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1. Africa-specific human genetic variation near CHD1L associates with HIV-1 load

Author

McLaren, Paul J., Porreca, Immacolata, Iaconis, Gennaro, Mok, Hoi Ping, Mukhopadhyay, Subhankar, Karakoc, Emre, Cristinelli, Sara, Pomilla, Cristina, Bartha, István, Thorball, Christian W., Tough, Riley H., Angelino, Paolo, Kiar, Cher S., Carstensen, Tommy, Fatumo, Segun, Porter, Tarryn, Jarvis, Isobel, Skarnes, William C., Bassett, Andrew, DeGorter, Marianne K., Sathya Moorthy, Mohana Prasad, Tuff, Jeffrey F., Kim, Eun-Young, Walter, Miriam, Simons, Lacy M., Bashirova, Arman, Buchbinder, Susan, Carrington, Mary, Cossarizza, Andrea, De Luca, Andrea, Goedert, James J., Goldstein, David B., Haas, David W., Herbeck, Joshua T., Johnson, Eric O., Kaleebu, Pontiano, Kilembe, William, Kirk, Gregory D., Kootstra, Neeltje A., Kral, Alex H., Lambotte, Olivier, Luo, Ma, Mallal, Simon, Martinez-Picado, Javier, Meyer, Laurence, Miro, José M., Moodley, Pravi, Motala, Ayesha A., Mullins, James I., Nam, Kireem, Obel, Niels, Pirie, Fraser, Plummer, Francis A., Poli, Guido, Price, Matthew A., Rauch, Andri, Theodorou, Ioannis, Trkola, Alexandra, Walker, Bruce D., Winkler, Cheryl A., Zagury, Jean-François, Montgomery, Stephen B., Ciuffi, Angela, Hultquist, Judd F., Wolinsky, Steven M., Dougan, Gordon, Lever, Andrew M. L., Gurdasani, Deepti, Groom, Harriet, Sandhu, Manjinder S., and Fellay, Jacques

Published
2023
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3. Epigenetic ageing accelerates before antiretroviral therapy and decelerates after viral suppression in people with HIV in Switzerland: a longitudinal study over 17 years

Author

Schoepf, Isabella C, Esteban-Cantos, Andrés, Thorball, Christian W, Rodés, Berta, Reiss, Peter, Rodríguez-Centeno, Javier, Riebensahm, Carlotta, Braun, Dominique L, Marzolini, Catia, Seneghini, Marco, Bernasconi, Enos, Cavassini, Matthias, Buvelot, Hélène, Thurnheer, Maria Christine, Kouyos, Roger D, Fellay, Jacques, Günthard, Huldrych F, Arribas, José R, Ledergerber, Bruno, and Tarr, Philip E

Published
2023
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5. Author Correction: Africa-specific human genetic variation near CHD1L associates with HIV-1 load

Author

McLaren, Paul J., Porreca, Immacolata, Iaconis, Gennaro, Mok, Hoi Ping, Mukhopadhyay, Subhankar, Karakoc, Emre, Cristinelli, Sara, Pomilla, Cristina, Bartha, István, Thorball, Christian W., Tough, Riley H., Angelino, Paolo, Kiar, Cher S., Carstensen, Tommy, Fatumo, Segun, Porter, Tarryn, Jarvis, Isobel, Skarnes, William C., Bassett, Andrew, DeGorter, Marianne K., Sathya Moorthy, Mohana Prasad, Tuff, Jeffrey F., Kim, Eun-Young, Walter, Miriam, Simons, Lacy M., Bashirova, Arman, Buchbinder, Susan, Carrington, Mary, Cossarizza, Andrea, De Luca, Andrea, Goedert, James J., Goldstein, David B., Haas, David W., Herbeck, Joshua T., Johnson, Eric O., Kaleebu, Pontiano, Kilembe, William, Kirk, Gregory D., Kootstra, Neeltje A., Kral, Alex H., Lambotte, Olivier, Luo, Ma, Mallal, Simon, Martinez-Picado, Javier, Meyer, Laurence, Miro, José M., Moodley, Pravi, Motala, Ayesha A., Mullins, James I., Nam, Kireem, Obel, Niels, Pirie, Fraser, Plummer, Francis A., Poli, Guido, Price, Matthew A., Rauch, Andri, Theodorou, Ioannis, Trkola, Alexandra, Walker, Bruce D., Winkler, Cheryl A., Zagury, Jean-François, Montgomery, Stephen B., Ciuffi, Angela, Hultquist, Judd F., Wolinsky, Steven M., Dougan, Gordon, Lever, Andrew M. L., Gurdasani, Deepti, Groom, Harriet, Sandhu, Manjinder S., and Fellay, Jacques

Published
2023
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6. Author Correction: Increased prevalence of clonal hematopoiesis of indeterminate potential amongst people living with HIV

Author

Bick, Alexander G., Popadin, Konstantin, Thorball, Christian W., Uddin, Md Mesbah, Zanni, Markella V., Yu, Bing, Cavassini, Matthias, Rauch, Andri, Tarr, Philip, Schmid, Patrick, Bernasconi, Enos, Günthard, Huldrych F., Libby, Peter, Boerwinkle, Eric, McLaren, Paul J., Ballantyne, Christie M., Grinspoon, Steven, Natarajan, Pradeep, and Fellay, Jacques

Published
2022
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7. Increased prevalence of clonal hematopoiesis of indeterminate potential amongst people living with HIV

Author

Bick, Alexander G., Popadin, Konstantin, Thorball, Christian W., Uddin, Md Mesbah, Zanni, Markella V., Yu, Bing, Cavassini, Matthias, Rauch, Andri, Tarr, Philip, Schmid, Patrick, Bernasconi, Enos, Günthard, Huldrych F., Libby, Peter, Boerwinkle, Eric, McLaren, Paul J., Ballantyne, Christie M., Grinspoon, Steven, Natarajan, Pradeep, and Fellay, Jacques

Published
2022
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9. Using viral diversity to identify HIV-1 variants under HLA-dependent selection in a systematic viral genome-wide screen.

Author

Neuner-Jehle, Nadia, Zeeb, Marius, Thorball, Christian W., Fellay, Jacques, Metzner, Karin J., Frischknecht, Paul, Neumann, Kathrin, Leeman, Christine, Rauch, Andri, Stöckle, Marcel, Huber, Michael, Perreau, Matthieu, Bernasconi, Enos, Notter, Julia, Hoffmann, Matthias, Leuzinger, Karoline, Günthard, Huldrych F., Pasin, Chloé, and Kouyos, Roger D.

Subjects
HLA histocompatibility antigens, WHOLE genome sequencing, VIRAL load, IMMUNE recognition, VIRAL mutation
Abstract

The pathogenesis of HIV-1 infection is governed by a highly dynamic, time-dependent interaction between the host and the viral genome. In this study, we developed a novel systematic approach to assess the host-virus interaction, using average pairwise viral diversity as a proxy for time since infection, and applied this method to nearly whole viral genome sequences (n = 4,464), human leukocyte antigen (HLA) genotyping data (n = 1,044), and viral RNA load (VL) measurements during the untreated chronic phase (n = 829) of Swiss HIV Cohort Study participants. Our systematic genome-wide screen revealed for 98 HLA/viral-variant pairs a signature of immune-driven selection in the form of an HLA-dependent effect of infection time on the presence of HIV amino acid variants. Of these pairs, 12 were found to have an effect on VL. Furthermore, 28/58 pairs were validated by time-to-event analyses and 48/92 by computational HLA-epitope predictions. Our diversity-based approach allows a powerful and systematic investigation of the interaction between the virus and cellular immunity, revealing a notable subset of such interaction effects. From an evolutionary perspective, these observations underscore the complexity of HLA-mediated selection pressures on the virus that shape viral evolution and pathogenesis. Author summary: The intricate interplay between viruses and the human immune system is reflected in dynamic associations between the viral and the human genomes. These often take the form of escape dynamics, in which the virus acquires mutations that allow it to evade immune recognition. We developed a novel viral diversity-based method to screen for such interactions across the viral genome systematically and applied it to a unique dataset of HIV-1 sequences and human leukocyte antigen (HLA) variants. We could identify time-dependent interactions between 98 pairs of HLA and viral variants. Among these pairs, 12 were associated with the concentration of viral RNA, longitudinal time-to-event analyses confirmed 28, and 48 were consistent with computational predictions of viral peptide binding to HLA molecules. Our results highlight how the highly dynamic interaction between the viral genome and the immune system shapes viral evolution, and our approach offers new opportunities to systematically study such interactions from real-world cross-sectional data. [ABSTRACT FROM AUTHOR]

Published
2024
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10. Predicting type 2 diabetes risk before and after solid organ transplantation using polygenic scores in a Danish cohort

