A Genome-wide Association Study Identifies Risk Alleles in Plasminogen and P4HA2 Associated with Giant Cell Arteritis

F.D. Carmona, A. Vaglio, S.L. Mackie, J. Hernández-Rodríguez, P.A. Monach, S. Castañeda, R. Solans, I.C. Morado, J. Narváez, M. Ramentol-Sintas, C.T. Pease, B. Dasgupta, R. Watts, N. Khalidi, C.A. Langford, S. Ytterberg, L. Boiardi, L. Beretta, M. Govoni, G. EmmiF. Bonatti, M.A. Cimmino, T. Witte, T. Neumann, J. Holle, V. Schönau, L. Sailler, T. Papo, J. Haroche, A. Mahr, L. Mouthon, Ø. Molberg, A.P. Diamantopoulos, A. Voskuyl, E. Brouwer, T. Daikeler, C.T. Berger, E.S. Molloy, L. O'Neill, D. Blockmans, B.A. Lie, P. Mclaren, T.J. Vyse, C. Wijmenga, Y. Allanore, B.P.C. Koeleman, J.L. Callejas, L. Caminal-Montero, M. Corbera-Bellalta, E. de Miguel, J.B.D. López, M.J. García-Villanueva, C. Gómez-Vaquero, M. Guijarro-Rojas, A. Hidalgo-Conde, B. Marí-Alfonso, A.M. Berriochoa, A.M. Zapico, V.M. Martínez-Taboada, J.A. Miranda-Filloy, J. Monfort, N. Ortego-Centeno, M. Pérez-Conesa, S. Prieto-González, E. Raya, R.R. Fernández, J. Sánchez-Martín, B. Sopeña, L. Tío, A. Unzurrunzaga, A. Gough, J.D. Isaacs, M. Green, N. McHugh, L. Hordon, S. Kamath, M. Nisar, Y. Patel, C.-S. Yee, R. Stevens, P. Nandi, A. Nandagudi, S. Jarrett, C. Li, S. Levy, S. Mollan, A. Salih, O. Wordsworth, E. Sanders, E. Roads, A. Gill, L. Carr, C. Routledge, K. Culfear, A. Nugaliyadde, L. James, J. Spimpolo, A. Kempa, F. Mackenzie, R. Fong, G. Peters, B. Rowbotham, Z. Masqood, J. Hollywood, P. Gondo, R. Wood, S. Martin, L.H. Rashid, J.I. Robinson, M. Morgan, L. Sorensen, J. Taylor, S. Carette, S. Chung, D. Cuthbertson, L.J. Forbess, O. Gewurz-Singer, G.S. Hoffman, C.L. Koening, K.M. Maksimowicz-McKinnon, C.A. McAlear, L.W. Moreland, C. Pagnoux, P. Seo, U. Specks, R.F. Spiera, A. Sreih, K.J. Warrington, M. Weisman, J.H. Barrett, M.C. Cid, C. Salvarani, P.A. Merkel, A.W. Morgan, M.A. González-Gay, J. Martín

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Giant cell arteritis (GCA) is the most common form of vasculitis in individuals older than 50 years in Western countries. To shed light onto the genetic background influencing susceptibility for GCA, we performed a genome-wide association screening in a well-powered study cohort. After imputation, 1,844,133 genetic variants were analyzed in 2,134 case subjects and 9,125 unaffected individuals from ten independent populations of European ancestry. Our data confirmed HLA class II as the strongest associated region (independent signals: rs9268905, p = 1.94 × 10−54, per-allele OR = 1.79; and rs9275592, p = 1.14 × 10−40, OR = 2.08). Additionally, PLG and P4HA2 were identified as GCA risk genes at the genome-wide level of significance (rs4252134, p = 1.23 × 10−10, OR = 1.28; and rs128738, p = 4.60 × 10−9, OR = 1.32, respectively). Interestingly, we observed that the association peaks overlapped with different regulatory elements related to cell types and tissues involved in the pathophysiology of GCA. PLG and P4HA2 are involved in vascular remodelling and angiogenesis, suggesting a high relevance of these processes for the pathogenic mechanisms underlying this type of vasculitis. © 2017 American Society of Human Genetics
Original languageEnglish
Pages (from-to)64-74
Number of pages11
JournalAmerican Journal of Human Genetics
Volume100
Issue number1
DOIs
Publication statusPublished - 2017

