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
AU - Kuijpers, Taco W.
AU - Hibberd, Martin L.
AU - Christiansen, Frank
AU - Witt, Campbell
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 - 2009/1/1
Y1 - 2009/1/1
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 (Academic Journal)
C2 - 19132087
AN - SCOPUS:59249099537
SN - 1553-7390
VL - 5
JO - PLoS Genetics
JF - PLoS Genetics
IS - 1
M1 - e1000319
ER -
