU - Pers, Jacques-Olivier

AU - Saraux, Alain

AU - Devauchelle-Pensec, Valérie

AU - Cornec, Divi

AU - Jousse-Joulin, Sandrine

AU - Lauwerys, Bernard

AU - Ducreux, Julie

AU - Maudoux, Anne-Lise

AU - Vasconcelos, Carlos

AU - Tavares, Ana

AU - Neves, Esmeralda

AU - Faria, Raquel

AU - Brandão, Mariana

AU - Campar, Ana

AU - Marinho, António

AU - Farinha, Fátima

AU - Almeida, Isabel

AU - Gonzalez-Gay, MA

AU - Blanco, Ricardo

AU - Corrales Martínez, Universidad de Cantabria. Epidemiology. Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases. DIVAL

AU - Cervera, Ricard

AU - Rodríguez-Pintó, Ignasi

AU - Espinosa, Gerard

AU - Lories, Rik

AU - De Langhe, Ellen

AU - Belz, Doreen

AU - Witte, Torsten

AU - Baerlecken, Niklas

AU - Stummvoll, Georg

AU - Zauner, Michael

AU - Lehner, Michaela

AU - Collantes Estevéz, Eduardo

AU - Ortega Castro, Rafaela

AU - Escudero Contreras, Alejandro

AU - Castro-Villegas, Ma Carmen

AU - Fernández Roldán, María Concepción

AU - Ortego, Norberto

AU - Raya, Enrique

AU - Jiménez Moleón, Inmaculada

AU - de Ramon, Enrique

AU - Díaz Quintero, Isabel

AU - Meroni, Pier Luigi

AU - Gerosa, Maria

AU - Schioppo, Tommaso

AU - Artusi, Carolina

AU - Chizzolini, Carlo

AU - Zuber, Aleksandra

AU - Wynar, Donatirnne

AU - Kovács, Laszló

AU - Balog, Attila

AU - Deák, Magdolna

AU - Bocskai, Márta

AU - Dulic, Sonja

AU - Kádár, Gabriella

AU - Hiepe, Falk

AU - Gerl, Velia

AU - Thiel, Silvia

AU - rodriguez Maresca, Manuel

AU - López-Berrio, Antonio

AU - Aguilar-Quesada, Rocío

AU - Navarro-Linares, Héctor

AU - Hunzelmann, Nicolas

AU - Moroncini, Gianluca

AU - de Vries-Bouwstra, Jeska K.

AU - Orozco, Gisela

AU - Barton, Anne

AU - Herrick, Ariane

AU - Terao, Chikashi

AU - Allanore, Yannick

AU - Fonseca, Carmen

AU - Alarcón-Riquelme, Marta E

AU - Radstake, Timothy R.D.J.

AU - Beretta, Lorenzo

AU - Denton, Christopher P.

AU - Mayes, Maureen D.

AU - Martín, Javier

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85139419835

U2 - 10.1038/s41525-022-00327-8

DO - 10.1038/s41525-022-00327-8

M3 - Article

C2 - 36198672

SN - 2056-7944

VL - 7

JO - npj Genomic Medicine

JF - npj Genomic Medicine

IS - 1

ER -

Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis

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