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European Mitochondrial Haplogroups

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European Mitochondrial Haplogroups Aldámiz‑Echevarría et al. J Transl Med (2019) 17:244 https://doi.org/10.1186/s12967‑019‑1997‑x Journal of Translational Medicine RESEARCH Open Access European mitochondrial haplogroups predict liver‑related outcomes in patients coinfected with HIV and HCV: a retrospective study Teresa Aldámiz‑Echevarría1,2, Salvador Resino3* , José M. Bellón1,2, María A. Jiménez‑Sousa3, Pilar Miralles1,2, Luz M. Medrano3, Ana Carrero1,2, Cristina Díez1,2, Leire Pérez‑Latorre1,2, Chiara Fanciulli1,2, Pilar Garcia‑Broncano3 and Juan Berenguer1,2 Abstract Background: Mitochondrial DNA (mtDNA) haplogroups have been associated with advanced liver fbrosis and cirrhosis in patients coinfected with human immunodefciency virus (HIV) and hepatitis C virus (HCV). Our aim was to determine whether mtDNA haplogroups are associated with liver‑related events (LREs) in HIV/HCV‑coinfected patients. Methods: We carried out a retrospective cohort study in HIV/HCV‑coinfected patients who were potential can‑ didates for therapy with interferon and ribavirin (IFN/Rib) between 2000 and 2009. The primary endpoint was the occurrence of LREs (decompensation or hepatocellular carcinoma). mtDNA genotyping was performed using the Sequenom MassARRAY platform. We used Fine and Gray proportional hazards model to test the association between mtDNA haplogroups and LREs, considering death as a competitive risk. Results: The study population comprised 243 patients, of whom 40 had advanced fbrosis or cirrhosis. After a median follow‑up of 7.7 years, 90 patients treated with IFN/Rib achieved sustained viral response (SVR), 18 patients had LREs, and 11 patients died. Patients with haplogroup H had lower cumulative incidence than patients with other haplogroups (p 0.012). However, patients with haplogroup T had higher cumulative incidence than patients with other haplogroups= (p 0.074). In the multivariate analysis, haplogroup T was associated with an increased hazard of developing LREs [adjusted= subhazard ratio (aSHR) 3.56 (95% CI 1.13;11.30); p 0.030]; whereas haplogroup H was not associated with lower hazard of LREs [aSHR 0.36= (95% CI 0.10;1.25); p 0.105].= When we excluded patients who achieved SVR during follow‑up, we obtained similar= SHR values. = Conclusions: European mitochondrial haplogroups may infuence the natural history of chronic hepatitis C. Keywords: Mitochondria, mtDNA haplogroups, HIV, Chronic hepatitis C, Cirrhosis, Liver‑related outcomes *Correspondence: [email protected] 3 Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Carretera Majadahonda‑Pozuelo, Km 2.2, 28220 Majadahonda, Madrid, Spain Full list of author information is available at the end of the article © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Aldámiz‑Echevarría et al. J Transl Med (2019) 17:244 Page 2 of 9 Background study of phenotypical efect of mutations in the mtDNA. Hepatitis C virus (HCV) infection is the leading cause of In this “in vitro” model, it has been observed that hap- end-stage liver disease, hepatocellular carcinoma (HCC), logroup H cybrids contain higher levels of mtDNA and and liver-related death in developed countries [1]. It is mRNA, growing faster, have a higher membrane poten- estimated that about 10–20% individuals with chronic tial, and consume more oxygen than haplogroup Uk and hepatitis C develop cirrhosis around 20 to 30 years after T cybrids. Other studies have reported that haplogroup J acquiring HCV and that those who develop cirrhosis cybrids have slower rate of assembly of the mitochondrial have a 1% to 5% annual risk of developing HCC and a 3% complexes and lower ATP and ROS production than hap- to 6% annual risk of liver decompensation [2, 3]. How- logroup H cybrids [11]. In addition, some of these fnd- ever, chronic hepatitis C is highly variable among indi- ings have also been described in patients, although the viduals, ranging from minimal histological changes to article number is smaller. extensive fbrosis and cirrhosis [3]. Preliminary studies have also shown associations Although we lack predictive models to estimate the risk between mtDNA haplogroups and clinical outcomes of fbrosis and clinical progression in individuals early in patients with HIV infection [12, 13], including clini- on in their HCV infection, several factors are associated cal progression [14–17], CD4+ T cell recovery after with increased risk of progression of liver fbrosis, includ- combination antiretroviral therapy (cART) [18], meta- ing age, male gender, high alcohol intake, obesity, insu- bolic disorders [19, 20], and toxicities due to nucleoside lin resistance, type 2 diabetes, coinfection with human reverse-transcriptase inhibitors (e.g., peripheral neu- immunodefciency virus (HIV) hepatitis B virus, and ropathy and