Author

dos Santos, Quenia, primary, Leung, Preston, additional, Thorball, Christian W., additional, Ledergerber, Bruno, additional, Fellay, Jacques, additional, MacPherson, Cameron R., additional, Hornum, Mads, additional, Terrones-Campos, Cynthia, additional, Rasmussen, Allan, additional, Gustafsson, Finn, additional, Perch, Michael, additional, Sørensen, Søren S., additional, Ekenberg, Christina, additional, Lundgren, Jens D., additional, Feldt‐Rasmussen, Bo, additional, and Reekie, Joanne, additional

Published
2023
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11. Host genomics of the HIV-1 reservoir size and its decay rate during suppressive antiretroviral treatment

Author

Thorball, Christian W., Borghesi, Alessandro, Bachmann, Nadine, Von Siebenthal, Chantal, Vongrad, Valentina, Turk, Teja, Neumann, Kathrin, Beerenwinkel, Niko, Bogojeska, Jasmina, Roth, Volker, Kok, Yik Lim, Parbhoo, Sonali, Wieser, Mario, Böni, Jürg, Perreau, Matthieu, Klimkait, Thomas, Yerly, Sabine, Battegay, Manuel, Rauch, Andri, Schmid, Patrick, Bernasconi, Enos, Cavassini, Matthias, Kouyos, Roger D., Günthard, Huldrych F., Metzner, Karin J., and Fellay, Jacques

Published
2020
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12. Genetic features and genomic targets of human KRAB-zinc finger proteins

Author

de Tribolet-Hardy, Jonas, primary, Thorball, Christian W., additional, Forey, Romain, additional, Planet, Evarist, additional, Duc, Julien, additional, Coudray, Alexandre, additional, Khubieh, Bara, additional, Offner, Sandra, additional, Pulver, Cyril, additional, Fellay, Jacques, additional, Imbeault, Michael, additional, Turelli, Priscilla, additional, and Trono, Didier, additional

Published
2023
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13. Autoantibodies neutralizing type I IFNs underlie West Nile virus encephalitis in ∼40% of patients

Author

Gervais, Adrian, primary, Rovida, Francesca, additional, Avanzini, Maria Antonietta, additional, Croce, Stefania, additional, Marchal, Astrid, additional, Lin, Shih-Ching, additional, Ferrari, Alessandro, additional, Thorball, Christian W., additional, Constant, Orianne, additional, Le Voyer, Tom, additional, Philippot, Quentin, additional, Rosain, Jérémie, additional, Angelini, Micol, additional, Pérez Lorenzo, Malena, additional, Bizien, Lucy, additional, Achille, Cristian, additional, Trespidi, Francesca, additional, Burdino, Elisa, additional, Cassaniti, Irene, additional, Lilleri, Daniele, additional, Fornara, Chiara, additional, Sammartino, José Camilla, additional, Cereda, Danilo, additional, Marrocu, Chiara, additional, Piralla, Antonio, additional, Valsecchi, Chiara, additional, Ricagno, Stefano, additional, Cogo, Paola, additional, Neth, Olaf, additional, Marín-Cruz, Inés, additional, Pacenti, Monia, additional, Sinigaglia, Alessandro, additional, Trevisan, Marta, additional, Volpe, Andrea, additional, Marzollo, Antonio, additional, Conti, Francesca, additional, Lazzarotto, Tiziana, additional, Pession, Andrea, additional, Viale, Pierluigi, additional, Fellay, Jacques, additional, Ghirardello, Stefano, additional, Aubart, Mélodie, additional, Ghisetti, Valeria, additional, Aiuti, Alessandro, additional, Jouanguy, Emmanuelle, additional, Bastard, Paul, additional, Percivalle, Elena, additional, Baldanti, Fausto, additional, Puel, Anne, additional, MacDonald, Margaret R., additional, Rice, Charles M., additional, Rossini, Giada, additional, Murray, Kristy O., additional, Simonin, Yannick, additional, Nagy, Anna, additional, Barzon, Luisa, additional, Abel, Laurent, additional, Diamond, Michael S., additional, Cobat, Aurélie, additional, Zhang, Shen-Ying, additional, Casanova, Jean-Laurent, additional, and Borghesi, Alessandro, additional

Published
2023
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16. Determinants of HIV-1 reservoir size and long-term dynamics during suppressive ART

Author

Bachmann, Nadine, von Siebenthal, Chantal, Vongrad, Valentina, Turk, Teja, Neumann, Kathrin, Beerenwinkel, Niko, Bogojeska, Jasmina, Fellay, Jaques, Roth, Volker, Kok, Yik Lim, Thorball, Christian W., Borghesi, Alessandro, Parbhoo, Sonali, Wieser, Mario, Böni, Jürg, Perreau, Matthieu, Klimkait, Thomas, Yerly, Sabine, Battegay, Manuel, Rauch, Andri, Hoffmann, Matthias, Bernasconi, Enos, Cavassini, Matthias, Kouyos, Roger D., Günthard, Huldrych F., Metzner, Karin J., and the Swiss HIV Cohort Study

Published
2019
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17. Association of a Polygenic Risk Score With Osteoporosis in People Living With HIV: The Swiss HIV Cohort Study

Author

Schwenke, Johannes M, Thorball, Christian W, Schoepf, Isabella C, Ryom, Lene, Hasse, Barbara, Lamy, Olivier, Calmy, Alexandra, Wandeler, Gilles, Marzolini, Catia; https://orcid.org/0000-0002-2312-7050, Kahlert, Christian R, Bernasconi, Enos, Kouyos, Roger D, Günthard, Huldrych F; https://orcid.org/0000-0002-1142-6723, Ledergerber, Bruno, Fellay, Jacques, Burkhalter, Felix, Tarr, Philip E; https://orcid.org/0000-0002-1488-5407, Swiss HIV Cohort Study, Schwenke, Johannes M, Thorball, Christian W, Schoepf, Isabella C, Ryom, Lene, Hasse, Barbara, Lamy, Olivier, Calmy, Alexandra, Wandeler, Gilles, Marzolini, Catia; https://orcid.org/0000-0002-2312-7050, Kahlert, Christian R, Bernasconi, Enos, Kouyos, Roger D, Günthard, Huldrych F; https://orcid.org/0000-0002-1142-6723, Ledergerber, Bruno, Fellay, Jacques, Burkhalter, Felix, Tarr, Philip E; https://orcid.org/0000-0002-1488-5407, and Swiss HIV Cohort Study

Abstract

BACKGROUND Bone mineral density (BMD) loss may be accelerated in people with HIV (PLWH). It is unknown whether a polygenic risk score (PRS) is associated with low BMD in PLWH. METHODS Swiss HIV Cohort Study participants of self-reported European descent underwent ≥2 per-protocol dual x-ray absorptiometry (DXA) measurements ≥2 years apart (2011-2020). Univariable and multivariable odds ratios (ORs) for DXA-defined osteoporosis were based on traditional and HIV-related risk factors and a genome-wide PRS built from 9413 single-nucleotide polymorphisms associated with low BMD in the general population. Controls were free from osteoporosis/osteopenia on all DXA measurements. RESULTS We included 438 participants: 149 with osteoporosis and 289 controls (median age, 53 years; 82% male, 95% with suppressed HIV RNA). Participants with unfavorable osteoporosis PRS (top vs bottom quintile) had univariable and multivariable-adjusted osteoporosis ORs of 4.76 (95% CI, 2.34-9.67) and 4.13 (1.86-9.18), respectively. For comparison, hepatitis C seropositivity, 5-year tenofovir disoproxil fumarate exposure, and parent history of hip fracture yielded univariable osteoporosis ORs of 2.26 (1.37-3.74), 1.84 (1.40-2.43), and 1.54 (0.82-2.9). CONCLUSIONS In PLWH in Switzerland, osteoporosis was independently associated with a BMD-associated PRS after adjustment for established risk factors, including exposure to tenofovir disoproxil fumarate.

