{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:52:00Z","timestamp":1791298320229,"version":"4.1.0"},"reference-count":34,"publisher":"National Academy of Sciences","issue":"8","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2013,2,19]]},"abstract":"<jats:p>\n                    Nuclear localization leucine-rich-repeat protein 1 (NLRP1) is a key regulator of the innate immune system, particularly in the skin where, in response to molecular triggers such as pathogen-associated or damage-associated molecular patterns, the NLRP1 inflammasome promotes caspase-1\u2013dependent processing of bioactive interleukin-1\u03b2 (IL-1\u03b2), resulting in IL-1\u03b2 secretion and downstream inflammatory responses.\n                    <jats:italic>NLRP1<\/jats:italic>\n                    is genetically associated with risk of several autoimmune diseases including generalized vitiligo, Addison disease, type 1 diabetes, rheumatoid arthritis, and others. Here we identify a repertoire of variation in\n                    <jats:italic>NLRP1<\/jats:italic>\n                    by deep DNA resequencing. Predicted functional variations in\n                    <jats:italic>NLRP1<\/jats:italic>\n                    reside in several common high-risk haplotypes that differ from the reference by multiple nonsynonymous substitutions. The haplotypes that are high risk for disease share two substitutions, L155H and M1184V, and are inherited largely intact due to extensive linkage disequilibrium across the region. Functionally, we found that peripheral blood monocytes from healthy subjects homozygous for the predominant high-risk haplotype 2A processed significantly greater (\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.0001) amounts of the IL-1\u03b2 precursor to mature bioactive IL-1\u03b2 under basal (resting) conditions and in response to Toll-like receptor (TLR) agonists (TLR2 and TLR4) compared with monocytes from subjects homozygous for the reference haplotype 1. The increase in basal release was 1.8-fold greater in haplotype 2A monocytes, and these differences between the two haplotypes were consistently observed three times over a 3-mo period; no differences were observed for IL-1\u03b1 or TNF\u03b1.\n                    <jats:italic>NLRP1<\/jats:italic>\n                    RNA and protein levels were not altered by the predominant high-risk haplotype, indicating that altered function of the corresponding multivariant NLRP1 polypeptide predisposes to autoimmune diseases by activation of the NLRP1 inflammasome.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1222808110","type":"journal-article","created":{"date-parts":[[2013,2,4]],"date-time":"2013-02-04T23:29:25Z","timestamp":1360020565000},"page":"2952-2956","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":200,"title":["<i>NLRP1<\/i>\n                    haplotypes associated with vitiligo and autoimmunity increase interleukin-1\u03b2 processing via the NLRP1 inflammasome"],"prefix":"10.1073","volume":"110","author":[{"given":"Cecilia B.","family":"Levandowski","sequence":"first","affiliation":[{"name":"Human Medical Genetics and Genomics Program and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina M.","family":"Mailloux","sequence":"additional","affiliation":[{"name":"Human Medical Genetics and Genomics Program and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracey M.","family":"Ferrara","sequence":"additional","affiliation":[{"name":"Human Medical Genetics and Genomics Program and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Gowan","sequence":"additional","affiliation":[{"name":"Human Medical Genetics and Genomics Program and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songtao","family":"Ben","sequence":"additional","affiliation":[{"name":"Human Medical Genetics and Genomics Program and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Jin","sequence":"additional","affiliation":[{"name":"Human Medical Genetics and Genomics Program and"},{"name":"Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly K.","family":"McFann","sequence":"additional","affiliation":[{"name":"Colorado Biostatistics Consortium, Colorado School of Public Health, Aurora, CO 80045; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulene J.","family":"Holland","sequence":"additional","affiliation":[{"name":"Human Medical Genetics and Genomics Program and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela R.","family":"Fain","sequence":"additional","affiliation":[{"name":"Human Medical Genetics and Genomics Program and"},{"name":"Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045;"},{"name":"Barbara Davis Center for Childhood Diabetes, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles A.","family":"Dinarello","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Spritz","sequence":"additional","affiliation":[{"name":"Human Medical Genetics and Genomics Program and"},{"name":"Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2013,2,4]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/90935"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1006\/clin.1997.4412"},{"key":"e_1_3_3_3_2","first-page":"244","article-title":"On the constitutional and local effects of disease of the suprarenal capsules","volume":"2","author":"Addison T","year":"1855","unstructured":"T Addison, On the constitutional and local effects of disease of the suprarenal capsules. 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