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Original Article

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Blood Res 2022; 57(3):

Published online September 30, 2022

https://doi.org/10.5045/br.2022.2022014

© The Korean Society of Hematology

Endothelial nitric oxide synthase Glu298Asp gene polymorphism in the cases of idiopathic thrombocytopenic purpura

Saadet Akarsu1, Feyzullah Necati Arslan2, Deniz Erol3

Author Info. +

1Division of Pediatric Hematology/Oncology, Firat University Faculty of Medicine, Elazig, 2Department of Pediatrics, Kahramanmaraş State Hospital, Kahramanmaraş, 3Medical Genetic, Firat University Faculty of Medicine, Elazig, Turkey

Correspondence to : Saadet Akarsu, M.D.
Division of Pediatric Hematology/Oncology, Firat University Faculty of Medicine, Fırat Üniversitesi Tıp Fakültesi Hastanesi, Elazig 23119, Turkey
E-mail: aksaadet@yahoo.com

*This study was supported by a grant from University of Firat Faculty of Medicine (approval no.: FÜBAP-1598).

Received: January 19, 2022; Revised: May 23, 2022; Accepted: July 22, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Background
Nitric oxide (NO) can induce apoptosis in megakaryocytes. Stimulatory function of NO on platelet production may be important in the pathophysiology of idiopathic thrombocytopenic purpura (ITP). NO is produced by three isoforms of NO synthase (NOS). The endothelial nitric oxide synthase (eNOS) isoform has been detected in platelets. Polymorphism of the eNOS gene, which supplies NO synthesis, changes the functions of this enzyme. In this study, the role of eNOS Glu298Asp gene polymorphism in etiopathogenesis, its course, and treatment of ITP was investigated.
Methods
Sixty-six patients [51 newly diagnosed ITP (ND-ITP), 15 chronic ITP (CH-ITP), and 60 healthy controls (HC)] were enrolled in this study.
Results
In all patients, the frequency of the GT genotype was 48.5%. The frequency of the GG genotype was determined to be 40.9% and the TT genotype was 10.6%. The most common allele in all patients was the G allele. eNOS Glu298Asp gene polymorphism might be a risk factor in the etiopathogenesis of ITP. Patients with the GG genotype were thought to have a high intention for CH-ITP. Patients with the GG genotype responded effectively to medical treatment using IVIG therapy. The presence of the G allele was observed to have a positive effect on the medical treatment of patients with CH-ITP, whereas the T allele exhibited a negative effect.
Conclusion
In the present study, a significant correlation was found between ITP and eNOS Glu298Asp gene polymorphism. This correlation suggested that eNOS Glu298Asp gene polymorphism might be a risk factor in the ethiopathogenesis of ITP.

Keywords Idiopathic thrombocytopenic purpura (ITP), Endothelial nitric oxide synthase (eNOS), Glu298Asp gene, Polymorphism

Article

Original Article

Blood Res 2022; 57(3): 223-228

Published online September 30, 2022 https://doi.org/10.5045/br.2022.2022014

Copyright © The Korean Society of Hematology.

Endothelial nitric oxide synthase Glu298Asp gene polymorphism in the cases of idiopathic thrombocytopenic purpura

Saadet Akarsu1, Feyzullah Necati Arslan2, Deniz Erol3

1Division of Pediatric Hematology/Oncology, Firat University Faculty of Medicine, Elazig, 2Department of Pediatrics, Kahramanmaraş State Hospital, Kahramanmaraş, 3Medical Genetic, Firat University Faculty of Medicine, Elazig, Turkey

Correspondence to:Saadet Akarsu, M.D.
Division of Pediatric Hematology/Oncology, Firat University Faculty of Medicine, Fırat Üniversitesi Tıp Fakültesi Hastanesi, Elazig 23119, Turkey
E-mail: aksaadet@yahoo.com

*This study was supported by a grant from University of Firat Faculty of Medicine (approval no.: FÜBAP-1598).

