Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease

Chiea Chuen Khor; Sonia Davila; Willemijn B. Breunis; Yi Ching Lee; Chisato Shimizu; Victoria J. Wright; Rae S.M. Yeung; Dennis E.K. Tan; Kar Seng Sim; Jie Jin Wang; Tien Yin Wong; Junxiong Pang; Paul Mitchell; Rolando Cimaz; Nagib Dahdah; Yiu Fai Cheung; Guo Ying Huang; Wanling Yang; In Sook Park; Jong Keuk Lee; Jer Yuarn Wu; Michael Levin; Jane C. Burns; David Burgner; Taco W. Kuijpers; Martin L. Hibberd; Yu Lung Lau; Jing Zhang; Xiao Jing Ma; Fang Liu; Lin Wu; Jeong Jin Yoo; Soo Jong Hong; Kwi Joo Kim; Jae Jung Kim; Young Mi Park; Young Mi Hong; Sejung Sohn; Gi Young Jang; Kee Soo Ha; Hyo Kyoung Nam; Jung Hye Byeon; Sin Weon Yun; Myung Ki Han; Kyung Yil Lee; Ja Young Hwang; Jung Woo Rhim; Min Seob Song; Hyoung Doo Lee; Dong Soo Kim; Jae Moo Lee; Jeng Sheng Chang; Fuu Jen Tsai; Chi Di Liang; Ming Ren Chen; Hsin Chi; Nan Chang Chiu; Fu Yuan Huang; Luan Yin Chang; Li Min Huang; Ho Chang Kuo; Kao Pin Huang; Meng Luen Lee; Betau Hwang; Yhu Chering Huang; Pi Chang Lee; Miranda Odam; Frank T. Christiansen; Campbell Witt; Paul Goldwater; Nigel Curtis; Pamela Palasanthiran; John Ziegler; Michael Nissen; Clare Nourse; Irene M. Kuipers; Jaap J. Ottenkamp; Judy Geissler; Maarten Biezeveld; Carline Tacke; Luc Filippini; Paul Brogan; Nigel Klein; Vanita Shah; Michael Dillon; Robert Booy; Delane Shingadia; Anu Bose; Thomas Mukasa; Robert Tulloh; Colin Michie; Jane W. Newburger; Annette L. Baker; Anne H. Rowley; Stanford T. Shulman; Wilbert Mason; Masato Takahashi; Marian E. Melish; Adriana H. Tremoulet; Ananth Viswanathan; Elena Rochtchina; John Attia; Rodney Scott; Elizabeth Holliday; Stephen Harrap

doi:10.1038/ng.981

Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease

Chiea Chuen Khor, Sonia Davila, Willemijn B. Breunis, Yi Ching Lee, Chisato Shimizu, Victoria J. Wright, Rae S.M. Yeung, Dennis E.K. Tan, Kar Seng Sim, Jie Jin Wang, Tien Yin Wong, Junxiong Pang, Paul Mitchell, Rolando Cimaz, Nagib Dahdah, Yiu Fai Cheung, Guo Ying Huang, Wanling Yang, In Sook Park, Jong Keuk LeeJer Yuarn Wu, Michael Levin^*, Jane C. Burns, David Burgner, Taco W. Kuijpers, Martin L. Hibberd, Yu Lung Lau, Jing Zhang, Xiao Jing Ma, Fang Liu, Lin Wu, Jeong Jin Yoo, Soo Jong Hong, Kwi Joo Kim, Jae Jung Kim, Young Mi Park, Young Mi Hong, Sejung Sohn, Gi Young Jang, Kee Soo Ha, Hyo Kyoung Nam, Jung Hye Byeon, Sin Weon Yun, Myung Ki Han, Kyung Yil Lee, Ja Young Hwang, Jung Woo Rhim, Min Seob Song, Hyoung Doo Lee, Dong Soo Kim, Jae Moo Lee, Jeng Sheng Chang, Fuu Jen Tsai, Chi Di Liang, Ming Ren Chen, Hsin Chi, Nan Chang Chiu, Fu Yuan Huang, Luan Yin Chang, Li Min Huang, Ho Chang Kuo, Kao Pin Huang, Meng Luen Lee, Betau Hwang, Yhu Chering Huang, Pi Chang Lee, Miranda Odam, Frank T. Christiansen, Campbell Witt, Paul Goldwater, Nigel Curtis, Pamela Palasanthiran, John Ziegler, Michael Nissen, Clare Nourse, Irene M. Kuipers, Jaap J. Ottenkamp, Judy Geissler, Maarten Biezeveld, Carline Tacke, Luc Filippini, Paul Brogan, Nigel Klein, Vanita Shah, Michael Dillon, Robert Booy, Delane Shingadia, Anu Bose, Thomas Mukasa, Robert Tulloh, Colin Michie, Jane W. Newburger, Annette L. Baker, Anne H. Rowley, Stanford T. Shulman, Wilbert Mason, Masato Takahashi, Marian E. Melish, Adriana H. Tremoulet, Ananth Viswanathan, Elena Rochtchina, John Attia, Rodney Scott, Elizabeth Holliday, Stephen Harrap

