Association between human leukocyte antigen gene polymorphisms and multiple EPIYA-C repeats in gastrointestinal disorders

doi:10.3748/wjg.v26.i32.4817

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World Journal of Gastroenterology

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World J Gastroenterol. Aug 28, 2020; 26(32): 4817-4832
Published online Aug 28, 2020. doi: 10.3748/wjg.v26.i32.4817

Table 1 PCR primers

Primer	Primer sequence (59R39)	Ref.
cagA-F	GATAACAGGCAAGCTTTTGAGG¹	[19,20]
cagA-R	CTGCAAAAGATTGTTTGGCAGA¹	[19,20]
cagA28F	TTCTCAAAGGAGCAATTGGC²	[21]
cagA-P1C	GTCCTGCTTTCTTTTTATTAACTTKAGC²
cagA-P2CG	TTTAGCAACTTGAGCGTAAATGGG²
cagA-P2TA	TTTAGCAACTTGAGTATAAATGGG²
cagA-P3E	ATCAATTGTAGCGTAAATGGG²
“cag empty PCR”	GCTTGCTTGTATTGGCCTTG / GCATGCACATTCCCTAAAGT³	[22]

All polymerase chain reactions (PCRs) were performed in a 50 μL final volume with 1.25 U Taq polymerase, 16 μL PCR buffer, 3 μL 2.5 mM MgCl₂ and 1 μL dNTP mix (10 mM each) with the described primers using the thermal profiles detailed.

¹: 95 ºC for 2 min initial denaturation, followed by 45 cycles of 30 s at 95 ºC, 45 s at 53 ºC and 45 s at 72 ºC, with a final elongation step performed for 5 min at 72 ºC.

²: 95 ºC for 2 min initial denaturation, followed by 50 cycles of 30 s at 95 ºC, 45 s at 57 ºC and 35 s at 72 ºC, with a final elongation step performed for 5 min at 72 ºC.

³: 95 ºC for 2 min initial denaturation, followed by 40 cycles of 30 s at 95 ºC, 30 s at 57 ºC, 20 s at 72 ºC, with a final elongation step performed for 5 min at 72 ºC. PCR: Polymerase chain reaction.

Table 2 Comparison of human leukocyte antigen alleles predisposing susceptibility and resistance to gastric cancer/duodenal ulcer in patient and control groups, n (%)

HLA alleles	*Patient groupGC + DU, H. pylori* (+) (n = 94, alleles = 198)**	*Control groupNUD + Asymptomatic, H. pylori* (+) (n = 86, alleles = 172)**	OR	95%CI		P value
HLA alleles			OR	Minimum	Maximum	P value
HLAs increasing susceptibility to GC/DU
HLA-A*02	52 (27.6)	38 (22)	1.34	0.833	2.182	0.2239
HLA-B*35	40 (21.3)	26 (15.1)	1.51	0.880	2.615	0.1329
HLA-DRB1*13	36 (19)	24 (14)	1.46	0.831	2.567	0.1880
HLA-DQA1*01	76 (40)	30 (17.4)	3.21	1.968	5.242	0.0001
HLA-DQB1*06	52 (27.6)	20 (11.6)	2.90	1.652	5.139	0.0002
HLAs making resistant to GC/DU
HLA-A*03	14 (7.4)	20 (11.6)	0.61	0.298	1.252	0.1787
HLA-B*50	0 (0)	10 (5.8)	0.08	0.010	0.680	0.0201
HLA-DRB1*04	16 (8.5)	24 (14)	0.57	0.293	1.120	0.1038
HLA-DQA1*05	28 (14.9)	54 (31.4)	0.38	0.228	0.639	0.0003
HLA-DQB1*03	42 (23)	64 (37.2)	0.48	0.305	0.770	0.0022

HLA: Human leukocyte antigen; H. pylori: Helicobacter pylori; GC: Gastric cancer; DU: Duodenal ulcer; NUD: Non-ulcer dyspepsia; CI: Confidence interval; OR: Odds ratio.

