Phenotype-specific associations of mosaic chromosomal alterations in systemic sclerosis

Mosaic chromosomal alterations (mCAs) increase with age and are associated with many diseases, including autoimmune diseases. The associations between mCAs and systemic sclerosis (SSc) and its clinical subtypes have not been explored.

We recruited study subjects from 2 independent datasets (set 1: 635 SSc, 4401 controls; set 2: 347 SSc, 2170 controls) and detected mCAs (loss, loss of heterozygosity [LOH], gain, and mosaic loss of the X chromosome [mLOX]) from their peripheral blood samples. Logistic regression analyses were conducted with covariates in each cohort, and the results were meta-analysed. We also conducted stratified analyses by age groups, the age at disease onset, clinical phenotypes based on the skin lesions, autoantibody profiles, and the presence of complications.

We observed a trend of increased loss in SSc, especially in old age (P = .0063). The association of loss was strengthened in certain subtypes of SSc, including lcSSc (odds ratio [OR] = 2.22, P = .019) and SSc with vascular complications (digital ulcers, pulmonary hypertension, or renal crisis; OR = 3.30, P = .0054). The effect sizes of Loss increased in patients with high cell fractions (CFs). We also observed that mLOX was significantly associated with SSc, limited cutaneous systemic sclerosis (lcSSc), and anticentromere antibody-positive systemic sclerosis (ACA-SSc) only for subjects with high CFs. mLOX was significantly associated with lcSSc and ACA-SSc even compared with dcSSc and ATA-SSc, respectively. These associations were consistently observed in each of the 2 datasets. Finally, we identified majority of the associations of Loss were mainly driven by SSc with late age at onset.

Loss and mLOX were significantly and differentially associated with SSc and its subtypes, underscoring potential phenotype-specific contributions of mCAs.