Clinical trial NCT05799118: Study of the Role of Genetic Modifiers in Hemoglobinopathies
Official title: Study of the Role of Genetic Modifiers in Hemoglobinopathies
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Sickle Cell Disease
Thalassemia, Beta
Thalassemia Alpha
Hemoglobinopathies
Keywords: GWAS
thalassemia
sickle cell disease
genetic modifiers
Lead sponsor: Cyprus Institute of Neurology and Genetics
Sponsor class: OTHER
First posted: 2023-04-05
Enrollment: 30000
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Individuals diagnosed with an inherited hemoglobinopathy and are under regular follow-up in the participating centers

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

Eligibility criteria: 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.

Primary outcomes:
measure: Genetic modifiers in haemoglobinopathies through GWAS
timeFrame: 5 years
Secondary outcomes:
Other outcomes:
Locations:
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Luanda
country: Angola
facility: Lucrecia Paím Maternity
city: Buenos Aires
country: Argentina
facility: University of Buenos Aires
city: Leuven
country: Belgium
facility: University Hospitals Leuven
city: Brunei
country: Brunei Darussalam
facility: Universiti Brunei Darussalam
city: Kinshasa
country: Congo, The Democratic Republic of the
facility: Centre Hospitalier Monkole
city: Larnaca
country: Cyprus
facility: Larnaca General Hospital
city: Limassol
country: Cyprus
facility: Limassol General Hospital
city: Nicosia
country: Cyprus
facility: Archbishop Makarios III Hospital
city: Paphos
country: Cyprus
facility: Paphos General Hospital
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Athens
country: Greece
facility: Hippokrateio Hospital of Athens
city: Athens
country: Greece
facility: Laiko General Hospital
city: Athens
country: Greece
facility: National and Kapodistrian University of Athens
city: Larissa
country: Greece
facility: General Hospital of Larissa
city: Afula
country: Israel
facility: Emek Medical Centre
city: Turin
country: Italy
facility: University of Turin
city: Ampang
country: Malaysia
facility: Ampang Hospital
city: Bangi
country: Malaysia
facility: Universiti Kebangsaan Malaysia
city: Kota Bharu
country: Malaysia
facility: Universiti Sains Malaysia
city: Abuja
country: Nigeria
facility: University of Abuja
city: Kaduna
country: Nigeria
facility: Kaduna State University
city: Zaria
country: Nigeria
facility: Ahmadu Bello University
city: Lahore
country: Pakistan
facility: University of Lahore
city: Coimbra
country: Portugal
facility: Centro Hospitalar e Universitário de Coimbra
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos
Study officials:
affiliation: Cyprus Institute of Neurology and Genetics
name: Petros Kountouris, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kountouris P, Stephanou C, Archer N, Bonifazi F, Giannuzzi V, Kuo KHM, Maggio A, Makani J, Manu-Pereira MDM, Michailidou K, Nkya S, Nnodu OE, Trompeter S, Tshilolo L, Wonkam A, Zilfalil BA, Inusa BPD, Kleanthous M; on behalf of the International Hemoglobinopathy Research Network (INHERENT). The International Hemoglobinopathy Research Network (INHERENT): An international initiative to study the role of genetic modifiers in hemoglobinopathies. Am J Hematol. 2021 Nov 1;96(11):E416-E420. doi: 10.1002/ajh.26323. Epub 2021 Aug 30. No abstract available.