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Article: Copy number, linkage disequilibrium and disease association in the FCGR locus

TitleCopy number, linkage disequilibrium and disease association in the FCGR locus
Authors
Issue Date2010
PublisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/
Citation
Human Molecular Genetics, 2010, v. 19 n. 16, p. 3282-3294 How to Cite?
AbstractThe response of a leukocyte to immune complexes (ICs) is modulated by receptors for the Fc region of IgG (FcγRs), and alterations in their affinity or function have been associated with risk of autoimmune diseases, including systemic lupus erythematosus (SLE). The low-affinity FcgR genomic locus is complex, containing regions of copy number variation (CNV) which can alter receptor expression and leukocyte responses to IgG. Combined paralogue ratio tests (PRTs) were used to distinguish three intervals within the FCGR locus which undergo CNV, and to determine FCGR gene copy number (CN). There were significant differences in FCGR3B and FCGR3A CNV profiles between Caucasian, East Asian and Kenyan populations. A previously noted association of low FCGR3B CN with SLE in Caucasians was supported [OR = 1.57 (1.08-2.27), P = 0.018], and replicated in Chinese [OR = 1.65 (1.25-2.18), P = 4 × 10 -4]. There was no association of FCGR3B CNV with vasculitis, nor with malarial or bacterial infection. Linkage disequilibrium (LD) between multi-allelic FCGR3B CNV and SLE-associated SNPs in the FCGR locus was defined for the first time. Despite LD between FCGR3B CNV and a variant in FcγRIIB (I232T) which abolishes inhibitory function, both reduced CN of FCGR3B and homozygosity of the FcγRIIB-232T allele were individually strongly associated with SLE risk. Thus CN of FCGR3B, which controls IC responses and uptake by neutrophils, and variations in FCGR2B, which controls factors such as antibody production and macrophage activation, are important in SLE pathogenesis. Further interpretations of contributions to pathogenesis by FcγRs must be made in the context of LD involving CNV regions. © The Author 2010. Published by Oxford University Press. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/125244
ISSN
2015 Impact Factor: 5.985
2015 SCImago Journal Rankings: 4.288
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Wellcome Trust083650/Z/07/Z
076934
081835
079895
National Institute for Health Research Cambridge Biomedical Research Centre
Shun Tak District Min Yuen Tong of Hong Kong
Funding Information:

H.A.N. is a Woolf Fisher Trust scholar, K.G.C.S. is a Lister Prize Fellow and L.C.W. is a Medical Research Council Clinical Training Fellow. This work was supported by the Wellcome Trust (programme grants 083650/Z/07/Z to K.G.C.S., grant 076934 to T.N.W. and 081835 to J.A.G.S.), and the National Institute for Health Research Cambridge Biomedical Research Centre. The Cambridge Institute for Medical Research is in receipt of a Wellcome Trust Strategic Award (Grant 079895). We also acknowledge a donation from Shun Tak District Min Yuen Tong of Hong Kong which helped in sample collection. Funding to pay the Open Access Charge was provided by a Wellcome trust grant to K.G.C.S. (083650/Z/07/Z).

References

 

