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Unraveling the Genetic Predisposition to Systemic Lupus Erythematosus

A collection of studies and commentary focus on the identification of genetic defects associated with risk for SLE.

It has long been suggested that patients who develop systemic lupus erythematosus (SLE) have a genetically determined predisposition. Researchers have noted that deficiency of the second component of complement is associated with SLE and with subacute cutaneous lupus erythematosus (SCLE). SLE is, perhaps, not just one disease; it has manifestations in many organs, and prognosis and the mechanisms by which inflammation develops differ depending on the organ systems involved.

Four recent reports and two excellent editorials published in the New England Journal of Medicine and Nature Genetics link different genetic defects to increased risk for SLE. These studies relied on analysis of single nucleotide polymorphisms (SNPs) in patients with SLE. Each defect affects different parts of the inflammatory cascade, and all of these areas present opportunities for further research into disease mechanisms and directed therapies. See this table, which summarizes the study findings.

An excellent review of genetic and epidemiologic factors, autoantibodies, and mechanisms of inflammation associated with SLE appears in the same issue of the New England Journal of Medicine.

The editorial by Crow focuses on the function of proteins and where in the immune-inflammatory process abnormalities leading to excess inflammation might occur.

Maier and Hafler present photographs of different stages in one patient’s course and suggest that while the initial disease was SCLE, the subsequent disease was psoriasis. They do not note whether the patient had compatible biopsy samples (and I have seen SCLE patients with papulosquamous lesions that mimic psoriasis). Unraveling the nature of the inflammatory reaction in cutaneous manifestations of LE requires precise definition of the skin disease; unfortunately, we dermatologists have not yet been able to convince our colleagues in rheumatology and immunology that this task is more difficult than they believe.

Rahman and Isenberg observe that not all predisposed individuals (e.g., monozygotic twins) develop disease and, therefore, the search for environmental factors and the nature of the immune response must continue. They discuss the role of T cells, B cells, autoantigens, and cytokines in SLE-associated inflammatory reactions and conclude that pathogenic autoantibodies are the primary cause of tissue damage. They attribute the production of these antibodies to "complex mechanisms involving every key facet of the immune system."

Comment: The bottom line is that geneticists are just beginning to identify abnormalities in the human genome that will lead to better understanding of complex diseases, better delineation of disease mechanisms, eventual discovery of more effective therapies, and best of all, possible prevention.

— Jeffrey P. Callen, MD

Published in Journal Watch Dermatology February 27, 2008

Citation(s):

Hom G et al. Association of systematic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N Engl J Med 2008 Feb 28; 358:900.

• Original article (Subscription may be required)
• Medline abstract (Free)

Kozyrev SV et al. Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus. Nat Genet 2008 Feb; 40:211.

• Medline abstract (Free)

Nath SK et al. A nonsynonymous functional variant in integrin-_M (encoded by ITGAM) is associated with systemic lupus erythematosus. Nat Genet 2008 Feb; 40:152.

• Medline abstract (Free)

International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN). Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet 2008 Feb; 40:204.

• Medline abstract (Free)

Crow MK. Collaboration, genetic associations, and lupus erythematosus. N Engl J Med 2008 Feb 28; 358:956.

• Original article (Subscription may be required)
• Medline abstract (Free)

Maier LM and Hafler DA. The developing mosaic of autoimmune disease risk. Nat Genet 2008 Feb; 40:131.

• Medline abstract (Free)

Rahman A and Isenberg DA. Systematic lupus erythematosus. N Engl J Med 2008 Feb 28; 358:929.

• Original article (Subscription may be required)
• Medline abstract (Free)