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Research involving genetic linkage, genetic association and large scale DNA sequencing has led to the identification of NALP1 as a susceptibility gene for vitiligo and epidemiologically associated autoimmune/autoinflammatory diseases. NALP1 encodes a protein that is involved in the regulation of the innate immune system and apoptosis. Further research to define the pathogenic pathways could identify new targets for treatment and prevention of diseases associated with NALP1 variants
The finding was reported in the March 22, 2007, issue of the New England Journal of Medicine, and is the latest published development in a project started more than a decade ago to look for genetic risk factors for vitiligo and epidemiologically associated autoimmune/autoinflammatory disorders.
"When we initiated this research, we were limited to being able to identify chromosomal regions that contribute to disease risk by means of genetic linkage studies in affected families - the only approach then available.
Early research led Dr. Spritz and coworkers to determine that genes on chromosomes 1, 7, 8, 9 and 17 might be involved, and they published that work in a series of papers in 2002, 2003 and 2004. Their 2007 paper describes research focused on pinpointing a gene on chromosome 17.
"Chromosome 17 was particularly interesting because a lupus linkage signal that was specific to families with vitiligo had previously been localized to chromosome 17. When we looked for that disease juxtaposition in our vitiligo families, we found that involvement of chromosome 17 was specific to those families having various other autoimmune diseases, suggesting there was a vitiligo-autoimmune disease gene at that spot. Interestingly, this chromosome 17 linkage has not been seen in similar studies of vitiligo families done in China," Dr. Spritz tells Dermatology Times.
The investigations involved association analysis in the 51 families studied originally that showed linkage to chromosome 17. Further studies were then conducted using DNA collected from 323 members of 63 additional similar families. All of the families were white and from the United States, Canada or England, and they all had at least two members with generalized vitiligo and at least one with another autoimmune disease (autoimmune thyroid disease, latent autoimmune diabetes in adults, rheumatoid arthritis, psoriasis, pernicious anemia, systemic lupus erythematosus or Addison's disease). Investigators at St. George's University of London collaborated in the research.
After localizing the highest lod scores to the 17p13 region, the investigators genotyped 177 single-nucleotide polymorphisms across the linkage peak. NALP1 and its adjacent promoter region stood out strongly as the candidate gene. DNA-sequencing studies and refined-association mapping identified disease-risk-contributing variants that contribute to vitiligo or to an extended autoimmune/autoinflammatory disease phenotype.
"This research corroborates the original linkage analyses using a more refined, sophisticated methodology, " Dr. Spritz says.
Dr. Spritz and colleagues have since gone on to confirm the association between NALP1 and vitiligo in an independent set of vitiligo patients, and that research is the subject of a submitted manuscript.
Dr. Spritz notes that genetic risk associated with NALP1 is probably very common in the population, with a gradient of risk ranging from fairly low to fairly high. Also noteworthy is that the association is stronger in people with vitiligo plus at least one other autoimmune disease versus those with vitiligo alone.
"That finding suggests that while NALP1 may predispose principally to vitiligo, it is a risk factor for a variety of autoimmmune diseases," he says.
There appears to be good biologic plausibility to support NALP1 as a susceptibility factor for vitiligo and other autoimmune/autoinflammatory diseases.