Factors aside from HbS itself undoubtedly contribute to the remark able inter-individual diversity of clinical phenotype in HbSS, but only a few have been identified thus far. Phenotypes could be significantly influenced by the environment, nutrition, socioeconomic status, endemic infectious agents, and availability of medical care. It is believed that phenotypic variability is most evident in countries where the survival of sickle patients is longer. The innumerable questions regarding phenotypic diversity are of great importance. In HbSS, why do some children, but not others, develop stroke? Why do only a small fraction of adults develop pulmonary hypertension, even though all have ongoing hemolysis? Why does pain severity vary so remarkably irrespective of globin genotype? And so on.

Level of Hemoglobin F

HbF level varies amongst individuals as a quantitative trait and is determined by approximately 80% by genetics.  After its decline over the first 6 months of life, most of the anti-sickling protection from its high level at birth is lost. HbF level varies among sickle adults over a 20-fold range, and this reflects the number of F cells, the amount of HbF per F cell, and the preferential survival of F cells.  It is estimated that a given sickle RBC requires > 10 pg HbF for polymerization to be effectively inhibited.

Known HbF determinants account for perhaps one-half of its variance: a polymorphic XmnI site (11p) upstream of the G γ gene; the HBSIL-MYB intergenic region (6q23); SNPs in TOX (8q12.1); and polymorphisms of BCL11A (2p16), a transcriptional silencer of the HBG gene.  HbF is somewhat higher levels in females, hinting at a contributing locus on the X chromosome. Polymorphisms in trans acting enhancers of BCL11A account for some, but not all, of the regional variations in the HbF level. Among the African autochthonous haplotypes, the Benin haplotype is associated with higher HbF levels; however, it is twice again as high among those with the Arab India haplotype.

α-Thalassemia

The normal genotype is α α / α α, but about 30% of African Americans have a single α deletion (- α / α α), so concordance with sickle cell dis ease is common; and homozygosity for the allele is seen (– α /– α). Its prevalence elsewhere varies regionally. An α -gene deletion has mini mal effect on the HbF level but results in improved RBC hydration, a lower ISC count, improved RBC survival, and less severe anemia. Perhaps the loss of one α gene nudges α / β chain balance toward nor mal, given the mild instability of β S globin. 2 Yet there is no amelioration of pain severity, and some complications (osteonecrosis, retinopathy) increase, possibly because of the higher blood viscosity.   

β-Globin Alleles

Compound heterozygosity for the sickle gene and another β allele affects clinical phenotype, for example, in the direction of amelioration from admixing β C or β +thal chains with β S. The resulting HbSC disease, however, presents a unique case. Although HbC impedes HbS polymer formation as well as HbA, HbSC disease is more similar to HbSS than it is to HbAS. The rea son is that HbC interacts more with the RBC membrane than HbA does, and it thereby stimulates RBC KCl cotransport, promoting RBC dehydration that increases HbS concentration. 28 Although pain and anemia are lessened a bit in HbSC disease, there is an increased propensity for retinopathy and osteonecrosis. It has been assumed that this derives from the somewhat higher blood viscosity when anemia is less severe. HbSC blood reveals footprints of greater pro-angiogenic tone compared to HbSS blood, consistent with the higher propensity for retinopathy. Other less common β gene alleles can likewise interact with HbS and affect clinical phenotype via impact on polymerization.

HbAS is typically associated with renal hyposthenuria, not sur prising given the several polymer-promoting influences of the renal milieu. More seriously, trait comprises risk for exertional sudden death, probably precipitated by effects of dehydration on RBC and blood viscosity. At an epidemiologic level, the trait also involves a heightened risk for thromboembolism and chronic renal disease, and it predisposes toward ischemic stroke. It is relevant that, unlike Hb tetramers that include either a γ or a β A2 globin chain, tetramers that include a β A or a β C globin chain are only partially inhibited from participating in polymerization.