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Giant Cell Arteritis
Plasminogen
Genome-Wide Association Study
Alleles
Vasculitis
Genome
Cohort Studies
Population
Genes

Cite this

Carmona, F. D., Vaglio, A., Mackie, S. L., Hernández-Rodríguez, J., Monach, P. A., Castañeda, S., ... Martín, J. (2017). A Genome-wide Association Study Identifies Risk Alleles in Plasminogen and P4HA2 Associated with Giant Cell Arteritis. American Journal of Human Genetics, 100(1), 64-74. https://doi.org/10.1016/j.ajhg.2016.11.013

A Genome-wide Association Study Identifies Risk Alleles in Plasminogen and P4HA2 Associated with Giant Cell Arteritis. / Carmona, F.D.; Vaglio, A.; Mackie, S.L.; Hernández-Rodríguez, J.; Monach, P.A.; Castañeda, S.; Solans, R.; Morado, I.C.; Narváez, J.; Ramentol-Sintas, M.; Pease, C.T.; Dasgupta, B.; Watts, R.; Khalidi, N.; Langford, C.A.; Ytterberg, S.; Boiardi, L.; Beretta, L.; Govoni, M.; Emmi, G.; Bonatti, F.; Cimmino, M.A.; Witte, T.; Neumann, T.; Holle, J.; Schönau, V.; Sailler, L.; Papo, T.; Haroche, J.; Mahr, A.; Mouthon, L.; Molberg, Ø.; Diamantopoulos, A.P.; Voskuyl, A.; Brouwer, E.; Daikeler, T.; Berger, C.T.; Molloy, E.S.; O'Neill, L.; Blockmans, D.; Lie, B.A.; Mclaren, P.; Vyse, T.J.; Wijmenga, C.; Allanore, Y.; Koeleman, B.P.C.; Callejas, J.L.; Caminal-Montero, L.; Corbera-Bellalta, M.; de Miguel, E.; López, J.B.D.; García-Villanueva, M.J.; Gómez-Vaquero, C.; Guijarro-Rojas, M.; Hidalgo-Conde, A.; Marí-Alfonso, B.; Berriochoa, A.M.; Zapico, A.M.; Martínez-Taboada, V.M.; Miranda-Filloy, J.A.; Monfort, J.; Ortego-Centeno, N.; Pérez-Conesa, M.; Prieto-González, S.; Raya, E.; Fernández, R.R.; Sánchez-Martín, J.; Sopeña, B.; Tío, L.; Unzurrunzaga, A.; Gough, A.; Isaacs, J.D.; Green, M.; McHugh, N.; Hordon, L.; Kamath, S.; Nisar, M.; Patel, Y.; Yee, C.-S.; Stevens, R.; Nandi, P.; Nandagudi, A.; Jarrett, S.; Li, C.; Levy, S.; Mollan, S.; Salih, A.; Wordsworth, O.; Sanders, E.; Roads, E.; Gill, A.; Carr, L.; Routledge, C.; Culfear, K.; Nugaliyadde, A.; James, L.; Spimpolo, J.; Kempa, A.; Mackenzie, F.; Fong, R.; Peters, G.; Rowbotham, B.; Masqood, Z.; Hollywood, J.; Gondo, P.; Wood, R.; Martin, S.; Rashid, L.H.; Robinson, J.I.; Morgan, M.; Sorensen, L.; Taylor, J.; Carette, S.; Chung, S.; Cuthbertson, D.; Forbess, L.J.; Gewurz-Singer, O.; Hoffman, G.S.; Koening, C.L.; Maksimowicz-McKinnon, K.M.; McAlear, C.A.; Moreland, L.W.; Pagnoux, C.; Seo, P.; Specks, U.; Spiera, R.F.; Sreih, A.; Warrington, K.J.; Weisman, M.; Barrett, J.H.; Cid, M.C.; Salvarani, C.; Merkel, P.A.; Morgan, A.W.; González-Gay, M.A.; Martín, J.

