Haptoglobin Polymorphism on Stroke in Sickle Cell Disease

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1		Sylvain Dore	--	9045	2022-04-13 05:23:29	\|
2	format	Jason Zhu	-4531 word(s)	4514	2022-04-14 04:27:50	\| \|
3	format	Jason Zhu	-1350 word(s)	3164	2022-04-15 10:15:00	\|

This entry is adapted from the peer-reviewed paper 10.3390/genes13010144

Haptoglobin (Hp) is a blood serum glycoprotein responsible for binding and removing toxic free hemoglobin from the vasculature. Understanding the role of the various Hp isoforms in patients with sickle cell disease (SCD) is critical in combating blood toxicity, inflammation, oxidative stress, and even stroke. Ischemic stroke occurs when a blocked vessel decreases oxygen delivery in the blood to cerebral tissue and is commonly associated with SCD, and Hp can potentially help to understand how this occur and how to potentially prevent the neurological damage..

brain ischemia genotype hemolytic anemia hospitalization precision medicine hemoglobin neuroinflammation therapy prevention prognostic

1. Introduction

1.1. Sickle Cell Disease

Sickle cell disease (SCD) is a group of autosomal recessive disorders that affect an estimated 20 to 25 million people worldwide ^[1], making it the most prevalent monogenic disorder and a serious public health concern. Inheritance of this disorder is concentrated in sub-Saharan African, South Asian, Middle Eastern, and Mediterranean regions ^[2]^[3]. Due to the recessive-trait nature of SCD, even larger populations carry sickle cell trait, maintaining the chances that SCD will be passed on through generations. Every year, an estimated 300,000 infants are born with SCD worldwide, adding to the existing millions of patients seeking treatment ^[2]. SCD is a hemolytic disorder caused by a range of mutations in the gene responsible for coding the β-globin (HBB) subunits of hemoglobin (Hb). These mutations usually result in abnormal versions of Hb, which are capable of polymerizing, leading to malformed, sickle-shaped red blood cells (RBCs). SCD is a form of hemolytic anemia, a class of disorders characterized by high rates of hemolysis. As these deformed and rigid RBCs travel through the vasculature and supply major organs, high levels of hemolysis occur, triggering signaling pathways that can lead to oxidative stress, free radical formation, chronic pain crises, and other detrimental symptoms that are characteristic of SCD. The resulting byproducts of hemolysis are of particular concern due to their high natural toxicity to the body’s life-sustaining organs. Free heme, a direct product of Hb destruction, is the main culprit of many symptoms associated with SCD. Among other detriments, the circulation of toxic free heme can cause vaso-occlusion-related pain crises, vasoconstriction, proinflammatory macrophage signaling and cytokine release, acute kidney injury, and silent cerebral infarction (SCI) ^[4]. These symptoms can aggravate existing SCD symptoms and worsen the independent quality of life of those suffering from chronic SCD. Widespread vasoconstriction exacerbates vaso-occlusion and resulting pain crises by further constricting existing blood flow blockages, in turn increasing premature hemolysis rates, worsening the severity of SCD pathophysiology, and increasing the risk of damaging critical organs. SCD is the umbrella term used to group the many subtypes of this monogenic disease because there are multiple possible Hb genotypic variations.

It is common for patients with SCD to experience chronic pain crises associated with VOC. The deformed RBCs stick to the endothelium and collect to form clots throughout the body, triggering premature hemolysis and anti-inflammatory response pathways at an exponentially increased rate. When these VOCs occur specifically within the cerebral vasculature, stroke occurrence also increases. These strokes are often silent or mini-strokes that do not present symptomatically. Alternatively, they can be overt ischemic strokes, causing severe, lasting symptoms in patients. SCD and stroke incidence are highly associated, especially in children, who have been shown to be 221 times more likely to experience stroke, which is 410 times more likely to be classified as cerebral infarction ^[5]. Stroke is of special interest due to the often irreversible damage it causes to the nervous system. This damage is particularly difficult to manage if the patient has pre-existing chronic conditions such as SCD. Thus, there is a clear rationale for studying the range in SCD symptoms and outcomes, particularly concerning genetic variations in this patient population, in hopes of designing more specialized treatment plans and palliative care.