^*Corresponding author for this work

Pediatrics

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

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Abstract

Kawasaki disease is a systemic vasculitis of unknown etiology, with clinical observations suggesting a substantial genetic contribution to disease susceptibility. We conducted a genome-wide association study and replication analysis in 2,173 individuals with Kawasaki disease and 9,383 controls from five independent sample collections. Two loci exceeded the formal threshold for genome-wide significance. The first locus is a functional polymorphism in the IgG receptor gene FCGR2A (encoding an H131R substitution) (rs1801274; P = 7.35 × 10 ^-11, odds ratio (OR) = 1.32), with the A allele (coding for histadine) conferring elevated disease risk. The second locus is at 19q13, (P = 2.51 × 10 ^-9, OR = 1.42 for the rs2233152 SNP near MIA and RAB4B; P = 1.68 × 10 ^-12, OR = 1.52 for rs28493229 in ITPKC), which confirms previous findings. The involvement of the FCGR2A locus may have implications for understanding immune activation in Kawasaki disease pathogenesis and the mechanism of response to intravenous immunoglobulin, the only proven therapy for this disease.

Original language	English (US)
Pages (from-to)	1241-1246
Number of pages	6
Journal	Nature Genetics
Volume	43
Issue number	12
DOIs	https://doi.org/10.1038/ng.981
State	Published - Dec 2011

Funding

We thank all the individuals with Kawasaki disease and their families for participating in this study. We are grateful to W.-Y. Meah, H.-B. Toh, X. Chen, K.-K. Heng, C.-H. Wong, P.-L. Ng, S.H.Y. Chen and J.-W. Tay for technical assistance, to J. Pancheri, N. Innocentini, D. Donati and S. Fernandez for subject data collection and to D. Scherrer for laboratory assistance. The authors acknowledge the contributions of The Kawasaki Syndrome Support Group (UK) for their assistance in recruitment of the UK collection. This study makes use of data generated by the Wellcome Trust Case Control Consortium 2. A full list of the investigators who contributed to the generation of this data is available from the WTCCC2 website (see URLs). This work was funded in part by internal funding from the Sainte-Justine Hospital research center (awarded to N.D.), by grants from the US National Institutes of Health, National Heart, Lung, Blood Institute (HL69413, awarded to J.C.B.), from the National Heart Foundation of Australia (to D.B.) and by the Agency for Science, Technology, and Research, Singapore. The Korean Kawasaki Disease Genetics Consortium was supported by a grant from the Ministry of Health & Welfare of the Republic of Korea (A010384). The Hong Kong Kawasaki Disease Genetics Consortium was supported by the Shun Tak District Min Yuen Tong. The Australian research activity was partly supported by the Victorian Government’s Operational Infrastructure Support Program.