In: American Journal of Human Genetics, Vol. 100, No. 1, 2017, p. 64-74.

Research output: Contribution to journalArticle

Carmona, FD, Vaglio, A, Mackie, SL, Hernández-Rodríguez, J, Monach, PA, Castañeda, S, Solans, R, Morado, IC, Narváez, J, Ramentol-Sintas, M, Pease, CT, Dasgupta, B, Watts, R, Khalidi, N, Langford, CA, Ytterberg, S, Boiardi, L, Beretta, L, Govoni, M, Emmi, G, Bonatti, F, Cimmino, MA, Witte, T, Neumann, T, Holle, J, Schönau, V, Sailler, L, Papo, T, Haroche, J, Mahr, A, Mouthon, L, Molberg, Ø, Diamantopoulos, AP, Voskuyl, A, Brouwer, E, Daikeler, T, Berger, CT, Molloy, ES, O'Neill, L, Blockmans, D, Lie, BA, Mclaren, P, Vyse, TJ, Wijmenga, C, Allanore, Y, Koeleman, BPC, Callejas, JL, Caminal-Montero, L, Corbera-Bellalta, M, de Miguel, E, López, JBD, García-Villanueva, MJ, Gómez-Vaquero, C, Guijarro-Rojas, M, Hidalgo-Conde, A, Marí-Alfonso, B, Berriochoa, AM, Zapico, AM, Martínez-Taboada, VM, Miranda-Filloy, JA, Monfort, J, Ortego-Centeno, N, Pérez-Conesa, M, Prieto-González, S, Raya, E, Fernández, RR, Sánchez-Martín, J, Sopeña, B, Tío, L, Unzurrunzaga, A, Gough, A, Isaacs, JD, Green, M, McHugh, N, Hordon, L, Kamath, S, Nisar, M, Patel, Y, Yee, C-S, Stevens, R, Nandi, P, Nandagudi, A, Jarrett, S, Li, C, Levy, S, Mollan, S, Salih, A, Wordsworth, O, Sanders, E, Roads, E, Gill, A, Carr, L, Routledge, C, Culfear, K, Nugaliyadde, A, James, L, Spimpolo, J, Kempa, A, Mackenzie, F, Fong, R, Peters, G, Rowbotham, B, Masqood, Z, Hollywood, J, Gondo, P, Wood, R, Martin, S, Rashid, LH, Robinson, JI, Morgan, M, Sorensen, L, Taylor, J, Carette, S, Chung, S, Cuthbertson, D, Forbess, LJ, Gewurz-Singer, O, Hoffman, GS, Koening, CL, Maksimowicz-McKinnon, KM, McAlear, CA, Moreland, LW, Pagnoux, C, Seo, P, Specks, U, Spiera, RF, Sreih, A, Warrington, KJ, Weisman, M, Barrett, JH, Cid, MC, Salvarani, C, Merkel, PA, Morgan, AW, González-Gay, MA & Martín, J 2017, 'A Genome-wide Association Study Identifies Risk Alleles in Plasminogen and P4HA2 Associated with Giant Cell Arteritis', American Journal of Human Genetics, vol. 100, no. 1, pp. 64-74. https://doi.org/10.1016/j.ajhg.2016.11.013
Carmona, F.D. ; Vaglio, A. ; Mackie, S.L. ; Hernández-Rodríguez, J. ; Monach, P.A. ; Castañeda, S. ; Solans, R. ; Morado, I.C. ; Narváez, J. ; Ramentol-Sintas, M. ; Pease, C.T. ; Dasgupta, B. ; Watts, R. ; Khalidi, N. ; Langford, C.A. ; Ytterberg, S. ; Boiardi, L. ; Beretta, L. ; Govoni, M. ; Emmi, G. ; Bonatti, F. ; Cimmino, M.A. ; Witte, T. ; Neumann, T. ; Holle, J. ; Schönau, V. ; Sailler, L. ; Papo, T. ; Haroche, J. ; Mahr, A. ; Mouthon, L. ; Molberg, Ø. ; Diamantopoulos, A.P. ; Voskuyl, A. ; Brouwer, E. ; Daikeler, T. ; Berger, C.T. ; Molloy, E.S. ; O'Neill, L. ; Blockmans, D. ; Lie, B.A. ; Mclaren, P. ; Vyse, T.J. ; Wijmenga, C. ; Allanore, Y. ; Koeleman, B.P.C. ; Callejas, J.L. ; Caminal-Montero, L. ; Corbera-Bellalta, M. ; de