CONCISE COMMUNICATION Interferon lambda 3/4 polymorphisms are associated with AIDS-related Kaposi’s sarcoma Stephanie Biberta, Agnieszka Wojtowicz a, Patrick Taffeb, Philip E. Tarrc, Enos Bernasconid, Hansjakob Furrere, f,g h i 11/22/2018 on BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3KirptPALrnDi+TL0TbiLtNhRYG30LMgOhEYax8qRJms= by https://journals.lww.com/aidsonline from Downloaded Downloaded Huldrych F. Gu¨nthard , Matthias Hoffmann , Laurent Kaiser , j k,l a from Michael Osthoff , Jacques Fellay , Matthias Cavassini , https://journals.lww.com/aidsonline M Pierre-Yves Bochuda, the Swiss HIV Cohort Study Background: Kaposi’s sarcoma, the most common AIDS-related cancer, represents a major public concern in resource-limited countries. Single nucleotide polymorphisms by within the Interferon lambda 3/4 region (IFNL3/4) determine the expression, function of BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3KirptPALrnDi+TL0TbiLtNhRYG30LMgOhEYax8qRJms= 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 ¼ 0.01 and 16 versus 10%, P ¼ 0.009, respectively). Diplotypes predicted to produce the active P70 form (cumu- lative incidence 16 versus 10%, P ¼ 0.01) but not the less active S70 (cumulative incidence 11 versus 10%, P ¼ 0.7) form of IFNL4 were associated with an increased risk of Kaposi’s sarcoma, compared with those predicted not to produce IFNL4. The | downloaded: 23.9.2021 associations remained significant in a multivariate Cox regression model after adjust- ment for age at infection, combination antiretroviral therapy, median CD4þ T-cell count aInfectious Diseases Service, Department of Medicine, bInstitute for Social and Preventive Medicine, University (IUMSP), Lausanne University Hospital, Lausanne, cDepartment of Medicine, Kantonspital Baselland, University of Basel, Bruderholz, on d e 11/22/2018 Division of Infectious diseases, Regional hospital of Lugano, Lugano, Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, fDivision of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, gInstitute of Medical Virology, University of Zurich, Zurich, hDivision of Infectious Diseases and Hospital Epidemiology, Department of Internal Medicine, Cantonal Hospital St. Gallen, St. Gallen, iLaboratory of Virology, Division of Infectious Diseases and Division of Laboratory Medicine, University Hospital of Geneva and Medical School, University of Geneva, Geneva, jDivision of Infectious Diseases and Hospital Epidemiology and Department of Internal Medicine, University Hospital Basel, Basel, kGlobal Health Institute, School of Life Sciences, Ecole Polytechnique Fed erale de Lausanne, and lPrecision Medicine unit, Lausanne University Hospital, Lausanne, Switzerland. Correspondence to Pierre-Yves Bochud, MD, Infectious Diseases Service, CHUV, Rue du Bugnon 46, 1011 Lausanne, Switzerland. Tel: +41 21 314 10 26; fax: +41 21 314 40 60; e-mail: [email protected] Ã Members of the Swiss HIV Cohort Study group are listed in the appendix. https://doi.org/10.7892/boris.121810 Received: 29 May 2018; accepted: 12 August 2018. DOI:10.1097/QAD.0000000000002004 source: ISSN 0269-9370 Copyright Q 2018 Wolters Kluwer Health, Inc. All rights reserved. 2759 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. 2760 AIDS 2018, Vol 32 No 18 nadir and CD4þ slopes (hazard ratio 1.42, 95% confidence interval 1.06–1.89, P ¼ 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. Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved. AIDS 2018, 32:2759–2765 Keywords: AIDS, HIV, interferon lambda 3, immunogenetics, Kaposi’s sarcoma, polymorphism Introduction other candidate genes (e.g. MHC-related or cytokines/ chemokines-related genes) were associated with Kaposi’s Kaposi’s sarcoma was initially described by Moritz Kaposi sarcoma in studies of AIDS patients [31,33–35] and two [1] in 1872 as a rare and relatively indolent angiopro- studies including patients with the classical form of liferative neoplasm affecting elderly men from countries Kaposi’s sarcoma [36,37]. surrounding the Mediterranean Sea (classical form of Kaposi’s sarcoma). Another form was described in sub- Single nucleotide polymorphisms (SNPs) in the region Saharan Africa in the 1950s, which affects middle aged encoding for interferon lambda 3 (IFNL3 previously adults and children (endemic form of Kaposi’s