ASJC Scopus subject areas

Genetics

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10.1038/ng.981

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Khor, C. C., Davila, S., Breunis, W. B., Lee, Y. C., Shimizu, C., Wright, V. J., Yeung, R. S. M., Tan, D. E. K., Sim, K. S., Wang, J. J., Wong, T. Y., Pang, J., Mitchell, P., Cimaz, R., Dahdah, N., Cheung, Y. F., Huang, G. Y., Yang, W., Park, I. S., ... Harrap, S. (2011). Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease. Nature Genetics, 43(12), 1241-1246. https://doi.org/10.1038/ng.981

@article{36ac40a3f6514578be06fd6acf8498f8,

title = "Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease",

abstract = "Kawasaki disease is a systemic vasculitis of unknown etiology, with clinical observations suggesting a substantial genetic contribution to disease susceptibility. We conducted a genome-wide association study and replication analysis in 2,173 individuals with Kawasaki disease and 9,383 controls from five independent sample collections. Two loci exceeded the formal threshold for genome-wide significance. The first locus is a functional polymorphism in the IgG receptor gene FCGR2A (encoding an H131R substitution) (rs1801274; P = 7.35 × 10 -11, odds ratio (OR) = 1.32), with the A allele (coding for histadine) conferring elevated disease risk. The second locus is at 19q13, (P = 2.51 × 10 -9, OR = 1.42 for the rs2233152 SNP near MIA and RAB4B; P = 1.68 × 10 -12, OR = 1.52 for rs28493229 in ITPKC), which confirms previous findings. The involvement of the FCGR2A locus may have implications for understanding immune activation in Kawasaki disease pathogenesis and the mechanism of response to intravenous immunoglobulin, the only proven therapy for this disease.",

author = "Khor, {Chiea Chuen} and Sonia Davila and Breunis, {Willemijn B.} and Lee, {Yi Ching} and Chisato Shimizu and Wright, {Victoria J.} and Yeung, {Rae S.M.} and Tan, {Dennis E.K.} and Sim, {Kar Seng} and Wang, {Jie Jin} and Wong, {Tien Yin} and Junxiong Pang and Paul Mitchell and Rolando Cimaz and Nagib Dahdah and Cheung, {Yiu Fai} and Huang, {Guo Ying} and Wanling Yang and Park, {In Sook} and Lee, {Jong Keuk} and Wu, {Jer Yuarn} and Michael Levin and Burns, {Jane C.} and David Burgner and Kuijpers, {Taco W.} and Hibberd, {Martin L.} and Lau, {Yu Lung} and Jing Zhang and Ma, {Xiao Jing} and Fang Liu and Lin Wu and Yoo, {Jeong Jin} and Hong, {Soo Jong} and Kim, {Kwi Joo} and Kim, {Jae Jung} and Park, {Young Mi} and Hong, {Young Mi} and Sejung Sohn and Jang, {Gi Young} and Ha, {Kee Soo} and Nam, {Hyo Kyoung} and Byeon, {Jung Hye} and Yun, {Sin Weon} and Han, {Myung Ki} and Lee, {Kyung Yil} and Hwang, {Ja Young} and Rhim, {Jung Woo} and Song, {Min Seob} and Lee, {Hyoung Doo} and Kim, {Dong Soo} and Lee, {Jae Moo} and Chang, {Jeng Sheng} and Tsai, {Fuu Jen} and Liang, {Chi Di} and Chen, {Ming Ren} and Hsin Chi and Chiu, {Nan Chang} and Huang, {Fu Yuan} and Chang, {Luan Yin} and Huang, {Li Min} and Kuo, {Ho Chang} and Huang, {Kao Pin} and Lee, {Meng Luen} and Betau Hwang and Huang, {Yhu Chering} and Lee, {Pi Chang} and Miranda Odam and Christiansen, {Frank T.} and Campbell Witt and Paul Goldwater and Nigel Curtis and Pamela Palasanthiran and John Ziegler and Michael Nissen and Clare Nourse and Kuipers, {Irene M.} and Ottenkamp, {Jaap J.} and Judy Geissler and Maarten Biezeveld and Carline Tacke and Luc Filippini and Paul Brogan and Nigel Klein and Vanita Shah and Michael Dillon and Robert Booy and Delane Shingadia and Anu Bose and Thomas Mukasa and Robert Tulloh and Colin Michie and Newburger, {Jane W.} and Baker, {Annette L.} and Rowley, {Anne H.} and Shulman, {Stanford T.} and Wilbert Mason and Masato Takahashi and Melish, {Marian E.} and Tremoulet, {Adriana H.} and Ananth Viswanathan and Elena Rochtchina and John Attia and Rodney Scott and Elizabeth Holliday and Stephen Harrap",