Published
2023

18. Leukocyte Count and Coronary Artery Disease Events in People With Human Immunodeficiency Virus: A Longitudinal Study

Author

Avery, Emma F, Kleynhans, Julia N, Ledergerber, Bruno; https://orcid.org/0000-0002-6881-4401, Schoepf, Isabella C, Thorball, Christian W; https://orcid.org/0000-0002-6869-6943, Kootstra, Neeltje A, Reiss, Peter; https://orcid.org/0000-0001-7896-6428, Ryom, Lene, Braun, Dominique L; https://orcid.org/0000-0003-4036-1030, Thurnheer, Maria Christine; https://orcid.org/0000-0003-1357-0347, Marzolini, Catia; https://orcid.org/0000-0002-2312-7050, Seneghini, Marco, Bernasconi, Enos; https://orcid.org/0000-0002-9724-8373, Cavassini, Matthias; https://orcid.org/0000-0003-0933-7833, Buvelot, Hélène, Kouyos, Roger D; https://orcid.org/0000-0002-9220-8348, Fellay, Jacques; https://orcid.org/0000-0002-8240-939X, Günthard, Huldrych F; https://orcid.org/0000-0002-1142-6723, Tarr, Philip E; https://orcid.org/0000-0002-1488-5407, Swiss HIV Cohort Study, Avery, Emma F, Kleynhans, Julia N, Ledergerber, Bruno; https://orcid.org/0000-0002-6881-4401, Schoepf, Isabella C, Thorball, Christian W; https://orcid.org/0000-0002-6869-6943, Kootstra, Neeltje A, Reiss, Peter; https://orcid.org/0000-0001-7896-6428, Ryom, Lene, Braun, Dominique L; https://orcid.org/0000-0003-4036-1030, Thurnheer, Maria Christine; https://orcid.org/0000-0003-1357-0347, Marzolini, Catia; https://orcid.org/0000-0002-2312-7050, Seneghini, Marco, Bernasconi, Enos; https://orcid.org/0000-0002-9724-8373, Cavassini, Matthias; https://orcid.org/0000-0003-0933-7833, Buvelot, Hélène, Kouyos, Roger D; https://orcid.org/0000-0002-9220-8348, Fellay, Jacques; https://orcid.org/0000-0002-8240-939X, Günthard, Huldrych F; https://orcid.org/0000-0002-1142-6723, Tarr, Philip E; https://orcid.org/0000-0002-1488-5407, and Swiss HIV Cohort Study

Abstract

BACKGROUND: People with human immunodeficiency virus (HIV; PWH) have increased cardiovascular risk. Higher leukocyte count has been associated with coronary artery disease (CAD) events in the general population. It is unknown whether the leukocyte-CAD association also applies to PWH. METHODS: In a case-control study nested within the Swiss HIV Cohort Study, we obtained uni- and multivariable odds ratios (OR) for CAD events, based on traditional and HIV-related CAD risk factors, leukocyte count, and confounders previously associated with leukocyte count. RESULTS: We included 536 cases with a first CAD event (2000-2021; median age, 56 years; 87% male; 84% with suppressed HIV RNA) and 1464 event-free controls. Cases had higher latest leukocyte count before CAD event than controls (median [interquartile range], 6495 [5300-7995] vs 5900 [4910-7200]; P < .01), but leukocytosis (>11 000/µL) was uncommon (4.3% vs 2.1%; P = .01). In the highest versus lowest leukocyte quintile at latest time point before CAD event, participants had univariable CAD-OR = 2.27 (95% confidence interval, 1.63-3.15) and multivariable adjusted CAD-OR = 1.59 (1.09-2.30). For comparison, univariable CAD-OR for dyslipidemia, diabetes, and recent abacavir exposure were 1.58 (1.29-1.93), 2.19 (1.59-3.03), and 1.73 (1.37-2.17), respectively. Smoking and, to a lesser degree, alcohol and ethnicity attenuated the leukocyte-CAD association. Leukocytes measured up to 8 years before the event were significantly associated with CAD events. CONCLUSIONS: PWH in Switzerland with higher leukocyte counts have an independently increased risk of CAD events, to a degree similar to traditional and HIV-related risk factors.

Published
2023

19. Predicting type 2 diabetes risk before and after solid organ transplantation using polygenic scores in a Danish cohort

Author

dos Santos, Quenia, Leung, Preston, Thorball, Christian W., Ledergerber, Bruno, Fellay, Jacques, MacPherson, Cameron R., Hornum, Mads, Terrones-Campos, Cynthia, Rasmussen, Allan, Gustafsson, Finn, Perch, Michael, Sørensen, Søren S., Ekenberg, Christina, Lundgren, Jens D., Feldt-Rasmussen, Bo, Reekie, Joanne, dos Santos, Quenia, Leung, Preston, Thorball, Christian W., Ledergerber, Bruno, Fellay, Jacques, MacPherson, Cameron R., Hornum, Mads, Terrones-Campos, Cynthia, Rasmussen, Allan, Gustafsson, Finn, Perch, Michael, Sørensen, Søren S., Ekenberg, Christina, Lundgren, Jens D., Feldt-Rasmussen, Bo, and Reekie, Joanne

Abstract

Type 2 diabetes mellitus (T2DM) can be multifactorial where both genetics and environmental factors play a role. We aimed to investigate the use of polygenic risk scores (PRS) in the prediction of pre-transplant T2DM and post-transplant diabetes mellitus (PTDM) among solid organ transplant (SOT) patients. Using non-genetic risk scores alone; and the combination with PRS, separate logistic regression models were built and compared using receiver operator curves. Patients were assessed pre-transplant and in three post-transplant periods: 0-45, 46-365 and >365 days. A higher PRS was significantly associated with increased odds of pre-transplant T2DM. However, no improvement was observed for pre-transplant T2DM prediction when comparing PRS combined with non-genetic risk scores to using non-genetic risk scores alone. This was also true for predictions of PTDM in all three post-transplant periods. This study demonstrated that polygenic risk was only associated with the risk of T2DM among SOT recipients prior to transplant and not for PTDM. Combining PRS with a clinical model of non-genetic risk scores did not significantly improve the predictive ability, indicating its limited clinical utility in identifying patients at high risk for T2DM before transplantation, suggesting that non-genetic or different genetic factors may contribute to PTDM.

Published
2023

20. Plasma soluble urokinase-type plasminogen activator receptor level is independently associated with coronary microvascular function in patients with non-obstructive coronary artery disease

Author

Mekonnen, Girum, Corban, Michel T., Hung, Olivia Y., Eshtehardi, Parham, Eapen, Danny J., Al-Kassem, Hatem, Rasoul-Arzrumly, Emad, Gogas, Bill D., McDaniel, Michael C., Pielak, Tomasz, Thorball, Christian W., Sperling, Laurence, Quyyumi, Arshed A., and Samady, Habib

Published
2015
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21. Polygenic Risk Scores for Prediction of Subclinical Coronary Artery Disease in Persons Living With HIV: The Swiss HIV Cohort Study

Author

Schoepf, Isabella C, Thorball, Christian W, Kovari, Helen, Ledergerber, Bruno, Buechel, Ronny R, Calmy, Alexandra, Weber, Rainer, Kaufmann, Philipp A, Nkoulou, René, Schwenke, Johannes M, Braun, Dominique L, Fellay, Jacques, Tarr, Philip E, Swiss HIV Cohort Study, and University of Zurich

Subjects
10234 Clinic for Infectious Diseases, 610 Medicine & health, 10181 Clinic for Nuclear Medicine
Published
2023
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22. Epigenetic ageing accelerates before antiretroviral therapy and decelerates after viral suppression in people with HIV in Switzerland: a longitudinal study over 17 years

Author

Schoepf, Isabella C., Esteban-Cantos, Andres, Thorball, Christian W., Rodes, Berta, Reiss, Peter, Rodriguez-Centeno, Javier, Riebensahm, Carlotta, Braun, Dominique L., Marzolini, Catia, Seneghini, Marco, Bernasconi, Enos, Cavassini, Matthias, Buvelot, Helene, Thurnheer, Maria Christine, Kouyos, Roger D., Fellay, Jacques, Gunthard, Huldrych F., Arribas, Jose R., Ledergerber, Bruno, and Tarr, Philip E.

Subjects
Psychiatry and Mental health, Health (social science), age, telomere length, 610 Medicine & health, Geriatrics and Gerontology, Family Practice, infection
Abstract

Background Accelerated epigenetic ageing can occur in untreated HIV infection and is partially reversible with effective antiretroviral therapy (ART). We aimed to make a long-term comparison of epigenetic ageing dynamics in people with HIV during untreated HIV infection and during suppressive ART., Methods In this longitudinal study, conducted over 17 years in HIV outpatient clinics in Switzerland, we applied 5 established epigenetic age estimators (epigenetic clocks) in peripheral blood mononuclear cells (PBMCs) in Swiss HIV Cohort Study participants before or during suppressive ART. All participants had a longitudinal set of PBMC samples available at four timepoints (T1-T4). T1 and T2 had to be 3 years or longer apart, as did T3 and T4. We assessed epigenetic age acceleration (EAA) and a novel rate of epigenetic ageing., Findings Between March 13, 1990, and Jan 18, 2018, we recruited 81 people with HIV from the Swiss HIV Cohort Study. We excluded one participant because a sample did not meet quality checks (transmission error). 52 (65%) of 80 patients were men, 76 (95%) were white, and the median patient age was 43 (IQR 37 center dot 5-47) years. Per year of untreated HIV infection (median observation 8 center dot 08 years, IQR 4 center dot 83-11 center dot 09), mean EAA was 0 center dot 47 years (95% CI 0 center dot 37 to 0 center dot 57) for Horvath's clock, 0 center dot 43 years (0 center dot 3 to 0 center dot 57) for Hannum's clock, 0 center dot 36 years (0 center dot 27 to 0 center dot 44) for SkinBlood clock, and 0 center dot 69 years (0 center dot 51 to 0 center dot 86) for PhenoAge. Per year of suppressive ART (median observation 9 center dot 8 years, IQR 7 center dot 2-11), mean EAA was -0 center dot 35 years (95% CI -0 center dot 44 to -0 center dot 27) for Horvath's clock, -0 center dot 39 years (-0 center dot 50 to -0 center dot 27) for Hannum's clock, -0 center dot 26 years (-0 center dot 33 to -0 center dot 18) for SkinBlood clock, and -0 center dot 49 years (-0 center dot 64 to -0 center dot 35) for PhenoAge. Our findings indicate that people with HIV epigenetically aged by a mean of 1 center dot 47 years for Horvath's clock, 1 center dot 43 years for Hannum's clock, 1 center dot 36 years for SkinBlood clock, and 1 center dot 69 years for PhenoAge per year of untreated HIV infection; and 0 center dot 65 years for Horvath's clock, 0 center dot 61 years for Hannum's clock, 0 center dot 74 years for SkinBlood clock, and 0 center dot 51 years for PhenoAge, per year of suppressive ART. GrimAge showed some change in the mean EAA during untreated HIV infection (0 center dot 10 years, 0 center dot 02 to 0 center dot 19) and suppressive ART (-0 center dot 05 years, -0 center dot 12 to 0 center dot 02). We obtained very similar results using the rate of epigenetic ageing. Contribution of multiple HIV-related, antiretroviral, and immunological variables, and of a DNA methylation-associated polygenic risk score to EAA was small., Interpretation In a longitudinal study over more than 17 years, epigenetic ageing accelerated during untreated HIV infection and decelerated during suppressive ART, highlighting the importance of limiting the duration of untreated HIV infection.

