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Genes Influencing Iron Overload State

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01158794
Recruitment Status : Completed
First Posted : July 8, 2010
Last Update Posted : September 18, 2019
Sponsor:
Information provided by (Responsible Party):
St. Jude Children's Research Hospital

Study Description
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Brief Summary:

Iron overload, which can be defined operationally as too much iron in the body, develops as a consequence of too many blood transfusions given, or due to genetic defects hereditary hemochromatosis). Iron accumulates in several organs in the body, such as the heart, liver, endocrine glands (pancreas, thyroid, etc.), and spleen. Excessive iron can damage organs and may even cause death. Iron overload needs to be appropriately monitored and treated to avoid unnecessary morbidity and mortality.

The present study, GENIOS, proposes to test prospectively the hypothesis that genetic modifiers influence the iron overload status of patients receiving transfusions. To test this hypothesis, the study will perform genetic studies to investigate possible genetic influences for iron accumulation in the body and will study iron accumulation not only in the liver, but also in the heart, pancreas, kidneys, and spleen. In addition: the study will investigate if these same genes have any role during treatment of iron overload, in other words, if certain genetic mutations will influence how iron exits the body. This study will also investigate how substances that are known to control the trafficking of iron in and out of the body and its damaging effects to the tissues (hepcidin and non transferrin-bound iron) are linked to the accumulation of iron in the heart and liver. Iron in the body will be measured by R2*MRI and no liver biopsies will be required. Genetic studies will be done by specialized tests using peripheral blood DNA.

Iron accumulates differently in different people and in different organs of the body. Some people accumulate iron faster than others, even when receiving the same number of blood transfusions


Condition or disease
Sickle Cell Disease Thalassemia Marrow Aplasia

Detailed Description:

This study will focus on the following primary objective:

  • To investigate the association of GSTM1 gene deletion and liver iron concentration in patients with sickle cell disease and transfusional iron-overload.

The Secondary Objectives of the study are:

  • To explore the role of other iron metabolism-associated candidate genes on liver iron concentration of sickle cell patients with transfusional iron-overload.
  • To explore the role of GSTM1 genotypes and other iron metabolism-associated candidate genes on maintenance and decline of liver iron concentration of patients with sickle cell disease and transfusional iron-overload.
  • To explore the role of GSTM1 genotypes and other iron metabolism-associated candidate genes on increase, maintenance, and decline of iron concentration in the heart, pancreas, kidneys, and spleen of patients with sickle cell disease and transfusional iron overload.
  • To explore the role of GSTM1 gene deletion and other iron metabolism-associated candidate genes on increase, maintenance, and decline of iron concentration in the liver, heart, pancreas, kidneys, and spleen of non-sickle cell patients with transfusional iron-overload.
  • To explore the relationship between Non-Transferrin Bound Iron (NTBI), hepcidin, organ function, and iron increase, maintenance, and decline in the liver, heart, pancreas, kidneys, and spleen of patients with transfusional iron overload.
Study Design
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Study Type : Observational
Actual Enrollment : 50 participants
Observational Model: Case-Only
Time Perspective: Prospective
Official Title: Genes Influencing Iron Overload State
Actual Study Start Date : September 21, 2010
Actual Primary Completion Date : July 31, 2016
Actual Study Completion Date : April 17, 2019

Resource links provided by the National Library of Medicine


Groups and Cohorts
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Group/Cohort
Study participants
Participants with sickle cell disease and transfusional iron-overload, and non-sickle cell disease (thalassemia major, cancer patients, etc.) and iron overload. Participants with iron overload, defined as too much iron in the body as a consequence of too many blood transfusions.


Outcome Measures
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Primary Outcome Measures :
  1. This study will measure genetic modifiers influencing the iron overload status of patients receiving transfusions. [ Time Frame: Once, at participant enrollment ]
    This study will measure the association between GSTM1 gene deletion and other candidate genes and the accumulation and clearance of body iron.