Miguel, E. ; López, J.B.D. ; García-Villanueva, M.J. ; Gómez-Vaquero, C. ; Guijarro-Rojas, M. ; Hidalgo-Conde, A. ; Marí-Alfonso, B. ; Berriochoa, A.M. ; Zapico, A.M. ; Martínez-Taboada, V.M. ; Miranda-Filloy, J.A. ; Monfort, J. ; Ortego-Centeno, N. ; Pérez-Conesa, M. ; Prieto-González, S. ; Raya, E. ; Fernández, R.R. ; Sánchez-Martín, J. ; Sopeña, B. ; Tío, L. ; Unzurrunzaga, A. ; Gough, A. ; Isaacs, J.D. ; Green, M. ; McHugh, N. ; Hordon, L. ; Kamath, S. ; Nisar, M. ; Patel, Y. ; Yee, C.-S. ; Stevens, R. ; Nandi, P. ; Nandagudi, A. ; Jarrett, S. ; Li, C. ; Levy, S. ; Mollan, S. ; Salih, A. ; Wordsworth, O. ; Sanders, E. ; Roads, E. ; Gill, A. ; Carr, L. ; Routledge, C. ; Culfear, K. ; Nugaliyadde, A. ; James, L. ; Spimpolo, J. ; Kempa, A. ; Mackenzie, F. ; Fong, R. ; Peters, G. ; Rowbotham, B. ; Masqood, Z. ; Hollywood, J. ; Gondo, P. ; Wood, R. ; Martin, S. ; Rashid, L.H. ; Robinson, J.I. ; Morgan, M. ; Sorensen, L. ; Taylor, J. ; Carette, S. ; Chung, S. ; Cuthbertson, D. ; Forbess, L.J. ; Gewurz-Singer, O. ; Hoffman, G.S. ; Koening, C.L. ; Maksimowicz-McKinnon, K.M. ; McAlear, C.A. ; Moreland, L.W. ; Pagnoux, C. ; Seo, P. ; Specks, U. ; Spiera, R.F. ; Sreih, A. ; Warrington, K.J. ; Weisman, M. ; Barrett, J.H. ; Cid, M.C. ; Salvarani, C. ; Merkel, P.A. ; Morgan, A.W. ; González-Gay, M.A. ; Martín, J. / A Genome-wide Association Study Identifies Risk Alleles in Plasminogen and P4HA2 Associated with Giant Cell Arteritis. In: American Journal of Human Genetics. 2017 ; Vol. 100, No. 1. pp. 64-74.
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title = "A Genome-wide Association Study Identifies Risk Alleles in Plasminogen and P4HA2 Associated with Giant Cell Arteritis",
abstract = "Giant cell arteritis (GCA) is the most common form of vasculitis in individuals older than 50 years in Western countries. To shed light onto the genetic background influencing susceptibility for GCA, we performed a genome-wide association screening in a well-powered study cohort. After imputation, 1,844,133 genetic variants were analyzed in 2,134 case subjects and 9,125 unaffected individuals from ten independent populations of European ancestry. Our data confirmed HLA class II as the strongest associated region (independent signals: rs9268905, p = 1.94 × 10−54, per-allele OR = 1.79; and rs9275592, p = 1.14 × 10−40, OR = 2.08). Additionally, PLG and P4HA2 were identified as GCA risk genes at the genome-wide level of significance (rs4252134, p = 1.23 × 10−10, OR = 1.28; and rs128738, p = 4.60 × 10−9, OR = 1.32, respectively). Interestingly, we observed that the association peaks overlapped with different regulatory elements related to cell types and tissues involved in the pathophysiology of GCA. PLG and P4HA2 are involved in vascular remodelling and angiogenesis, suggesting a high relevance of these processes for the pathogenic mechanisms underlying this type of vasculitis. {\circledC} 2017 American Society of Human Genetics",