Published
2023
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23. Leukocyte Count and Coronary Artery Disease Events in People with HIV: A Longitudinal Study

Author

Avery, Emma F, Kleynhans, Julia N, Ledergerber, Bruno, Schoepf, Isabella C, Thorball, Christian W, Kootstra, Neeltje A, Reiss, Peter, Ryom, Lene, Braun, Dominique L, Thurnheer, Maria C, Marzolini, Catia, Seneghini, Marco, Bernasconi, Enos, Cavassini, Matthias, Buvelot, Hélène, Kouyos, Roger D, Fellay, Jacques, Günthard, Huldrych F, and Tarr, Philip E

Subjects
610 Medizin und Gesundheit
Abstract

BACKGROUND People with HIV (PWH) have increased cardiovascular risk. Higher leukocyte count has been associated with coronary artery disease (CAD) events in the general population. It is unknown whether the leukocyte-CAD association also applies to PWH. METHODS In a case-control study nested within the Swiss HIV Cohort Study, we obtained uni- and multivariable odds ratios (OR) for CAD events, based on traditional and HIV-related CAD risk factors, leukocyte count, and confounders previously associated with leukocyte count. RESULTS We included 536 cases with a first CAD event (2000-2021; median age 56 years, 87% male, 84% with suppressed HIV-RNA) and 1464 event-free controls. Cases had higher latest leukocyte count prior to CAD event than controls (median [interquartile range], 6495 [5300-7995] vs. 5900 [4910-7200]; p 11000/uL) was uncommon (4.3% vs. 2.1%; p = 0.01). In the highest vs. lowest leukocyte quintile at latest time point prior to CAD event, participants had univariable CAD-OR = 2.27 (95% confidence interval, 1.63-3.15) and multivariable adjusted CAD-OR = 1.59 (1.09-2.30). For comparison, univariable CAD-OR for dyslipidemia, diabetes, and recent abacavir exposure were 1.58 (1.29-1.93), 2.19 (1.59-3.03), and 1.73 (1.37-2.17), respectively. Smoking and, to a lesser degree, alcohol and ethnicity attenuated the leukocyte-CAD association. Leukocytes measured up to 8 years pre-event were significantly associated with CAD events. CONCLUSIONS PWH in Switzerland with higher leukocyte counts have an independently increased risk of CAD events, to a degree similar to traditional and HIV-related risk factors.

Published
2023
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25. Combining European and U.S. risk prediction models with polygenic risk scores to refine cardiovascular prevention: the CoLaus|PsyCoLaus Study

Author

de La Harpe, Roxane, primary, Thorball, Christian W, additional, Redin, Claire, additional, Fournier, Stephane, additional, Müller, Olivier, additional, Strambo, Davide, additional, Michel, Patrik, additional, Vollenweider, Peter, additional, Marques-Vidal, Pedro, additional, Fellay, Jacques, additional, and Vaucher, Julien, additional

Published
2023
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27. Determinants of HIV-1 broadly neutralizing antibody induction

Author

Rusert, Peter, Kouyos, Roger D, Kadelka, Claus, Ebner, Hanna, Schanz, Merle, Huber, Michael, Braun, Dominique L, Hozé, Nathanael, Scherrer, Alexandra, Magnus, Carsten, Weber, Jacqueline, Uhr, Therese, Cippa, Valentina, Thorball, Christian W, Kuster, Herbert, Cavassini, Matthias, Bernasconi, Enos, Hoffmann, Matthias, Calmy, Alexandra, Battegay, Manuel, Rauch, Andri, Yerly, Sabine, Aubert, Vincent, Klimkait, Thomas, Böni, Jürg, Fellay, Jacques, Regoes, Roland R, Günthard, Huldrych F, Trkola, Alexandra, Bucher, Heiner C, Ciuffi, Angela, Dollenmaier, Günther, Egger, Matthias, Elzi, Luigia, Fehr, Jan, Furrer, Hansjakob, Fux, Christoph A, Haerry, David, Hasse, Barbara, Hirsch, Hans H, Hösli, Irene, Kahlert, Christian, Kaiser, Laurent, Keiser, Olivia, Kovari, Helen, Ledergerber, Bruno, Martinetti, Gladys, de Tejada, Begoña Martinez, Marzolini, Catia, Metzner, Karin J, Müller, Nicolas, Nicca, Dunja, Pantaleo, Giuseppe, Paioni, Paolo, Rudin, Christoph, Schmid, Patrick, Speck, Roberto, Stöckle, Marcel, Tarr, Philip, Vernazza, Pietro, Wandeler, Gilles, and Weber, Rainer

Subjects
Observations, Care and treatment, Development and progression, Host-virus relationships, HIV infections -- Development and progression -- Care and treatment, Antibodies -- Observations, Immune response -- Observations
Abstract

Author(s): Peter Rusert [1]; Roger D Kouyos [1, 2]; Claus Kadelka [1, 2]; Hanna Ebner [1]; Merle Schanz [1]; Michael Huber [1]; Dominique L Braun [1, 2]; Nathanael Hozé [3]; [...], Broadly neutralizing antibodies (bnAbs) are a focal component of HIV-1 vaccine design, yet basic aspects of their induction remain poorly understood. Here we report on viral, host and disease factors that steer bnAb evolution using the results of a systematic survey in 4,484 HIV-1-infected individuals that identified 239 bnAb inducers. We show that three parameters that reflect the exposure to antigen--viral load, length of untreated infection and viral diversity--independently drive bnAb evolution. Notably, black participants showed significantly (P = 0.0086-0.038) higher rates of bnAb induction than white participants. Neutralization fingerprint analysis, which was used to delineate plasma specificity, identified strong virus subtype dependencies, with higher frequencies of CD4-binding-site bnAbs in infection with subtype B viruses (P = 0.02) and higher frequencies of V2-glycan-specific bnAbs in infection with non-subtype B viruses (P = 1 x 10[sup.-5]). Thus, key host, disease and viral determinants, including subtype-specific envelope features that determine bnAb specificity, remain to be unraveled and harnessed for bnAb-based vaccine design.

Published
2016
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28. Variability of Primary Sjögren's Syndrome Is Driven by Interferon α and Interferon α Blood Levels Are Associated With the Class II HLA–DQ Locus

