Sickle cell disease has been shown to demonstrate extensive variability in disease severity among and between individuals, the variability highlighted by differing genetic haplotypes. Despite the abundance of reports of functional significance due to polymorphisms of endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1) genes, the role of these polymorphisms in mediating sickle cell disease pathophysiology among African Americans is presently unclear. To deconvolute their potential significance among African Americans with sickle cell disease, we examined the genetic diversity and haplotype frequency of eNOS and ET-1 polymorphisms in disease (n = 331) and control (n = 379) groups, with a polymerase–chain reaction restriction fragment length polymorphism assay. We report that genotypic and allelic frequencies of eNOS variants are not significantly different between groups. eNOS homozygote mutants, which had been shown to have clinical significance elsewhere, showed no statistical significance in our study. On the other hand, and contrary to previous report among Africans with sickle cell disease, the endothelin-1 homozygous mutant variant showed significant difference in genotypic (p = 2.84E-12) and allelic frequencies (p = 2.20E-16) between groups. The most common haplotype is the combination of T786C homozygote wild-type variant with homozygote mutant variants of G5665T (ET-1) and Glu298Asp (eNOS). These results show that endothelin-1 (rs5370) polymorphism, rather than endothelial nitric oxide synthase polymorphism might play a significant role in disease severity or individual clinical outcomes among African Americans with sickle cell disease. This would have profound implications for designing and/or advancing personalized care for sickle cell patients and relieving disease complications.
Backgroundp24/transmembrane Emp24 domain (TMED) proteins are a set of evolutionarily conserved, single pass transmembrane proteins that have been shown to facilitate protein secretion and selection of cargo proteins to transport vesicles in the cellular secretion pathway. However, their functions in animal development are incompletely understood.ResultsThe C. elegans genome encodes eight identified TMED genes, with at least one member from each defined subfamily (α, β, γ, δ). TMED gene mutants exhibit a shared set of defects in embryonic viability, animal movement, and vulval morphology. Two γ subfamily genes, tmed‐1 and tmed‐3, exhibit the ability to compensate for each other, as defects in movement and vulva morphology are only apparent in double mutants. TMED mutants also exhibit a delay in breakdown of basement membrane during vulva development.ConclusionsThe results establish a genetic and experimental framework for the study of TMED gene function in C. elegans, and argue that a functional protein from each subfamily is important for a shared set of developmental processes. A specific function for TMED genes is to facilitate breakdown of the basement membrane between the somatic gonad and vulval epithelial cells, suggesting a role for TMED proteins in tissue reorganization during animal development.
Sickle cell disease (SCD) presents with multiple complications and marked variability in severity among individuals and possible underlying differences in ethnic-specific disease pathogenesis. The CD209 gene otherwise called DC-SIGN encodes a transmembrane receptor and is expressed on the surface of dendritic cells with multiple studies showing association between its variants and susceptibility to infections. In SCD, vaso-occlusive crises and infections are common occurrences, and the role of CD209 is currently unknown. We examined the genotypic and allelic diversity of CD209 gene and determined its association with SCD in African children. Genomic DNA from 145 children (HbSS) and 244 controls (HbAA) were analyzed for polymorphic variants of CD209 by PCR-RFLP. All SNPs follow Hardy-Weinberg equilibrium (P>0.05). There was a significant difference in both genotypic and allelic frequencies (P=0.004 and P=0.015 respectively) of a promoter variant in CD209, DC-SIGN1-336 between SCD and controls. Additionally, genotype GG variant is less frequent (10.3% versus 22.1%) and significantly associated with sickle cell disease (OR=0.3868; P=0.0010) and this reduced frequency reveals an impaired or reduced capacity to mount an immune response to infectious pathogens. The implications of this finding for delineating disease co-morbidity or as genetic modifiers of SCD pathophysiology, and its significance in African American children with SCD will be explored
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