Influence of interleukin polymorphisms on development of gastric cancer and peptic ulcer

Table 1 Association of IL-2 polymorphism and gastroduodenal diseases

Position	Disease	Authors	Year		n
-330 T/G						T/T	T/G	G/G
	GC	Wu et al[37]	2009	GC	1026	491	441	94	GCC: T/T: 0.7 (0.4-1.0)
				NUD	1083	516	480	87
	GC	Shin et al[35]	2008	GC	122	79	35	8	NS
				NUD	100	72	16	12
	PU	Shin et al[35]	2008	PU	220	159	45	16	NS
				NUD	100	72	16	12
	Atrophy	Togawa et al[34]	2005	Atrophy	152	80	63	9	T/T: 2.8 (1.3-6.2)
				NUD	443	202	196	45
-384 G/T						G/G	G/T	T/T
	GCC	Savage et al[36]	2004	GC	87	16	47	20	NS
				NUD	379	96	174	109
+114 G/T						G/G	G/T	T/T
	GCC	Savage et al[36]	2004	GC	82	33	35	14	NS
				NUD	377	149	148	80

GC: Gastric cancer; GCC: Gastric cardia cancer; PU: Peptic ulcer; IL: Interleukin; NUD: Non-ulcer dyspepsia; NS: Not significant.

Table 2 Association of IL-4 polymorphism and gastroduodenal diseases

Position	Disease	Authors	Year		n
-168 T/C						T/T	T/C	C/C
	GC	Wu et al[37]	2009	GC	1042	744	271	27	C carrier: 0.8 (0.7-1.0)
				NUD	1099	743	332	24
-590 C/T						C/C	C/T	T/T
	GC	Zambon et al[57]	2008	GC	40	32	7	1	NS
				NUD	171	124	43	4
	GC	García-González et al[56]	2007	GC	404	283	107	14	NS
				NUD	404	267	123	14
	GC	Lai et al[54]	2005	GC	123	83	38	2	NS
				NUD	162	105	50	7
	GC	El-Omar et al[53]	2003	GC	122	78	37	7	NS
				NUD	209	153	46	10
	GC	Wu et al[52]	2003	GC	220	146	69	5	C carrier (diffuse-type): 1.6 (1.0-2.7)
				NUD	230	163	55	12
	DU	Zambon et al[57]	2008	DU	171	124	43	4	NS
				NUD	107	79	26	2
	Atrophy	Kato et al[51]	2006	Atrophy	788	398	308	82	NS
				Dys	115	51	48	16
				NUD	1020	506	414	100
-33 C/T						C/C	C/T	T/T
	Atrophy	Togawa et al[34]	2005	Atrophy	157	10	70	77	T/C: 2.2 (1.0-4.9)
				NUD	452	42	183	227
984, 2983						AA/AA	AA/GC	AA/GA
	GC	Seno et al[55]	2007	Atrophy	100	52	29	7	AA/GA: 0.3 (0.1-0.9)
				NUD	93	40	27	17

Although Seno et al[55] investigated nine SNPs (IL-4-590, -33, 3437, 3557, 4047, 4144, 4271, 4367 and 8427), data concerning the exclusion of IL-4+984 and 2983 were unclear. Dys: Dysplasia; DU: Duodenal ulcer.

Table 3 Association of IL-6 polymorphism and gastroduodenal diseases

Position	Disease	Authors	Year		n
-174 C/G						C/C	C/G	G/G
	GC	Gatti et al[81]	2007	GC	56	1	13	42	GG: 11.0 (1.2-96.7)
				NUD	112	11	53	48
	GCC	Deans et al[82]	2007	GC	197	43	83	71	NS
				NUD	224	44	101	79
	GC	Kamangar et al[83]	2006	GC	102	27	54	21	GC: 2.2 (1.2-4.0) vs G/G
				NUD	152	43	58	51
	GC	El-Omar et al[53]	2003	GC	123	16	52	55	NS
				NUD	209	28	98	83
	GC	Hwang et al[77]	2003	GC	60	2	9	49	-
	PU	Chakravorty et al[84]	2008	GU	91	1	18	72	NS
				NUD	62	1	7	54
	DU	Hwang et al[77]	2003	DU	60	0	0	30	-
-572 G/C						C/C	C/G	G/G
	GC	Kang et al[85]	2009	GC	284	154	113	17	NS
				NUD	278	140	123	15
	GC	Hwang et al[77]	2003	GC	60	19	29	12	-
	PU	Kang et al[85]	2009	PU	434	249	167	20	DU: GG 0.3 (0.1-0.9)
				NUD	278	140	123	15
	PU	Chakravorty et al[84]	2008	PU	91	57	27	7	NS
				NUD	62	37	20	5
	DU	Hwang et al[77]	2003	DU	60	21	20	19	-
-597 G/A						G/G	G/A	A/A
	GC	Kamangar et al[83]	2006	GC	110	25	59	26	NS
				NUD	203	61	86	56
	GC	Hwang et al[77]	2003	GC	60	50	8	2	-
	PU	Chakravorty et al[84]	2008	PU	91	53	29	10	NS
				NUD	62	41	16	5
	DU	Hwang et al[77]	2003	GC	60	52	8	0	-
-634 C/T						C/C	C/T	T/T
	GC	Liao et al[72]	2008	GC	155	96	55	4	NS
				NUD	211	118	84	9

