NALP1 in Vitiligo-Associated Multiple Autoimmune Disease
Ying Jin, M.D., Ph.D., Christina M. Mailloux, B.S., Katherine Gowan, B.S., Sheri L. Riccardi, B.S., Greggory LaBerge, M.S., Dorothy C. Bennett, Ph.D., Pamela R. Fain, Ph.D., and Richard A. Spritz, M.D.
Background Autoimmune and autoinflammatory diseases involveinteractions between genetic risk factors and environmentaltriggers. We searched for a gene on chromosome 17p13 that contributesto a group of epidemiologically associated autoimmune and autoinflammatorydiseases. The group includes various combinations of generalizedvitiligo, autoimmune thyroid disease, latent autoimmune diabetesin adults, rheumatoid arthritis, psoriasis, pernicious anemia,systemic lupus erythematosus, and Addison's disease.
Methods We tested 177 single-nucleotide polymorphisms (SNPs)spanning the 17p13 linkage peak for association with diseaseand identified a strong candidate gene. We then sequenced DNAin and around the gene to identify additional SNPs. We carriedout a second round of tests of association using some of theseadditional SNPs, thus elucidating the association with diseasein the gene and its extended promoter region in fine detail.
Results Association analyses resulted in our identifying asa candidate gene NALP1, which encodes NACHT leucine-rich-repeatprotein 1, a regulator of the innate immune system. Fine-scaleassociation mapping with the use of DNA from affected familiesand additional SNPs in and around NALP1 showed an associationof specific variants with vitiligo alone, with an extended autoimmuneand autoinflammatory disease phenotype, or with both. Conditionallogistic-regression analysis of NALP1 SNPs indicated that atleast two variants contribute independently to the risk of disease.
Conclusions DNA sequence variants in the NALP1 region are associatedwith the risk of several epidemiologically associated autoimmuneand autoinflammatory diseases, implicating the innate immunesystem in the pathogenesis of these disorders.
Source Information
From the Human Medical Genetics Program (Y.J., C.M.M., K.G., S.L.R., G.L., P.R.F., R.A.S.) and the Barbara Davis Center for Childhood Diabetes (P.R.F.), University of Colorado at Denver and Health Sciences Center, Aurora; and the Division of Basic Medical Sciences, St. George's, University of London, London (D.C.B.).
Address reprint requests to Dr. Spritz at the Human Medical Genetics Program, University of Colorado at Denver and Health Sciences Center, P.O. Box 6511, Mailstop 8300, Aurora, CO 80045, or at richard.spritz{at}uchsc.edu.
Leitenberger, J. J., Cayce, R. L., Haley, R. W., Adams-Huet, B., Bergstresser, P. R., Jacobe, H. T.
(2009). Distinct Autoimmune Syndromes in Morphea: A Review of 245 Adult and Pediatric Cases. Arch Dermatol
145: 545-550
[Abstract][Full Text]
Mogensen, T. H.
(2009). Pathogen Recognition and Inflammatory Signaling in Innate Immune Defenses. Clin. Microbiol. Rev.
22: 240-273
[Abstract][Full Text]
Faustin, B., Chen, Y., Zhai, D., Negrate, G. L., Lartigue, L., Satterthwait, A., Reed, J. C.
(2009). Mechanism of Bcl-2 and Bcl-XL inhibition of NLRP1 inflammasome: Loop domain-dependent suppression of ATP binding and oligomerization. Proc. Natl. Acad. Sci. USA
106: 3935-3940
[Abstract][Full Text]
Netea, M. G., Nold-Petry, C. A., Nold, M. F., Joosten, L. A. B., Opitz, B., van der Meer, J. H. M., van de Veerdonk, F. L., Ferwerda, G., Heinhuis, B., Devesa, I., Funk, C. J., Mason, R. J., Kullberg, B. J., Rubartelli, A., van der Meer, J. W. M., Dinarello, C. A.
(2009). Differential requirement for the activation of the inflammasome for processing and release of IL-1{beta} in monocytes and macrophages. Blood
113: 2324-2335
[Abstract][Full Text]
Lord, C. A., Savitsky, D., Sitcheran, R., Calame, K., Wright, J. R., Ting, J. P.-Y., Williams, K. L.
(2009). Blimp-1/PRDM1 Mediates Transcriptional Suppression of the NLR Gene NLRP12/Monarch-1. J. Immunol.
182: 2948-2958
[Abstract][Full Text]
Bryan, N. B., Dorfleutner, A., Rojanasakul, Y., Stehlik, C.
(2009). Activation of Inflammasomes Requires Intracellular Redistribution of the Apoptotic Speck-Like Protein Containing a Caspase Recruitment Domain. J. Immunol.
182: 3173-3182
[Abstract][Full Text]
Taieb, A., Picardo, M.
(2009). Vitiligo. NEJM
360: 160-169
[Full Text]
Granell, M., Urbano-Ispizua, A., Pons, A., Arostegui, J. I., Gel, B., Navarro, A., Jansa, S., Artells, R., Gaya, A., Talarn, C., Fernandez-Aviles, F., Martinez, C., Rovira, M., Carreras, E., Rozman, C., Juan, M., Yague, J., Montserrat, E., Monzo, M.
(2008). Common variants in NLRP2 and NLRP3 genes are strong prognostic factors for the outcome of HLA-identical sibling allogeneic stem cell transplantation. Blood
112: 4337-4342
[Abstract][Full Text]
Anderson, M. S.
(2008). Update in Endocrine Autoimmunity. J. Clin. Endocrinol. Metab.
93: 3663-3670
[Abstract][Full Text]
Fahy, R. J., Exline, M. C., Gavrilin, M. A., Bhatt, N. Y., Besecker, B. Y., Sarkar, A., Hollyfield, J. L., Duncan, M. D., Nagaraja, H. N., Knatz, N. L., Hall, M., Wewers, M. D.
(2008). Inflammasome mRNA Expression in Human Monocytes during Early Septic Shock. Am. J. Respir. Crit. Care Med.
177: 983-988
[Abstract][Full Text]
Jeru, I., Duquesnoy, P., Fernandes-Alnemri, T., Cochet, E., Yu, J. W., Lackmy-Port-Lis, M., Grimprel, E., Landman-Parker, J., Hentgen, V., Marlin, S., McElreavey, K., Sarkisian, T., Grateau, G., Alnemri, E. S., Amselem, S.
(2008). Mutations in NALP12 cause hereditary periodic fever syndromes. Proc. Natl. Acad. Sci. USA
105: 1614-1619
[Abstract][Full Text]
Wilmanski, J. M., Petnicki-Ocwieja, T., Kobayashi, K. S.
(2008). NLR proteins: integral members of innate immunity and mediators of inflammatory diseases. J. Leukoc. Biol.
83: 13-30
[Abstract][Full Text]
(2007). A New Gene Linked to Vitiligo and Susceptibility to Autoimmune Disorders. Journal Watch Dermatology
2007: 1-1
[Full Text]
Gregersen, P. K.
(2007). Modern Genetics, Ancient Defenses, and Potential Therapies. NEJM
356: 1263-1266
[Full Text]
Previous