note = "Funding Information: We thank all the individuals with Kawasaki disease and their families for participating in this study. We are grateful to W.-Y. Meah, H.-B. Toh, X. Chen, K.-K. Heng, C.-H. Wong, P.-L. Ng, S.H.Y. Chen and J.-W. Tay for technical assistance, to J. Pancheri, N. Innocentini, D. Donati and S. Fernandez for subject data collection and to D. Scherrer for laboratory assistance. The authors acknowledge the contributions of The Kawasaki Syndrome Support Group (UK) for their assistance in recruitment of the UK collection. This study makes use of data generated by the Wellcome Trust Case Control Consortium 2. A full list of the investigators who contributed to the generation of this data is available from the WTCCC2 website (see URLs). This work was funded in part by internal funding from the Sainte-Justine Hospital research center (awarded to N.D.), by grants from the US National Institutes of Health, National Heart, Lung, Blood Institute (HL69413, awarded to J.C.B.), from the National Heart Foundation of Australia (to D.B.) and by the Agency for Science, Technology, and Research, Singapore. The Korean Kawasaki Disease Genetics Consortium was supported by a grant from the Ministry of Health & Welfare of the Republic of Korea (A010384). The Hong Kong Kawasaki Disease Genetics Consortium was supported by the Shun Tak District Min Yuen Tong. The Australian research activity was partly supported by the Victorian Government{\textquoteright}s Operational Infrastructure Support Program.",

year = "2011",

month = dec,

doi = "10.1038/ng.981",

language = "English (US)",

volume = "43",

pages = "1241--1246",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "12",

}

Khor, CC, Davila, S, Breunis, WB, Lee, YC, Shimizu, C, Wright, VJ, Yeung, RSM, Tan, DEK, Sim, KS, Wang, JJ, Wong, TY, Pang, J, Mitchell, P, Cimaz, R, Dahdah, N, Cheung, YF, Huang, GY, Yang, W, Park, IS, Lee, JK, Wu, JY, Levin, M, Burns, JC, Burgner, D, Kuijpers, TW, Hibberd, ML, Lau, YL, Zhang, J, Ma, XJ, Liu, F, Wu, L, Yoo, JJ, Hong, SJ, Kim, KJ, Kim, JJ, Park, YM, Hong, YM, Sohn, S, Jang, GY, Ha, KS, Nam, HK, Byeon, JH, Yun, SW, Han, MK, Lee, KY, Hwang, JY, Rhim, JW, Song, MS, Lee, HD, Kim, DS, Lee, JM, Chang, JS, Tsai, FJ, Liang, CD, Chen, MR, Chi, H, Chiu, NC, Huang, FY, Chang, LY, Huang, LM, Kuo, HC, Huang, KP, Lee, ML, Hwang, B, Huang, YC, Lee, PC, Odam, M, Christiansen, FT, Witt, C, Goldwater, P, Curtis, N, Palasanthiran, P, Ziegler, J, Nissen, M, Nourse, C, Kuipers, IM, Ottenkamp, JJ, Geissler, J, Biezeveld, M, Tacke, C, Filippini, L, Brogan, P, Klein, N, Shah, V, Dillon, M, Booy, R, Shingadia, D, Bose, A, Mukasa, T, Tulloh, R, Michie, C, Newburger, JW, Baker, AL, Rowley, AH , Shulman, ST, Mason, W, Takahashi, M, Melish, ME, Tremoulet, AH, Viswanathan, A, Rochtchina, E, Attia, J, Scott, R, Holliday, E & Harrap, S 2011, 'Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease', Nature Genetics, vol. 43, no. 12, pp. 1241-1246. https://doi.org/10.1038/ng.981

TY - JOUR

T1 - Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease

AU - Khor, Chiea Chuen

AU - Davila, Sonia

AU - Breunis, Willemijn B.

