Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene polymorphisms in a cohort of Egyptian patients with immune thrombocytopenia (ITP)

Doaa Mohamed El Demerdash; Maha Mohamed Saber; Alia Ayad; Kareeman Gomaa; Mohamed Abdelkader Morad

doi:10.1007/s44313-024-00011-z

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Blood Res (2024) 59:8

Published online March 1, 2024

https://doi.org/10.1007/s44313-024-00011-z

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene polymorphisms in a cohort of Egyptian patients with immune thrombocytopenia (ITP)

Doaa Mohamed El Demerdash^1*, Maha Mohamed Saber¹, Alia Ayad¹, Kareeman Gomaa² and Mohamed Abdelkader Morad¹

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¹Internal Medicine Department, Faculty of Medicine, Teaching Kasr AL-Ainy Hospital, Cairo University, Al Kasr Al Aini, Old Cairo 4240310, Cairo Governorate, Egypt
²Clinical and Chemical Pathology Department, Faculty of Medicine, Kasr AL-Ainy Hospital, Cairo University, Cairo, Egypt

Correspondence to : *Doaa Mohamed El Demerdash
dr_eldemerdash@kasralainy.edu.eg; dr_eldemerdash@cu.edu.eg

Received: July 27, 2023; Accepted: February 5, 2024

Abstract

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Abstract

Background Immune thrombocytopenia (ITP) is characterized by immune response dysregulations. Cytotoxic T lymphocyte‐associated antigen‐4 (CTLA‐4) plays a central role in immune checkpoint pathways and preventing autoimmune diseases by regulating immune tolerance. We aimed to explore the potential association between CTLA-4 gene polymorphisms and ITP as well as study their impact on the response to therapy.
Methods We investigated two CTLA-4 single‐nucleotide polymorphisms (SNPs; rs: 231775 and rs: 3087243) using real-time PCR as well as the plasma levels of CTLA-4 by ELISA in 88 patients with ITP and 44 healthy participants (HC).
Results CTLA-4 (rs: 3087243) A > G polymorphism analysis showed most HC had the homozygous AA genotype, which was statistically significant compared to patients with ITP. Plasma levels of CTLA4 were statistically lower in patients with acute ITP. There was no correlation between CTLA-4 (rs: 231775 and rs: 3087243) A/G SNPs were not correlated to the response to all lines of therapy assessed (corticosteroids, thrombopoietin receptor agonists, splenectomy, and rituximab).
Conclusion CTLA-4 CT 60 A/G may affect the susceptibility of ITP, but both CTLA-4 + 49 A/G and CT60 A/G did not impact the response of patients with ITP to different lines of therapy.

Keywords ITP, SNPs, Immune thrombocytopenia, Immune checkpoints, CTLA-4

Article

RESEARCH

Blood Res 2024; 59():

Published online March 1, 2024 https://doi.org/10.1007/s44313-024-00011-z

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene polymorphisms in a cohort of Egyptian patients with immune thrombocytopenia (ITP)

Doaa Mohamed El Demerdash^1*, Maha Mohamed Saber¹, Alia Ayad¹, Kareeman Gomaa² and Mohamed Abdelkader Morad¹

Correspondence to:*Doaa Mohamed El Demerdash
dr_eldemerdash@kasralainy.edu.eg; dr_eldemerdash@cu.edu.eg

Received: July 27, 2023; Accepted: February 5, 2024

Abstract

Keywords: ITP, SNPs, Immune thrombocytopenia, Immune checkpoints, CTLA-4

Abstract

Table 1 . The clinical characteristics of patients with ITP (N, 88).

Parameter		Subcategory	Frequency	Percentage
Sex		M	23	26.1
Sex		F	65	73.9
Bleeding score		0	7	7.9
		1	67	76.1
		2	15	17
Type of bleeding		Muco-cutaneous	79	89.7
		gastrointestinal	7	8.5
		Genitourinary	38	43
		Internal bleeding	1	1.1
ITP Phase		Newly diagnosed	4	4.5
		Persistent	11	12.5
		Chronic	37	42
Number of lines of therapies		1	4	4.5
		2	59	67
		3	18	18
		4	7	8
Steroid dependency		Dependent	52	63.4
Steroid dependency		Non-dependent	30	36.6
Second line therapies		Yes	84	48.7
Second line therapies		No	4	51.2
Response to therapies	Corticosteroids (N, 88)	CR	8	9.1
		R	64	72.7
		NR	16	18.2
	TPO-RAs (N, 67)	CR	18	26.9
		R	33	49.3
		NR	16	23.9
	Rituximab (N, 38)	CR	10	26.3
		R	16	42.1
		NR	12	31.6
	Splenectomy (N, 11)	CR	4	36.4
		R	4	36.4
		NR	3	27.3

ITP Immune thrombocytopenia, N Number, TPO-RAs Thrombopoietin receptor agonists, M Male, F Female, CR Complete response, R Response, NR No response.

Table 2 . Genotypes of CTLA-4 rs231775 and rs3087243 in Patients with ITP and HC.

SNPs	Genotype	Cases (%)N, 88	HC (%)N, 44	P-value
rs231775	GG	44 (50)	15 (34.1)	0.206
	GA	35 (39.8)	24 (54.5)
	AA	9 (10.2)	5 (11.4)
rs3087243	GG	23 (26.1)	9 (20.5)	0.001^*
	GA	31 (35.2)	0 (0)
	AA	34 (38.6)	35 (79.5)

* Significance difference (P < 0.05); CTLA-4: cytotoxic T lymphocyte‐associated antigen‐4; ITP: immune thrombocytopenia; HC: healthy participants; SNPs: single‐nucleotide polymorphisms; N: number.

