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dc.contributor.authorFernando, Michelle M. A
dc.contributor.authorStevens, Christine R.
dc.contributor.authorSabeti, Pardis Christine
dc.contributor.authorWalsh, Emily C
dc.contributor.authorMcWhinnie, Alasdair J. M
dc.contributor.authorShah, Anila
dc.contributor.authorGreen, Todd
dc.contributor.authorRioux, John D
dc.contributor.authorVyse, Timothy J
dc.contributor.authorGibson, Greg
dc.date.accessioned2010-09-30T14:15:40Z
dc.date.issued2007
dc.identifier.citationFernando, 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.issn1553-7390en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:4454176
dc.description.abstractThe 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.sponsorshipOrganismic and Evolutionary Biologyen_US
dc.language.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofdoi:10.1371/journal.pgen.0030192en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2065882/pdf/en_US
dash.licenseLAA
dc.titleIdentification of Two Independent Risk Factors for Lupus within the MHC in United Kingdom Familiesen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalPLoS Geneticsen_US
dash.depositing.authorSabeti, Pardis Christine
dc.date.available2010-09-30T14:15:40Z
dc.identifier.doi10.1371/journal.pgen.0030192*
dash.contributor.affiliatedSabeti, Pardis


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