Author

Trutschel, Diana, Bost, Pierre, Mariette, Xavier, Bondet, Vincent, Llibre, Alba, Posseme, Celine, Charbit, Bruno, Thorball, Christian W., Jonsson, Roland, Lessard, Christopher J., Felten, Renaud, Ng, Wan Fai, Chatenoud, Lucienne, Dumortier, Hélène, Sibilia, Jean, Fellay, Jacques, Brokstad, Karl A., Appel, Silke, Tarn, Jessica R., Quintana‐Murci, Lluis, Mingueneau, Michael, Meyer, Nicolas, Duffy, Darragh, Schwikowski, Benno, Gottenberg, Jacques Eric, Dernis, Emmanuelle, Devauchelle‐Pensec, Valerie, Dieude, Philippe, Dubost, Jean‐Jacques, Fauchais, Anne‐Laure, Goeb, Vincent, Hachulla, Eric, Hatron, Pierre Yves, Larroche, Claire, Le Guern, Véronique, Morel, Jacques, Perdriger, Aleth, Salliot, Carinne, Rist, Stephanie, Saraux, Alain, Vittecoq, Olivier, Nocturne, Gaétane, Ravaud, Philippe, Seror, Raphaèle, Abel, Laurent, Alcover, Andres, Aschard, Hugues, Astrom, Kalla, Bousso, Philippe, Bruhns, Pierre, Cumano, Ana, Demangel, Caroline, Deriano, Ludovic, Di Santo, James, Dromer, Françoise, Eberl, Gérard, Enninga, Jost, Gelpi, Odile, GompertsBoneca, Ivo, Hasan, Milena, Hercberg, Serge, Lantz, Olivier, Leclerc, Claude, Mouquet, Hugo, Pellegrini, Sandra, Pol, Stanislas, Rausell, Antonio, Rogge, Lars, Sakuntabhai, Anavaj, Schwartz, Olivier, Shorte, Spencer, Soumelis, Vassili, Tangy, Frédéric, Tartour, Eric, Toubert, Antoine, Touvier, Mathilde, Ungeheuer, Marie‐Noëlle, Albert, Matthew L., Biomédecine computationelle des systèmes / Computational systems biomedicine, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Universität Zürich [Zürich] = University of Zurich (UZH), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Service de Rhumatologie [CHU Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Projet NECESSITY (PN), Hôpitaux Universitaires Paris Sud [AP-HP] (HUPS)-Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Immunologie Translationnelle - Translational Immunology lab, Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Ecole Polytechnique Fédérale de Lausanne (EPFL), Université de Lausanne = University of Lausanne (UNIL), Lausanne University Hospital, University of Bergen (UiB), Oklahoma Medical Research Foundation (OMRF), University of Oklahoma Health Sciences Center (OUHSC), Université de Strasbourg (UNISTRA), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Newcastle University [Newcastle], Newcastle Upon Tyne Hospitals NHS Foundation Trust, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Immunologie, Immunopathologie et Chimie Thérapeutique (I2CT), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Biogen Inc. [Cambridge, MA, USA], Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Supported by the Innovative Medicines Initiative 2 Joint Undertaking (JU) (grant 806975). The JU receives support from the European Union’s Horizon 2020 research and innovation program and the European Unionand the European Federation of Pharmaceutical Industries and Associations. This work was also supported by the National Institutes of Health (National Institute of Arthritis and Musculoskeletal Skin Disease grant R01-AR-065953). The Assessment of Systemic Signs and Evolution in Sjögren’s Syndrome(ASSESS) national multicenter prospective cohort was formed in 2006 with aFrench Ministry of Health grant (Programme Hospitalier de Recherche Clinique 2005 P060228). The ASSESS cohort is promoted by the French Society of Rheumatology and receives research grants from the French Society of Rheumatology. Dr. Gottenberg’s work was supported by Bristol Myers Squibbfor transcriptomic analysis of the ASSESS and Norwegian cohorts and by Geneviève Garnier (Association Française du Syndrome de Gougerot-Sjögrenet des syndromes secs). Drs. Trutschel’s and Schwikowski’s work was supported by Geneviève Garnier (Association Française du Syndrome de Gougerot-Sjögren et des syndromes secs)., Milieu Intérieur Consortium, ASSESS study investigators, and NECESSITY Consortium: Emmanuelle Dernis, Valerie Devauchelle-Pensec, Philippe Dieude, Jean-Jacques Dubost, Anne-Laure Fauchais, Vincent Goeb, Eric Hachulla, Pierre Yves Hatron, Claire Larroche, Véronique Le Guern, Jacques Morel, Aleth Perdriger, Carinne Salliot, Stephanie Rist, Alain Saraux, Jean Sibilia, Olivier Vittecoq, Gaétane Nocturne, Philippe Ravaud, Raphaèle Seror, Laurent Abel, Andres Alcover, Hugues Aschard, Kalla Astrom, Philippe Bousso, Pierre Bruhns, Ana Cumano, Caroline Demangel, Ludovic Deriano, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay, Odile Gelpi, Ivo GompertsBoneca, Milena Hasan, Serge Hercberg, Olivier Lantz, Claude Leclerc, Hugo Mouquet, Sandra Pellegrini, Stanislas Pol, Antonio Rausell, Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Vassili Soumelis, Frédéric Tangy, Eric Tartour, Antoine Toubert, Mathilde Touvier, Marie-Noëlle Ungeheuer, Matthew L Albert, Darragh Duffy, Lluis Quintana-Murci., European Project: 806975,NECESSITY, Clauss, Isabelle, and NEw Clinical Endpoints in primary Sjögren’s Syndrome: an Interventional Trial based on stratifYing patients - NECESSITY - 0000-00-00 - 0000-00-00 - 806975 - VALID

Subjects
Proteomics, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Sjogren's Syndrome, Rheumatology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, HLA-DQ Antigens, Immunology, Humans, Interferon-alpha, Immunology and Allergy, Prospective Studies
Abstract

Objective: Primary Sjögren's syndrome (SS) is the second most frequent systemic autoimmune disease, affecting 0.1% of the general population. To characterize the molecular and clinical variabilities among patients with primary SS, we integrated transcriptomic, proteomic, cellular, and genetic data with clinical phenotypes in a cohort of 351 patients with primary SS. Methods: We analyzed blood transcriptomes and genotypes of 351 patients with primary SS who were participants in a multicenter prospective clinical cohort. We replicated the transcriptome analysis in 3 independent cohorts (n = 462 patients). We determined circulating interferon-α (IFNα) and IFNγ protein concentrations using digital single molecular arrays (Simoa). Results: Transcriptome analysis of the prospective cohort showed a strong IFN gene signature in more than half of the patients; this finding was replicated in the 3 independent cohorts. Because gene expression analysis did not discriminate between type I IFN and type II IFN, we used Simoa to demonstrate that the IFN transcriptomic signature was driven by circulating IFNα and not by IFNγ protein levels. IFNα protein levels, detectable in 75% of patients, were significantly associated with clinical and immunologic features of primary SS disease activity at enrollment and with increased frequency of systemic complications over the 5-year follow-up. Genetic analysis revealed a significant association between IFNα protein levels, a major histocompatibility (MHC) class II haplotype, and anti-SSA antibody. Additional cellular analysis revealed that an MHC class II HLA–DQ locus acts through up-regulation of HLA class II molecules on conventional dendritic cells. Conclusion: We identified the predominance of IFNα as a driver of primary SS variability, with IFNα demonstrating an association with HLA gene polymorphisms., Arthritis & Rheumatology, 74 (12), ISSN:2326-5191, ISSN:2326-5205

Published
2022
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29. Pathway-Specific Aggregate Biomarker Risk Score Is Associated With Burden of Coronary Artery Disease and Predicts Near-Term Risk of Myocardial Infarction and Death

Author

Ghasemzadeh, Nima, Hayek, Salim S., Ko, Yi-An, Eapen, Danny J., Patel, Riyaz S., Manocha, Pankaj, Al Kassem, Hatem, Khayata, Mohamed, Veledar, Emir, Kremastinos, Dimitrios, Thorball, Christian W., Pielak, Tomasz, Sikora, Sergey, Zafari, A. Maziar, Lerakis, Stamatios, Sperling, Laurence, Vaccarino, Viola, Epstein, Stephen E., and Quyyumi, Arshed A.

Published
2017
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30. A Baseline Cellular Antiviral State Is Maintained by cGAS and Its Most Frequent Naturally Occurring Variant rs610913

Author

Kazmierski, Julia, primary, Elsner, Carina, additional, Döhner, Katinka, additional, Xu, Shuting, additional, Ducroux, Aurélie, additional, Pott, Fabian, additional, Jansen, Jenny, additional, Thorball, Christian W., additional, Zeymer, Ole, additional, Zhou, Xiaoyi, additional, Fedorov, Roman, additional, Fellay, Jacques, additional, Löffler, Markus W., additional, Weber, Alexander N. R., additional, Sodeik, Beate, additional, and Goffinet, Christine, additional

Published
2022
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31. A polygenic risk score to predict sudden cardiac arrest in patients with coronary artery disease

Author

Porcu, Eleonora, primary, Thorball, Christian W., additional, Porretta, Alessandra Pia, additional, Pruvot, Etienne, additional, Wiskott, Kim, additional, Gilardi, Federica, additional, Thomas, Aurelien, additional, Redin, Claire, additional, Kutalik, Zoltán, additional, Fracasso, Tony, additional, Müller, Olivier, additional, and Fellay, Jacques, additional

Published
2022
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32. Telomere Length Declines In Persons Living With HIV Before Antiretroviral Therapy Start But Not After Viral Suppression: A Longitudinal Study Over >17 Years

Author

Schoepf, Isabella C, Thorball, Christian W, Ledergerber, Bruno, Kootstra, Neeltje A, Reiss, Peter, Raffenberg, Marieke, Engel, Tanja, Braun, Dominique L, Hasse, Barbara, Thurnheer, Christine, Marzolini, Catia, Seneghini, Marco, Bernasconi, Enos, Cavassini, Matthias, Buvelot, Hélène, Arribas, José R, Kouyos, Roger D, Fellay, Jacques, Günthard, Huldrych F, Tarr, Philip E, Swiss HIV Cohort Study, and University of Zurich

