{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T07:31:46Z","timestamp":1770276706306,"version":"3.49.0"},"reference-count":32,"publisher":"The Journal of Rheumatology","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Rheumatol"],"published-print":{"date-parts":[[2019,2]]},"abstract":"<jats:sec><jats:title>Objective.<\/jats:title><jats:p>Findings from previous genome-wide association studies indicated an association of the<jats:italic>NOTCH4<\/jats:italic>gene with systemic sclerosis (SSc). This is a followup study to fine-map exonic variants of<jats:italic>NOTCH4<\/jats:italic>in SSc.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods.<\/jats:title><jats:p>All exons of<jats:italic>NOTCH4<\/jats:italic>were sequenced and analyzed in a total of 1006 patients with SSc and 1004 controls of US white ancestry with the Ion Torrent system. Identified SSc-associated variants were confirmed with Sanger sequencing, and then examined in a Chinese Han cohort consisting of 576 patients with SSc and 574 controls. The<jats:italic>NOTCH4<\/jats:italic>variants were analyzed for association with SSc as a whole and with SSc clinical and autoantibody subtypes with and without the influence of specific HLA-class II alleles that had been previously identified as major genetic factors in SSc.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results.<\/jats:title><jats:p>A total of 12 SSc-associated and SSc subtype\u2013associated exonic variants of<jats:italic>NOTCH4<\/jats:italic>were identified in the US cohort. Three of them are nonsynonymous single-nucleotide polymorphisms and 1 is a CTG tandem repeat that encodes for a poly-leucine, all of which are located in the<jats:italic>NOTCH4<\/jats:italic>extracellular domain (NECD). Conditional logistic regression analysis on SSc-associated HLA-class II alleles indicated an independent association of the<jats:italic>NOTCH4<\/jats:italic>variants with SSc autoantibody subtypes. Analysis of the Chinese cohort supported a genetic contribution of<jats:italic>NOTCH4<\/jats:italic>to SSc and its subtypes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion.<\/jats:title><jats:p>Multiple<jats:italic>NOTCH4<\/jats:italic>exonic variants were associated with SSc and\/or SSc subtypes. Several of these variants encode nonsynonymous sequence changes occurring in the NECD, which implicates a potentially functional effect of<jats:italic>NOTCH4<\/jats:italic>.<\/jats:p><\/jats:sec>","DOI":"10.3899\/jrheum.180094","type":"journal-article","created":{"date-parts":[[2018,11,15]],"date-time":"2018-11-15T12:23:09Z","timestamp":1542284589000},"page":"184-189","source":"Crossref","is-referenced-by-count":8,"title":["Associations of Multiple<i>NOTCH4<\/i>Exonic Variants with Systemic Sclerosis"],"prefix":"10.3899","volume":"46","author":[{"given":"Xiaodong","family":"Zhou","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongye","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shicheng","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiucun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunhua","family":"Shi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maribel","family":"Espitia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinjian","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qingwen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengyuan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shervin","family":"Assassi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John D.","family":"Reveille","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maureen D.","family":"Mayes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"2262","published-online":{"date-parts":[[2018,11,15]]},"reference":[{"key":"2019020109251866000_46.2.184.1","unstructured":"Medsger TA . 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