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

Fernando, Michelle M. A.; Stevens, Christine R.; Sabeti, Pardis C.; Walsh, Emily C.; McWhinnie, Alasdair J. M.; Shah, Anila; Green, Todd; Rioux, John D.; Vyse, Timothy J.
November 2007
PLoS Genetics;Nov2007, Vol. 3 Issue 11, pe192
Academic Journal
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 HLADRB1 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 x 10-8, permuted p < 0.0001, OR = 2.3) and the T allele of SNP rs419788 (nominal p = 4.3 x 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.


Related Articles

  • Haplotypic single nucleotide polymorphisms in the central MHC gene IKBL, a potential regulator of NF-κB function. Allcock, Richard J.N.; Baluchova, Katarina; Cheong, Karey Y.M.; Price, Patricia // Immunogenetics;Jan2001, Vol. 52 Issue 3/4, p289 

    Presents a study which focuses on the haplotypic single nucleotide polymorphisms in the central major histocompatibility complex gene IKBL. Potential the gene IKBL as a regulator of NF-kB function. Characterization of the exonic sequence of IKBL; Identification of a polymorphism of IKBL coding...

  • Novel polymorphisms and the definition of promoter ‘alleles’ of the tumor necrosis factor and lymphotoxin a loci: inclusion in HLA haplotypes. Posch, P. E.; Cruz, I.; Bradshaw, D.; Medhekar, B. A. // Genes & Immunity;Dec2003, Vol. 4 Issue 8, p547 

    Tumor necrosis factor (TNF) and lymphotoxin alpha (LTA) influence a variety of cellular responses and play a complex role in the immune response. Several single nucleotide polymorphisms (SNPs) have been reported in these major histocompatibility complex (MHC)-linked loci; however, a...

  • TNF and LTA Gene, Allele, and Extended HLA Haplotype Associations with Severe Dengue Virus Infection in Ethnic Thais. Vejbaesya, Sasijit; Luangtrakool, Panpimon; Luangtrakool, Komon; Kalayanarooj, Siripen; Vaughn, David W.; Endy, Timothy P.; Mammen, Mammen P.; Green, Sharone; Libraty, Daniel H.; Ennis, Francis A.; Rothman, Alan L.; Stephens, Henry A. F. // Journal of Infectious Diseases;5/15/2009, Vol. 199 Issue 10, p1442 

    Severe dengue virus (DENV) infection is characterized by a cascade of cytokine production, including the production of tumor necrosis factor-α (TNF-α) and lymphotoxin-α (LT-α). We have analyzed a variety of polymorphisms in the TNF and LTA genes of 435 ethnic Thais who had...

  • BoLA class I allele diversity and polymorphism in a herd of cattle. Babiuk, Shawn; Horseman, Benjamin; Chenhong Zhang; Bickis, Mik; Kusalik, Anthony; Schook, Lawrence B.; Abrahamsen, Mitchell S.; Pontarollo, Reno // Immunogenetics;Feb2007, Vol. 59 Issue 2, p167 

    Major histocompatibility complex class I genes are among the most polymorphic genes characterized. The high level of polymorphism is essential for generating host immune responses. In humans, three distinct genomic loci encode human leukocyte antigen (HLA) class I genes, allowing individuals to...

  • Defining genetic architecture of the populations in the Indian subcontinent: Impact of human leukocyte antigen diversity studies. Mehra, N. K. // Indian Journal of Human Genetics;Sep-Dec2010, Vol. 16 Issue 3, p105 

    The author explores the contributions of the human leukocyte antigen (HLA) and the major histocompatibility complex (MHC) to genetic polymorphism in Indian population. It traces back the history of India's cultural diversity, demography, and tribal customs dating back to ancient migration of the...

  • Understanding rheumatoid arthritis: Glossary of immunologic terms.  // Geriatrics;Jun1993, Vol. 48 Issue 6, p31 

    The article presents a glossary of immunologic terms understanding rheumatoid arthritis. Antigen presenting cell is a specialized type of cell, bearing cell surface class II major histocompatibility complex antigens, involved in processing and presentation of antigen to helper T cells. Tumor...

  • Generation of three-dimensional pannus-like tissues in vitro from single cell suspensions of synovial fluid cells from arthritis patients. Solomon, Samuel; Masilamani, Madhan; Mohanty, Subhasis; Schwab, Jörg E.; Boneberg, Eva-Maria; Illges, Harald // Rheumatology International;Mar2004, Vol. 24 Issue 2, p71 

    Using single cell suspensions from synovial fluid cells of arthritis patients, we observed differentiation of three-dimensional tissues in vitro. This new model of pannus-like tissue (PLT) might be useful to study pannus tissue formation and differentiation. In the PLT cultures, we observed two...

  • Associations of Tumor Necrosis Factor α and HLA Polymorphisms with Adult Dermatomyositis: Implications for a Unique Pathogenesis1. Werth, Victoria P.; Callen, Jeffrey P.; Ang, Gina; Sullivan, Kathleen E. // Journal of Investigative Dermatology;Sep2002, Vol. 119 Issue 3, p617 

    We recently reported that the -308A tumor necrosis factor α promoter polymorphism is associated with the photosensitive disorder subacute cutaneous lupus erythematosus and mediates an exaggerated tumor necrosis factor α response to ultraviolet B. We now sought to examine the association of...

  • Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects. Patsopoulos, Nikolaos A.; Barcellos, Lisa F.; Hintzen, Rogier Q.; Schaefer, Catherine; van Duijn, Cornelia M.; Noble, Janelle A.; Raj, Towfique; Gourraud, Pierre-Antoine; Stranger, Barbara E.; Oksenberg, Jorge; Olsson, Tomas; Taylor, Bruce V.; Sawcer, Stephen; Hafler, David A.; Carrington, Mary; De Jager, Philip L.; de Bakker, Paul I. W. // PLoS Genetics;Nov2013, Vol. 9 Issue 11, p1 

    The major histocompatibility complex (MHC) region is strongly associated with multiple sclerosis (MS) susceptibility. HLA-DRB1*15:01 has the strongest effect, and several other alleles have been reported at different levels of validation. Using SNP data from genome-wide studies, we imputed and...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics