Unraveling the genetic landscape of sickle cell disease in India: A literature review

INTRODUCTION

First reported by JB Herrick and by Walter Clement Noel, in 1910,^[1] sickle cell disease was described as a molecular disease in 1949 by Linus Pauling.^[2] The βS mutation is one of the most common single-gene mutations in man.^[3] About 7% of the world’s population carries globin gene mutations.^[4] Approximately 300,000 children are born with SCD and nearly 80% of these births occur in poor socio-economic countries^[5] occurring predominantly in the Mediterranean, the Middle East, Central Africa, India, and America^[6] Although SCD is a monogenic disorder, a whole spectrum of clinical presentations is seen^[7] Significant diversity in clinical severity and the correlation between genotype and phenotype in SCD have been observed.^[8] The first case in India was described in the Nilgiri Hills region of Tamil Nadu.^[9] The Arab-Indian haplotype seen in the Indian population is associated with higher fetal hemoglobin (HbF) levels and splenomegaly, and fewer complications. Senegal and the Bantu haplotype are common in people of African origin.^[10]

SCD patients are at higher risk of severe infection following infection with Severe Acute Respiratory Syndrome Coronavirus 2 due to splenic dysfunction and systemic vasculopathy, which predisposes them to thrombosis and end-organ dysfunction.^[11]

Four main processes in development of SCD are hemoglobin S polymerization, adhesion-mediated vaso-occlusion, hemolysis, and sterile inflammation^[12] but recent developments show that sterile inflammation also plays a role.^[13] In the setting of hypoxia, valine forms a hydrophobic bond with the nearest valine of other β-globin chains and forms a polymer, which changes the shape of a normal red blood cell (RBC) into a sickle-shaped RBC (SRBC).^[14] Clinical features of SCD include anemia, vasoocclusive crisis, osteonecrosis, leg ulcers, retinopathy, acute chest syndrome (ACS), focal segmental glomerulosclerosis, gallstones, pain, and recurrent infections.^[15,16]

Although SCD was the first human monogenic disorder to be characterized at a molecular level,^[17] the genetic complexity of its pathophysiology is yet to be understood. α thalassemia^[18] and increased levels of HbF^[19] are known modifiers in SCD. HbF is one of the most established genetic modulators to identify the severity of SCD. Studies have located three quantitative trait loci harboring single-nucleotide polymorphisms with strong association with HbF level in SCA patients.^[20]

Knowing that about 7% of the world’s population carries globin gene-mutations,^[21] it becomes essential to study the effects of SCD on each organ and postulate possible complications of COVID disease that may arise in SCD patients, particularly in countries like India, which have marked genetic diversity and variability.^[22]

With this review, we attempt to identify non-globin genetic modifiers of SCD in the Indian cohort and to analyze the effects of SCD on the organs of the human body.

METHODOLOGY

A review was conducted on studies that were carried out and published in peer-reviewed journals about SCD in patients of all age groups and ethnicities. The non-globin genes modifying the clinical presentation of SCD specific to the Indian cohort were identified and compared to the non-Indian cohorts. An advanced PubMed search was done using the keywords “sickle cell disease” AND “genetics” AND “India,” yielding 300 hits. Out of these articles, those regarding genes affecting the pathophysiology of SCD were filtered manually.

After identifying the genes that have been studied with respect to the pathophysiology of SCD in India, the role of these genes in other cohorts was reviewed using PubMed, and the results were studied.

In summary, an extensive search was conducted with respect to organ damage in SCD.

This review is an attempt to analyze the clinical features of SCD system-wise, i.e., cardiovascular system, respiratory system, and so forth.

DISCUSSION

Various studies from India show that SCD is a multigenic disorder.