sarcoma) named IL-28B) and interferon lambda 4 (IFNL4) [2]. In 1981, a potentially fatal form of Kaposi’s sarcoma represent major factors in the ability of individuals to was described among young homosexual men as a clear hepatitis C virus (HCV) [38–41]. They determine characteristic feature of the AIDS epidemics (epidemic different haplotypic combinations (diplotypes) based on form of Kaposi’s sarcoma), a population in which it still their capacity to produce IFNL4, that is, no production represents one of the most common AIDS-related cancer versus production as an active P70 or less active S70 form [3–8]. An invasive form can also affect patients with non- [42–44]. IFNL3/4 SNPs are increasingly known to AIDS immune suppression, in particular, solid organ influence the susceptibility to or the clinical course of transplant (SOT) recipients (iatrogenic form of Kaposi’s infections due to viruses other than HCV, including sarcoma, reviewed in [2]). herpes viruses such as cytomegalovirus (CMV) and Epstein–Barr virus (EBV) [45–47]. Here, we hypothe- Although the four epidemiological forms of Kaposi’s size that IFNL3/4 polymorphisms influence the risk of sarcoma share the same histological characteristics [9] and AIDS patients to develop Kaposi’s sarcoma. are all subsequent to human herpes virus 8 (HHV-8) infection [10,11], the development of distinct clinical features seems to rely on a combination of host and environmental factors. Although HIV-related or drug- Material and methods related immune suppression is inherent to the epidemic and iatrogenic forms (AIDS and SOT), genetic predis- Study patients position may be required for the classical (Mediterranean The Swiss HIV Cohort Study (SHCS) is an ongoing and Jewish ancestry) [12–14] and endemic forms (sub- multicenter prospective study of HIV-infected patients Saharan Africa) [15]. Hormonal factors [16–19] have enrolled at seven major Swiss hospitals and their local been proposed to explain the male predominance of all affiliated centers since 1988 [48]. For the present study, forms of Kaposi sarcoma. Environmental conditions Caucasian MSM with available DNA for genotyping and relative to potential routes of infection (soil, animal a written informed consent for genetic studies were vectors) have been proposed to influence susceptibility to included. In order to account for the time at risk, only different forms of Kaposi’s sarcoma [20–25]. Although patients with an estimated date of HIV infection were viral factors may influence clinical presentation, evidence selected [49]. Demographic characteristics including age, for a definite link between a specific subtype strain and a duration of HIV infection, CD4þ T-cell count nadir, Kaposi’s sarcoma type is still lacking [26–29]. other opportunistic infections, HIV maximal viral load and HAART use were extracted from the SHCS clinical Several investigators have analyzed the role of host genetic database. Kaposi’s sarcoma was defined according to factors in susceptibility to Kaposi’s sarcoma within a given predefined clinical and histological criteria. population at risk. The most relevant was a polymor- phism within the IL-6 promoter, which was consistently Single nucleotide polymorphism genotyping more frequent among Kaposi’s sarcoma patients versus Genomic DNA isolated either from blood or cell pellets controls in two cohorts of AIDS patients [30,31] and a was genotyped for haplotype tagging SNPs rs8099917 small cohort of SOT patients [32]. Polymorphisms in and rs12980275 using a customized GoldenGate Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. IFNL3/4 polymorphism and Kaposi’s sarcoma Bibert et al. 2761 Genotyping Assay on Veracode platform (Illumina , San (a) rs12980275 Diego, California, USA). These SNPs were used as 0.20 surrogates for rs368234815 and rs117648444, respec- 0.18 A/G or G/G, P=0.01 tively, based on previously published linkage disequilib- 0.16 0.14 rium (LD) values, which were shown to determine the 0.12 three main diplotypic forms of IFNL4. 0.10 0.08 A/A, reference 0.06 Probability of KSA 0.04 Statistical analysis 0.02 Statistical analyses were performed using Stata (version 0.00 14.2, StataCorp LP, College Station, Texas, USA). 0 6 12 18 24 Years from HIV infection Hardy–Weinberg equilibrium (HWE) was verified using Number at