TIM3 and CTLA4 immune checkpoint polymorphisms are associated with acute myeloid leukemia in Saudi Arabia

Figures & data

Table 1. Characteristics of selected polymorphisms involved in the CTLA-4 rs231775 and TIM-3 rs105157460.

Gene	SNP ID	Chromosome position	Nucleotide change	Region	MAF in Human populations (1000genomes Study)
					Global	European	American	South Asian	East Asian	Qatar
CTLA-4	rs231775	Chr2/ 203867991	A > G	Exon1	0.43	0.36	0.46	0.31	0.64	0.20
TIM-3	rs10515746	Chr5/ 157109557	A > C	promoter at −574	0.15	0.19	0.12	0.04	0.02	0.30

MAF: minor allele frequency;

Table 2. Association between AML and CTLA-4 rs10515746 SNP.

Locus	Model	Genotype	Control (%) N = 131	AML (%) N = 98	OR (95% CI)	P*-value	AIC
CTLA-4 rs231775 A > G	Alleles	A	0.7	0.79	1.00	0.031
		G	0.3	0.21	0.622 (0.404–0.959)
	Codominant	AA	58 (45.3%)	60 (61.2%)	1.00	0.058	309.6
		AG	62 (48.4%)	34 (34.7%)	0.53 (0.31–0.92)
		GG	8 (6.2%)	4 (4.1%)	0.48 (0.14–1.69)
	Dominant	AA	58 (45.3%)	60 (61.2%)	1.00	0.017	307.6
		AG + GG	70 (54.7%)	38 (38.8%)	0.52 (0.31–0.90)
	Recessive	AA + AG	120 (93.8%)	94 (95.9%)	1.00	0.47	312.8
		GG	8 (6.2%)	4 (4.1%)	0.64 (0.19–2.18)
	Log-Additive				0.59 (0.37–0.94)	0.023	308.1

AML, acute myeloid leukemia; OR, odds ratio; CI, 95% confidence interval; AIC, akaike information criterion; significant associations are depicted in bold.

Table 3. Association between TIM-3 rs10515746 SNP with AML.

Locus	Model	Genotype	Control (%) N = 131	AML (%) N = 98	OR (95% CI)	P*-value	AIC
TIM-3 rs10515746A > C	Alleles	A	0.76	0.35	1.00	<0.0001
		C	0.24	0.65	6.01(3.99–9.05)
	Codominant	AA	69 (53.1%)	8 (8.2%)	1.00	<0.0001	221.4
		AC	60 (46.1%)	52 (53.1%)	7.48 (3.29–16.99)
		CC	1 (0.8%)	38 (38.8%)	327.75 (39.48–2720)
	Dominant	AA	69 (53.1%)	8 (8.2%)	1.00	<0.0001	259.1
		AC + CC	61 (46.9%)	90 (91.8%)	12.73 (5.71–28.35)
	Recessive	AA + AC	129 (99.2%)	60 (61.2%)	1.00	<0.0001	249.5
		CC	1 (0.8%)	38 (38.8%)	81.70 (10.96–609.20)
	Log-Additive				11.89 (5.97–23.69)	<0.0001	222.6

AML, acute myeloid leukemia; OR, odds ratio; CI, 95% confidence interval; AIC, akaike information criterion; significant associations are depicted in bold.

Table 4. Correlation between CTLA-4 rs231775 and TIM-3 rs10515746 SNPs with AML after gender stratification.

Locus	Model	Genotype	AML Female N = 44	AML Male N = 54	OR (95% CI)	P-value	AIC
CTLA-4 rs231775A > G	Alleles	A	0.81	0.77	Ref	0.6
		G	0.19	0.23	1.25 (0.62–2.51)
	Codominant	AA	29 (65.9%)	31 (57.4%)	1.00	0.62	139.9
		AG	13 (29.6%)	21 (38.9%)	1.51 (0.64–3.56)
		GG	2 (4.5%)	2 (3.7%)	0.94 (0.12–7.08)
	Dominant	AA	29 (65.9%)	31 (57.4%)	1.00	0.39	138.1
		AG + GG	15 (34.1%)	23 (42.6%)	1.43 (0.63–3.27)
	Recessive	AA + AG	42 (95.5%)	52 (96.3%)	1.00	0.83	138.8
		GG	2 (4.5%)	2 (3.7%)	0.81 (0.11–5.98)
		AG	13 (29.6%)	21 (38.9%)	1.52 (0.65–3.54)
	Log-Additive				1.27 (0.63–2.57)	0.51	138.4
TIM-3 rs10515746A > C	Alleles	A	0.34 (30)	0.35 (38)	ref	0.88
		C	0.66 (58)	0.65 (70)	1.05(.58–1.86)
	Codominant	CC	18 (40.9%)	20 (37%)	1.00	0.85	140.5
		AC	22 (50%)	30 (55.6%)	1.23 (0.53–2.85)
		AA	4 (9.1%)	4 (7.4%)	0.90 (0.20–4.14)
	Dominant	CC	18 (40.9%)	20 (37%)	1.00	0.7	138.7
		AC + AA	26 (59.1%)	34 (63%)	1.18 (0.52–2.66)
	Recessive	CC + AC	40 (90.9%)	50 (92.6%)	1.00	0.76	138.7
		AA	4 (9.1%)	4 (7.4%)	0.80 (0.19–3.40)
		AC	22 (50%)	30 (55.6%)	1.25 (0.56–2.78)
	Log-Additive				1.06 (0.55–2.03)	0.86	138.8