Table 3 The comparison of human leukocyte antigen alleles which increase or decrease the gastric cancer risk in gastric cancer subgroup cases in terms of CagA+ (≥ 2) EPIYA-C, n (%)

	GC (≥ 2) EPIYA-C (n = 26, alleles = 52)	GC (< 2) EPIYA-C (n = 18, alleles = 36)	OR	95%CI			P value
	GC (≥ 2) EPIYA-C (n = 26, alleles = 52)	GC (< 2) EPIYA-C (n = 18, alleles = 36)	OR	Minimum	Maximum		P value
HLA-A*02	12 (23)	10 (27)	0.78	0.29		2.06	0.6170
HLA-B*35	12 (23)	10 (27)	0.78	0.29		2.06	0.6170
HLA-DRB1*13	12 (23)	12 (33)	0.60	0.23		1.54	0.2903
HLA-DQA1*01	24 (46)	16 (44)	1.07	0.45		2.51	0.8742
HLA-DQB1*06	12 (23)	16 (44)	0.37	1.14		2.90	0.0369

HLA: Human leukocyte antigen; GC: Gastric cancer; CI: Confidence interval; OR: Odds ratio.

Table 4 The comparison of human leukocyte antigen alleles which increase or decrease the duodenal ulcer risk in duodenal ulcer subgroup in terms of CagA+(≥ 2) EPIYA-C, n (%)

	DU (≥ 2) EPIYA-C (n = 14, alleles = 28)	DU (< 2) EPIYA-C (n = 36, alleles = 72)	OR^c	95%CI			P value
	DU (≥ 2) EPIYA-C (n = 14, alleles = 28)	DU (< 2) EPIYA-C (n = 36, alleles = 72)	OR^c	Minimum	Maximum		P value
HLA-A*02	10 (36)	20 (27)	1.44	0.53		3.62	0.4380
HLA-B*35	4 (14)	14 (19)	0.80	0.24		0.680	0.0201
HLA-DRB1*13	6 (21)	6 (8)	3	0.87		10.26	0.0801
HLA-DQA1*01	10 (36)	26 (36)	0.9	0.39		2.44	0.9704
HLA-DQB1*06	8 (28)	16 (22)	1.4	0.52		3.75	0.5340

HLA: Human leukocyte antigen; DU: Duodenal ulcer; CI: Confidence interval; OR: Odds ratio.

Table 5 The comparison of human leukocyte antigen alleles which increase or decrease the gastric cancer/duodenal ulcer risk in gastric cancer and duodenal ulcer subgroups in terms of CagA+(≥ 2) EPIYA-C, n (%)

	GC(≥ 2) EPIYA-C (n = 26, alleles=52)	DU(≥ 2) EPIYA-C (n = 14, alleles=28)	OR	95%CI			P value
	GC(≥ 2) EPIYA-C (n = 26, alleles=52)	DU(≥ 2) EPIYA-C (n = 14, alleles=28)	OR	Minimum	Maximum		P value
HLA-A*02	12 (23)	10 (36)	0.54	0.19		1.47	0.2302
HLA-B*35	12 (23)	4 (14)	1.80	0.52		6.21	0.3527
HLA-DRB1*13	12 (23)	6 (21)	1.10	0.36		3.83	0.8663
HLA-DQA1*01	24 (46)	10 (36)	1.54	0.59		3.97	0.3689
HLA-DRB1*06	12 (23)	8 (28)	0.75	0.26		2.12	0.5889

HLA: Human leukocyte antigen; GC: Gastric cancer; DU: Duodenal ulcer; CI: Confidence interval; OR: Odds ratio.

Table 6 Results of logistic regressions analysis according to the variables in patient group (gastric cancer and duodenal ulcer cases)

	P value	OR	95%CI
	P value	OR	Lower	Upper
HLA-DQA1*01	0.004	1.848	1.215	2.811
HLA-DQA1*05	0.050
HLA-DQB1*03	0.061
HLA-DQB1*06	0.009	1.821	1.163	2.850
HLA-A*02	0.040	1.579	1.021	2.442
HLA-A*25	0.999

Variable(s) entered on step 1: QA1, QA5, QB3, QB6, A2, A25, B35. HLA: Human leukocyte antigen; CI: Confidence interval; OR: Odds ratio.

