Genetic modifiers of long‐term survival in sickle cell anemia

Abstract

Background Sickle 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. Methods Against 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. Results In 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. Conclusions This study provides new gene sets that contribute to variability in clinical expression of SCA. Identified genes and pathways suggest new avenues for other interventions.

Distribution of HbS Allele and Haplotypes in a Multi-Ethnic Population of Guinea Bissau, West Africa: Implications for Public Health Screening

“…While the different ethnic distribution of the HbS allele warrants a deeper understanding of the genetic background of the population and further research ( 28 – 30 ), it can also aid to prioritize actions for SCD, such as starting awareness campaigns and screening in areas of the country or sectors of the city where the highest rate of carriers is living. Unfortunately, Guinea Bissau has very limited resources allocated to health care and other urgent health priorities like infectious diseases -HIV, TB, and cholera which catalyzed health care energy and resources in the past years.…”

Incomplete Penetrance and Variable Expressivity: From Clinical Studies to Population Cohorts

“…Cystic fibrosis CFTR TGFB1 (Racanelli et al, 2018) Increased severity of lung disease IFRD1 (Gu et al, 2009) Earlier age of the onset of chronic infection DCTN4 (Emond et al, 2012;Viel et al, 2016) Sickle cell disease HBB BCL11A (Bae et al, 2012) Prolonged production of fetal hemoglobin and reduced disease severity HBS1L-MYB (Bae et al, 2012;Steinberg and Sebastiani, 2012;Chang et al, 2018;Allard et al, 2021) Decrease in disease severity CLCN6 (Wonkam et al, 2020) OGHDL (Wonkam et al, 2020) Long QT syndrome KCNQ1 NOS1AP (Crotti et al, 2009) Modulate the risk of arrythmias KCHN2 SCN5A…”

Anemia: Considerations for the Dental Practitioner

“…Thalassemia is a genetic disorder that involves atypical Hgb synthesis, consequently defective RBCs [8,10] It belongs to the microcytic hemolytic type of anemia and comprises two types, α and β [2,9]. In major thalassemia, the unsuccessful erythropoiesis augments the volume of plasma and progressively leads to a splenomegaly and bone marrow expansion resulting in osteomalacia and craniofacial deformities (Chipmunk facies) [8,11].…”