Study of the Role of Genetic Modifiers in Hemoglobinopathies

Recruiting

• Conditions: Hemoglobinopathies; Sickle Cell Disease; Thalassemia, Beta; Thalassemia Alpha
• Interventions: Genetic: GWAS

• Registration Number: NCT05799118
• Lead Sponsor: Cyprus Institute of Neurology and Genetics

Brief Summary

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

Detailed Description

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:

1. Worldwide demography, including numbers of patients, main genotypes, and overall disease severity/burden in participating centres

2. Genetic modifiers affecting clinical or laboratory phenotypes of hemoglobinopathies, including

1. overall survival in SCD and/or thalassemia,

2. stroke and/or decreased neurocognitive function in SCD and/or thalassemia,

3. renal impairment in SCD and/or thalassemia,

4. leg ulcers in SCD,

5. priapism in SCD,

6. mild or severe acute pain and/or chronic pain syndromes in SCD,

7. pulmonary hypertension in SCD and/or thalassemia,

8. hyperhemolysis in SCD and/or thalassemia,

9. fetal hemoglobin levels,

10. degree of ineffective erythropoiesis,

11. hepatic fibrosis/cirrhosis and/or cardiac siderosis,

3. Genetic modifiers affecting response to treatment, including

1. response to hydroxyurea,

2. response to iron chelation treatment,

3. response to emerging therapeutic agents

Study Timeline

• Study Start: 2022-10-01
• Study First Submitted: 2023-03-10
• Study First Submitted QC: 2023-03-22
• Study First Posted: 2023-04-05
• Status Verified: 2024-03
• Last Update Submitted: 2024-03-19
• Last Update Posted: 2024-03-20
• Primary Completion: 2027-09-30
• Study Completion: 2027-09-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 30000

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.

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Cohort	GWAS	Individuals with hemoglobinopathies

Primary Outcome Measures

Name	Time	Method
Genetic modifiers in haemoglobinopathies through GWAS	5 years	Number of genetic variants (SNPs) associated with disease-specific phenotypes

Trial Locations

Locations (26)

Boston Children's Hospital; 🇺🇸 Boston, Massachusetts, United States

Lucrecia Paím Maternity; 🇦🇴 Luanda, Angola

Universiti Brunei Darussalam; 🇧🇳 Brunei, Brunei Darussalam

University of Buenos Aires; 🇦🇷 Buenos Aires, Argentina

Larnaca General Hospital; 🇨🇾 Larnaca, Cyprus

Paphos General Hospital; 🇨🇾 Paphos, Cyprus

University of Lahore; 🇵🇰 Lahore, Pakistan

Centro Hospitalar e Universitário de Coimbra; 🇵🇹 Coimbra, Portugal

University Hospitals Leuven; 🇧🇪 Leuven, Belgium

Centre Hospitalier Monkole; 🇨🇩 Kinshasa, Congo, The Democratic Republic of the

Limassol General Hospital; 🇨🇾 Limassol, Cyprus

Hippokrateio Hospital of Athens; 🇬🇷 Athens, Greece

Hospital Clínico San Carlos; 🇪🇸 Madrid, Spain

Universiti Sains Malaysia; 🇲🇾 Kota Bharu, Malaysia

Ahmadu Bello University; 🇳🇬 Zaria, Nigeria

Rigshospitalet; 🇩🇰 Copenhagen, Denmark

Archbishop Makarios III Hospital; 🇨🇾 Nicosia, Cyprus

Laiko General Hospital; 🇬🇷 Athens, Greece

National and Kapodistrian University of Athens; 🇬🇷 Athens, Greece

Ampang Hospital; 🇲🇾 Ampang, Malaysia

Universiti Kebangsaan Malaysia; 🇲🇾 Bangi, Malaysia

General Hospital of Larissa; 🇬🇷 Larissa, Greece

Emek Medical Centre; 🇮🇱 Afula, Israel

University of Turin; 🇮🇹 Turin, Italy

Kaduna State University; 🇳🇬 Kaduna, Nigeria

University of Abuja; 🇳🇬 Abuja, Nigeria