author = "F.D. Carmona and A. Vaglio and S.L. Mackie and J. Hern{\'a}ndez-Rodr{\'i}guez and P.A. Monach and S. Casta{\~n}eda and R. Solans and I.C. Morado and J. Narv{\'a}ez and M. Ramentol-Sintas and C.T. Pease and B. Dasgupta and R. Watts and N. Khalidi and C.A. Langford and S. Ytterberg and L. Boiardi and L. Beretta and M. Govoni and G. Emmi and F. Bonatti and M.A. Cimmino and T. Witte and T. Neumann and J. Holle and V. Sch{\"o}nau and L. Sailler and T. Papo and J. Haroche and A. Mahr and L. Mouthon and {\O}. Molberg and A.P. Diamantopoulos and A. Voskuyl and E. Brouwer and T. Daikeler and C.T. Berger and E.S. Molloy and L. O'Neill and D. Blockmans and B.A. Lie and P. Mclaren and T.J. Vyse and C. Wijmenga and Y. Allanore and B.P.C. Koeleman and J.L. Callejas and L. Caminal-Montero and M. Corbera-Bellalta and {de Miguel}, E. and J.B.D. L{\'o}pez and M.J. Garc{\'i}a-Villanueva and C. G{\'o}mez-Vaquero and M. Guijarro-Rojas and A. Hidalgo-Conde and B. Mar{\'i}-Alfonso and A.M. Berriochoa and A.M. Zapico and V.M. Mart{\'i}nez-Taboada and J.A. Miranda-Filloy and J. Monfort and N. Ortego-Centeno and M. P{\'e}rez-Conesa and S. Prieto-Gonz{\'a}lez and E. Raya and R.R. Fern{\'a}ndez and J. S{\'a}nchez-Mart{\'i}n and B. Sope{\~n}a and L. T{\'i}o and A. Unzurrunzaga and A. Gough and J.D. Isaacs and M. Green and N. McHugh and L. Hordon and S. Kamath and M. Nisar and Y. Patel and C.-S. Yee and R. Stevens and P. Nandi and A. Nandagudi and S. Jarrett and C. Li and S. Levy and S. Mollan and A. Salih and O. Wordsworth and E. Sanders and E. Roads and A. Gill and L. Carr and C. Routledge and K. Culfear and A. Nugaliyadde and L. James and J. Spimpolo and A. Kempa and F. Mackenzie and R. Fong and G. Peters and B. Rowbotham and Z. Masqood and J. Hollywood and P. Gondo and R. Wood and S. Martin and L.H. Rashid and J.I. Robinson and M. Morgan and L. Sorensen and J. Taylor and S. Carette and S. Chung and D. Cuthbertson and L.J. Forbess and O. Gewurz-Singer and G.S. Hoffman and C.L. Koening and K.M. Maksimowicz-McKinnon and C.A. McAlear and L.W. Moreland and C. Pagnoux and P. Seo and U. Specks and R.F. Spiera and A. Sreih and K.J. Warrington and M. Weisman and J.H. Barrett and M.C. Cid and C. Salvarani and P.A. Merkel and A.W. Morgan and M.A. Gonz{\'a}lez-Gay and J. Mart{\'i}n",
note = "Cited By :2 Export Date: 30 October 2017 CODEN: AJHGA Correspondence Address: Carmona, F.D.; Instituto de Parasitolog{\'i}a y Biomedicina “L{\'o}pez-Neyra”, CSIC, PTS GranadaSpain; email: dcarmona@ipb.csic.es",
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pages = "64--74",
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TY - JOUR

