Abstract
Objective. Systemic sclerosis (SSc) is a systemic connective tissue disease caused by a genetic aberrant. The involvement of the copy number variations (CNV) in the pathogenesis of SSc is unclear. We tried to identify some CNV that are involved with the susceptibility to SSc.
Methods. A genome-wide CNV screening was performed in 20 patients with SSc. Five SSc-associated common CNV that included HLA-DRB5, HLA-DQA1, IRGM, CDC42EP3, and APOBEC3A/3B were identified from the screening and were then validated in 365 patients with SSc and 369 matched healthy controls.
Results. Three hundred forty-four CNV (140 gains and 204 losses) and 2 CNV hotspots (6q21.3 and 22q11.2) were found in the SSc genomes (covering 24.2 megabases), suggesting that CNV were ubiquitous in the SSc genome and played important roles in the pathogenesis of SSc. The high copy number of HLA-DQA1 was a significantly protective factor for SSc (OR 0.07, p = 2.99 × 10−17), while the high copy number of APOBEC3A/B was a significant risk factor (OR 3.45, p = 6.4 × 10−18), adjusted with sex and age. The risk prediction model based on genetic factors in logistic regression showed moderate prediction ability, with area under the curve = 0.80 (95% CI 0.77–0.83), which demonstrated that APOBEC3A/B and HLA-DQA1 were powerful biomarkers for SSc risk evaluation and contributed to the susceptibility to SSc.
Conclusion. CNV of HLA-DQA1 and APOBEC3A/B contribute to the susceptibility to SSc in a Chinese Han population.
- SYSTEMIC SCLEROSIS
- GENETIC PREDISPOSITION TO DISEASE
- HLA ANTIGENS
- COPY NUMBER VARIATION
- CASE-CONTROL STUDIES
Footnotes
Supported by research grants from the National Basic Research Program (2012CB944604), National Science Foundation of China (81270120, 81470254), International S&T Cooperation Program of China (2013DFA30870), the 111 Project (B13016), and the US National Institutes of Health (NIH) NIAID UO1, 1U01AI09090. The computations involved in this study were supported by Fudan University High-End Computing Center. Mr. Xiong was supported by Grant 1R01AR057120–01 and 1R01HL106034-01, from the NIH and the US National Heart, Lung, and Blood Institute.
- Accepted for publication January 26, 2016.