AU - Lee, Yi Ching

AU - Shimizu, Chisato

AU - Wright, Victoria J.

AU - Yeung, Rae S.M.

AU - Tan, Dennis E.K.

AU - Sim, Kar Seng

AU - Wang, Jie Jin

AU - Wong, Tien Yin

AU - Pang, Junxiong

AU - Mitchell, Paul

AU - Cimaz, Rolando

AU - Dahdah, Nagib

AU - Cheung, Yiu Fai

AU - Huang, Guo Ying

AU - Yang, Wanling

AU - Park, In Sook

AU - Lee, Jong Keuk

AU - Wu, Jer Yuarn

AU - Levin, Michael

AU - Burns, Jane C.

AU - Burgner, David

AU - Kuijpers, Taco W.

AU - Hibberd, Martin L.

AU - Lau, Yu Lung

AU - Zhang, Jing

AU - Ma, Xiao Jing

AU - Liu, Fang

AU - Wu, Lin

AU - Yoo, Jeong Jin

AU - Hong, Soo Jong

AU - Kim, Kwi Joo

AU - Kim, Jae Jung

AU - Park, Young Mi

AU - Hong, Young Mi

AU - Sohn, Sejung

AU - Jang, Gi Young

AU - Ha, Kee Soo

AU - Nam, Hyo Kyoung

AU - Byeon, Jung Hye

AU - Yun, Sin Weon

AU - Han, Myung Ki

AU - Lee, Kyung Yil

AU - Hwang, Ja Young

AU - Rhim, Jung Woo

AU - Song, Min Seob

AU - Lee, Hyoung Doo

AU - Kim, Dong Soo

AU - Lee, Jae Moo

AU - Chang, Jeng Sheng

AU - Tsai, Fuu Jen

AU - Liang, Chi Di

AU - Chen, Ming Ren

AU - Chi, Hsin

AU - Chiu, Nan Chang

AU - Huang, Fu Yuan

AU - Chang, Luan Yin

AU - Huang, Li Min

AU - Kuo, Ho Chang

AU - Huang, Kao Pin

AU - Lee, Meng Luen

AU - Hwang, Betau

AU - Huang, Yhu Chering

AU - Lee, Pi Chang

AU - Odam, Miranda

AU - Christiansen, Frank T.

AU - Witt, Campbell

AU - Goldwater, Paul

AU - Curtis, Nigel

AU - Palasanthiran, Pamela

AU - Ziegler, John

AU - Nissen, Michael

AU - Nourse, Clare

AU - Kuipers, Irene M.

AU - Ottenkamp, Jaap J.

AU - Geissler, Judy

AU - Biezeveld, Maarten

AU - Tacke, Carline

AU - Filippini, Luc

AU - Brogan, Paul

AU - Klein, Nigel

AU - Shah, Vanita

AU - Dillon, Michael

AU - Booy, Robert

AU - Shingadia, Delane

AU - Bose, Anu

AU - Mukasa, Thomas

AU - Tulloh, Robert

AU - Michie, Colin

AU - Newburger, Jane W.

AU - Baker, Annette L.

AU - Rowley, Anne H.

AU - Shulman, Stanford T.

AU - Mason, Wilbert

AU - Takahashi, Masato

AU - Melish, Marian E.

AU - Tremoulet, Adriana H.

