A Functional Polymorphism in C3 is Associated with Worse CLAD-Free Survival

H. S. Kulkarni, L. K. Tague, D. R. Calabrese, J. Bajwa, B. Mittler, C. Chen, H. J. Huang, D. E. Byers, R. R. Hachem, D. Kreisel, C. A. Witt, J. R. Greenland, J. P. Atkinson, A. E. Gelman

Research output: Contribution to journalArticlepeer-review


PURPOSE: Excessive activation of the complement system has been associated with fibrosis and other adverse outcomes in multiple organ systems. We hypothesized that lung transplant (LTx) recipients with a genetic predisposition to complement activation would be at increased risk for chronic lung allograft dysfunction (CLAD). METHODS: We conducted a retrospective study of adult primary LTx recipients from 2008-2015 at Barnes-Jewish Hospital. Genotyping was done using the Taqman assay on salivary DNA for rs2230199, a known functional polymorphism (C3R102G, minor allele frequency (C)=15%), which is associated with more efficient complement activation on hemolysis assays. Our primary outcome was CLAD-free survival. Analysis included Kaplan-Meier curves with Chi-Square testing, and a multivariable Cox regression model for CLAD-free survival. External validation was conducted in LTx recipients at the University of California, San Francisco. RESULTS: 176 patients were included. 111 (63%) had wild-type C3 (G/G), whereas 64 (36%) had the C3R102G polymorphism (57 - C/G, 7 - C/C). C3R102G was associated with increased risk for CLAD (HR 2.71, 95% CI 1.27 - 5.79, p= 0.01). There was no increased risk for primary graft dysfunction or acute cellular rejection. In a multivariable Cox-proportional hazards model including age, sex, race, LTx type, and pre-LTx diagnosis, C3R102G was associated with increased risk of the composite outcome (CLAD or death, Figure). In the validation cohort, C3R102G remained a significant risk factor for this composite outcome on multivariable analysis (n=322, aHR 1.5, 95% CI 1.03 - 2.2, p=0.03). In a subgroup analysis in both cohorts, C3R102G remained a significant risk factor for CLAD or death when accounting for age, lung allocation score, post-LTx Gram-negative infection and donor-specific antibodies. CONCLUSION: In two independent cohorts, recipient C3R102G risk alleles are associated with worse CLAD-free survival. These findings support a mechanistic link between complement activation and CLAD.

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine
  • Transplantation

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