PT - JOURNAL ARTICLE 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 TI - Associations of Multiple <em>NOTCH4</em> Exonic Variants with Systemic Sclerosis AID - 10.3899/jrheum.180094 DP - 2018 Nov 15 TA - The Journal of Rheumatology PG - jrheum.180094 4099 - http://www.jrheum.org/content/early/2018/11/12/jrheum.180094.short 4100 - http://www.jrheum.org/content/early/2018/11/12/jrheum.180094.full AB - 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.