A genome-wide association study identifies novel and functionally related susceptibility loci for Kawasaki disease

David Burgner, Sonia Davila, Willemijn B. Breunis, Sarah B. Ng, Yi Li, Carine Bonnard, Ling Ling, Victoria J. Wright, Anbupalam Thalamuthu, Miranda Odam, Chisato Shimizu, Jane C. Burns, Michael E Levin, Taco W. Kuijpers, Martin L. Hibberd, Frank Christiansen, Campbell S Witt, Paul Goldwater, Nigel Curtis, Pamela Palasanthiran & 26 others John Ziegler, Michael Nissan, Clare Nourse, Irene M. Kuipers, Jaap J. Ottenkamp, Judy Geissler, Maarten Biezeveld, Luc Filippini, Paul Brogan, Nigel Klein, Vanita Shah, Michael Dillon, Robert Booy, Delane Shingadia, Anu Bose, Thomas Mukasa, Robert Tulloh, Colin Michie, Hiroko Shike, Caroline M Nievergelt, Nicholas J Schork, Jane W. Newburger, Annette L. Baker, Robert P. Sundel, Anne H. Rowley, Stanford T. Shulman

Research output: Contribution to journalArticleResearchpeer-review

179 Citations (Scopus)

Abstract

Kawasaki disease (KD) is a pediatric vasculitis that damages the coronary arteries in 25% of untreated and approximately 5% of treated children. Epidemiologic data suggest that KD is triggered by unidentified infection(s) in genetically susceptible children. To investigate genetic determinants of KD susceptibility, we performed a genome-wide association study (GWAS) in 119 Caucasian KD cases and 135 matched controls with stringent correction for possible admixture, followed by replication in an independent cohort and subsequent fine-mapping, for a total of 893 KD cases plus population and family controls. Significant associations of 40 SNPs and six haplotypes, identifying 31 genes, were replicated in an independent cohort of 583 predominantly Caucasian KD families, with NAALADL2 (rs17531088, pcombined = 1.13×10-6) and ZFHX3 (rs7199343, pcombined = 2.37×10-6) most significantly associated. Sixteen associated variants with a minor allele frequency of >0.05 that lay within or close to known genes were fine-mapped with HapMap tagging SNPs in 781 KD cases, including 590 from the discovery and replication stages. Original or tagging SNPs in eight of these genes replicated the original findings, with seven genes having further significant markers in adjacent regions. In four genes (ZFHX3, NAALADL2, PPP1R14C, and TCP1), the neighboring markers were more significantly associated than the originally associated variants. Investigation of functional relationships between the eight fine-mapped genes using Ingenuity Pathway Analysis identified a single functional network (p=10-13) containing five fine-mapped genes - LNX1, CAMK2D, ZFHX3, CSMD1, and TCP1 - with functional relationships potentially related to inflammation, apoptosis, and cardiovascular pathology. Pair-wise blood transcript levels were measured during acute and convalescent KD for all fine-mapped genes, revealing a consistent trend of significantly reduced transcript levels prior to treatment. This is one of the first GWAS in an infectious disease. We have identified novel, plausible, and functionally related variants associated with KD susceptibility that may also be relevant to other cardiovascular diseases.

Original languageEnglish
Article numbere1000319
JournalPLoS Genetics
Volume5
Issue number1
DOIs
Publication statusPublished - Jan 2009