Received: January 19, 2022; Revised: May 23, 2022; Accepted: July 22, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background
Nitric oxide (NO) can induce apoptosis in megakaryocytes. Stimulatory function of NO on platelet production may be important in the pathophysiology of idiopathic thrombocytopenic purpura (ITP). NO is produced by three isoforms of NO synthase (NOS). The endothelial nitric oxide synthase (eNOS) isoform has been detected in platelets. Polymorphism of the eNOS gene, which supplies NO synthesis, changes the functions of this enzyme. In this study, the role of eNOS Glu298Asp gene polymorphism in etiopathogenesis, its course, and treatment of ITP was investigated.
Methods
Sixty-six patients [51 newly diagnosed ITP (ND-ITP), 15 chronic ITP (CH-ITP), and 60 healthy controls (HC)] were enrolled in this study.
Results
In all patients, the frequency of the GT genotype was 48.5%. The frequency of the GG genotype was determined to be 40.9% and the TT genotype was 10.6%. The most common allele in all patients was the G allele. eNOS Glu298Asp gene polymorphism might be a risk factor in the etiopathogenesis of ITP. Patients with the GG genotype were thought to have a high intention for CH-ITP. Patients with the GG genotype responded effectively to medical treatment using IVIG therapy. The presence of the G allele was observed to have a positive effect on the medical treatment of patients with CH-ITP, whereas the T allele exhibited a negative effect.
Conclusion
In the present study, a significant correlation was found between ITP and eNOS Glu298Asp gene polymorphism. This correlation suggested that eNOS Glu298Asp gene polymorphism might be a risk factor in the ethiopathogenesis of ITP.

Keywords: Idiopathic thrombocytopenic purpura (ITP), Endothelial nitric oxide synthase (eNOS), Glu298Asp gene, Polymorphism

Fig 1.

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Figure 1.eNOS gene polymorphisms (exon 7: G894T polymorphism= Glu298Asp polymorphism) [15].
Blood Research 2022; 57: 223-228https://doi.org/10.5045/br.2022.2022014

Fig 2.

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Figure 2.Agarose gel electrophoresis and schematic view of PCR products cut by Ban II enzyme of eNOS gene Glu298Asp polymorphism. Case 1 and 2: GG genotype, Case 3 and 4: GT genotype, Case 5 and 6: TT genotype. T allele 248 base couple (bc), G allele 163 and 85 bc. M: 100 bc DNA dimension marker.
Blood Research 2022; 57: 223-228https://doi.org/10.5045/br.2022.2022014

Fig 3.

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Figure 3.Dispersion of eNOS Glu298Asp G/T genotype in the patient and control groups. 1a–4a=P<0.05, 1b–4b=P<0.05, 3c–4c=P<0.05, 2a–4a=P<0.05, 2b–4b=P<0.05, 3a–4a=P<0.05, 3b–4b=P<0.05.
Blood Research 2022; 57: 223-228https://doi.org/10.5045/br.2022.2022014

Table 1 . Demographic characteristics in idiopathic thrombocytopenic purpura (ITP) and control groups..

Total ITP (a)ND-ITP (b)CH-ITP (c)HC (d)P<0.05
N66511560
Age (mean±SD, yr)7.24±3.906.33±3.6210.33±3.267.45±3.76b-c, c-d
Sex (%)34 M/32 F (52/48)29 M/22 F (57/43)5 M/10 F (33/67)39 M/21 F (65/35)b-c, c-d

Abbreviations: F, female; M, male; Mean, arithmetic mean; N, patient number; SD, standard deviation..

Table 2 . Primer sequences of the eNOS gene..

F-5’-AAGGCAGGAGACAGTGGATGGA 3’
R-5’-CCCAGTCAATCCCTTTGGTGCTCA 3’

Table 3 . Dispersion of genotype and frequency of G/T allele of eNOS gene polymorphism in the patient and control groups..

