Identification of susceptibility loci for Takayasu arteritis through a large multi-ancestral genome-wide association study

Lourdes Ortiz-Fernández; Güher Saruhan-Direskeneli; Fatma Alibaz-Oner; Sema Kaymaz-Tahra; Patrick Coit; Xiufang Kong; Allan P. Kiprianos; Robert T. Maughan; Sibel Z. Aydin; Kenan Aksu; Gokhan Keser; Sevil Kamali; Murat Inanc; Jason Springer; Servet Akar; Fatos Onen; Nurullah Akkoc; Nader A. Khalidi; Curry Koening; Omer Karadag; Sedat Kiraz; Lindsy Forbess; Carol A. Langford; Carol A. McAlear; Zeynep Ozbalkan; Sule Yavuz; Gozde Yildirim Çetin; Nilufer Alpay-Kanitez; Sharon Chung; Askin Ates; Yasar Karaaslan; Kathleen McKinnon-Maksimowicz; Paul A. Monach; Hüseyin T.E. Ozer; Emire Seyahi; Izzet Fresko; Ayse Cefle; Philip Seo; Kenneth J. Warrington; Mehmet A. Ozturk; Steven R. Ytterberg; Veli Cobankara; Ahmet Mesut Onat; Nurşen Duzgun; Muge Bıcakcıgil; Sibel P. Yentür; Lindsay Lally; Angelo A. Manfredi; Elena Baldissera; Eren Erken; Ayten Yazici; Bünyamin Kısacık; Timuçin Kaşifoğlu; Ediz Dalkilic; David Cuthbertson; Christian Pagnoux; Antoine Sreih; Guillermo Reales; Chris Wallace; Jonathan D. Wren; Deborah S. Cunninghame-Graham; Timothy J. Vyse; Ying Sun; Huiyong Chen; Peter C. Grayson; Enrico Tombetti; Lindi Jiang; Justin C. Mason; Peter A. Merkel; Haner Direskeneli; Amr H. Sawalha

doi:10.1016/j.ajhg.2020.11.014

Identification of susceptibility loci for Takayasu arteritis through a large multi-ancestral genome-wide association study

Lourdes Ortiz-Fernández, Güher Saruhan-Direskeneli, Fatma Alibaz-Oner, Sema Kaymaz-Tahra, Patrick Coit, Xiufang Kong, Allan P. Kiprianos, Robert T. Maughan, Sibel Z. Aydin, Kenan Aksu, Gokhan Keser, Sevil Kamali, Murat Inanc, Jason Springer, Servet Akar, Fatos Onen, Nurullah Akkoc, Nader A. Khalidi, Curry Koening, Omer KaradagSedat Kiraz, Lindsy Forbess, Carol A. Langford, Carol A. McAlear, Zeynep Ozbalkan, Sule Yavuz, Gozde Yildirim Çetin, Nilufer Alpay-Kanitez, Sharon Chung, Askin Ates, Yasar Karaaslan, Kathleen McKinnon-Maksimowicz, Paul A. Monach, Hüseyin T.E. Ozer, Emire Seyahi, Izzet Fresko, Ayse Cefle, Philip Seo, Kenneth J. Warrington, Mehmet A. Ozturk, Steven R. Ytterberg, Veli Cobankara, Ahmet Mesut Onat, Nurşen Duzgun, Muge Bıcakcıgil, Sibel P. Yentür, Lindsay Lally, Angelo A. Manfredi, Elena Baldissera, Eren Erken, Ayten Yazici, Bünyamin Kısacık, Timuçin Kaşifoğlu, Ediz Dalkilic, David Cuthbertson, Christian Pagnoux, Antoine Sreih, Guillermo Reales, Chris Wallace, Jonathan D. Wren, Deborah S. Cunninghame-Graham, Timothy J. Vyse, Ying Sun, Huiyong Chen, Peter C. Grayson, Enrico Tombetti, Lindi Jiang, Justin C. Mason, Peter A. Merkel, Haner Direskeneli, Amr H. Sawalha

Rheumatology

Research output: Contribution to journal › Article › peer-review

Abstract

Takayasu arteritis is a rare inflammatory disease of large arteries. We performed a genetic study in Takayasu arteritis comprising 6,670 individuals (1,226 affected individuals) from five different populations. We discovered HLA risk factors and four non-HLA susceptibility loci in VPS8, SVEP1, CFL2, and chr13q21 and reinforced IL12B, PTK2B, and chr21q22 as robust susceptibility loci shared across ancestries. Functional analysis proposed plausible underlying disease mechanisms and pinpointed ETS2 as a potential causal gene for chr21q22 association. We also identified >60 candidate loci with suggestive association (p < 5 × 10⁻⁵) and devised a genetic risk score for Takayasu arteritis. Takayasu arteritis was compared to hundreds of other traits, revealing the closest genetic relatedness to inflammatory bowel disease. Epigenetic patterns within risk loci suggest roles for monocytes and B cells in Takayasu arteritis. This work enhances understanding of the genetic basis and pathophysiology of Takayasu arteritis and provides clues for potential new therapeutic targets.