1.2. Haptoglobin Polymorphism

Hp is a glycoprotein mainly synthesized by the liver in response to increased inflammatory signaling associated with hemolysis ^[6]. Hp primarily functions to remove toxic, free, oxygen-loaded Hb from circulation to prevent the formation of free radicals and subsequent oxidative tissue damage. Hp binds cell-free Hb with high affinity and is later taken up by macrophages and monocytes via the receptor CD163. This functional ability has been found to rely heavily on the inherited genotype of an individual and is particularly relevant to SCD pathophysiology. The Hp gene is coded on chromosome 16 (16q22) by two wholly expressed alleles, HP 1 and HP 2, resulting in the exhibition of three possible genotypes in humans: Hp 1-1, Hp 2-1, and Hp 2-2 ^[7]. The HP 1 allele is unique in its expression as either fast (HP 1F) or slow (HP 1S), referencing its relative speeds dependent on the inherited α-chain type ^[6]. This HP 1 amino acid variant provides six detailed genotypes: Hp 1S-1F, Hp 1S-1F, Hp 1F-1F, Hp 2-1S, Hp 2-1F, and Hp 2-2 ^[7]. Literature suggests that the HP 1 allele may be biologically advantageous due to its shorter α-chain, resulting in smaller size and quicker exportation of Hb and increased antioxidative abilities ^[6]^[8]. In contrast, the HP 2 allele has been correlated with a lower blood concentration of Hp and a decreased ability to bind to Hb ^[9]. Previous literature has provided strong evidence that a Hp 2-2 genotype increases the risk of cardiovascular events such as stroke in patients with diabetes ^[10], which raises the question of how the Hp genotype affects stroke incidence in other populations susceptible to stroke, such as patients with SCD. Current study has also previously reviewed the role of Hp polymorphism in subarachnoid hemorrhage (SAH). Researchers found strong evidence that Hp 1-1 can be taken up by cells faster, as well as cross the blood–brain barrier, which may ameliorate secondary injury after SAH ^[11]. However, it should be noted that researchers did not previously distinguish between the HP 1S and HP 1F alleles.

1.3. Critical Role of Haptoglobin

RBCs contain high levels of Hb tetramers, which are released into the body after hemolysis. A single RBC has been shown to contain at least 250 million Hb molecules, which upon lysis become free in the blood ^[11]. Free Hb can then travel in its broken-down dimeric form, allowing quicker transport to the kidneys, where Hb is highly toxic. In normal hemolysis, Hp molecules will bind to free Hb dimers and form Hb-Hp complexes, which are taken to the liver for breakdown and excretion. In SCD, however, hemolysis occurs at a much higher rate that is often too much for the body to handle. As a result, free oxidized Hb escapes excretion and remains within the circulation. Free oxidized hemoglobin (met-hemoglobin) and heme, byproducts of hemolysis, are ligands of the Toll-like receptors (TLRs). When these molecules are not bound to Hp after RBC rupture, they can bind to TLRs, which can trigger the nuclear factor kappa B (NFκB) transcription factor. Signaling NFκB activity leads to increased expression of proinflammatory genes that code for a variety of immune responders, including inflammatory cytokines, immature neutrophils that can increase production of reactive oxygen species (ROS), and other cycles that promote large organ dysfunction ^[12]. This futile cycle of proinflammatory response may explain the chronic pain crises commonly experienced by patients with SCD. NFκB becomes especially important in the event of ischemic stroke because proinflammatory molecules can further damage the affected tissue and cause cell death ^[13]. Hp has, therefore, been identified as a probable key identifier of chronic disease progression of SCD. For example, a biologically reduced concentration or functionality of Hp could severely impact the body’s ability to cause a large enough immune response to manage the increased rates of hemolysis caused by SCD. Hp is also known to play an antioxidative role in preventing oxidative tissue stress. Cell-free Hb is broken down into heme, iron, and globin. The most relevant major downstream pathway of free heme is free radical formation via the Fenton iron reaction; these free radicals interact with iron to produce ROS, which are harmful to the surrounding cells and tissue. In addition to this component that causes oxidative stress, free heme has the added effect of scavenging available nitric oxide (NO), an important upregulating molecule for vasodilation ^[14]. The scavenging and consequential depletion of NO in the bloodstream lead to vasoconstriction, which can exacerbate the natural pathophysiology of SCD and stroke ^[15].

This complex cascade of harmful reactions can be prevented by the correct interplay of the Hp–Hb binding mechanism. However, in patients diagnosed with a hemolytic anemia disorder, this mechanism is often inadequate. A hemolytic patient’s supply of free unbound Hp is constantly being depleted and cannot match the body’s increased demand resulting from the above-average hemolysis rates. This concept has been corroborated by previous findings that link Hp and hemopexin depletion with Hb-mediated oxidative stress ^[16]. Toxic species can escape removal from the organs and bloodstream and cause serious damage to critical major organs, specifically the kidneys. Introducing the significance of the Hp polymorphism and its subsequent phenotypes into this discussion only supports the need for investigating the different roles of Hp, their affinities to the various Hb variants, and its consequences on vaso-occlusion and free radical damage and inflammation. If current and future clinical trials can identify a more biochemically active and clinically advantageous Hp allele (HP 1F, HP 1S, HP 2) with consistent significance, researchers may be able to predict and prevent SCD disease progression more accurately via new therapies such as Hp infusions. Preclinical models of Hp infusion have also shown a linked reduction in kidney damage, oxidative stress, and vascular injury, all of which are major complications of SCD in humans ^[17].