lipoatrophy) [21, 22]. In previous reports, immunosuppressive therapy [3]. Host nuclear genetic an association between major European mtDNA haplo- factors also infuence the natural history of HCV infec- groups and liver fbrosis in HIV/HCV-coinfected patients tion and include viral clearance, progression of fbrosis, were also found [23, 24], but the design of this studies and development of cirrhosis and HCC [3, 4]. was cross-sectional. In the last decade, the role of mitochondrial genetics in human disease has been increasingly recognized. Mito- Objective chondria provide energy to eukaryotic cells via oxidative In the current study, we aimed to determine whether phosphorylation and regulate cellular survival via con- mtDNA haplogroups are associated with clinical out- trol of apoptosis [5]. Mutations in mitochondrial DNA comes, including liver-related events (LREs) and death, (mtDNA) have been acquired throughout history by in HIV/HCV-coinfected patients through a longitudinal natural selection owing to adaptation to environmental study. conditions [6]. Consequently, the human population can be subdivided into several mitochondrial clades or hap- Materials and methods logroups, which are defned based on specifc mtDNA Study population polymorphisms [7]. In Europe, macro-haplogroups HV, We carried out retrospective study in a cohort of 243 U, and JT are about 90% of the population [8]. Of them, HIV/HCV-coinfected patients who had been evaluated 50% of the Europeans belongs to the macro-haplogroup for interferon and ribavirin therapy at Hospital Gregorio HV and 45% are haplogroup H. Te macro-haplogroups Marañón (Madrid, Spain) between 2000 and 2009. Te U is divided into many sub-haplogroups that comprise patients were negative for hepatitis B surface antigen, and approximately 20% of the Caucasian population. Te a DNA sample was available for each one. Te selection macro-haplogroup JT is subdivided in haplogroups J (8% criteria for anti-HCV therapy at the time were detectable of the population) and T (9% of Europeans). HCV RNA by polymerase chain reaction (PCR), no clini- MtDNA haplogroups have been increasingly recog- cal evidence of hepatic decompensation, CD4+ lympho- nized as contributors to diseases such as cancer, sepsis, cyte count higher than 200 cells/µL, and stable cART for diabetes, and degenerative diseases [9, 10]. However, at least 6 months or no need for cART according to the there is now clear evidence that mtDNA variants within guidelines used during the study period. Patients with haplogroups may be the trigger of the large number of active opportunistic infections and severe concurrent diseases with which mtDNA haplogroups have been medical conditions (e.g., poorly controlled hyperten- linked. Functional studies are scarce and technically com- sion, heart failure, poorly controlled diabetes mellitus, plicated because the likely biochemical efect of mtDNA and severely reduced renal function) were excluded. A polymorphisms may be subtle. In addition, many of period of at least 6 months of abstinence from heroin and these mtDNA polymorphisms are found in genomes cocaine was also required in patients with a history of that contain other polymorphisms, which may be inter- injection drug use. In addition, 162 healthy blood donors acting [11]. Cybrid technology is widely used for the (negative for HIV, HCV, and hepatitis B virus infection) Aldámiz‑Echevarría et al. J Transl Med (2019) 17:244 Page 3 of 9 from the “Centro de Transfusión de la Comunidad de imaging tests or pathology fndings [28]. Te administra- Madrid” participated as a control group. Teir age and tive censoring date was June 30, 2013. gender matched those of the HIV-infected patients. Te study was conducted in accordance with the Dec- mtDNA genotyping laration of Helsinki and patients gave their informed con- Total DNA was extracted from peripheral blood using sent for the study. Te Institutional Review Board and the Qiagen columns (QIAamp DNA Blood Midi/Maxi, Qia- Research Ethic Committee of the Instituto de Salud Car- gen, Hilden, Germany). DNA samples were genotyped los III approved the study (# CEI PI 41_2014). Patients using the MassARRAY platform (Sequenom, San Diego, included in this study signed a written informed consent. CA, USA) based on the iPLEX® Gold assay design. All individuals were classifed within the European macro- Clinical and laboratory data cluster of N and further separated into the most common Baseline clinical and epidemiological data were recorded haplogroups or major groups (HV, IWX, U, and JT) and the day the liver biopsy was performed or the day the haplogroups (H, V, pre-V, J, T, I, W and X) according to patients were evaluated for interferon and ribavirin 14 polymorphisms in the mtDNA (see Additional fle 1: therapy if a liver biopsy was not performed. We consid- Figure S1), as previously described [18].
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