Original language	English (US)
Pages (from-to)	84-99
Number of pages	16
Journal	American journal of human genetics
Volume	108
Issue number	1
DOIs	https://doi.org/10.1016/j.ajhg.2020.11.014
State	Published - Jan 7 2021

Keywords

GWAS
HLA
Takayasu arteritis
chromatin interaction
eQTL
epigenetic
genetic association
genetic risk scroe
vasculitis

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1016/j.ajhg.2020.11.014

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Ortiz-Fernández, L., Saruhan-Direskeneli, G., Alibaz-Oner, F., Kaymaz-Tahra, S., Coit, P., Kong, X., Kiprianos, A. P., Maughan, R. T., Aydin, S. Z., Aksu, K., Keser, G., Kamali, S., Inanc, M., Springer, J., Akar, S., Onen, F., Akkoc, N., Khalidi, N. A., Koening, C., ... Sawalha, A. H. (2021). Identification of susceptibility loci for Takayasu arteritis through a large multi-ancestral genome-wide association study. American journal of human genetics, 108(1), 84-99. https://doi.org/10.1016/j.ajhg.2020.11.014

Ortiz-Fernández, L, Saruhan-Direskeneli, G, Alibaz-Oner, F, Kaymaz-Tahra, S, Coit, P, Kong, X, Kiprianos, AP, Maughan, RT, Aydin, SZ, Aksu, K, Keser, G, Kamali, S, Inanc, M, Springer, J, Akar, S, Onen, F, Akkoc, N, Khalidi, NA, Koening, C, Karadag, O, Kiraz, S, Forbess, L, Langford, CA, McAlear, CA, Ozbalkan, Z, Yavuz, S, Çetin, GY, Alpay-Kanitez, N, Chung, S, Ates, A, Karaaslan, Y, McKinnon-Maksimowicz, K, Monach, PA, Ozer, HTE, Seyahi, E, Fresko, I, Cefle, A, Seo, P, Warrington, KJ, Ozturk, MA, Ytterberg, SR, Cobankara, V, Onat, AM, Duzgun, N, Bıcakcıgil, M, Yentür, SP, Lally, L, Manfredi, AA, Baldissera, E, Erken, E, Yazici, A, Kısacık, B, Kaşifoğlu, T, Dalkilic, E, Cuthbertson, D, Pagnoux, C, Sreih, A, Reales, G, Wallace, C, Wren, JD, Cunninghame-Graham, DS, Vyse, TJ, Sun, Y, Chen, H, Grayson, PC, Tombetti, E, Jiang, L, Mason, JC, Merkel, PA, Direskeneli, H & Sawalha, AH 2021, 'Identification of susceptibility loci for Takayasu arteritis through a large multi-ancestral genome-wide association study', American journal of human genetics, vol. 108, no. 1, pp. 84-99. https://doi.org/10.1016/j.ajhg.2020.11.014

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abstract = "Takayasu arteritis is a rare inflammatory disease of large arteries. We performed a genetic study in Takayasu arteritis comprising 6,670 individuals (1,226 affected individuals) from five different populations. We discovered HLA risk factors and four non-HLA susceptibility loci in VPS8, SVEP1, CFL2, and chr13q21 and reinforced IL12B, PTK2B, and chr21q22 as robust susceptibility loci shared across ancestries. Functional analysis proposed plausible underlying disease mechanisms and pinpointed ETS2 as a potential causal gene for chr21q22 association. We also identified >60 candidate loci with suggestive association (p < 5 × 10−5) and devised a genetic risk score for Takayasu arteritis. Takayasu arteritis was compared to hundreds of other traits, revealing the closest genetic relatedness to inflammatory bowel disease. Epigenetic patterns within risk loci suggest roles for monocytes and B cells in Takayasu arteritis. This work enhances understanding of the genetic basis and pathophysiology of Takayasu arteritis and provides clues for potential new therapeutic targets.",

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doi = "10.1016/j.ajhg.2020.11.014",

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T1 - Identification of susceptibility loci for Takayasu arteritis through a large multi-ancestral genome-wide association study

AU - Ortiz-Fernández, Lourdes

AU - Saruhan-Direskeneli, Güher

AU - Alibaz-Oner, Fatma

AU - Kaymaz-Tahra, Sema

AU - Coit, Patrick

AU - Kong, Xiufang

AU - Kiprianos, Allan P.

AU - Maughan, Robert T.

AU - Aydin, Sibel Z.