T1 - A Genome-wide Association Study Identifies Risk Alleles in Plasminogen and P4HA2 Associated with Giant Cell Arteritis

AU - Carmona, F.D.

AU - Vaglio, A.

AU - Mackie, S.L.

AU - Hernández-Rodríguez, J.

AU - Monach, P.A.

AU - Castañeda, S.

AU - Solans, R.

AU - Morado, I.C.

AU - Narváez, J.

AU - Ramentol-Sintas, M.

AU - Pease, C.T.

AU - Dasgupta, B.

AU - Watts, R.

AU - Khalidi, N.

AU - Langford, C.A.

AU - Ytterberg, S.

AU - Boiardi, L.

AU - Beretta, L.

AU - Govoni, M.

AU - Emmi, G.

AU - Bonatti, F.

AU - Cimmino, M.A.

AU - Witte, T.

AU - Neumann, T.

AU - Holle, J.

AU - Schönau, V.

AU - Sailler, L.

AU - Papo, T.

AU - Haroche, J.

AU - Mahr, A.

AU - Mouthon, L.

AU - Molberg, Ø.

AU - Diamantopoulos, A.P.

AU - Voskuyl, A.

AU - Brouwer, E.

AU - Daikeler, T.

AU - Berger, C.T.

AU - Molloy, E.S.

AU - O'Neill, L.

AU - Blockmans, D.

AU - Lie, B.A.

AU - Mclaren, P.

AU - Vyse, T.J.

AU - Wijmenga, C.

AU - Allanore, Y.

AU - Koeleman, B.P.C.

AU - Callejas, J.L.

AU - Caminal-Montero, L.

AU - Corbera-Bellalta, M.

AU - de Miguel, E.

AU - López, J.B.D.

AU - García-Villanueva, M.J.

AU - Gómez-Vaquero, C.

AU - Guijarro-Rojas, M.

AU - Hidalgo-Conde, A.

AU - Marí-Alfonso, B.

AU - Berriochoa, A.M.

AU - Zapico, A.M.

AU - Martínez-Taboada, V.M.

AU - Miranda-Filloy, J.A.

AU - Monfort, J.

AU - Ortego-Centeno, N.

AU - Pérez-Conesa, M.

AU - Prieto-González, S.

AU - Raya, E.

AU - Fernández, R.R.

AU - Sánchez-Martín, J.

AU - Sopeña, B.

AU - Tío, L.

AU - Unzurrunzaga, A.

AU - Gough, A.

AU - Isaacs, J.D.

AU - Green, M.

AU - McHugh, N.

AU - Hordon, L.

AU - Kamath, S.

AU - Nisar, M.

AU - Patel, Y.

AU - Yee, C.-S.

AU - Stevens, R.

AU - Nandi, P.

AU - Nandagudi, A.

AU - Jarrett, S.

AU - Li, C.

AU - Levy, S.

AU - Mollan, S.

AU - Salih, A.

AU - Wordsworth, O.

AU - Sanders, E.

AU - Roads, E.

AU - Gill, A.

AU - Carr, L.

AU - Routledge, C.

AU - Culfear, K.

AU - Nugaliyadde, A.

AU - James, L.

AU - Spimpolo, J.

AU - Kempa, A.

AU - Mackenzie, F.

AU - Fong, R.

AU - Peters, G.

AU - Rowbotham, B.