1.4. Blood Exchange Transfusions

One of the most common therapeutic agents available to chronic and acute cases of SCD is blood exchange transfusion therapy. Traditional blood transfusions consist of transferring nutrient-rich blood from a healthy donor into the veins of a naturally deficient patient, usually to supply nutrients to a patient who is not capable of producing or maintaining proper nutrient levels in the circulatory system. In patients with SCD, blood exchange transfusions aid in supplying healthy hemoglobin (HbA) and normal biconcave RBCs, increasing the oxygen-carrying capacity of the blood and reducing the complications and likelihood of VOC ^[18]. In essence, these transfusions can temporarily reverse the effect of the mutated gene responsible for producing HbS by keeping the levels of HbS below 30%; maintaining this balance of HbA and HbS has been shown to reduce symptoms of anemia in patients with SCD ^[19]. In addition, patients who receive transfusions often have reduced symptoms of anemia because the transfused blood volume compensates for the decreased blood viscosity associated with SCD ^[8]. Stroke occurrence is also reduced in patients with SCD who regularly receive blood exchange transfusions. Consistent participation in long-term blood exchange transfusions tends to decrease the severity of pain crises, likely related to decreased VOC. researchers previously discussed how blood transfusion should be minimized because of side effects and should be part of a formal hospital blood management program ^[20]. Such transfusion, when necessary, also tends to slow disease progression compared to patients with little or no history of blood exchange transfusion treatment ^[19].

2. Current Evidence Regarding Hp Genotypes and Stroke

Among the first to study the role of Hp genotype in SCD, Atkinson et al. showed how the Hp polymorphism might acutely affect the hemolytic response ^[9]. When children living in malarial regions were surveyed by their Hp group, a notable increase in Hb clearance was observed in children with double HP 2 inheritance, meaning that the HP 2 allele was correlated with an increased risk for anemia ^[9]. Although there is overwhelming evidence that there is no association between Hp genotype and SCD, researchers are still interested in collecting data on how the Hp genotype may influence SCD outcomes because this disease can manifest in a variety of unique ways ^[9]^[21]. From the literature , researchers observed that most clinical outcomes were insignificantly correlated with the Hp genotype. The relationship of the Hp genotype to stroke incidence found by Barbosa et al. suggests that Hp 1F-1F may be advantageous due to the correlation with lower stroke incidence ^[8]. In contrast, Olatunya et al. reported no remarkable trends of a similar nature ^[22]. As previously mentioned, studies on Hp have theorized that the HP 2 allele predicts a poorer prognosis for outstanding conditions, including SCD ^[23]. Adekile and Haider identified some clinical significance regarding the HP 2 allele; in the Kuwaiti population with SCD, HP 2 dominance was correlated with higher hemolysis rates than in the South Nigerian population ^[24]. According to the assumption that South Nigerian patients with SCD present with more severe cases, higher hemolysis rates and dominance of the “inferior” HP 2 allele should have been observed in the South Nigerian population. In fact, the Kuwaiti populations showed the highest inheritance of the HP 2 allele and frequent VOC, but when stratified, no correlation was found between variables. Researchers noted that the number of insignificant results may have been caused by the small sample sizes used to generalize large regional populations, which may also have a skewed representation of genotypic variation ^[24]. Only one of these clinical studies, Barbosa et al., conducted polymerase chain reaction (PCR) runs to differentiate the two subtypes of the HP 1 allele, HP 1F and HP 1S, delineating relative size and speed. To fully understand how Hp polymorphism affects SCD and stroke occurrence, researchers must expand current knowledge on the implications of this mutation alone ^[8].

Adekile and Haider produced a unique study to identify the significance of Hp polymorphism in patients with SCD from Kuwait and South Nigeria, using respective control groups for comparison ^[24]. These populations were chosen for their previously studied SCD complications; Kuwaiti patients typically display milder SCD subphenotypes than South Nigerian patients’ more chronic, severe subphenotypes. Both the Kuwaiti and the South Nigerian populations showed insignificant Hp genotype intragroup distribution (p = 0.78, p = 0.41) but statistically significant intergroup distribution between the two SCD groups (χ² = 31.4, p < 0.01). The lack of significant intragroup HP allele distribution supports the theory that Hp genotypes are heavily influenced by ethnicity and patterns of geographical spreading. No significant distribution regarding HP 2 inheritance and VOC frequency among the Kuwaiti group was found; Kuwaiti patients with SCD demonstrated frequent VOCs with low stroke incidence, which researchers concluded was more significantly correlated to other genetic markers (AI β haplotype and higher fetal Hb levels) than Hp genotype. According to the literature, the HP 1 allele was predominant in the South Nigerian SCD group, which should have predicted higher hemolysis rates due to the more efficient Hb-binding ability of HP 1.