Subjects
10028 Institute of Medical Virology, 10234 Clinic for Infectious Diseases, 570 Life sciences, biology, 610 Medicine & health
Published
2022

33. A Phylogeny-aware GWAS Framework to Correct for Heritable Pathogen Effects on Infectious Disease Traits

Author

Nadeau, Sarah; https://orcid.org/0000-0003-1008-8918, Thorball, Christian W; https://orcid.org/0000-0002-6869-6943, Kouyos, Roger; https://orcid.org/0000-0002-9220-8348, Günthard, Huldrych F; https://orcid.org/0000-0002-1142-6723, Böni, Jürg; https://orcid.org/0000-0001-7925-4852, Yerly, Sabine; https://orcid.org/0000-0003-1668-696X, Perreau, Matthieu, Klimkait, Thomas; https://orcid.org/0000-0003-4945-6511, Rauch, Andri; https://orcid.org/0000-0001-5297-6062, Hirsch, Hans H; https://orcid.org/0000-0003-0883-0423, Cavassini, Matthias; https://orcid.org/0000-0003-0933-7833, Vernazza, Pietro; https://orcid.org/0000-0002-6849-6941, Bernasconi, Enos; https://orcid.org/0000-0002-9724-8373, Fellay, Jacques; https://orcid.org/0000-0002-8240-939X, Mitov, Venelin; https://orcid.org/0000-0002-5227-5191, Stadler, Tanja; https://orcid.org/0000-0001-6431-535X, Swiss HIV Cohort Study (SHCS), Nadeau, Sarah; https://orcid.org/0000-0003-1008-8918, Thorball, Christian W; https://orcid.org/0000-0002-6869-6943, Kouyos, Roger; https://orcid.org/0000-0002-9220-8348, Günthard, Huldrych F; https://orcid.org/0000-0002-1142-6723, Böni, Jürg; https://orcid.org/0000-0001-7925-4852, Yerly, Sabine; https://orcid.org/0000-0003-1668-696X, Perreau, Matthieu, Klimkait, Thomas; https://orcid.org/0000-0003-4945-6511, Rauch, Andri; https://orcid.org/0000-0001-5297-6062, Hirsch, Hans H; https://orcid.org/0000-0003-0883-0423, Cavassini, Matthias; https://orcid.org/0000-0003-0933-7833, Vernazza, Pietro; https://orcid.org/0000-0002-6849-6941, Bernasconi, Enos; https://orcid.org/0000-0002-9724-8373, Fellay, Jacques; https://orcid.org/0000-0002-8240-939X, Mitov, Venelin; https://orcid.org/0000-0002-5227-5191, Stadler, Tanja; https://orcid.org/0000-0001-6431-535X, and Swiss HIV Cohort Study (SHCS)

Abstract

Infectious diseases are particularly challenging for genome-wide association studies (GWAS) because genetic effects from two organisms (pathogen and host) can influence a trait. Traditional GWAS assume individual samples are independent observations. However, pathogen effects on a trait can be heritable from donor to recipient in transmission chains. Thus, residuals in GWAS association tests for host genetic effects may not be independent due to shared pathogen ancestry. We propose a new method to estimate and remove heritable pathogen effects on a trait based on the pathogen phylogeny prior to host GWAS, thus restoring independence of samples. In simulations, we show this additional step can increase GWAS power to detect truly associated host variants when pathogen effects are highly heritable, with strong phylogenetic correlations. We applied our framework to data from two different host-pathogen systems, HIV in humans and X. arboricola in A. thaliana. In both systems, the heritability and thus phylogenetic correlations turn out to be low enough such that qualitative results of GWAS do not change when accounting for the pathogen shared ancestry through a correction step. This means that previous GWAS results applied to these two systems should not be biased due to shared pathogen ancestry. In summary, our framework provides additional information on the evolutionary dynamics of traits in pathogen populations and may improve GWAS if pathogen effects are highly phylogenetically correlated amongst individuals in a cohort.

Published
2022

34. Author Correction: Increased prevalence of clonal hematopoiesis of indeterminate potential amongst people living with HIV

Author

Bick, Alexander G, Popadin, Konstantin, Thorball, Christian W, Uddin, Md Mesbah, Zanni, Markella V, Yu, Bing, Cavassini, Matthias, Rauch, Andri, Tarr, Philip, Schmid, Patrick, Bernasconi, Enos, Günthard, Huldrych F, et al, Bick, Alexander G, Popadin, Konstantin, Thorball, Christian W, Uddin, Md Mesbah, Zanni, Markella V, Yu, Bing, Cavassini, Matthias, Rauch, Andri, Tarr, Philip, Schmid, Patrick, Bernasconi, Enos, Günthard, Huldrych F, and et al

Published
2022

35. Increased prevalence of clonal hematopoiesis of indeterminate potential amongst people living with HIV

Author

Bick, Alexander G, Popadin, Konstantin, Thorball, Christian W, Uddin, Md Mesbah, Zanni, Markella V, Yu, Bing, Cavassini, Matthias, Rauch, Andri, Tarr, Philip, Schmid, Patrick, Bernasconi, Enos, Günthard, Huldrych F, et al, Bick, Alexander G, Popadin, Konstantin, Thorball, Christian W, Uddin, Md Mesbah, Zanni, Markella V, Yu, Bing, Cavassini, Matthias, Rauch, Andri, Tarr, Philip, Schmid, Patrick, Bernasconi, Enos, Günthard, Huldrych F, and et al

Abstract

People living with human immunodeficiency virus (PLWH) have significantly increased risk for cardiovascular disease in part due to inflammation and immune dysregulation. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related acquisition and expansion of hematopoietic stem cells due to leukemogenic driver mutations, increases risk for both hematologic malignancy and coronary artery disease (CAD). Since increased inflammation is hypothesized to be both a cause and consequence of CHIP, we hypothesized that PLWH have a greater prevalence of CHIP. We searched for CHIP in multi-ethnic cases from the Swiss HIV Cohort Study (SHCS, n = 600) and controls from the Atherosclerosis Risk in the Communities study (ARIC, n = 8111) from blood DNA-derived exome sequences. We observed that HIV is associated with a twofold increase in CHIP prevalence, both in the whole study population and in a subset of 230 cases and 1002 matched controls selected by propensity matching to control for demographic imbalances (SHCS 7%, ARIC 3%, p = 0.005). We also observed that ASXL1 is the most commonly mutated CHIP-associated gene in PLWH. Our results suggest that CHIP may contribute to the excess cardiovascular risk observed in PLWH.

Published
2022

36. Associations of genetic and infectious risk factors with coronary heart disease

Author

Hodel, Flavia, primary, Xu, Zhi Ming, additional, Thorball, Christian W, additional, de La Harpe, Roxane, additional, Letang-Mathieu, Prunelle, additional, Brenner, Nicole, additional, Butt, Julia, additional, Bender, Noemi, additional, Waterboer, Tim, additional, Marques-Vidal, Pedro, additional, Vollenweider, Peter, additional, Vaucher, Julien, additional, and Fellay, Jacques, additional

Published
2022
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37. A Phylogeny-aware GWAS Framework to Correct for Heritable Pathogen Effects on Infectious Disease Traits

Author

Nadeau, Sarah, Thorball, Christian W, Kouyos, Roger, Günthard, Huldrych F, Böni, Jürg, Yerly, Sabine, Perreau, Matthieu, Klimkait, Thomas, Rauch, Andri, Hirsch, Hans H, Cavassini, Matthias, Vernazza, Pietro, Bernasconi, Enos, Fellay, Jacques, Mitov, Venelin, Stadler, Tanja, Swiss HIV Cohort Study (SHCS), University of Zurich, and Stadler, Tanja

Subjects
10028 Institute of Medical Virology, 10234 Clinic for Infectious Diseases, phylogenetic mixed model, 1105 Ecology, Evolution, Behavior and Systematics, genome-wide association study, 1311 Genetics, infectious disease, 1312 Molecular Biology, 570 Life sciences, biology, 610 Medicine & health, heritability
Abstract

Infectious diseases are particularly challenging for genome-wide association studies (GWAS) because genetic effects from two organisms (pathogen and host) can influence a trait. Traditional GWAS assume individual samples are independent observations. However, pathogen effects on a trait can be heritable from donor to recipient in transmission chains. Thus, residuals in GWAS association tests for host genetic effects may not be independent due to shared pathogen ancestry. We propose a new method to estimate and remove heritable pathogen effects on a trait based on the pathogen phylogeny prior to host GWAS, thus restoring independence of samples. In simulations, we show this additional step can increase GWAS power to detect truly associated host variants when pathogen effects are highly heritable, with strong phylogenetic correlations. We applied our framework to data from two different host-pathogen systems, HIV in humans and X. arboricola in A. thaliana. In both systems, the heritability and thus phylogenetic correlations turn out to be low enough such that qualitative results of GWAS do not change when accounting for the pathogen shared ancestry through a correction step. This means that previous GWAS results applied to these two systems should not be biased due to shared pathogen ancestry. In summary, our framework provides additional information on the evolutionary dynamics of traits in pathogen populations and may improve GWAS if pathogen effects are highly phylogenetically correlated amongst individuals in a cohort., Molecular Biology and Evolution, 39 (8), ISSN:0737-4038, ISSN:1537-1719