AML acute myeloid leukemia, OR odds ratio, 95% CI 95% confidence interval, *p < 0.05 was considered significant and are depicted in bold.

Table 5. Correlation between CTLA-4 rs231775 and TIM-3 rs10515746 SNPs with AML after age stratification.

Locus	Model	Genotype	AML ≥ 29 (%) N = 55	AML < 29 (%) N = 43	OR (95% CI)	P-value	AIC
CTLA-4 rs231775A > G	Alleles	A	0.81	0.75	Ref	0.38
		G	0.19	0.25	1.36 (0/69–2.71)
	Codominant	AA	35 (63.6%)	25 (58.1%)	1.00	0.42	138.7
		AG	19 (34.5%)	15 (34.9%)	1.11 (0.47–2.58)
		GG	1 (1.8%)	3 (7%)	4.20 (0.41–42.77)
	Dominant	AA	35 (63.6%)	25 (58.1%)	1.00	0.58	138.1
		AG + GG	20 (36.4%)	18 (41.9%)	1.26 (0.56–2.85)
	Recessive	AA + AG	54 (98.2%)	40 (93%)	1.00	0.2	136.7
		GG	1 (1.8%)	3 (7%)	4.05 (0.41–40.39)
	Overdominant	AA + GG	36 (65.5%)	28 (65.1%)	1.00	0.97	138.4
		AG	19 (34.5%)	15 (34.9%)	1.02 (0.44–2.35)
	Log-Additive				1.38 (0.69–2.79)	0.36	137.5
TIM-3 rs10515746A > C	Alleles	A	0.69	0.64	ref	0.76
		C	0.31	0.36	1.12 (0.61–2.00)
	Codominant	CC	21 (38.2%)	17 (39.5%)	1.00	0.5	139
		AC	31 (56.4%)	21 (48.8%)	0.84 (0.36–1.95)
		AA	3 (5.5%)	5 (11.6%)	2.06 (0.43–9.87)
	Dominant	CC	21 (38.2%)	17 (39.5%)	1.00	0.89	138.4
		AC + AA	34 (61.8%)	26 (60.5%)	0.94 (0.42–2.14)
	Recessive	CC + AC	52 (94.5%)	38 (88.4%)	1.00	0.27	137.2
		AA	3 (5.5%)	5 (11.6%)	2.28 (0.51–10.13)
	Overdominant	CC + AA	24 (43.6%)	22 (51.2%)	1.00	0.46	137.8
		AC	31 (56.4%)	21 (48.8%)	0.74 (0.33–1.65)
	Log-Additive				1.14 (0.59–2.18)	0.7	138.2

AML acute myeloid leukemia, OR odds ratio, 95% CI 95% confidence interval, *p < 0.05 was considered significant and are depicted in bold.

Figure 1. A, Expression of CTLA-4 in blood of AML patients (red) and normal blood (black). Each bar indicates the average level of expression of CTLA-4. Data were obtained from the GEPIA database were extracted (http://gepia.cancer-pku.cn). B: Kaplan-Meier analysis obtained plot from in the UALCAN database (http://ualcan.path.uab.edu/).

Figure 2. A: Expression of TIM-3 (HAVCR2) in blood of AML patients (red) and normal blood (black). Each bar indicates the average level of expression of TIM-3. Data were obtained from the GEPIA database were extracted (http://gepia.cancer-pku.cn). B: Kaplan-Meier analysis obtained plot of TIM-3 obtained from in the UALCAN database (http://ualcan.path.uab.edu/).

Data availability statement

All data relevant to the study are included in the article.