title: The search for genetic modifiers of disease severity in the β-hemoglobinopathies.
abstract: Sickle cell disease (SCD) and β-thalassemia, two monogenic diseases caused by mutations in the β-globin gene, affect millions of individuals worldwide. These hemoglobin disorders are characterized by extreme clinical heterogeneity, complicating patient management and treatment. A better understanding of this patient-to-patient clinical variability would dramatically improve care and might also guide the development of novel therapies. Studies of the natural history of these β-hemoglobinopathies have identified fetal hemoglobin levels and concomitant α-thalassemia as important modifiers of disease severity. Several small-scale studies have attempted to identify additional genetic modifiers of SCD and β-thalassemia, without much success. Fortunately, improved knowledge of the human genome and the development of new genomic tools, such as genome-wide genotyping arrays and next-generation DNA sequencers, offer new opportunities to use genetics to better understand the causes of the many complications observed in β-hemoglobinopathy patients. Here I discuss the most important factors to consider when planning an experiment to find associations between β-hemoglobinopathy-related complications and DNA sequence variants, with a focus on how to successfully perform a genome-wide association study. I also review the literature and explain why most published findings in the field of SCD modifier genetics are likely to be false-positive reports, with the goal to draw lessons allowing investigators to design better genetic experiments.
authors.affiliation: Montreal Heart Institute and Université Montréal, Montréal, Québec H1T 1C8, Canada. guillaume.lettre@mhi-humangenetics.org
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lettre
mesh_terms: D000755:Anemia, Sickle Cell / Q000150:complications / Q000235:genetics*; D005319:Fetal Hemoglobin / Q000235:genetics* / Q000378:metabolism; D060045:Genes, Modifier; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006453:Hemoglobinopathies / Q000235:genetics*; D006801:Humans; D009154:Mutation; D055544:beta-Globins / Q000235:genetics*; D017086:beta-Thalassemia / Q000235:genetics*
chemical_list: D055544:beta-Globins; D005319:Fetal Hemoglobin