Endothelial nitric oxide synthase gene polymorphism is associated with sickle cell disease patients in India

Abstract

Patients with sickle cell disease (SCD) produce significantly low levels of plasma nitric oxide (NO) during acute vaso-occlusive crisis. In transgenic sickle cell mice, NO synthesized by endothelial nitric oxide synthase (eNOS) enzyme of vascular endothelial cells has been found to protect the mice from vaso-occlusive events. Therefore, the present study aims to explore possible association of eNOS gene polymorphism as a potential genetic modifier in SCD patients. A case control study involving 150 SCD patients and age- and ethnicity-matched 150 healthy controls were genotyped by PCR-restriction fragment length polymorphism techniques for three important eNOS gene polymorphisms-eNOS 4a/b, eNOS 894G>T and eNOS -786T>C. It was observed that SCD patients had significantly higher frequencies of mutant alleles besides heterozygous and homozygous mutant genotypes of these three eNOS gene polymorphisms and low levels of plasma nitrite (NO2) as compared with control groups. The SCD severe group had significantly lower levels of plasma NO2 and higher frequencies of mutant alleles of these three SNPs of eNOS gene in contrast to the SCD mild group of patients. Haplotype analysis revealed that frequencies of one mutant haplotype '4a-T-C' (alleles in order of eNOS 4a/b, eNOS 894G>T and eNOS -786T>C) were significantly high in the severe SCD patients (P<0.0001), whereas the frequency of a wild haplotype '4b-G-T' was found to be significantly high (P<0.0001) in the SCD mild patients, which indicates that eNOS gene polymorphisms are associated with SCD patients in India and may act as a genetic modifier of the phenotypic variation of SCD patients.

Endothelin-1 but not Endothelial Nitric Oxide Synthase Gene Polymorphism is Associated with Sickle Cell Disease in Africa

“…Conclusively, endothelial nitric oxide synthase mutants are less frequent and lack any functional significance among patients with sickle cell disease in Africa, contrary to other reports 11–13. In addition, we found a potential role for endothelin-1 polymorphisms in sickle cell disease that might impact clinical outcome in African cases.…”

“…The eNOS VNTR has been associated with the mean plasma nitric oxide level, while C-786 variant has been found to reduce eNOS gene promoter activity and is a genetic risk factor for acute chest syndrome in adult female sickle cell anemia patients 11,12. A recently published report found a higher prevalence of mutant alleles and genotypes of all three eNOS single nucleotide polymorphisms in sickle cell disease individuals, implying an association between eNOS gene polymorphisms and sickle cell disease in India 13. The finding of higher incidence of mutant alleles and genotypes among the SCD severe group in contrast to higher incidence of wild alleles and genotypes among the SCD mild group of patients indicate the eNOS gene probably acting as a genetic modifier of phenotypic variation among Indian patients 13.…”

Endothelial nitric oxide synthase gene polymorphisms and the risk of vasculopathy in sickle cell disease

“…The eNOS gene polymorphisms (eNOS 4a/b, eNOS 894G>T, and eNOS 786T>C) play a pivotal role in eNOS gene expression and subsequently serum level of NO in SCD patients. 12,21 Obvious relation between eNOS gene polymorphisms and vasculopathy had been found in various diseases. [22][23][24][25] Therefore, the present study aimed at exploring possible association of eNOS gene polymorphisms and severity of SCD manifestations in Egyptian SCD patients, as eNOS gene polymorphisms may be considered as a potential genetic modifier in SCD.…”

Polymorphism of the endothelin-1 gene (rs5370) is a potential contributor to sickle cell disease pathophysiology

“… 1 , 2 , 3 The greatest toll of disease in the United States is in the black community among African Americans and immigrant populations from sub-Saharan Africa, some parts of the Middle East and Caribbean with an African descent, in addition to cases and other closely-related red cell disorders from the Indian sub-continent. 4 Since sickle cell disease has a genetic basis, its pathophysiology (vaso-occlusive crises, stroke, leg ulceration, acute chest syndrome, pulmonary hypertension etc.) has been found to vary widely, at times following an interethnic pattern.…”