Study of the Role of Genetic Modifiers in Hemoglobinopathies

Study Overview
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Brief Summary
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This study will investigate the role of genetic modifiers in hemoglobinopathies through a large-scale, multi-ethnic genome-wide association study (GWAS).

Detailed Description
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Hemoglobinopathies, including sickle cell disease (SCD) and beta-thalassemia, are prevalent diseases with variable clinical manifestation and severity that are thought to be governed, in part, by genetic modifiers. Despite the identification and characterization of a few putative genetic modifiers by previous studies, these are as yet insufficient to guide treatment recommendations or risk-stratify patients reliably. Also, it is expected that many additional genetic variants exist that can modify disease and its severity. This large-scale genome-wide association study (GWAS) will utilize SNP chips to investigate the genetic profile of individuals with hemoglobinopathies, thereby addressing the challenges of previous studies related to small sample sizes and low statistical power, while promoting the participation of diverse populations worldwide. The study aims to i) discover new genetic modifiers of hemoglobinopathies, ii) validate previously reported genetic modifiers, iii) pool and analyze existing genomic data, iv) standardize phenotypic descriptions, v) develop a research resource of disease-specific data generated in INHERENT, including genomic, phenotypic, and functional data, and vi) develop risk scores that can be used for patient stratification. The main endpoints include: Worldwide demography, including numbers of patients, main genotypes, and overall disease severity/burden in participating centres Genetic modifiers affecting clinical or laboratory phenotypes of hemoglobinopathies, including overall survival in SCD and/or thalassemia, stroke and/or decreased neurocognitive function in SCD and/or thalassemia, renal impairment in SCD and/or thalassemia, leg ulcers in SCD, priapism in SCD, mild or severe acute pain and/or chronic pain syndromes in SCD, pulmonary hypertension in SCD and/or thalassemia, hyperhemolysis in SCD and/or thalassemia, fetal hemoglobin levels, degree of ineffective erythropoiesis, hepatic fibrosis/cirrhosis and/or cardiac siderosis, Genetic modifiers affecting response to treatment, including response to hydroxyurea, response to iron chelation treatment, response to emerging therapeutic agents

Official Title
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Study of the Role of Genetic Modifiers in Hemoglobinopathies

Conditions
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Sickle Cell Disease, Thalassemia, Beta, Thalassemia Alpha, Hemoglobinopathies

Intervention / Treatment
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* Genetic: GWAS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of an inherited hemoglobinopathy, including sickle cell disease (SCD), β-thalassemia, and α-thalassemia; all genotypes will be considered. Age ≥ 2 years old at the time of the collection of the phenotypic data. There will be no limits on study participants in terms of gender, ethnicity, morbidities. Exclusion Criteria: Patients treated with stem cell transplantation or genetic therapy. Age < 2 years old at the time of the collection of the phenotypic data. Patient or legal representative for minors unwilling or unable to give consent.

Ages Eligible for Study
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Minimum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cohort<br>Individuals with hemoglobinopathies | Genetic: GWAS<br>* The study will perform a GWAS experiments for all recruited subjects. The blood sample will be collected during routine clinical visits, only if DNA is not already available in existing biobanks. All individuals will provide consent for participation in the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Genetic modifiers in haemoglobinopathies through GWAS | Number of genetic variants (SNPs) associated with disease-specific phenotypes | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GWAS, thalassemia, sickle cell disease, genetic modifiers