Table 3 . Correlation between Genotypes of CTLA-4 rs231775 and rs3087243 and Response to Therapies in Patients with ITP.

Line of therapy	Response	rs231775 cases (%)			P-value	rs3087243cases (%)			P-value^*
Line of therapy	Response	GG	GA	AA	P-value	GG	GA	AA	P-value^*
Corticosteroids (N, 88)	CR	5 (11.5)	3 (8.6)	0 (0)	0.948	2 (8.7)	4 (12.9)	2 (5.9)	0.861
	R	32 (72.5)	25 (71.4)	7 (77.8)		16 (69.6)	22 (71)	26 (76.5)
	NR	7 (15.9)	7 (20)	2 (22.2)		5 (21.7)	5 (16.1)	6 (17.6)
TPO-RAs (N, 67)	CR	8 (25)	6 (22)	4 (50)	0.437	3 (18.8)	9 (36)	6 (23.1)	0.676
	R	15 (46.9)	16 (59.3)	2 (25)		8 (50)	12 (48)	13 (50)
	NR	9 (28.7)	5 (18.5)	2 (25)		5 (31.1)	4 (16)	7 (26.9)
Rituximab (N, 38)	CR	6 (31.6)	3 (20)	1 (25)	0.926	2 (16.7)	6 (54.5)	2 (13.3)	0.129
	R	8 (42.1)	6 (40)	2 (50)		5 (41.7)	2 (18.2)	9 (60)
	NR	5 (26.3)	6 (40)	1 (25)		5 (41.7)	3 (27.3)	4 (26.7)
Splenectomy (N, 11)	CR	1 (25)	2 (33.3)	1 (100)	1	1 (25)	1 (50)	2 (40)	1
	R	2 (50)	2 (33.3)	0 (0)		2 (50)	1 (50)	1 (20)
	NR	1 (25)	2 (33.3)	0 (0)		1 (25)	0 (0)	2 (40)

CTLA-4 Cytotoxic T lymphocyte‐associated antigen‐4, ITP Immune thrombocytopenia, TPO-RAs Thrombopoietin receptor agonists, N Number, CR Complete response, R Response, NR No response; *Significance difference (P < 0.05).

Table 4 . Immune checkpoint-related gene polymorphisms in ITP.

Reference	N	Sex	Mean age (Y)	Studied polymorphisms	Conclusions
Wang et al., [22]	307	F 62%. M 38%.	44.92 ± 14.02	TIM3 rs10515746. CD28 rs1980422. TNFSF4 rs2205960. CTLA4 rs231779. PD1 rs36084323. ICOS rs6726035. DNAM1 rs763361. LAG3 rs870849.	CD28 rs1980422 was associated with an increased risk of ITP after false discovery rate correction (P = 0.006). The T allele of PD1 rs36084323 was a risk factor for ITP severity and the T allele of DNAM1 rs763361 for corticosteroid-resistance. The combination of TIM3 rs10515746, CD28 rs1980422, and ICOS rs6726035 best predicted a high risk of ITP.
Chen et al., [20]	32	F 84.5%. M 15.5%.	60 (median)	12 SNPs analysis mainly focused on the promoter region of CTLA-4 and CD28	CTLA-4 rs11571315 was a susceptible SNP for primary ITP in the Taiwan population. CTLA-4 rs5742909 was related to secondary ITP caused by autoimmune disease CTLA4 was associated with ITP but not CD28.
Kasamatsu et al., [19]	119	F 73%. M 27%.	64 (median)	DCD1 SNPs: (606 G/A, + 7209 C/T, + 63379C/T) CTLA4 SNPs: (1722 A/G, 1577 A/G, + 49 A/G, CT60 A/G)	PDCD1 + 7209 C/T SNP is associated with susceptibility to cITP. no significant differences in CTLA4 SNPs between cITP patients and healthy individuals CTLA4 1577 A/G and CT60 A/G polymorphisms may affect the severity of cITP.
Aktürk et al., [23]	62	NA	NA	CTLA-4 A49G.	no association between the A49G polymorphism of the CTLA-4 gene and ITP
Yao et al., [21]	102	F 70.7%. M29.3%.	5.43 ± 3.21 (pediatric)	CTLA-4. rs11571315 and rs3087243.	CTLA4 gene is suggested to correlate with ITP through its abnormal expression level instead of gene site mutation
Li et al., [24]	186			CTLA-4. 318 and CT60.	these two SNPs in CTLA-4 are not associated with susceptibility to ITP in a Chinese population
Radwan et al., [25]	100	F 58%. M 42%.	7.3 ± 4.4 (pediatric)	CTLA-4. exon1 49 A > G.	It did not detect a relation. between the selected CTLA-4 SNP and susceptibility to ITP in Egyptian children.
Our presented research	88	F 74%. M 26%.	32.5 (median)	CTLA-4. rs: 231,775. rs: 3,087,243.	CTLA-4 rs: 3,087,243 may affect the susceptibility of ITP. but there was no impact of both studied SNPs (rs: 231,775 and rs: 3,087,243) of CTLA-4 on the response to different lines of therapy in adult ITP patients.

ITP Immune thrombocytopenia, CTLA-4 cytotoxic T lymphocyte‐associated antigen‐4, N number; %: percentage, Y years, M male, F female, NA None applicable; *Significance difference (P < 0.05).