Table 7 Frequency of detected human leukocyte antigen class I alleles and the class II alleles in patients with cancer and ulcer and in the control groups, n (%)

*HLA-A*	Allele frequency		HLA-B	Allele frequency		HLA-DRB1	Allele frequency		HLA-DQA1	Allele frequency		HLA-DQB1	Allele frequency
Alleles	Cases (n = 94)	Control (n = 86)	Alleles	Cases (n = 94)	Control (n = 86)	Alleles	Cases (n = 94)	Control (n = 86)	Alleles	Cases (n = 94)	Control (n = 86)	Alleles	Cases (n = 94)	Control (n = 86)
01	22 (11.4)	24 (13.9)	07	18 (9.5)	22 (12.8)	01	14 (7.4)	8 (4.6)	01	76 (40)	30 (17.4)	02	20 (10.6)	26 (15.1)
02	52 (27.6)	38 (22)	08	6 (3.2)	6 (3.5)	03	10 (5.3)	10 (5.8)	02	20 (10.6)	20 (11.6)	03	42 (23)	64 (37.2)
03	14 (7.4)	20 (11.6)	13	6 (3.2)	4 (2.3)	04	16 (8.5)	22 (12.7)	03	12 (6.4)	22 (12.8)	04	26 (13.8)	28 (16.2)
11	18 (9.5)	18 (10.4)	14	6 (3.2)	4 (2.3)	07	10 (5.3)	20 (11.6)	04	16 (8.5)	20 (11.6)	05	48 (25.5)	34 (19.8)
23	10 (5.3)	4 (2.3)	15	2 (1)	6 (3.5)	08	4 (2.1)	6 (3.5)	05	28 (14.9)	54 (31.4)	06	52 (27.6)	20 (11.6)
24	26 (13.8)	24 (13.9)	18	10 (5.3)	10 (5.8)	10	6 (3.2)	4 (2.3)	06	36 (19.1)	26 (15.1)
25	0 (0)	2 (1.1)	27	6 (3.2)	4 (2.3)	11	34 (18)	42 (24.4)
26	4 (2.1)	4 (2.3)	35	40 (21.3)	26 (15.1)	12	6 (3.2)	2 (1.2)
29	8 (4.2)	8 (4.6)	37	4 (2.1)	0 (0)	13	36 (19)	24 (14)
30	4 (2.1)	6 (3.4)	38	8 (4.2)	2 (1.2)	14	18 (9.5)	8 (4.6)
31	2 (1)	4 (2.3)	39	0 (0)	4 (2.3)	15	28 (14.9)	22 (12.8)
32	16 (8.5)	10 (5.8)	40	6 (3.2)	6 (3.5)	16	6 (3.2)	4 (2.3)
33	6 (3.1)	4 (2.3)	41	4 (2.1)	2 (1.2)
68	4 (2.1)	6 (3.4)	44	8 (4.2)	14 (8.1)
69	2 (1)	0 (0)	45	0 (0)	2 (1.2)
			48	2 (1)	2 (1.2)
			49	6 (3.2)	4 (2.3)
			50	0 (0)	10 (5.8)
			51	24 (12)	30 (17.4)
			52	14 (7.4)	2 (1.2)
			53	0 (0)	2 (1.2)
			54	2 (1)	0 (0)
			55	6 (3.2)	8 (4.6)
			57	2 (1)	2 (1.2)
			58	8 (4.2)	0 (0)
			78	0 (0)	0 (0)

HLA: Human leukocyte antigen.

Table 8 The distribution of EPIYA motifs for study and control groups, n (%)

EPIYA-C repeat patterns	Patient group				Control group				Total (n = 140)
EPIYA-C repeat patterns	Gastric cancer		Duodenal ulcer		Non-ulcer dyspepsia		Individuals with normal gastrointestinal system		Total (n = 140)
ABC	12	(27.2)	34	(68)	28	(93.3)	16	(100)	90
AC	2	(4.5)	2	(4)	-		-		4
BC	2	(4.5)	-		-		-		2
ABCC	16	(36.4)	8	(16)	-		-		24
BCC	2	(4.6)	2	(4)	2	(6.7)	-		6
ACCC	-		-		-		-		-
ABCC	8	(18.2)	4	(8)	-		-		12
AB	2	(4.6)	-		-		-		2
Total	44	(100)	50	(100)	30	(100)	16	(100)	140

HLA: Human leukocyte antigen.

Citation: Saribas S, Demiryas S, Yilmaz E, Uysal O, Kepil N, Demirci M, Caliskan R, Dinc HO, Akkus S, Gareayaghi N, Kirmusaoglu S, Ozbey D, Tokman HB, Koksal SS, Tasci I, Kocazeybek B. Association between human leukocyte antigen gene polymorphisms and multiple EPIYA-C repeats in gastrointestinal disorders. World J Gastroenterol 2020; 26(32): 4817-4832
URL: https://www.wjgnet.com/1007-9327/full/v26/i32/4817.htm
DOI: https://dx.doi.org/10.3748/wjg.v26.i32.4817