Stéphanie Bibert1, Agnieszka Wójtowicz1, Patrick Taffé2, Philip E Tarr3, Enos Bernasconi4, Hansjakob Furrer5, Huldrych F Günthard6,7, Matthias Hoffmann8, Laurent Kaiser9, Michael Osthoff10, Jacques Fellay11,12, Matthias Cavassini1, Pierre-Yves Bochud1. 1. Infectious Diseases Service, Department of Medicine. 2. Institute for Social and Preventive Medicine, University (IUMSP), Lausanne University Hospital, Lausanne. 3. Department of Medicine, Kantonspital Baselland, University of Basel, Bruderholz. 4. Division of Infectious diseases, Regional hospital of Lugano, Lugano. 5. Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern. 6. Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich. 7. Institute of Medical Virology, University of Zurich, Zurich. 8. Division of Infectious Diseases and Hospital Epidemiology, Department of Internal Medicine, Cantonal Hospital St. Gallen, St. Gallen. 9. Laboratory of Virology, Division of Infectious Diseases and Division of Laboratory Medicine, University Hospital of Geneva and Medical School, University of Geneva, Geneva. 10. Division of Infectious Diseases and Hospital Epidemiology and Department of Internal Medicine, University Hospital Basel, Basel. 11. Global Health Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne. 12. Precision Medicine unit, Lausanne University Hospital, Lausanne, Switzerland.
Abstract
BACKGROUND: Kaposi's sarcoma, the most common AIDS-related cancer, represents a major public concern in resource-limited countries. Single nucleotide polymorphisms within the Interferon lambda 3/4 region (IFNL3/4) determine the expression, function of IFNL4, and influence the clinical course of an increasing number of viral infections. OBJECTIVES: To analyze whether IFNL3/4 variants are associated with susceptibility to AIDS-related Kaposi's sarcoma among MSM enrolled in the Swiss HIV Cohort Study (SHCS). METHODS: The risk of developing Kaposi's sarcoma according to the carriage of IFNL3/4 SNPs rs8099917 and rs12980275 and their haplotypic combinations was assessed by using cumulative incidence curves and Cox regression models, accounting for relevant covariables. RESULTS: Kaposi's sarcoma was diagnosed in 221 of 2558 MSM Caucasian SHCS participants. Both rs12980275 and rs8099917 were associated with an increased risk of Kaposi's sarcoma (cumulative incidence 15 versus 10%, P = 0.01 and 16 versus 10%, P = 0.009, respectively). Diplotypes predicted to produce the active P70 form (cumulative incidence 16 versus 10%, P = 0.01) but not the less active S70 (cumulative incidence 11 versus 10%, P = 0.7) form of IFNL4 were associated with an increased risk of Kaposi's sarcoma, compared with those predicted not to produce IFNL4. The associations remained significant in a multivariate Cox regression model after adjustment for age at infection, combination antiretroviral therapy, median CD4+ T-cell count nadir and CD4+ slopes (hazard ratio 1.42, 95% confidence interval 1.06-1.89, P = 0.02 for IFLN P70 versus no IFNL4). CONCLUSION: This study reports for the first time an association between IFNL3/4 polymorphisms and susceptibility to AIDS-related Kaposi's sarcoma.
BACKGROUND:Kaposi's sarcoma, the most common AIDS-related cancer, represents a major public concern in resource-limited countries. Single nucleotide polymorphisms within the Interferon lambda 3/4 region (IFNL3/4) determine the expression, function of IFNL4, and influence the clinical course of an increasing number of viral infections. OBJECTIVES: To analyze whether IFNL3/4 variants are associated with susceptibility to AIDS-related Kaposi's sarcoma among MSM enrolled in the Swiss HIV Cohort Study (SHCS). METHODS: The risk of developing Kaposi's sarcoma according to the carriage of IFNL3/4 SNPs rs8099917 and rs12980275 and their haplotypic combinations was assessed by using cumulative incidence curves and Cox regression models, accounting for relevant covariables. RESULTS:Kaposi's sarcoma was diagnosed in 221 of 2558 MSM Caucasian SHCS participants. Both rs12980275 and rs8099917 were associated with an increased risk of Kaposi's sarcoma (cumulative incidence 15 versus 10%, P = 0.01 and 16 versus 10%, P = 0.009, respectively). Diplotypes predicted to produce the active P70 form (cumulative incidence 16 versus 10%, P = 0.01) but not the less active S70 (cumulative incidence 11 versus 10%, P = 0.7) form of IFNL4 were associated with an increased risk of Kaposi's sarcoma, compared with those predicted not to produce IFNL4. The associations remained significant in a multivariate Cox regression model after adjustment for age at infection, combination antiretroviral therapy, median CD4+ T-cell count nadir and CD4+ slopes (hazard ratio 1.42, 95% confidence interval 1.06-1.89, P = 0.02 for IFLN P70 versus no IFNL4). CONCLUSION: This study reports for the first time an association between IFNL3/4 polymorphisms and susceptibility to AIDS-related Kaposi's sarcoma.