Total ITP N=66 (1)ND-ITP N=51 (2)CH-ITP N=15 (3)HC N=60 (4)P<0.05
G/T dispersion of genotype
GG (N, %)27 (40.9)20 (39.2)7 (46.7)13 (21.7)1-4
2-4
3-4
GT (N, %)32 (48.5)26 (51)6 (40)42 (70)1-4
2-4
3-4
TT (N, %)7 (10.6)5 (9.8)2 (13.3)5 (8.3)3-4
Frequency of allele
G (N, %)86 (65.1)66 (64.7)20 (66.7)68 (56.7)1-4
2-4
3-4
T (N, %)46 (34.8)36 (35.3)10 (33.3)52 (43.3)1-4
3-4

Abbreviation: ITP, idiopathic thrombocytopenic purpura..

Table 4 . Distribution of eNOS Glu298Asp GG/GT/TT genotypes among groups and its relation with age and thrombocyte parameters..

ND-ITP (1)CH-ITP (2)HC (3)
GG
N=20 (a)		GT
N=26 (b)		TT
N=5 (c)		GG
N=7 (a)		GT
N=6 (b)		TT
N=2 (c)		GG
N=13 (a)		GT
N=42 (b)		TT
N=5 (c)
Age (yr) (mean±SD)5.92±3.806.11±3.479.1±2.9610.42±2.689.75±3.5611.75±6.018.57±4.357.51±3.564±1.62
PNSNS3a-3c=P<0.05, 3b-3c=P<0.05
Platelet (109/L) (mean±SD)15.30±13.6015.06±13.585.40±3.5024.71±30.78.16±4.0228.0±35.35304.4±71.56332.80±83.51363.20±69.11
P1a-1c=P<0.052a-2b=P<0.05, 2b-2c=P<0.05NS
MPV (fL) (mean±SD)11.8±12.0211.99±1.5412.28±0.7012.51±1.4113.30±3.6512.60±0.5610.95±1.8210.32±1.5810.98±1.82
P1a-1c=P<0.05NSNS
PDW (mean±SD)33.89±7.3630.98±8.1532.52±9.8233.80±7.9538.13±9.3934.25±4.5929.67±5.7431.59±6.7627.16±6.86
PNSNSNS

Abbreviation: NS, not significant..

Table 5 . Treatment responses categorized according to genotypes of the patients in the ND-ITP group..

ND-ITP (N=51)
GG genotype (N=20, 39.2%)4 (HDMP, 2 [50%] CR, 1[25%] PR, 1[25%] UR)
3 (SDP, 2 [66.6%] CR, 1[33.3%] UR)
5 (IVIG, [100%] CR)
7 (anti-D, 2 [28.5%] CR
1 [14.25%] PR, 4 [57%] UR)
GT genotype (N=26, 51%)6 (HDMP, 5 [83.3%] CR)
3 (SDP, 3 [100%] UR)
10 (IVIG, 8 [80%] CR)
5 (anti-D, 1 [20%] CR)
TT genotype (N=5, 9.8%)1 (HDMP, 1 [100%] CR)
1 (SDP, 1 [100%] CR)
2 (anti-D, 2 [100%] CR)

Abbreviations: CR, complete response; PR, partial response; UR, unresponsive..

Table 6 . Treatment responses categorized according to genotypes of the patients in the CH-ITP group..

CH-ITP (N=15)
Complete response (N=3, 20%)3 (GG, IVIG)
Partial response (N=4, 27.7%)
Refractory to treatment (N=8, 53.3%)4 (GT)
3 (GG)
1 (TT)
GG genotype (N=7, 46.7%)6 (4 HDMP, 1 SDP, 2 IVIG, 1 [50%] CR, 1 [50%] PR-Anti-D CR)
GT genotype (N=6 40%)4 (HDMP, 2 [50%] CR, 2 [50%] PR-Vincristine [100%] CR-splenectomi)
1 (SDP, 1 [100%] UR-splenectomi)
1 (IVIG, 1 [100%] PR)
TT genotype (N=2; 13.3%)1 (HDMP, 1 [100%] UR-IVIG [100%] PR)
1 (SDP, 1 [100%] PR-IVIG [100%] UR)

Abbreviations: CR, complete response; PR, partial response; UR, unresponsive..
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