TY - JOUR T1 - Associations of Multiple <em>NOTCH4</em> Exonic Variants with Systemic Sclerosis JF - The Journal of Rheumatology JO - J Rheumatol SP - 184 LP - 189 DO - 10.3899/jrheum.180094 VL - 46 IS - 2 AU - Xiaodong Zhou AU - Hongye Li AU - Shicheng Guo AU - Jiucun Wang AU - Chunhua Shi AU - Maribel Espitia AU - Xinjian Guo AU - Qingwen Wang AU - Mengyuan Liu AU - Shervin Assassi AU - John D. Reveille AU - Maureen D. Mayes Y1 - 2019/02/01 UR - http://www.jrheum.org/content/46/2/184.abstract N2 - Objective. Findings from previous genome-wide association studies indicated an association of the NOTCH4 gene with systemic sclerosis (SSc). This is a followup study to fine-map exonic variants of NOTCH4 in SSc.Methods. All exons of NOTCH4 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 NOTCH4 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.Results. A total of 12 SSc-associated and SSc subtype–associated exonic variants of NOTCH4 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 NOTCH4 extracellular domain (NECD). Conditional logistic regression analysis on SSc-associated HLA-class II alleles indicated an independent association of the NOTCH4 variants with SSc autoantibody subtypes. Analysis of the Chinese cohort supported a genetic contribution of NOTCH4 to SSc and its subtypes.Conclusion. Multiple NOTCH4 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 NOTCH4. ER -