AU - Viswanathan, Ananth

AU - Rochtchina, Elena

AU - Attia, John

AU - Scott, Rodney

AU - Holliday, Elizabeth

AU - Harrap, Stephen

N1 - Funding Information: We thank all the individuals with Kawasaki disease and their families for participating in this study. We are grateful to W.-Y. Meah, H.-B. Toh, X. Chen, K.-K. Heng, C.-H. Wong, P.-L. Ng, S.H.Y. Chen and J.-W. Tay for technical assistance, to J. Pancheri, N. Innocentini, D. Donati and S. Fernandez for subject data collection and to D. Scherrer for laboratory assistance. The authors acknowledge the contributions of The Kawasaki Syndrome Support Group (UK) for their assistance in recruitment of the UK collection. This study makes use of data generated by the Wellcome Trust Case Control Consortium 2. A full list of the investigators who contributed to the generation of this data is available from the WTCCC2 website (see URLs). This work was funded in part by internal funding from the Sainte-Justine Hospital research center (awarded to N.D.), by grants from the US National Institutes of Health, National Heart, Lung, Blood Institute (HL69413, awarded to J.C.B.), from the National Heart Foundation of Australia (to D.B.) and by the Agency for Science, Technology, and Research, Singapore. The Korean Kawasaki Disease Genetics Consortium was supported by a grant from the Ministry of Health & Welfare of the Republic of Korea (A010384). The Hong Kong Kawasaki Disease Genetics Consortium was supported by the Shun Tak District Min Yuen Tong. The Australian research activity was partly supported by the Victorian Government’s Operational Infrastructure Support Program.

PY - 2011/12

Y1 - 2011/12

N2 - Kawasaki disease is a systemic vasculitis of unknown etiology, with clinical observations suggesting a substantial genetic contribution to disease susceptibility. We conducted a genome-wide association study and replication analysis in 2,173 individuals with Kawasaki disease and 9,383 controls from five independent sample collections. Two loci exceeded the formal threshold for genome-wide significance. The first locus is a functional polymorphism in the IgG receptor gene FCGR2A (encoding an H131R substitution) (rs1801274; P = 7.35 × 10 -11, odds ratio (OR) = 1.32), with the A allele (coding for histadine) conferring elevated disease risk. The second locus is at 19q13, (P = 2.51 × 10 -9, OR = 1.42 for the rs2233152 SNP near MIA and RAB4B; P = 1.68 × 10 -12, OR = 1.52 for rs28493229 in ITPKC), which confirms previous findings. The involvement of the FCGR2A locus may have implications for understanding immune activation in Kawasaki disease pathogenesis and the mechanism of response to intravenous immunoglobulin, the only proven therapy for this disease.

AB - Kawasaki disease is a systemic vasculitis of unknown etiology, with clinical observations suggesting a substantial genetic contribution to disease susceptibility. We conducted a genome-wide association study and replication analysis in 2,173 individuals with Kawasaki disease and 9,383 controls from five independent sample collections. Two loci exceeded the formal threshold for genome-wide significance. The first locus is a functional polymorphism in the IgG receptor gene FCGR2A (encoding an H131R substitution) (rs1801274; P = 7.35 × 10 -11, odds ratio (OR) = 1.32), with the A allele (coding for histadine) conferring elevated disease risk. The second locus is at 19q13, (P = 2.51 × 10 -9, OR = 1.42 for the rs2233152 SNP near MIA and RAB4B; P = 1.68 × 10 -12, OR = 1.52 for rs28493229 in ITPKC), which confirms previous findings. The involvement of the FCGR2A locus may have implications for understanding immune activation in Kawasaki disease pathogenesis and the mechanism of response to intravenous immunoglobulin, the only proven therapy for this disease.

UR - http://www.scopus.com/inward/record.url?scp=82255186670&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=82255186670&partnerID=8YFLogxK

U2 - 10.1038/ng.981

DO - 10.1038/ng.981

M3 - Article

C2 - 22081228

AN - SCOPUS:82255186670

SN - 1061-4036

VL - 43

SP - 1241

EP - 1246

JO - Nature Genetics

JF - Nature Genetics

IS - 12

ER -

Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease

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