Identification of Two Independent Risk Factors for Lupus within the MHC in United Kingdom Families

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Identification of Two Independent Risk Factors for Lupus within the MHC in United Kingdom Families

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dc.contributor.author Fernando, Michelle M. A
dc.contributor.author Walsh, Emily C
dc.contributor.author McWhinnie, Alasdair J. M
dc.contributor.author Shah, Anila
dc.contributor.author Green, Todd
dc.contributor.author Rioux, John D
dc.contributor.author Vyse, Timothy J
dc.contributor.author Gibson, Greg
dc.contributor.author Stevens, Christine R.
dc.contributor.author Sabeti, Pardis Christine
dc.date.accessioned 2010-09-30T14:15:40Z
dc.date.issued 2007
dc.identifier.citation Fernando, Michelle M. A, Christine R. Stevens, Pardis C. Sabeti, Emily C. Walsh, Alasdair J. M. McWhinnie, Anila Shah, Todd Green, John D. Rioux, Timothy J. Vyse, and Greg Gibson. 2007. Identification of Two Independent Risk Factors for Lupus within the MHC in United Kingdom Families. PLoS Genetics 3(11). en_US
dc.identifier.issn 1553-7390 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:4454176
dc.description.abstract The association of the major histocompatibility complex (MHC) with SLE is well established yet the causal variants arising from this region remain to be identified, largely due to inadequate study design and the strong linkage disequilibrium demonstrated by genes across this locus. The majority of studies thus far have identified strong association with classical class II alleles, in particular HLA-DRB1*0301 and HLA-DRB1*1501. Additional associations have been reported with class III alleles; specifically, complement C4 null alleles and a tumor necrosis factor promoter SNP (TNF-308G/A). However, the relative effects of these class II and class III variants have not been determined. We have thus used a family-based approach to map association signals across the MHC class II and class III regions in a cohort of 314 complete United Kingdom Caucasian SLE trios by typing tagging SNPs together with classical typing of the HLA-DRB1 locus. Using TDT and conditional regression analyses, we have demonstrated the presence of two distinct and independent association signals in SLE: HLA-DRB1*0301 (nominal p = 4.9 × 10−8, permuted p < 0.0001, OR = 2.3) and the T allele of SNP rs419788 (nominal p = 4.3 × 10−8, permuted p < 0.0001, OR = 2.0) in intron 6 of the class III region gene SKIV2L. Assessment of genotypic risk demonstrates a likely dominant model of inheritance for HLA-DRB1*0301, while rs419788-T confers susceptibility in an additive manner. Furthermore, by comparing transmitted and untransmitted parental chromosomes, we have delimited our class II signal to a 180 kb region encompassing the alleles HLA-DRB1*0301-HLA-DQA1*0501-HLA-DQB1*0201 alone. Our class III signal importantly excludes independent association at the TNF promoter polymorphism, TNF-308G/A, in our SLE cohort and provides a potentially novel locus for future genetic and functional studies. en_US
dc.description.sponsorship Organismic and Evolutionary Biology en_US
dc.language.iso en_US en_US
dc.publisher Public Library of Science en_US
dc.relation.isversionof doi:10.1371/journal.pgen.0030192 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2065882/pdf/ en_US
dash.license LAA
dc.title Identification of Two Independent Risk Factors for Lupus within the MHC in United Kingdom Families en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal PLoS Genetics en_US
dash.depositing.author Sabeti, Pardis Christine
dc.date.available 2010-09-30T14:15:40Z

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  • FAS Scholarly Articles [6463]
    Peer reviewed scholarly articles from the Faculty of Arts and Sciences of Harvard University

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