Published
2022
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38. Polygenic Risk Scores for Prediction of Subclinical Coronary Artery Disease in Persons Living with HIV: The Swiss HIV Cohort Study

Author

Schoepf, Isabella C, Thorball, Christian W, Kovari, Helen, Ledergerber, Bruno, Buechel, Ronny R, Calmy, Alexandra, Weber, Rainer, Kaufmann, Philipp A, Nkoulou, René, Schwenke, Johannes M, Braun, Dominique L, Fellay, Jacques, and Tarr, Philip E

Subjects
hiv infection, aging, multivariable analysis, association, heart, tomography, infection, atherosclerotic cardiovascular-disease, polygenic risk score, loci, angiography, subclinical coronary artery disease, intima-media thickness, 610 Medicine & health, events
Abstract

Background. In people living with human immunodeficiency virus (HIV) (PLWH), individual polygenic risk scores (PRSs) are associated with coronary artery disease (CAD) events. Whether PRSs are associated with subclinical CAD is unknown., Methods. In Swiss HIV Cohort Study participants of European descent, we defined subclinical CAD as presence of soft, mixed, or high-risk plaque (SMHRP) on coronary computed tomography (CT) angiography, or as participants in the top tertile of the study population's coronary artery calcium (CAC) score, using noncontrast CT. We obtained univariable and multivariable odds ratios (ORs) for subclinical CAD endpoints based on nongenetic risk factors, and validated genome-wide PRSs built from single nucleotide polymorphisms associated with CAD, carotid intima-media thickness (IMT), or longevity in the general population., Results. We included 345 genotyped participants (median age, 53 years; 89% male; 96% suppressed HIV RNA); 172 and 127 participants had SMHRP and CAC, respectively. CAD-associated PRS and IMT-associated PRS were associated with SMHRP and CAC (all P < .01), but longevity PRS was not. Participants with unfavorable CAD-PRS (top quintile) had an adjusted SMHRP OR = 2.58 (95% confidence interval [CI], 1.18-5.67), and a CAC OR = 3.95 (95% CI, 1.45-10.77) vs. bottom quintile. Unfavorable nongenetic risk (top vs. bottom quintile) was associated with adjusted SMHRP OR = 24.01 (95% CI, 9.75-59.11), and a CAC-OR = 65.07 (95% CI, 18.48-229.15). Area under the receiver operating characteristic curve increased when we added CAD-PRS to nongenetic risk factors (SMHRP: 0.75 and 0.78, respectively; CAC: 0.80 and 0.83, respectively)., Conclusions. In Swiss PLWH, subclinical CAD is independently associated with an individual CAD-associated PRS. Combining nongenetic and genetic cardiovascular risk factors provided the most powerful subclinical CAD prediction.

Published
2022
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40. Impact of Delaying Antiretroviral Treatment during Primary HIV Infection on Telomere Length

Author

Raffenberg, Marieke, Engel, Tanja, Schoepf, Isabella C, Kootstra, Neeltje A, Reiss, Peter, Braun, Dominique L, Thorball, Christian W, Fellay, Jacques, Kouyos, Roger D, Ledergerber, Bruno, Günthard, Huldrych F, Tarr, Philip E, Zurich Primary HIV Infection Study, Swiss HIV Cohort Study, and University of Zurich

Subjects
10234 Clinic for Infectious Diseases, 10028 Institute of Medical Virology, 610 Medicine & health
Published
2021

41. Coronary Artery Disease-associated and Longevity-associated Polygenic Risk Scores for Prediction of Coronary Artery Disease Events in Persons Living with HIV: The Swiss HIV Cohort Study

Author

Schoepf, Isabella C, Thorball, Christian W, Ledergerber, Bruno, Engel, Tanja, Raffenberg, Marieke, Kootstra, Neeltje A, Reiss, Peter, Hasse, Barbara, Marzolini, Catia, Thurnheer, Christine, Seneghini, Marco, Bernasconi, Enos, Cavassini, Matthias, Buvelot, Hélène, Kouyos, Roger, Günthard, Huldrych F, Fellay, Jacques, Tarr, Philip E, Swiss HIV Cohort Study, and University of Zurich

Subjects
10234 Clinic for Infectious Diseases, 10028 Institute of Medical Virology, 610 Medicine & health
Published
2021

42. Telomere Length Declines in Persons With Human Immunodeficiency Virus Before Antiretroviral Therapy Start but Not After Viral Suppression: A Longitudinal Study Over &gt;17 Years

Author

Schoepf, Isabella C, primary, Thorball, Christian W, additional, Ledergerber, Bruno, additional, Kootstra, Neeltje A, additional, Reiss, Peter, additional, Raffenberg, Marieke, additional, Engel, Tanja, additional, Braun, Dominique L, additional, Hasse, Barbara, additional, Thurnheer, Christine, additional, Marzolini, Catia, additional, Seneghini, Marco, additional, Bernasconi, Enos, additional, Cavassini, Matthias, additional, Buvelot, Hélène, additional, Arribas, José R, additional, Kouyos, Roger D, additional, Fellay, Jacques, additional, Günthard, Huldrych F, additional, and Tarr, Philip E, additional

Published
2021
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43. Africa-specific human genetic variation near CHD1Lassociates with HIV-1 load

Author

McLaren, Paul J., Porreca, Immacolata, Iaconis, Gennaro, Mok, Hoi Ping, Mukhopadhyay, Subhankar, Karakoc, Emre, Cristinelli, Sara, Pomilla, Cristina, Bartha, István, Thorball, Christian W., Tough, Riley H., Angelino, Paolo, Kiar, Cher S., Carstensen, Tommy, Fatumo, Segun, Porter, Tarryn, Jarvis, Isobel, Skarnes, William C., Bassett, Andrew, DeGorter, Marianne K., Sathya Moorthy, Mohana Prasad, Tuff, Jeffrey F., Kim, Eun-Young, Walter, Miriam, Simons, Lacy M., Bashirova, Arman, Buchbinder, Susan, Carrington, Mary, Cossarizza, Andrea, De Luca, Andrea, Goedert, James J., Goldstein, David B., Haas, David W., Herbeck, Joshua T., Johnson, Eric O., Kaleebu, Pontiano, Kilembe, William, Kirk, Gregory D., Kootstra, Neeltje A., Kral, Alex H., Lambotte, Olivier, Luo, Ma, Mallal, Simon, Martinez-Picado, Javier, Meyer, Laurence, Miro, José M., Moodley, Pravi, Motala, Ayesha A., Mullins, James I., Nam, Kireem, Obel, Niels, Pirie, Fraser, Plummer, Francis A., Poli, Guido, Price, Matthew A., Rauch, Andri, Theodorou, Ioannis, Trkola, Alexandra, Walker, Bruce D., Winkler, Cheryl A., Zagury, Jean-François, Montgomery, Stephen B., Ciuffi, Angela, Hultquist, Judd F., Wolinsky, Steven M., Dougan, Gordon, Lever, Andrew M. L., Gurdasani, Deepti, Groom, Harriet, Sandhu, Manjinder S., and Fellay, Jacques

Abstract

HIV-1 remains a global health crisis1, highlighting the need to identify new targets for therapies. Here, given the disproportionate HIV-1 burden and marked human genome diversity in Africa2, we assessed the genetic determinants of control of set-point viral load in 3,879 people of African ancestries living with HIV-1 participating in the international collaboration for the genomics of HIV3. We identify a previously undescribed association signal on chromosome 1 where the peak variant associates with an approximately 0.3 log10-transformed copies per ml lower set-point viral load per minor allele copy and is specific to populations of African descent. The top associated variant is intergenic and lies between a long intergenic non-coding RNA (LINC00624) and the coding gene CHD1L, which encodes a helicase that is involved in DNA repair4. Infection assays in iPS cell-derived macrophages and other immortalized cell lines showed increased HIV-1 replication in CHD1L-knockdown and CHD1L-knockout cells. We provide evidence from population genetic studies that Africa-specific genetic variation near CHD1Lassociates with HIV replication in vivo. Although experimental studies suggest that CHD1L is able to limit HIV infection in some cell types in vitro, further investigation is required to understand the mechanisms underlying our observations, including any potential indirect effects of CHD1L on HIV spread in vivo that our cell-based assays cannot recapitulate.

Published
2023
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44. Polygenic Risk Scores for Prediction of Subclinical Coronary Artery Disease in Persons With Human Immunodeficiency Virus (HIV): The Swiss HIV Cohort Study.