AU - Masqood, Z.

AU - Hollywood, J.

AU - Gondo, P.

AU - Wood, R.

AU - Martin, S.

AU - Rashid, L.H.

AU - Robinson, J.I.

AU - Morgan, M.

AU - Sorensen, L.

AU - Taylor, J.

AU - Carette, S.

AU - Chung, S.

AU - Cuthbertson, D.

AU - Forbess, L.J.

AU - Gewurz-Singer, O.

AU - Hoffman, G.S.

AU - Koening, C.L.

AU - Maksimowicz-McKinnon, K.M.

AU - McAlear, C.A.

AU - Moreland, L.W.

AU - Pagnoux, C.

AU - Seo, P.

AU - Specks, U.

AU - Spiera, R.F.

AU - Sreih, A.

AU - Warrington, K.J.

AU - Weisman, M.

AU - Barrett, J.H.

AU - Cid, M.C.

AU - Salvarani, C.

AU - Merkel, P.A.

AU - Morgan, A.W.

AU - González-Gay, M.A.

AU - Martín, J.

N1 - Cited By :2 Export Date: 30 October 2017 CODEN: AJHGA Correspondence Address: Carmona, F.D.; Instituto de Parasitología y Biomedicina “López-Neyra”, CSIC, PTS GranadaSpain; email: dcarmona@ipb.csic.es

PY - 2017

Y1 - 2017

N2 - Giant cell arteritis (GCA) is the most common form of vasculitis in individuals older than 50 years in Western countries. To shed light onto the genetic background influencing susceptibility for GCA, we performed a genome-wide association screening in a well-powered study cohort. After imputation, 1,844,133 genetic variants were analyzed in 2,134 case subjects and 9,125 unaffected individuals from ten independent populations of European ancestry. Our data confirmed HLA class II as the strongest associated region (independent signals: rs9268905, p = 1.94 × 10−54, per-allele OR = 1.79; and rs9275592, p = 1.14 × 10−40, OR = 2.08). Additionally, PLG and P4HA2 were identified as GCA risk genes at the genome-wide level of significance (rs4252134, p = 1.23 × 10−10, OR = 1.28; and rs128738, p = 4.60 × 10−9, OR = 1.32, respectively). Interestingly, we observed that the association peaks overlapped with different regulatory elements related to cell types and tissues involved in the pathophysiology of GCA. PLG and P4HA2 are involved in vascular remodelling and angiogenesis, suggesting a high relevance of these processes for the pathogenic mechanisms underlying this type of vasculitis. © 2017 American Society of Human Genetics

AB - Giant cell arteritis (GCA) is the most common form of vasculitis in individuals older than 50 years in Western countries. To shed light onto the genetic background influencing susceptibility for GCA, we performed a genome-wide association screening in a well-powered study cohort. After imputation, 1,844,133 genetic variants were analyzed in 2,134 case subjects and 9,125 unaffected individuals from ten independent populations of European ancestry. Our data confirmed HLA class II as the strongest associated region (independent signals: rs9268905, p = 1.94 × 10−54, per-allele OR = 1.79; and rs9275592, p = 1.14 × 10−40, OR = 2.08). Additionally, PLG and P4HA2 were identified as GCA risk genes at the genome-wide level of significance (rs4252134, p = 1.23 × 10−10, OR = 1.28; and rs128738, p = 4.60 × 10−9, OR = 1.32, respectively). Interestingly, we observed that the association peaks overlapped with different regulatory elements related to cell types and tissues involved in the pathophysiology of GCA. PLG and P4HA2 are involved in vascular remodelling and angiogenesis, suggesting a high relevance of these processes for the pathogenic mechanisms underlying this type of vasculitis. © 2017 American Society of Human Genetics

U2 - 10.1016/j.ajhg.2016.11.013

DO - 10.1016/j.ajhg.2016.11.013

M3 - Article

VL - 100

SP - 64

EP - 74

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 1

ER -