AU - Aksu, Kenan

AU - Keser, Gokhan

AU - Kamali, Sevil

AU - Inanc, Murat

AU - Springer, Jason

AU - Akar, Servet

AU - Onen, Fatos

AU - Akkoc, Nurullah

AU - Khalidi, Nader A.

AU - Koening, Curry

AU - Karadag, Omer

AU - Kiraz, Sedat

AU - Forbess, Lindsy

AU - Langford, Carol A.

AU - McAlear, Carol A.

AU - Ozbalkan, Zeynep

AU - Yavuz, Sule

AU - Çetin, Gozde Yildirim

AU - Alpay-Kanitez, Nilufer

AU - Chung, Sharon

AU - Ates, Askin

AU - Karaaslan, Yasar

AU - McKinnon-Maksimowicz, Kathleen

AU - Monach, Paul A.

AU - Ozer, Hüseyin T.E.

AU - Seyahi, Emire

AU - Fresko, Izzet

AU - Cefle, Ayse

AU - Seo, Philip

AU - Warrington, Kenneth J.

AU - Ozturk, Mehmet A.

AU - Ytterberg, Steven R.

AU - Cobankara, Veli

AU - Onat, Ahmet Mesut

AU - Duzgun, Nurşen

AU - Bıcakcıgil, Muge

AU - Yentür, Sibel P.

AU - Lally, Lindsay

AU - Manfredi, Angelo A.

AU - Baldissera, Elena

AU - Erken, Eren

AU - Yazici, Ayten

AU - Kısacık, Bünyamin

AU - Kaşifoğlu, Timuçin

AU - Dalkilic, Ediz

AU - Cuthbertson, David

AU - Pagnoux, Christian

AU - Sreih, Antoine

AU - Reales, Guillermo

AU - Wallace, Chris

AU - Wren, Jonathan D.

AU - Cunninghame-Graham, Deborah S.

AU - Vyse, Timothy J.

AU - Sun, Ying

AU - Chen, Huiyong

AU - Grayson, Peter C.

AU - Tombetti, Enrico

AU - Jiang, Lindi

AU - Mason, Justin C.

AU - Merkel, Peter A.

AU - Direskeneli, Haner

AU - Sawalha, Amr H.

PY - 2021/1/7

Y1 - 2021/1/7

N2 - Takayasu arteritis is a rare inflammatory disease of large arteries. We performed a genetic study in Takayasu arteritis comprising 6,670 individuals (1,226 affected individuals) from five different populations. We discovered HLA risk factors and four non-HLA susceptibility loci in VPS8, SVEP1, CFL2, and chr13q21 and reinforced IL12B, PTK2B, and chr21q22 as robust susceptibility loci shared across ancestries. Functional analysis proposed plausible underlying disease mechanisms and pinpointed ETS2 as a potential causal gene for chr21q22 association. We also identified >60 candidate loci with suggestive association (p < 5 × 10−5) and devised a genetic risk score for Takayasu arteritis. Takayasu arteritis was compared to hundreds of other traits, revealing the closest genetic relatedness to inflammatory bowel disease. Epigenetic patterns within risk loci suggest roles for monocytes and B cells in Takayasu arteritis. This work enhances understanding of the genetic basis and pathophysiology of Takayasu arteritis and provides clues for potential new therapeutic targets.

AB - Takayasu arteritis is a rare inflammatory disease of large arteries. We performed a genetic study in Takayasu arteritis comprising 6,670 individuals (1,226 affected individuals) from five different populations. We discovered HLA risk factors and four non-HLA susceptibility loci in VPS8, SVEP1, CFL2, and chr13q21 and reinforced IL12B, PTK2B, and chr21q22 as robust susceptibility loci shared across ancestries. Functional analysis proposed plausible underlying disease mechanisms and pinpointed ETS2 as a potential causal gene for chr21q22 association. We also identified >60 candidate loci with suggestive association (p < 5 × 10−5) and devised a genetic risk score for Takayasu arteritis. Takayasu arteritis was compared to hundreds of other traits, revealing the closest genetic relatedness to inflammatory bowel disease. Epigenetic patterns within risk loci suggest roles for monocytes and B cells in Takayasu arteritis. This work enhances understanding of the genetic basis and pathophysiology of Takayasu arteritis and provides clues for potential new therapeutic targets.

KW - GWAS

KW - HLA

KW - Takayasu arteritis

KW - chromatin interaction

KW - eQTL

KW - epigenetic

KW - genetic association

KW - genetic risk scroe

KW - vasculitis

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AN - SCOPUS:85098505408

SN - 0002-9297

VL - 108

SP - 84

EP - 99

JO - American journal of human genetics

JF - American journal of human genetics

IS - 1

ER -

Identification of susceptibility loci for Takayasu arteritis through a large multi-ancestral genome-wide association study

Abstract

Keywords

ASJC Scopus subject areas

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