Document resource
Introduction Mosaic Chromosomal Alterations (mCAs) increase with aging and associate with diverse disease risks, including various autoimmune diseases. A large-scale analysis of mCAs in systemic sclerosis (SSc) has not yet been conducted to date. Thus, we investigated the associations of mCAs with the susceptibility to SSc and its clinical subtypes.Material and Methods We analyzed age and sex-matched two independent Japanese datasets (Set 1: 633 SSc, 4,405 controls; Set 2: 346 SSc, 2,170 controls) and detected mCAs (Loss, LOH, Gain, and mLOX) based on SNP-array intensity data from peripheral blood samples. A logistic regression model adjusted for age and sex (except for mLOX) was applied to each cohort, and the results were meta-analyzed by an inverse-variance fixed-effect model. We also conducted stratified analyses by age groups and clinical phenotypes, including disease subsets (lcSSc, dcSSc), autoantibody status (ATA, ACA), and selected organ involvement (vascular complications (digital ulcers, pulmonary hypertension, or scleroderma renal crisis) [VC], interstitial lung disease [ILD]). Cell-fraction (CF)-dependence was tested using the CF threshold of 5%(CF>0.05).Results We found significant increase of autosomal loss (Loss) in SSc (OR = 1.87, P = 0.025), while mLOX tended to be decreased (OR = 0.79, P = 0.12). In particular, patients aged over 60 years presented significant associations with both Loss (OR = 2.58, P = 0.0092) and mLOX (OR = 0.58, P = 0.0050). Loss was increased in the subjects with lcSSc (OR = 2.28, P = 0.0082) but not with dcSSc, whereas mLOX was significantly decreased in dcSSc (OR = 0.26, P = 0.00050) but not in lcSSc. The same trends were observed in the stratified analyses based on subtype-specific autoantibodies. Loss was significantly increased in the subjects with VC (OR = 3.02, P = 0.0038), whereas mLOX was significantly decreased in the subjects with ILD (OR = 0.54, P = 0.022). Importantly, the associations with VC and ILD remained even after conditioning on the autoantibody status. Furthermore, we identified the CF-dependent associations of autosomal Loss with lcSSc and VC.Conclusions Our study showed that Loss and mLOX were significantly and differentially associated with SSc phenotypes, underscoring phenotype-enriched associations of mCA. These findings suggest mCAs as potential biomarkers of SSc, not only for the development of the disease, but also for better clinical management based on clinical phenotypes after the disease onset.Abstract P.003 Figure 1