研究者发现白癫风易感基因

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Researchers indentify susceptibility gene for vitiligo

Dec 1, 2007
By:Cheryl Guttman
Dermatology Times （皮肤科时讯）


Dr. Spritz

Aurora, Colo. — DNA sequence variants of NALP1 (NACHT leucine-rich-repeat protein 1) on chromosome 17 appear to be associated with genetic susceptibility to vitiligo and other autoimmune diseases. This finding suggests a pathogenic role of the innate immune system in the development of those disorders, and possibly new targets for therapy and prevention, says Richard A. Spritz, M.D.

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.

With advances in technology allowing genetic association studies and large-scale DNA sequencing, we have now been able to pinpoint a specific gene,\" says Dr. Spritz, professor and director, Human Medical Genetics Program, University of Colorado at Denver and Health Sciences Center, Aurora.

Gene involvement

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.

Risk factors

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.

\"NALP1 controls two major pathways. One is an inflammatory pathway that may be involved in initiating the immune response, and the other regulates cellular apoptosis that may also play a role in autoimmunity,\" he explains.

Dr. Spritz postulates that NALP1 could be involved in initiating the inflammatory response and/or cell apoptosis following exposure to some environmental trigger, and research is under way to elucidate the underlying cellular mechanisms. If it turns out NALP1 mediates its pathogenic function principally via heightening the inflammatory pathway, that could suggest new approaches for treating vitiligo by use of agents that downregulate those pathways.

\"There are drugs already on the market or in development pipelines that block the inflammatory pathways. Conceivably, these drugs might be used as adjuncts to UV irradiation therapy to improve clinical response. We hope to pursue that research as well,\" Dr. Spritz says.
美国科罗拉多州奥罗拉消息，位于人类第17号染色体上NALP1（NACHT富含亮氨酸重复序列型蛋白1）的DNA序列突变体似乎与遗传易感性白癜风和其他自身免疫性疾病有关。Richard A. Spritz博士说，这一研究结果表明，先天免疫系统紊乱的病人发育过程中，免疫系统也会扮演成病原引起机体发病，同时该研究也为治疗和预防这类疾病提供了潜在的治疗靶点。