DC FieldValueLanguage
dc.contributor.authorNiederer, HAen_HK
dc.contributor.authorWillcocks, LCen_HK
dc.contributor.authorRayner, TFen_HK
dc.contributor.authorYang, Wen_HK
dc.contributor.authorLau, YLen_HK
dc.contributor.authorWilliams, TNen_HK
dc.contributor.authorScott, JAGen_HK
dc.contributor.authorUrban, BCen_HK
dc.contributor.authorPeshu, Nen_HK
dc.contributor.authorDunstan, SJen_HK
dc.contributor.authorHien, TTen_HK
dc.contributor.authorPhu, NHen_HK
dc.contributor.authorPadyukov, Len_HK
dc.contributor.authorGunnarsson, Ien_HK
dc.contributor.authorSvenungsson, Een_HK
dc.contributor.authorSavage, COen_HK
dc.contributor.authorWatts, RAen_HK
dc.contributor.authorLyons, PAen_HK
dc.contributor.authorClayton, DGen_HK
dc.contributor.authorSmith, KGen_HK
dc.date.accessioned2010-10-31T11:19:38Z-
dc.date.available2010-10-31T11:19:38Z-
dc.date.issued2010en_HK
dc.identifier.citationHuman Molecular Genetics, 2010, v. 19 n. 16, p. 3282-3294en_HK
dc.identifier.issn0964-6906en_HK
dc.identifier.urihttp://hdl.handle.net/10722/125244-
dc.description.abstractThe response of a leukocyte to immune complexes (ICs) is modulated by receptors for the Fc region of IgG (FcγRs), and alterations in their affinity or function have been associated with risk of autoimmune diseases, including systemic lupus erythematosus (SLE). The low-affinity FcgR genomic locus is complex, containing regions of copy number variation (CNV) which can alter receptor expression and leukocyte responses to IgG. Combined paralogue ratio tests (PRTs) were used to distinguish three intervals within the FCGR locus which undergo CNV, and to determine FCGR gene copy number (CN). There were significant differences in FCGR3B and FCGR3A CNV profiles between Caucasian, East Asian and Kenyan populations. A previously noted association of low FCGR3B CN with SLE in Caucasians was supported [OR = 1.57 (1.08-2.27), P = 0.018], and replicated in Chinese [OR = 1.65 (1.25-2.18), P = 4 × 10 -4]. There was no association of FCGR3B CNV with vasculitis, nor with malarial or bacterial infection. Linkage disequilibrium (LD) between multi-allelic FCGR3B CNV and SLE-associated SNPs in the FCGR locus was defined for the first time. Despite LD between FCGR3B CNV and a variant in FcγRIIB (I232T) which abolishes inhibitory function, both reduced CN of FCGR3B and homozygosity of the FcγRIIB-232T allele were individually strongly associated with SLE risk. Thus CN of FCGR3B, which controls IC responses and uptake by neutrophils, and variations in FCGR2B, which controls factors such as antibody production and macrophage activation, are important in SLE pathogenesis. Further interpretations of contributions to pathogenesis by FcγRs must be made in the context of LD involving CNV regions. © The Author 2010. Published by Oxford University Press. All rights reserved.en_HK
dc.languageengen_HK
dc.publisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/en_HK
dc.relation.ispartofHuman Molecular Geneticsen_HK
dc.subject.meshAfrican Continental Ancestry Group - genetics-
dc.subject.meshGene Dosage-
dc.subject.meshGenetic Predisposition to Disease - ethnology - genetics-
dc.subject.meshLinkage Disequilibrium-
dc.subject.meshReceptors, IgG - genetics-
dc.titleCopy number, linkage disequilibrium and disease association in the FCGR locusen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0964-6906&volume=19&issue=6&spage=3282&epage=3294&date=2010&atitle=Copy+number,+linkage+disequilibrium+and+disease+association+in+the+FCGR+locusen_HK
dc.identifier.emailYang, W:yangwl@hkucc.hku.hken_HK
dc.identifier.emailLau, YL:lauylung@hkucc.hku.hken_HK
dc.identifier.authorityYang, W=rp00524en_HK
dc.identifier.authorityLau, YL=rp00361en_HK
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1093/hmg/ddq216en_HK
dc.identifier.pmid20508037-
dc.identifier.pmcidPMC2908468-
dc.identifier.scopuseid_2-s2.0-77955029498en_HK
dc.identifier.hkuros180157en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77955029498&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume19en_HK
dc.identifier.issue16en_HK
dc.identifier.spage3282en_HK
dc.identifier.epage3294en_HK
dc.identifier.isiWOS:000280280800015-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridNiederer, HA=24073463900en_HK
dc.identifier.scopusauthoridWillcocks, LC=24464597300en_HK
dc.identifier.scopusauthoridRayner, TF=12762835400en_HK
dc.identifier.scopusauthoridYang, W=23101349500en_HK
dc.identifier.scopusauthoridLau, YL=7201403380en_HK
dc.identifier.scopusauthoridWilliams, TN=35430527200en_HK
dc.identifier.scopusauthoridScott, JAG=7407334081en_HK
dc.identifier.scopusauthoridUrban, BC=7102326026en_HK
dc.identifier.scopusauthoridPeshu, N=7004438094en_HK
dc.identifier.scopusauthoridDunstan, SJ=7003855751en_HK
dc.identifier.scopusauthoridHien, TT=7005271267en_HK
dc.identifier.scopusauthoridPhu, NH=6701323673en_HK
dc.identifier.scopusauthoridPadyukov, L=6603725900en_HK
dc.identifier.scopusauthoridGunnarsson, I=7003730060en_HK
dc.identifier.scopusauthoridSvenungsson, E=6601974801en_HK
dc.identifier.scopusauthoridSavage, CO=25625574900en_HK
dc.identifier.scopusauthoridWatts, RA=7401740971en_HK
dc.identifier.scopusauthoridLyons, PA=7102522977en_HK
dc.identifier.scopusauthoridClayton, DG=35351466200en_HK
dc.identifier.scopusauthoridSmith, KG=7410186181en_HK
dc.identifier.citeulike7421526-

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