Unexplained Phenotypic Diversity

Beyond these well-defined influences, there is still enormous unexplained variability in the clinical phenotype of HbSS. The disparate biologic processes that participate in SCA pathophysiology high light the certainty that phenotypic heterogeneity will be influenced by underlying genetic variations affecting adhesion biology, cation homeostasis, inflammatory signaling, vasoregulation, and so on. Indeed, the spectrum of potential foci at which genetic variation might exert effects and be relevant to sickle disease phenotypic diversity is as vast and complex as human biology itself.

The single-nucleotide polymorphisms (SNPs) that have been detected in association with specific clinical complications are far too numerous to describe here.  Of course, much work is still needed to discern whether such associations are actually informative vis à vis pathogenic specifics. However, several SNPs seem particularly interesting. A TNF (-308) promoter polymorphism is associated with large vessel stroke in sickle children. Polymorphisms affecting the HO-1 promoter create heterogeneity in GT repeat lengths (the shorter of which enable greater HO-1 responsiveness, e.g., to heme) and are described as being associated with a lower hospitalization rate for ACS in children. Interestingly, a TLR4 polymorphic haplotype prevalent only in sub-Saharan Africa leads to greater inflammatory responsiveness to TLR4 ligands; it is protective in malaria, but it could well adversely impact sickle biology. Similarly, the Duffy null phenotype prevalent in Sub-Saharan Africa appears to confer heightened severity for acute lung injury; its presence may likewise promote ACS in sickle disease.

A wholly different approach to this general problem was pro vided by examination of gene expression and inflammatory response of endothelial cells derived from living subjects. Those from sickle children with circle of Willis disease predicted an augmented inflammatory response, that was experimentally verified as an exaggerated NF κ B activation response to stimulation with TNF/IL-1.  Certainly, the contribution of various non-globin genetic influences will continue to be identified as modern and creative approaches are being applied to the problem of phenotypic diversity in HbSS.

اخر الاخبار

اخبار العتبة العباسية المقدسة

سماحة السيد الصافي: عهد الإمام علي (عليه السلام) لمالك الأشتر ضرورة لكل قيادي وإداري في المجتمعات

قسم المعارف: كتاب (الكواكب السماوية) يقدم مادة علمية تخدم الباحثين في مجالات الأدب والعقيدة والبلاغة

قسم الصيانة يجري أعمال الإدامة الدورية لجدران حرم مرقد أبي الفضل العباس (عليه السلام) وصحنه الشريف

قسم الشؤون الفكرية يعلن انضمام الجامعة العراقية لمشروع حفظ النتاج العلمي العراقي

المزيد

الآخبار الصحية

السجائر الإلكترونية والإقلاع عن التدخين.. نتائج متباينة تثير الجدل العلمي

مصر تحقق إنجازاً دولياً جديداً في منظمة الصحة العالمية

دراسة: السباحة فعّالة أكثر من الجري في الحفاظ على صحة القلب

عامل خطر في بداية الحمل يؤخر تطور الكلام والمهارات الحركية لدى الرضع

المزيد

الآخبار التكنلوجية

أحلامك ليست عشوائية.. إليك ما يفعله دماغك أثناء نومك

روسيا.. العلماء يضاعفون الاستقرار الحراري للألواح الشمسية ثلاث مرات

علماء يكشفون سر سرعة الدلافين في السباحة

سلمي أو دموي.. هكذا تنتقل السلطة في مجتمع الجرذان

المزيد

مواضيع ذات صلة

Severe Iodine Deficiency and natural Goitrogens

Iatrogenic Hypothyroidism

The Unique Systems Biology of Sickle Cell Anemia

Abnormalities of Sickle Red Blood Cells

Abnormal Molecular Behaviors of Sickle Hemoglobin

Clinical Assessment and Systemic Manifestations of Hypothyroidism: Diagnostic Accuracy

Clinical Aspects of Hypothyroidism due to Different Aetiologies

Clinical Aspects of Hypothyroidism at Different Ages

Thalassemic Structural Variants

Chronic Care of the Adult Patient With Thalassemia : Novel Therapeutic Approaches

Chronic Care of the Adult Patient With Thalassemia : Hematopoietic Stem Cell Transplantation

Survival in Patients With Thalassemia Major