PI-07: THE INTERNATIONAL HEMOGLOBINOPATHY RESEARCH NETWORK (INHERENT): AN INTERNATIONAL INITIATVE TO STUDY THE ROLE OF GENETIC MODIFIERS IN HEMOGLOBINOPATHIES
2022; Wolters Kluwer; Volume: 6; Linguagem: Inglês
10.1097/01.hs9.0000872888.56941.7d
ISSN2572-9241
AutoresPetros Kountouris, Coralea Stephanou, Natasha M. Archer, Fedele Bonifazi, Viviana Giannuzzi, KUO K., Aurelio Maggio, Julie Makani, MAÑÚ PEREIRA M., K Kyriaki Michailidou, Siana Nkya, O. NNODU, Sara Trompeter, Léon Tshilolo, Ambroise Wonkam, Bin Alwi Zilfalil, B. INUSA, Marina Kleanthous,
Tópico(s)Hemoglobinopathies and Related Disorders
ResumoPurpose: Haemoglobinopathies, including sickle cell disease (SCD) and thalassaemia syndromes, represent the commonest monogenic diseases in the world. Although their pathogenicity is well established, the diverse clinical manifestations and the varying degree of severity are less understood and are thought to be governed, in part, by genetic modifiers. Despite the identification and characterisation of a few genetic modifiers by previous studies, these are as yet insufficient to guide treatment recommendations or stratify patients reliably. Larger, multi-ethnic studies are needed to identify and validate further disease modifiers that can be used for patient stratification and personalised treatment. There is a growing need for deeper insight into the availability of novel targeted therapies and potentially curative options like gene therapy in both SCD and thalassemia. The International Haemoglobinopathy Research Network (INHERENT) is a recently established network with the aim of investigating the role of genetic modifiers in haemoglobinopathies, through a large-scale, multi-ethnic genome-wide association study (GWAS). Materials and methods: INHERENT brings together nine existing international or regional consortia in the field of haemoglobinopathies, namely ITHANET, RADeep, ARISE, SPARCO, SADaCC, REDAC, the HVP Global Globin Network, the International Health Repository, and the ClinGen Haemoglobinopathy VCEP. The activities of INHERENT are currently divided into five working groups, as follows: clinical, genotyping, data management and analysis, ethics, and knowledge translation. Participation in INHERENT is open for any group that can submit a minimum number of samples with their core phenotypic description. INHERENT membership is international and interdisciplinary and, currently, includes over 200 experts from over 105 organisations, spanning 43 countries worldwide. INHERENT aims to recruit over 30,000 hemoglobinopathy patients, which is larger than any previous GWAS in the field. Results: A survey amongst 67 of the participating centres revealed that INHERENT has the potential to recruit over 73 500 patients, of which 53755 are SCD, 15691 are β thalassemia (62% transfusion-dependent), 4179 (α thalassemia). A sample size of 10000 individuals can detect associations down to MAF=0.05 with an OR=1.5 in binary phenotypes assuming a case/control ratio of 0.3 and p-value of 5x10-8. For survival endpoints, 5000 individuals will be sufficient to detect an HR of 1.5 and MAF of 0.05, if we assume an event rate of 30%. Conclusion: We demonstrate that the current membership of INHERENT has the potential to reach this sample size target. The large increase in the sample size and the diversity in the studied populations will enable novel discoveries and expand knowledge on haemoglobinopathy genetics, thus paving the way for advancing the science of personalised diagnosis and treatment.INHERENT patient distributionPower calculations F. BONIFAZI declares a conflict of interest: Research support/Scientific studies: EU grants: 1. ARISE project (EU Horizon 2020 research and innovation programme, Marie Skłodowska-Curie Grant Agreement No 824021); 2. c4c project (Grant Agreement n. 777389 - c4c - H2020-JTI-IMI2-2016-10-two-stage); 3. ID-EPTRI project (Infradev – European Paediatric Translational Research Infrastructure, Grant Agreement n. 777554). National/local grants: 1. Integrazione dei modelli di farmacocinetica e farmacodinamica all’analisi decisionale a criteri multipli (MCDA) per la valutazione prospettica del rapporto rischio/beneficio dei chelanti orali del ferro in pazienti pediatrici con emoglobinopatie trasfusione-dipendenti (Regione Puglia, 30/10/2020 e 05/11/2020) K. KUO declares a conflict of interest: Consultancy, Expert: Agios, Alexion, Aruvant, Bluebirdbio, Celgene/BMS, Forma, Novartis, Pfizer Research support/Scientific studies: NHLBI/NIH: 1R33HL147845, Thalassemia Foundation Canada, Peter Munk Cardiac Centre, University of Toronto, Cincinnati Children’s Hospital Medical Center, Canadian Hematology Society, Pfizer Other: Chair of Data Safety Monitoring Board: Bioverativ/Sanofi B. INUSA declares a conflict of interest: Consultancy, Expert: Novartis global therapeutics vertex Invitation to national or international congresses: Saudi medical society National Blood transfusion service, Nigeria Mumbai Haematology india haematology society Patent or product inventor: None Research support/Scientific studies: Horizon 2020, Marie Curie ARISE Paget foundation NIHR Stock shareholder: Not applicable Trainings, Teaching: academy for sickle cell and thalassaemia sickle cell disease association of america
Referência(s)