In a study done by Meher et al.^[65] on the population of western Odisha, it was observed that the C677T gene polymorphism could lead to increased complications of vaso occlusion, like ischemic stroke. This is because the C677T gene influences the enzyme methylenetetrahydrofolate reductase (MTHFR). The deficiency of MTHFR can increase the homocysteine (Hcy) levels in the body. Increased Hcy levels trigger collagen type 1 protein, which activates platelet glycoprotein VI and the integrin α2β1 pathway. This mechanism can trigger vasoocclusive events like ischemic stroke [Figure 1]. MTHFR enzyme activity decreases by around 35% in the heterozygous state (CT) and by approximately 70% in the homozygous state (TT) of the C677T gene polymorphism.^[65] Factor V Leiden was also linked to increased risk of developing vascular complications.^[66]

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Figure 1:

Molecular sequence causing vasoocclusive events due to C677T polymorphism.

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In another study, it was found that people with severe SCD had significantly higher frequencies of mutant alleles (“4a,” “T” and “C”), mutant genotypes of eNOS and vasoocclusive events like ACS when compared to patients with mild SCD and those of the controls. This is because the eNOS gene is responsible for the production of endothelial nitric oxide, which causes vasodilation and decreases the affinity toward platelet adhesion. Polymorphism of this gene leads to dysfunction of the above-mentioned properties, leading to vaso-occlusive events. This also explains the decreased plasma NO₂ levels in severe SCD patients [Figure 2].^[67] The eNOS gene has also been reported to affect the onset of menarche in SCD females in the Indian population. Female patients with severe SCD and late onset of menarche showed polymorphic eNOS gene alleles. A positive correlation between lower plasma NO2 levels was seen in these patients, as compared to controls and early-onset mild SCD patients.^[68]

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Figure 2:

Molecular sequence causing vaso-occlusive events due to ENOS polymorphism.

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The BCL11A gene was the most strongly associated polymorphism with increased HbF levels in the milder SCD patients as compared to the severe patients,^[69] while a study conducted in Eastern India showed the highest attribution to XmnI polymorphism.^[70]

HbF is a major genetic modulator in SCD patients, since it has an ameliorative effect by preventing the deoxygenation of sickle RBC and helps maintain the structure of RBC.^[71]

Expression of HbF is dependent on various genetic factors. This might influence the phenotypic variations in SCD patients. A study done on the tribal population of Raipur and Chhattisgarh in North-western India showed that the rs14407 locus of the gene BCL11A influences HbF levels. The population with dominant alleles has higher levels of HbF and thus fewer phenotypic variants of SCD.^[71] The Kruppel-like factor (KLF) gene also influences the severity of SCD through HbF. The KLF1 gene acts as a positive regulator in the activation of the beta globin gene and helps in the conversion of HbF to adult hemoglobin (HbA). Variations in the KLF1 gene cause a delay in the conversion of HbF to HBA. This decreases the phenotypic severity in SCD patients.^[72] The prevalence of the KLF1 mutation was found to be higher in the thalassemia endemic region.^[73]

Another study, done by Dadheech et al., reported that increased γG-globin expression associated with Xmn1 polymorphism decreases the clinical severity in β-thalassemia and SCD.^[74]

CONCLUSION

In our review, we found that subjects with SCD having mutations of the Factor V Leiden gene and MTHFR C677T polymorphisms were prone to vascular complications. This could be attributed to the fact that SCD patients with these mutations were linked to higher levels of prothrombin fragments (F1 + 2), D-dimer, thrombin-antithrombin, and lower levels of protein C. Another study showed that an association of the eNOS gene polymorphism was linked as a potential genetic modifier, potentially causing vaso-occlusive crisis. eNOS polymorphs, particularly eNOS 4a/4b, eNOS 894G>T G/T,eNOS-786T>C T/C, were linked to the delayed onset of menarche in the SCD-affected female population. Furthermore, other studies showed an association of BCL11A with an increased level of HbF in the Indian population. Increases in HbF levels were also associated with the XMN1 gene in patients with SCD and thalassemia.

In contrast with other review studies done in India, focusing on a specific gene, our review covers all genes associated with sickling of the cell. Further, our study extensively covered mutations in various populations and their correlation with the pathophysiology of SCD.

Most studies done with significant genetic modification, however, had a small sample size. This illustrates the need for further studies with a larger sample size to establish the prevalence of these genetic modifications in the Indian population. To conclude, the population groups discussed above differ widely in terms of culture and daily practices. The impact of these such as diet, climate, age, and gender, needs to be implicated in having effects on certain populations as well.