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1.
Genes Immun ; 15(4): 210-7, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24598797

ABSTRACT

Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease affecting multiple organ systems and characterized by autoantibody formation to nuclear components. Although genetic variation within the major histocompatibility complex (MHC) is associated with SLE, its role in the development of clinical manifestations and autoantibody production is not well defined. We conducted a meta-analysis of four independent European SLE case collections for associations between SLE sub-phenotypes and MHC single-nucleotide polymorphism genotypes, human leukocyte antigen (HLA) alleles and variant HLA amino acids. Of the 11 American College of Rheumatology criteria and 7 autoantibody sub-phenotypes examined, anti-Ro/SSA and anti-La/SSB antibody subsets exhibited the highest number and most statistically significant associations. HLA-DRB1*03:01 was significantly associated with both sub-phenotypes. We found evidence of associations independent of MHC class II variants in the anti-Ro subset alone. Conditional analyses showed that anti-Ro and anti-La subsets are independently associated with HLA-DRB1*0301, and that the HLA-DRB1*03:01 association with SLE is largely but not completely driven by the association of this allele with these sub-phenotypes. Our results provide strong evidence for a multilevel risk model for HLA-DRB1*03:01 in SLE, where the association with anti-Ro and anti-La antibody-positive SLE is much stronger than SLE without these autoantibodies.


Subject(s)
Autoantibodies , HLA-DRB1 Chains , Lupus Erythematosus, Systemic/genetics , Models, Genetic , Autoantibodies/genetics , Autoantibodies/immunology , Europe , Female , HLA-DRB1 Chains/genetics , HLA-DRB1 Chains/immunology , Humans , Lupus Erythematosus, Systemic/immunology , Male
2.
Rheumatology (Oxford) ; 45(9): 1062-7, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16769771

ABSTRACT

Defining the polymorphisms that contribute to the development of complex genetic disease traits is a challenging, although increasingly tractable problem. Historically, the technical difficulties in conducting association studies across the entire human genome are such that murine models have been used to generate candidate genes for analysis in human complex diseases, such as SLE. In this article we discuss the advantages and disadvantages of this approach and specifically address some assumptions made in the transition from studying one species to another, using lupus as an example. These issues include differences in genetic structure and genetic organisation which are a reflection on the population history. Clearly there are major differences in the histories of the human population and inbred laboratory strains of mice. Both human and murine genomes do exhibit structure at the genetic level. That is to say, they comprise haplotypes which are genomic regions that carry runs of polymorphisms that are not independently inherited. Haplotypes therefore reduce the number of combinations of the polymorphisms in the DNA in that region and facilitate the identification of disease susceptibility genes in both mice and humans. There are now novel means of generating candidate genes in SLE using mutagenesis (with ENU) in mice and identifying mice that generate antinuclear autoimmunity. In addition, murine models still provide a valuable means of exploring the functional consequences of genetic variation. However, advances in technology are such that human geneticists can now screen large fractions of the human genome for disease associations using microchip technologies that provide information on upwards of 100,000 different polymorphisms. These approaches are aimed at identifying haplotypes that carry disease susceptibility mutations and rely less on the generation of candidate genes.


Subject(s)
Lupus Erythematosus, Systemic/genetics , Mice, Inbred NZB , Models, Animal , Polymorphism, Genetic , Animals , Genetic Predisposition to Disease , Genome , Haplotypes , Humans , Mice , Species Specificity
3.
Ann Rheum Dis ; 64(4): 524-7, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15769911

ABSTRACT

A century ago syphilis was regarded as the great masquerader. Its modern equivalent is lupus. It may present to a wide range of specialists and its outcome, while much improved, remains uncertain in a significant number of patients.


Subject(s)
Lupus Erythematosus, Systemic/diagnosis , Biomarkers/blood , Cardiovascular Diseases/etiology , Female , Health Status Indicators , Humans , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/rehabilitation , Male , Osteoporosis/etiology
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