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Article: Multipoint linkage analysis of a candidate gene locus in rheumatoid arthritis demonstrates significant evidence of linkage and association with the corticotropin-releasing hormone genomic region

TitleMultipoint linkage analysis of a candidate gene locus in rheumatoid arthritis demonstrates significant evidence of linkage and association with the corticotropin-releasing hormone genomic region
Authors
KeywordsChemicals And Cas Registry Numbers
Issue Date2000
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.interscience.wiley.com/jpages/0004-3591/
Citation
Arthritis And Rheumatism, 2000, v. 43 n. 8, p. 1673-1678 How to Cite?
AbstractObjective. Rheumatoid arthritis (RA) is the most common disabling autoimmune disease, affecting -1% of the population. The disease etiology is unknown, but it involves inflammation and immune dysregulation and is influenced by genetic variation at both HLA and other, as-yet-unidentified genetic loci. Corticotropin-releasing hormone (CRH; or corticotropin-releasing factor), a primary regulator of the hypothalamic-pituitary-adrenal axis and a key element in the response to stress and inflammation, is a strong candidate gene for RA. We examined the role of DNA variation across the region containing this gene in multicase families with RA. Methods. We genotyped fluorescently labeled simple tandem repeat genetic markers from chromosome 8q13 in 295 families with multiple cases of RA. Single-point and multipoint nonparametric linkage analysis and association analysis using transmission disequilibrium testing (TDT) were also used. Results. Single-point linkage analysis using a microsatellite within 30 kb of the CRH locus (CRH.PCR at position 8ql3) showed a significant excess of allele sharing in 295 United Kingdom RA families with at least 2 affected members (MapMaker/Sibs logarithm of odds [LOD] 1.4; P = 5.5 x 10 -3; mean identity by descent [ibd] sharing 55.9%). To provide a more detailed linkage map, a multipoint analysis was conducted with an additional 7 dinucleotide microsatellite markers (average heterozygosity 0.75) flanking the CRH locus. Significant linkage was detected over a 22-cM region between D8S285 and D8S530, with the maximum single-point LOD score of 1.77 at D8S1723 (MapMaker/Sibs P = 2.2 x 10 -3; mean ibd sharing 59.3%). Multipoint analysis showed strongest evidence for linkage at the same marker (multipoint LOD 1.78, P = 2.1 x 10 -3, mean ibd sharing 55.8%). TDT analysis showed significant association at the CRH locus (P = 2.6 x 10 -3). CRH has a sibling relative risk of 1.14, and contributes <10% to the sibling relative risk of RA. Conclusion. With the exception of HLA, this is the strongest evidence yet of a genetic locus that is both linked to and associated with RA, and provides an avenue for further genetic characterization and potentially novel therapeutic intervention.
Persistent Identifierhttp://hdl.handle.net/10722/91606
ISSN
2015 Impact Factor: 8.955
2015 SCImago Journal Rankings: 3.206
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorIp, WKen_HK
dc.contributor.authorLau, YLen_HK
dc.contributor.authorChan, SYen_HK
dc.contributor.authorMok, CCen_HK
dc.contributor.authorChan, Den_HK
dc.contributor.authorTong, KKen_HK
dc.contributor.authorLau, CSen_HK
dc.date.accessioned2010-09-17T10:22:06Z-
dc.date.available2010-09-17T10:22:06Z-
dc.date.issued2000en_HK
dc.identifier.citationArthritis And Rheumatism, 2000, v. 43 n. 8, p. 1673-1678en_HK
dc.identifier.issn0004-3591en_HK
dc.identifier.urihttp://hdl.handle.net/10722/91606-