Cox et al., one of the first groups that sought to connect Hp genotype with stroke in patients with SCD, found inconclusive results that contradicted their hypothesis regarding Hp ^[25]. They conducted a study in a population of healthy pediatric patients with SCD in Tanzania and focused on measuring cerebral blood flow (CBF) using transcranial Doppler (TCD). Their reasoning behind the study was that they would be able to assess how CBF in patients with SCD was affected by three polymorphisms: glucose-6-phosphate dehydrogenase (G6PD), α-thalassemia, and the Hp genotype. The study provided evidence reinforcing the theory that α-thalassemia has a significant effect on CBF and, subsequently, stroke; however, it also failed to find any significant differences between the genotypes of the other two polymorphisms, G6PD and Hp, in terms of CBF ^[25]. These negative results may be related to the researchers’ decision to exclude patients with a history of stroke, recent transfusion, or recent manifestation of SCD. By excluding the more severe cases of SCD, it is possible that researchers inadvertently obscured the effects of Hp genotype. Researchers also stated that any adverse effects of the Hp 2-2 genotype may either be overwhelmed by the sheer amount of cell-free Hb that is present in the disease, compensated for by heme oxygenase 1, or some combination of the two factors. Either way, more research is needed to address whether the Hp genotype can cause increased vasoconstriction and subsequently worse outcomes during stroke.

While Cox et al. focused on the occlusion and perfusion aspects of SCD in Tanzania ^[25], Barbosa et al. conducted a similar cross-sectional study in the Brazilian population focused on the iron overload aspect of SCD ^[8]. Researchers conducted a cross-sectional clinical study using a convenience sample of 78 Brazilian patients with HbSS SCA with the goal of identifying significant differences between those with normal iron levels and acquired iron overload in relation to their respective Hp genotypes. This population in Federal District, Brazil, was selected for its ethnic diversity to eliminate extraneous independent variables capable of influencing genetic inheritance. Acquired secondary iron overload is common in patients with hemolytic anemia disorders due to frequent blood exchange transfusions. Researchers concluded that there was no statistically significant distribution of Hp genotypes among patients with SCA with and without iron overload. Hp 1F-1S and Hp 1F-1F were observed in only 15% of the participants, possibly suggesting that the HP 1 allele is less common among patients with SCA. There was a significantly higher stroke incidence in patients with Hp 1S-2 than predicted by the Hardy–Weinberg equilibrium (HWE) equation used prior to conducting the study (p = 0.005). Contrary to outcomes predicted with the HWE, patients with Hp 1S-2 had the highest hospitalization for stroke (OR = 6.346, p = 0.005) and stroke sequelae (OR = 6.556, p = 0.005). Conversely, Hp 1F-1F patients had the lowest hospitalization for stroke and stroke sequelae, which was less than that predicted by HWE using the notion that the smaller size of the HP 1 allele should allow quicker entrance into the interstitial fluid, reducing seizure recurrence. No statistical comparison was provided between ages due to inconsistent biological values obtained and only two participants in the ≥60 age range. It is also important to note that patients had varied and inconsistent treatment histories for their condition. Out of the 78 patients, 41 had a history of blood exchange transfusion therapy.

Olatunya et al. conducted the most recent cross-sectional clinical study associating genotypic variation with SCA phenotypes ^[22]. Researchers of the study aimed to identify any significant distribution of Hp genotypes between 101 young (2–21 years old) Nigerian patients with SCA and 64 healthy Nigerian control patients. Researchers reported that the HP 1 allele had the highest inheritance among patients with SCA, occurring in approximately 62%, but the control group showed even higher inheritance, at approximately 73%. The high representation of the HP 1 allele in this patient population opposes the previous findings from Barbosa et al. Still, it contributes to the existing theory that Hp allele distribution is influenced more by ethnic origin than SCA diagnosis. Researchers also found no significant relationship (p = 0.375) between stroke incidence and any Hp genotype. Only five (4.9%) of the 101 patients with SCA had a history of hospitalization for stroke; two were Hp 1-1, one was Hp 2-1, and two were Hp 2-2. This low incidence of stroke should not be generalized to the entire SCA population because the oldest patient was 21 years old, although it should be noted that pediatric patients with SCD are at a higher risk for stroke, with an estimated 11% of patients with SCD experiencing stroke before age 20. Furthermore, Hp 2-2 showed an insignificant (p = 0.922) correlation to increased VOC, which had been previously characterized by the lower antioxidant and anti-inflammatory capabilities of the HP 2 allele.

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