Cite this

Burgner, David ; Davila, Sonia ; Breunis, Willemijn B. ; Ng, Sarah B. ; Li, Yi ; Bonnard, Carine ; Ling, Ling ; Wright, Victoria J. ; Thalamuthu, Anbupalam ; Odam, Miranda ; Shimizu, Chisato ; Burns, Jane C. ; Levin, Michael E ; Kuijpers, Taco W. ; Hibberd, Martin L. ; Christiansen, Frank ; Witt, Campbell S ; Goldwater, Paul ; Curtis, Nigel ; Palasanthiran, Pamela ; Ziegler, John ; Nissan, Michael ; Nourse, Clare ; Kuipers, Irene M. ; Ottenkamp, Jaap J. ; Geissler, Judy ; Biezeveld, Maarten ; Filippini, Luc ; Brogan, Paul ; Klein, Nigel ; Shah, Vanita ; Dillon, Michael ; Booy, Robert ; Shingadia, Delane ; Bose, Anu ; Mukasa, Thomas ; Tulloh, Robert ; Michie, Colin ; Shike, Hiroko ; Nievergelt, Caroline M ; Schork, Nicholas J ; Newburger, Jane W. ; Baker, Annette L. ; Sundel, Robert P. ; Rowley, Anne H. ; Shulman, Stanford T. / A genome-wide association study identifies novel and functionally related susceptibility loci for Kawasaki disease. In: PLoS Genetics. 2009 ; Vol. 5, No. 1.
@article{1ad2ab2755024127890ece6806b75dc7,
title = "A genome-wide association study identifies novel and functionally related susceptibility loci for Kawasaki disease",
abstract = "Kawasaki disease (KD) is a pediatric vasculitis that damages the coronary arteries in 25{\%} of untreated and approximately 5{\%} of treated children. Epidemiologic data suggest that KD is triggered by unidentified infection(s) in genetically susceptible children. To investigate genetic determinants of KD susceptibility, we performed a genome-wide association study (GWAS) in 119 Caucasian KD cases and 135 matched controls with stringent correction for possible admixture, followed by replication in an independent cohort and subsequent fine-mapping, for a total of 893 KD cases plus population and family controls. Significant associations of 40 SNPs and six haplotypes, identifying 31 genes, were replicated in an independent cohort of 583 predominantly Caucasian KD families, with NAALADL2 (rs17531088, pcombined = 1.13×10-6) and ZFHX3 (rs7199343, pcombined = 2.37×10-6) most significantly associated. Sixteen associated variants with a minor allele frequency of >0.05 that lay within or close to known genes were fine-mapped with HapMap tagging SNPs in 781 KD cases, including 590 from the discovery and replication stages. Original or tagging SNPs in eight of these genes replicated the original findings, with seven genes having further significant markers in adjacent regions. In four genes (ZFHX3, NAALADL2, PPP1R14C, and TCP1), the neighboring markers were more significantly associated than the originally associated variants. Investigation of functional relationships between the eight fine-mapped genes using Ingenuity Pathway Analysis identified a single functional network (p=10-13) containing five fine-mapped genes - LNX1, CAMK2D, ZFHX3, CSMD1, and TCP1 - with functional relationships potentially related to inflammation, apoptosis, and cardiovascular pathology. Pair-wise blood transcript levels were measured during acute and convalescent KD for all fine-mapped genes, revealing a consistent trend of significantly reduced transcript levels prior to treatment. This is one of the first GWAS in an infectious disease. We have identified novel, plausible, and functionally related variants associated with KD susceptibility that may also be relevant to other cardiovascular diseases.",
author = "David Burgner and Sonia Davila and Breunis, {Willemijn B.} and Ng, {Sarah B.} and Yi Li and Carine Bonnard and Ling Ling and Wright, {Victoria J.} and Anbupalam Thalamuthu and Miranda Odam and Chisato Shimizu and Burns, {Jane C.} and Levin, {Michael E} and Kuijpers, {Taco W.} and Hibberd, {Martin L.} and Frank Christiansen and Witt, {Campbell S} and Paul Goldwater and Nigel Curtis and Pamela Palasanthiran and John Ziegler and Michael Nissan and Clare Nourse and Kuipers, {Irene M.} and Ottenkamp, {Jaap J.} and Judy Geissler and Maarten Biezeveld 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 Hiroko Shike and Nievergelt, {Caroline M} and Schork, {Nicholas J} and Newburger, {Jane W.} and Baker, {Annette L.} and Sundel, {Robert P.} and Rowley, {Anne H.} and Shulman, {Stanford T.}",
year = "2009",
month = "1",
doi = "10.1371/journal.pgen.1000319",
language = "English",
volume = "5",
journal = "PLoS Genetics",
issn = "1553-7390",
publisher = "Public Library of Science",
number = "1",