Secondary Outcome Measures :
  1. To explore the role of other iron metabolism-associated candidate genes on liver iron concentration of sickle cell patients with transfusional iron-overload. [ Time Frame: Once, at participant enrollment ]
  2. To explore the role of GSTM1 genotypes and other iron metabolism-associated candidate genes on maintenance and decline of liver iron concentration of patients with sickle cell disease and transfusional iron-overload. [ Time Frame: Once at baseline compared to 3 years after participant enrollment ]
  3. Explore the role of GSTM1 genotypes and other iron metabolism-associated candidate genes on increase, maintenance, and decline of iron concentration patients with sickle cell disease and transfusional iron overload. [ Time Frame: Once at baseline compared to 3 years after participant enrollment ]
    Decline of iron concentration is in the heart, pancreas, kidneys, and spleen.

  4. Explore the role of GSTM1 gene deletion and other iron metabolism-associated candidate genes on increase, maintenance, and decline of iron concentration of non-sickle cell patients* with transfusional iron-overload. [ Time Frame: Once at baseline compared to 3 years after participant enrollment ]
    Decline of iron concentration in the liver, heart, pancreas, kidneys, and spleen of non-sickle cell patients with transfusional iron-overload.

  5. Explore the relationship between Non-Transferrin Bound Iron (NTBI), hepcidin, organ function, and iron increase, maintenance, and decline in the liver, heart, pancreas, kidneys, and spleen of patients with transfusional iron overload. [ Time Frame: Once at baseline compared to 3 years after participant enrollment ]

Biospecimen Retention:   Samples With DNA
The total volume of blood transfused (in ml/kg) will be collected and stored in the study database. Cumulative transfused blood volume (in ml/kg) will be captured. Serum samples will be stored frozen at -20°C until the time of analysis. In addition to the protocol-specific testing of specimens, study participants will be offered the option of allowing any leftover purified DNA, serum, or blood cells to be saved or shared for future analyses. Leftover purified genomic DNA, serum, and blood cells from subjects enrolled in the GENIOS protocol will be de-identified prior to storage or any future testing and/or sharing.

Eligibility Criteria
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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Study participants will be patients who receive medical care at St. Jude Children's Research Hospital and have developed iron overload secondary to multiple transfusions. Patients will be approached during regular outpatient visits and will be invited to participate in this study if they meet the inclusion/exclusion criteria and consent to participate in the study. Non-sickle cell patients with transfusional iron overload includes patients with thalassemia, bone marrow failure syndromes, and patients who have received multiple blood transfusions due to marrow aplasia secondary to the use of chemotherapeutic agents. About 40 participants with sickle cell disease are targeted. About 10 participants with non-sickle cell disease are targeted.
Criteria

Inclusion Criteria:

  • History of ≥ 12 lifetime erythrocyte transfusions who have not yet initiated treatment to unload iron (iron chelation or therapeutic phlebotomy), or
  • History of ≥ 12 lifetime erythrocyte transfusions who have initiated treatment to unload iron, but had liver iron content measurement (by R2*MRI) within 3 months prior to initiation of iron unloading treatment

Exclusion Criteria

  • Known contraindication to performance of MRI (e.g.: presence of MRI-incompatible ferromagnetic material in the body)
  • Prior participation on the St. Jude MRIRON protocol
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01158794


Locations
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United States, Tennessee
St. Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105
Sponsors and Collaborators
St. Jude Children's Research Hospital
Investigators
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Principal Investigator: Jane Hankins, MD, MS St. Jude Children's Research Hospital
More Information
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Additional Information:

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Responsible Party: St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier: NCT01158794    
Other Study ID Numbers: GENIOS
First Posted: July 8, 2010    Key Record Dates
Last Update Posted: September 18, 2019
Last Verified: September 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by St. Jude Children's Research Hospital:
Iron overload
Blood Transfusion
Additional relevant MeSH terms:
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Anemia, Sickle Cell
Thalassemia
Iron Overload
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
 Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Iron Metabolism Disorders
Metabolic Diseases