dc.description.abstractObjective. Rheumatoid arthritis (RA) is the most common disabling autoimmune disease, affecting -1% of the population. The disease etiology is unknown, but it involves inflammation and immune dysregulation and is influenced by genetic variation at both HLA and other, as-yet-unidentified genetic loci. Corticotropin-releasing hormone (CRH; or corticotropin-releasing factor), a primary regulator of the hypothalamic-pituitary-adrenal axis and a key element in the response to stress and inflammation, is a strong candidate gene for RA. We examined the role of DNA variation across the region containing this gene in multicase families with RA. Methods. We genotyped fluorescently labeled simple tandem repeat genetic markers from chromosome 8q13 in 295 families with multiple cases of RA. Single-point and multipoint nonparametric linkage analysis and association analysis using transmission disequilibrium testing (TDT) were also used. Results. Single-point linkage analysis using a microsatellite within 30 kb of the CRH locus (CRH.PCR at position 8ql3) showed a significant excess of allele sharing in 295 United Kingdom RA families with at least 2 affected members (MapMaker/Sibs logarithm of odds [LOD] 1.4; P = 5.5 x 10 -3; mean identity by descent [ibd] sharing 55.9%). To provide a more detailed linkage map, a multipoint analysis was conducted with an additional 7 dinucleotide microsatellite markers (average heterozygosity 0.75) flanking the CRH locus. Significant linkage was detected over a 22-cM region between D8S285 and D8S530, with the maximum single-point LOD score of 1.77 at D8S1723 (MapMaker/Sibs P = 2.2 x 10 -3; mean ibd sharing 59.3%). Multipoint analysis showed strongest evidence for linkage at the same marker (multipoint LOD 1.78, P = 2.1 x 10 -3, mean ibd sharing 55.8%). TDT analysis showed significant association at the CRH locus (P = 2.6 x 10 -3). CRH has a sibling relative risk of 1.14, and contributes <10% to the sibling relative risk of RA. Conclusion. With the exception of HLA, this is the strongest evidence yet of a genetic locus that is both linked to and associated with RA, and provides an avenue for further genetic characterization and potentially novel therapeutic intervention.en_HK
dc.languageengen_HK
dc.publisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.interscience.wiley.com/jpages/0004-3591/en_HK
dc.relation.ispartofArthritis and Rheumatismen_HK
dc.subjectChemicals And Cas Registry Numbersen_HK
dc.subject.meshAdulten_HK
dc.subject.meshAllelesen_HK
dc.subject.meshArthritis, Rheumatoid - geneticsen_HK
dc.subject.meshChilden_HK
dc.subject.meshCorticotropin-Releasing Hormone - geneticsen_HK
dc.subject.meshFalse Positive Reactionsen_HK
dc.subject.meshFamily Healthen_HK
dc.subject.meshFemaleen_HK
dc.subject.meshGenetic Linkageen_HK
dc.subject.meshGenetic Predisposition to Diseaseen_HK
dc.subject.meshHumansen_HK
dc.subject.meshLod Scoreen_HK
dc.subject.meshMaleen_HK
dc.subject.meshMicrosatellite Repeatsen_HK
dc.titleMultipoint linkage analysis of a candidate gene locus in rheumatoid arthritis demonstrates significant evidence of linkage and association with the corticotropin-releasing hormone genomic regionen_HK
dc.typeArticleen_HK
dc.identifier.emailLau, YL:lauylung@hkucc.hku.hken_HK
dc.identifier.emailChan, D:chand@hkucc.hku.hken_HK
dc.identifier.emailLau, CS:cslau@hku.hken_HK
dc.identifier.authorityLau, YL=rp00361en_HK
dc.identifier.authorityChan, D=rp00540en_HK
dc.identifier.authorityLau, CS=rp01348en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1002/1529-0131(200008)43:8<1673::AID-ANR2>3.0.CO;2-Yen_HK
dc.identifier.pmid10943856-
dc.identifier.scopuseid_2-s2.0-0033884253en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0033884253&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume43en_HK
dc.identifier.issue8en_HK
dc.identifier.spage1673en_HK
dc.identifier.epage1678en_HK
dc.identifier.isiWOS:000088659500002-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridIp, WK=35083568800en_HK
dc.identifier.scopusauthoridLau, YL=7201403380en_HK
dc.identifier.scopusauthoridChan, SY=7404255960en_HK
dc.identifier.scopusauthoridMok, CC=34668219600en_HK
dc.identifier.scopusauthoridChan, D=7402216545en_HK
dc.identifier.scopusauthoridTong, KK=7102473457en_HK
dc.identifier.scopusauthoridLau, CS=14035682100en_HK

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