Author

Schoepf, Isabella C, Thorball, Christian W, Kovari, Helen, Ledergerber, Bruno, Buechel, Ronny R, Calmy, Alexandra, Weber, Rainer, Kaufmann, Philipp A, Nkoulou, René, Schwenke, Johannes M, Braun, Dominique L, Fellay, Jacques, Tarr, Philip E, and Study, for the Swiss HIV Cohort

Subjects
*HIV-positive persons, *CARDIOVASCULAR diseases risk factors, *CONFIDENCE intervals, *RISK assessment, *GENOME-wide association studies, *CORONARY artery disease, *GENOTYPES, *SWISS, *COMPUTED tomography, *ODDS ratio, *LONGITUDINAL method, *DISEASE risk factors
Abstract

Background In people with human immunodeficiency virus (HIV) (PWH), individual polygenic risk scores (PRSs) are associated with coronary artery disease (CAD) events. Whether PRSs are associated with subclinical CAD is unknown. Methods In Swiss HIV Cohort Study participants of European descent, we defined subclinical CAD as presence of soft, mixed, or high-risk plaque (SMHRP) on coronary computed tomography (CT) angiography, or as participants in the top tertile of the study population's coronary artery calcium (CAC) score, using noncontrast CT. We obtained univariable and multivariable odds ratios (ORs) for subclinical CAD endpoints based on nongenetic risk factors, and validated genome-wide PRSs built from single nucleotide polymorphisms associated with CAD, carotid intima-media thickness (IMT), or longevity in the general population. Results We included 345 genotyped participants (median age, 53 years; 89% male; 96% suppressed HIV RNA); 172 and 127 participants had SMHRP and CAC, respectively. CAD-associated PRS and IMT-associated PRS were associated with SMHRP and CAC (all P <.01), but longevity PRS was not. Participants with unfavorable CAD-PRS (top quintile) had an adjusted SMHRP OR = 2.58 (95% confidence interval [CI], 1.18–5.67), and a CAC OR = 3.95 (95% CI, 1.45–10.77) vs. bottom quintile. Unfavorable nongenetic risk (top vs. bottom quintile) was associated with adjusted SMHRP OR = 24.01 (95% CI, 9.75–59.11), and a CAC-OR = 65.07 (95% CI, 18.48–229.15). Area under the receiver operating characteristic curve increased when we added CAD-PRS to nongenetic risk factors (SMHRP: 0.75 and 0.78, respectively; CAC: 0.80 and 0.83, respectively). Conclusions In Swiss PWH, subclinical CAD is independently associated with an individual CAD-associated PRS. Combining nongenetic and genetic cardiovascular risk factors provided the most powerful subclinical CAD prediction. [ABSTRACT FROM AUTHOR]

Published
2023
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45. Rapid progression of kidney dysfunction in Swiss people living with HIV: contribution of polygenic risk score and D:A:D clinical risk score

Author

Dietrich, Léna G, Thorball, Christian W, Ryom, Lene, Burkhalter, Felix, Hasse, Barbara, Thurnheer, Maria Christine, Weisser, Maja, Schmid, Patrick, Bernasconi, Enos, Darling, Kathrine E A, Buvelot, Hélène, Fellay, Jacques, Ledergerber, Bruno, Tarr, Philip E, Swiss HIV Cohort Study, and University of Zurich

Subjects
10234 Clinic for Infectious Diseases, 610 Medicine & health
Published
2021

47. Telomere Length Declines In Persons Living With HIV Before Antiretroviral Therapy Start But Not After Viral Suppression: A Longitudinal Study Over >17 Years

Author

Schoepf, Isabella C, Thorball, Christian W, Ledergerber, Bruno, Kootstra, Neeltje A, Reiss, Peter, Raffenberg, Marieke, Engel, Tanja, Braun, Dominique L, Hasse, Barbara, Thurnheer, Christine, Marzolini, Catia, Seneghini, Marco, Bernasconi, Enos, Cavassini, Matthias, Buvelot, H��l��ne, Arribas, Jos�� R, Kouyos, Roger D, Fellay, Jacques, G��nthard, Huldrych F, and Tarr, Philip E

Subjects
610 Medicine & health
Abstract

BACKGROUND In people living with HIV (PWH), long-term telomere length (TL) change without/with suppressive antiretroviral therapy (ART) and the contribution of genetic background to TL are incompletely understood. METHODS We measured TL change in peripheral blood mononuclear cells by quantitative PCR in 107 Swiss HIV Cohort Study participants with longitudinal samples available both before and during suppressive ART. We applied mixed effects multi-level regression to obtain uni-/multivariable estimates for longitudinal TL dynamics including age, sex, and CD4:CD8 ratio. We assessed the effect of individual antiretrovirals and of an individual TL-polygenic risk score (TL-PRS; based on 239 single nucleotide polymorphisms) on TL in 798 additional participants from our previous longitudinal studies. RESULTS During untreated HIV infection (median observation, 7.7 [interquartile range, IQR, 4.7-11] years), TL declined significantly (median -2.12%/year; IQR, -3.48% to -0.76%/year; p=0.002). During suppressive ART (median observation, 9.8 [IQR, 7.1-11.1] years), there was no evidence of TL decline or increase (median +0.54%/year; IQR, -0.55% to +1.63%/year; p=0.329). TL-PRS contributed to TL change (global p=0.019) but particular antiretrovirals did not (all p>0.15). DISCUSSION In PWH, TL is associated with an individual polygenic risk score. TL declined significantly during untreated chronic HIV infection but no TL change occurred during suppressive ART.

Published
2021
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48. A base-line cellular antiviral state is maintained by cGAS and its most frequent naturally occurring variant rs610913

Author

Kazmierski, Julia, primary, Elsner, Carina, additional, Döhner, Katinka, additional, Xu, Shuting, additional, Ducroux, Aurélie, additional, Pott, Fabian, additional, Jansen, Jenny, additional, Thorball, Christian W., additional, Zeymer, Ole, additional, Zhou, Xiaoyi, additional, Fedorov, Roman, additional, Fellay, Jacques, additional, Löffler, Markus W., additional, Weber, Alexander N. R., additional, Sodeik, Beate, additional, and Goffinet, Christine, additional

Published
2021
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49. Immunological lessons from genome-wide association studies of infections

Author

Thorball, Christian W., Fellay, Jacques, Borghesi, Alessandro, Thorball, Christian W., Fellay, Jacques, and Borghesi, Alessandro

Abstract

Over the past few years, genome-wide association studies (GWAS) have been increasingly applied to identify host genetic factors influencing clinical and laboratory traits related to immunity and infection, and to understand the interplay between the host and the microbial genomes. By screening large cohorts of individuals suffering from various infectious diseases, GWAS explored resistance against infection, natural history of the disease, development of life-threatening clinical signs, and innate and adaptive immune responses. These efforts provided fundamental insight on the role of major genes in the interindividual variability in the response to infection and on the mechanisms of the immune response against human pathogens both at the individual and population levels.

Published
2021
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50. Genetic variation near CXCL12 is associated with susceptibility to HIV-related non-Hodgkin lymphoma

Author

Thorball, Christian W, Oudot-Mellakh, Tiphaine, Ehsan, Nava, Hammer, Christian, Santoni, Federico A, Niay, Jonathan, Costagliola, Dominique, Goujard, Cécile, Meyer, Laurence, Wang, Sophia S, Hussain, Shehnaz K, Theodorou, Ioannis, Cavassini, Matthias, Rauch, Andri, Battegay, Manuel, Hoffmann, Matthias, Schmid, Patrick, Bernasconi, Enos, Günthard, Huldrych F, Mohammadi, Pejman, McLaren, Paul J, Rabkin, Charles S, Besson, Caroline, Fellay, Jacques, Thorball, Christian W, Oudot-Mellakh, Tiphaine, Ehsan, Nava, Hammer, Christian, Santoni, Federico A, Niay, Jonathan, Costagliola, Dominique, Goujard, Cécile, Meyer, Laurence, Wang, Sophia S, Hussain, Shehnaz K, Theodorou, Ioannis, Cavassini, Matthias, Rauch, Andri, Battegay, Manuel, Hoffmann, Matthias, Schmid, Patrick, Bernasconi, Enos, Günthard, Huldrych F, Mohammadi, Pejman, McLaren, Paul J, Rabkin, Charles S, Besson, Caroline, and Fellay, Jacques

Abstract

Human immunodeficiency virus (HIV) infection is associated with an increased risk of non-Hodgkin lymphoma (NHL). Even in the era of suppressive antiretroviral treatment, HIV-infected individuals remain at higher risk of developing NHL compared to the general population. To identify potential genetic risk loci, we performed case-control genome-wide association studies and a meta-analysis across three cohorts of HIV+ patients of European ancestry, including a total of 278 cases and 1924 matched controls. We observed a significant association with NHL susceptibility in the C-X-C motif chemokine ligand 12 (CXCL12) region on chromosome 10. A fine mapping analysis identified rs7919208 as the most likely causal variant (P = 4.77e-11), with the G>A polymorphism creating a new transcription factor binding site for BATF and JUND. These results suggest a modulatory role of CXCL12 regulation in the increased susceptibility to NHL observed in the HIV-infected population.

Published
2021

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