}

Burgner, D, Davila, S, Breunis, WB, Ng, SB, Li, Y, Bonnard, C, Ling, L, Wright, VJ, Thalamuthu, A, Odam, M, Shimizu, C, Burns, JC, Levin, ME, Kuijpers, TW, Hibberd, ML, Christiansen, F, Witt, CS, Goldwater, P, Curtis, N, Palasanthiran, P, Ziegler, J, Nissan, M, Nourse, C, Kuipers, IM, Ottenkamp, JJ, Geissler, J, Biezeveld, M, Filippini, L, Brogan, P, Klein, N, Shah, V, Dillon, M, Booy, R, Shingadia, D, Bose, A, Mukasa, T, Tulloh, R, Michie, C, Shike, H, Nievergelt, CM, Schork, NJ, Newburger, JW, Baker, AL, Sundel, RP, Rowley, AH & Shulman, ST 2009, 'A genome-wide association study identifies novel and functionally related susceptibility loci for Kawasaki disease', PLoS Genetics, vol. 5, no. 1, e1000319. https://doi.org/10.1371/journal.pgen.1000319

A genome-wide association study identifies novel and functionally related susceptibility loci for Kawasaki disease. / Burgner, David; Davila, Sonia; Breunis, Willemijn B.; Ng, Sarah B.; Li, Yi; Bonnard, Carine; Ling, Ling; Wright, Victoria J.; Thalamuthu, Anbupalam; Odam, Miranda; Shimizu, Chisato; Burns, Jane C.; Levin, Michael E; Kuijpers, Taco W.; Hibberd, Martin L.; Christiansen, Frank; Witt, Campbell S; Goldwater, Paul; Curtis, Nigel; Palasanthiran, Pamela; Ziegler, John; Nissan, Michael; Nourse, Clare; Kuipers, Irene M.; Ottenkamp, Jaap J.; Geissler, Judy; Biezeveld, Maarten; Filippini, Luc; Brogan, Paul; Klein, Nigel; Shah, Vanita; Dillon, Michael; Booy, Robert; Shingadia, Delane; Bose, Anu; Mukasa, Thomas; Tulloh, Robert; Michie, Colin; Shike, Hiroko; Nievergelt, Caroline M; Schork, Nicholas J; Newburger, Jane W.; Baker, Annette L.; Sundel, Robert P.; Rowley, Anne H.; Shulman, Stanford T.

In: PLoS Genetics, Vol. 5, No. 1, e1000319, 01.2009.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A genome-wide association study identifies novel and functionally related susceptibility loci for Kawasaki disease

AU - Burgner, David

AU - Davila, Sonia

AU - Breunis, Willemijn B.

AU - Ng, Sarah B.

AU - Li, Yi

AU - Bonnard, Carine

AU - Ling, Ling

AU - Wright, Victoria J.

AU - Thalamuthu, Anbupalam

AU - Odam, Miranda

AU - Shimizu, Chisato

AU - Burns, Jane C.

AU - Levin, Michael E

AU - Kuijpers, Taco W.

AU - Hibberd, Martin L.

AU - Christiansen, Frank

AU - Witt, Campbell S

AU - Goldwater, Paul

AU - Curtis, Nigel

AU - Palasanthiran, Pamela

AU - Ziegler, John

AU - Nissan, Michael

AU - Nourse, Clare

AU - Kuipers, Irene M.

AU - Ottenkamp, Jaap J.

AU - Geissler, Judy

AU - Biezeveld, Maarten

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 - Shike, Hiroko

AU - Nievergelt, Caroline M

AU - Schork, Nicholas J

AU - Newburger, Jane W.

AU - Baker, Annette L.

AU - Sundel, Robert P.

AU - Rowley, Anne H.

AU - Shulman, Stanford T.

