TY - JOUR
T1 - Extensive Ethnic Variation and Linkage Disequilibrium at the FCGR2/3 Locus: Different Genetic Associations Revealed in Kawasaki Disease
AU - International Kawasaki Disease Genetics Consortium
AU - Nagelkerke, Sietse Q.
AU - Tacke, Carline E.
AU - Breunis, Willemijn B.
AU - Tanck, Michael W. T.
AU - Geissler, Judy
AU - Png, Eileen
AU - Hoang, Long T.
AU - van der Heijden, Joris
AU - Naim, Ahmad N. M.
AU - Yeung, Rae S. M.
AU - Levin, Michael L.
AU - Wright, Victoria J.
AU - Burgner, David P.
AU - Ponsonby, Anne-Louise
AU - Ellis, Justine A.
AU - Cimaz, Rolando
AU - Shimizu, Chisato
AU - Burns, Jane C.
AU - Fijnvandraat, Karin
AU - van den Berg, Timo K.
AU - de Boer, Martin
AU - Davila, Sonia
AU - Hibberd, Martin L.
AU - Kuijpers, Taco W.
AU - Dahdah, Nagib
AU - Kone-Paut, Isabelle
N1 - Funding Information: 1Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands, 2Pediatric Hematology, Immunology and Infectious Diseases, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands, 3Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands, 4Infectious Diseases, Genome Institute of Singapore, Singapore, Singapore, 5Division of Rheumatology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada, 6Department of Pediatrics, Imperial College London, London, United Kingdom, 7Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, VIC, Australia, 8Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia, 9Faculty of Health, Centre for Social and Early Emotional Development, Deakin University, Burwood, VIC, Australia, 10Rheumatology Unit, Meyer Children’s Hospital, University of Florence, Florence, Italy, 11Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA, United States, 12Department of Plasma Proteins, Sanquin Research, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands, 13Department of Molecular Cell Biology and Immunology, Amsterdam Infection and Immunity Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands, 14Human Genetics, Genome Institute of Singapore, Singapore, Singapore, 15Department of Pathogen Biology, London School of Hygiene and Tropical Medicine, London, United Kingdom Funding Information: We thank Prof. Dirk Roos and Prof. Raoul Hennekam for critical reading of the manuscript, Dr. C. C. Khor, Dr. Joep Sins, Mrs. Aicha Ait Soussan, and Dr. Lonneke Haer-Wigman for help in sample collection, and the GERMS platform at Genome Institute Singapore for technical support. This work was supported by a grant from the Landsteiner Foundation for Bloodtransfusion Research (LSBR 0916) awarded to TK. Funding Information: CT has received a grant from the Ter Meulen Fund, Royal Netherlands Academy of Arts and Sciences (TMF2012/227). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: Copyright © 2019 Nagelkerke, Tacke, Breunis, Tanck, Geissler, Png, Hoang, van der Heijden, Naim, Yeung, Levin, Wright, Burgner, Ponsonby, Ellis, Cimaz, Shimizu, Burns, Fijnvandraat, van der Schoot, van den Berg, de Boer, Davila, Hibberd, Kuijpers and the International Kawasaki Disease Genetics Consortium. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - The human Fc-gamma receptors (FcγRs) link adaptive and innate immunity by binding immunoglobulin G (IgG). All human low-affinity FcγRs are encoded by the FCGR2/3 locus containing functional single nucleotide polymorphisms (SNPs) and gene copy number variants. This locus is notoriously difficult to genotype and high-throughput methods commonly used focus on only a few SNPs. We performed multiplex ligation-dependent probe amplification for all relevant genetic variations at the FCGR2/3 locus in >4,000 individuals to define linkage disequilibrium (LD) and allele frequencies in different populations. Strong LD and extensive ethnic variation in allele frequencies was found across the locus. LD was strongest for the FCGR2C-ORF haplotype (rs759550223+rs76277413), which leads to expression of FcγRIIc. In Europeans, the FCGR2C-ORF haplotype showed strong LD with, among others, rs201218628 (FCGR2A-Q27W, r 2 = 0.63). LD between these two variants was weaker (r 2 = 0.17) in Africans, whereas the FCGR2C-ORF haplotype was nearly absent in Asians (minor allele frequency <0.005%). The FCGR2C-ORF haplotype and rs1801274 (FCGR2A-H131R) were in weak LD (r 2 = 0.08) in Europeans. We evaluated the importance of ethnic variation and LD in Kawasaki Disease (KD), an acute vasculitis in children with increased incidence in Asians. An association of rs1801274 with KD was previously shown in ethnically diverse genome-wide association studies. Now, we show in 1,028 European KD patients that the FCGR2C-ORF haplotype, although nearly absent in Asians, was more strongly associated with susceptibility to KD than rs1801274 in Europeans. Our data illustrate the importance of interpreting findings of association studies concerning the FCGR2/3 locus with knowledge of LD and ethnic variation.
AB - The human Fc-gamma receptors (FcγRs) link adaptive and innate immunity by binding immunoglobulin G (IgG). All human low-affinity FcγRs are encoded by the FCGR2/3 locus containing functional single nucleotide polymorphisms (SNPs) and gene copy number variants. This locus is notoriously difficult to genotype and high-throughput methods commonly used focus on only a few SNPs. We performed multiplex ligation-dependent probe amplification for all relevant genetic variations at the FCGR2/3 locus in >4,000 individuals to define linkage disequilibrium (LD) and allele frequencies in different populations. Strong LD and extensive ethnic variation in allele frequencies was found across the locus. LD was strongest for the FCGR2C-ORF haplotype (rs759550223+rs76277413), which leads to expression of FcγRIIc. In Europeans, the FCGR2C-ORF haplotype showed strong LD with, among others, rs201218628 (FCGR2A-Q27W, r 2 = 0.63). LD between these two variants was weaker (r 2 = 0.17) in Africans, whereas the FCGR2C-ORF haplotype was nearly absent in Asians (minor allele frequency <0.005%). The FCGR2C-ORF haplotype and rs1801274 (FCGR2A-H131R) were in weak LD (r 2 = 0.08) in Europeans. We evaluated the importance of ethnic variation and LD in Kawasaki Disease (KD), an acute vasculitis in children with increased incidence in Asians. An association of rs1801274 with KD was previously shown in ethnically diverse genome-wide association studies. Now, we show in 1,028 European KD patients that the FCGR2C-ORF haplotype, although nearly absent in Asians, was more strongly associated with susceptibility to KD than rs1801274 in Europeans. Our data illustrate the importance of interpreting findings of association studies concerning the FCGR2/3 locus with knowledge of LD and ethnic variation.
KW - FCGR polymorphism
KW - Fc-gamma receptor
KW - Immunogenetics
KW - Kawasaki disease (KD)
KW - Linkage disequilibrium
UR - http://www.scopus.com/inward/record.url?scp=85064324604&partnerID=8YFLogxK
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85064324604&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30949161
U2 - https://doi.org/10.3389/fimmu.2019.00185
DO - https://doi.org/10.3389/fimmu.2019.00185
M3 - Article
C2 - 30949161
SN - 1664-3224
VL - 10
SP - 185
JO - Frontiers in immunology
JF - Frontiers in immunology
IS - MAR
M1 - 185
ER -