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Genetic modifiers of sickle cell disease.

ABSTRACT: Sickle cell anemia is associated with unusual clinical heterogeneity for a Mendelian disorder. Fetal hemoglobin concentration and coincident ? thalassemia, both which directly affect the sickle erythrocyte, are the major modulators of the phenotype of disease. Understanding the genetics underlying the heritable subphenotypes of sickle cell anemia would be prognostically useful, could inform personalized therapeutics, and might help the discovery of new "druggable" pathophysiologic targets. Genotype-phenotype association studies have been used to identify novel genetic modifiers. In the future, whole genome sequencing with its promise of discovering hitherto unsuspected variants could add to our understanding of the genetic modifiers of this disease.

SUBMITTER: Steinberg MH

PROVIDER: S-EPMC4562292 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Genetic modifiers of sickle cell disease.

Steinberg Martin H MH Sebastiani Paola P

American journal of hematology 20120528 8

Sickle cell anemia is associated with unusual clinical heterogeneity for a Mendelian disorder. Fetal hemoglobin concentration and coincident α thalassemia, both which directly affect the sickle erythrocyte, are the major modulators of the phenotype of disease. Understanding the genetics underlying the heritable subphenotypes of sickle cell anemia would be prognostically useful, could inform personalized therapeutics, and might help the discovery of new "druggable" pathophysiologic targets. Genot ...[more]

PMID: 22641398

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Project description:BackgroundSickle cell anemia (SCA) is a clinically heterogeneous, monogenic disorder. Medical care has less-than-optimal impact on clinical outcomes in SCA in Africa due to several factors, including patient accessibility, poor access to resources, and non-availability of specific effective interventions for SCA.MethodsAgainst this background, we investigated 192 African participants who underwent whole exome sequencing. Participants included 105 SCA patients spanning variable clinical expression: a "long survivor" group (age over 40 years), a "stroke" group (at least one episode of overt stroke), and a "random" group (patients younger than 40 years without overt cerebrovascular disease). Fifty-eight ethnically matched homozygous hemoglobin A controls were also studied. Findings were validated in an independently recruited sample of 29 SCA patients. Statistical significance of the mutational burden of deleterious and loss-of-function variants per gene against a null model was estimated for each group, and gene-set association tests were conducted to test differences between groups.ResultsIn the "long survivor" group, deleterious/loss-of-function variants were enriched in genes including CLCN6 (a voltage-dependent chloride channel for which rare deleterious variants have been associated with lower blood pressure) and OGHDL (important in arginine metabolism, which is a therapeutic target in SCA). In the "stroke" group, significant genes implicated were associated with increased activity of the blood coagulation cascade and increased complement activation, for example, SERPINC1, which encodes antithrombin. Oxidative stress and glutamate biosynthesis pathways were enriched in "long survivors" group. Published transcriptomic evidence provides functional support for the role of the identified pathways.ConclusionsThis study provides new gene sets that contribute to variability in clinical expression of SCA. Identified genes and pathways suggest new avenues for other interventions.

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Genetic modifiers of sickle cell disease.

Publications

Genetic modifiers of sickle cell disease.

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