PY - 2009/1

Y1 - 2009/1

N2 - Kawasaki disease (KD) is a pediatric vasculitis that damages the coronary arteries in 25% of untreated and approximately 5% of treated children. Epidemiologic data suggest that KD is triggered by unidentified infection(s) in genetically susceptible children. To investigate genetic determinants of KD susceptibility, we performed a genome-wide association study (GWAS) in 119 Caucasian KD cases and 135 matched controls with stringent correction for possible admixture, followed by replication in an independent cohort and subsequent fine-mapping, for a total of 893 KD cases plus population and family controls. Significant associations of 40 SNPs and six haplotypes, identifying 31 genes, were replicated in an independent cohort of 583 predominantly Caucasian KD families, with NAALADL2 (rs17531088, pcombined = 1.13×10-6) and ZFHX3 (rs7199343, pcombined = 2.37×10-6) most significantly associated. Sixteen associated variants with a minor allele frequency of >0.05 that lay within or close to known genes were fine-mapped with HapMap tagging SNPs in 781 KD cases, including 590 from the discovery and replication stages. Original or tagging SNPs in eight of these genes replicated the original findings, with seven genes having further significant markers in adjacent regions. In four genes (ZFHX3, NAALADL2, PPP1R14C, and TCP1), the neighboring markers were more significantly associated than the originally associated variants. Investigation of functional relationships between the eight fine-mapped genes using Ingenuity Pathway Analysis identified a single functional network (p=10-13) containing five fine-mapped genes - LNX1, CAMK2D, ZFHX3, CSMD1, and TCP1 - with functional relationships potentially related to inflammation, apoptosis, and cardiovascular pathology. Pair-wise blood transcript levels were measured during acute and convalescent KD for all fine-mapped genes, revealing a consistent trend of significantly reduced transcript levels prior to treatment. This is one of the first GWAS in an infectious disease. We have identified novel, plausible, and functionally related variants associated with KD susceptibility that may also be relevant to other cardiovascular diseases.

AB - Kawasaki disease (KD) is a pediatric vasculitis that damages the coronary arteries in 25% of untreated and approximately 5% of treated children. Epidemiologic data suggest that KD is triggered by unidentified infection(s) in genetically susceptible children. To investigate genetic determinants of KD susceptibility, we performed a genome-wide association study (GWAS) in 119 Caucasian KD cases and 135 matched controls with stringent correction for possible admixture, followed by replication in an independent cohort and subsequent fine-mapping, for a total of 893 KD cases plus population and family controls. Significant associations of 40 SNPs and six haplotypes, identifying 31 genes, were replicated in an independent cohort of 583 predominantly Caucasian KD families, with NAALADL2 (rs17531088, pcombined = 1.13×10-6) and ZFHX3 (rs7199343, pcombined = 2.37×10-6) most significantly associated. Sixteen associated variants with a minor allele frequency of >0.05 that lay within or close to known genes were fine-mapped with HapMap tagging SNPs in 781 KD cases, including 590 from the discovery and replication stages. Original or tagging SNPs in eight of these genes replicated the original findings, with seven genes having further significant markers in adjacent regions. In four genes (ZFHX3, NAALADL2, PPP1R14C, and TCP1), the neighboring markers were more significantly associated than the originally associated variants. Investigation of functional relationships between the eight fine-mapped genes using Ingenuity Pathway Analysis identified a single functional network (p=10-13) containing five fine-mapped genes - LNX1, CAMK2D, ZFHX3, CSMD1, and TCP1 - with functional relationships potentially related to inflammation, apoptosis, and cardiovascular pathology. Pair-wise blood transcript levels were measured during acute and convalescent KD for all fine-mapped genes, revealing a consistent trend of significantly reduced transcript levels prior to treatment. This is one of the first GWAS in an infectious disease. We have identified novel, plausible, and functionally related variants associated with KD susceptibility that may also be relevant to other cardiovascular diseases.

UR - http://www.scopus.com/inward/record.url?scp=59249099537&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1000319

DO - 10.1371/journal.pgen.1000319

M3 - Article

VL - 5

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 1

M1 - e1000319

ER -