Although Kang et al and Savage et al investigated the association with IL-6-174 C/G polymorphism and gastric cancer, data were not described in detail (> 99% of patients were of the IL-6-174 G/G genotype).

Table 4 Association of IL-8 polymorphism and gastroduodenal diseases

	Disease	Authors	Year		n
-251 A/T						T/T	T/A	A/A
	GC	Kang et al[85]	2009	GC	284	106	136	43	AA: 2.0 (1.2-3.6)
				NUD	275	125	125	25
	GC	Canedo et al[94]	2008	GC	333	111	169	53	NS
				NUD	880	265	445	170
	GC	Garza-Gonzalez et al[58]	2007	GC	78	15	47	16	A carrier: 2.1 (1.1-4.2)
				NUD	230	76	107	47
	GC	Kamali-Sarvestani et al[95]	2006	GC	19	4	6	9	AT: 4.5 (1.5-12.9)
				NUD	153	57	74	22
	GC	Shirai et al[96]	2006	GC	181	83	78	20	MSI (+): TT 5.2 (1.5-18.0)
				NUD	268	211	208	49
	GC	Savage et al[97]	2006	GC	287	71	140	76	NS
				NUD	426	106	205	117
	GC	Kamangar et al[83]	2006	GC	112	42	56	14	NS
				NUD	207	72	111	24
	GC	Taguchi et al[98]	2005	GC	396	161	191	44	AA: 2.2 (1.1-4.6)
				NUD	252	125	105	22
	GC	Lee et al[99]	2005	GC	470	198	213	59	TT: 1.9 (1.3-3.0)
				NUD	308	108	138	62
	GC	Ohyauchi et al[100]	2005	GC	212	93	106	13	A carrier: 1.8 (1.1-2.8)
				NUD	195	106	74	15
	GCC	Savage et al[101]	2004	GC	88	26	39	23	AA: 2.0 (1.0-3.8)
				NUD	429	147	207	75
	GC	Lu et al[102]	2005	GC	250	94	102	54	AA: 1.9 (1.2-3.2)
				NUD	300	119	144	37
	PU	Kang et al[85]	2009	PU	447	160	223	64	GU: AA: 2.7 (1.5-4.8)
				NUD	275	125	125	25
	PU	Garza-Gonzalez et al[58]	2007	PU	29	11	14	4	NS
				NUD	230	76	107	47
	GU	Kamali-Sarvestani et al[95]	2006	GU	61	19	28	14	NS
				NUD	153	57	74	22
	GU	Ohyauchi et al[100]	2005	PU	283	134	127	22	GU:A carrier: 1.8 (1.1-3.0)
				NUD	195	106	74	15
	PU	Chakravorty et al[84]	2008	PU	91	20	46	25	NS
				NUD	62	18	28	16
	DU	Hofner et al[103]	2007	DU	85	15	49	21	AA: 2.3 (1.5-6.4)
				NUD	211	61	106	44
	DU	Gyulai et al[104]	2004	DU	69	11	45	13	A carrier: 4.4 (1.9-10.5)
				NUD	47	21	17	9
	IM	Leung et al[105]	2006	IM	123	23	56	44	NS
				NUD	179	36	92	51
	Atrophy	Taguchi et al[98]	2005	Atrophy	215	90	99	26	AA: 2.4 (1.1-4.9)
				NUD	252	125	105	22
	NUD	Hamajima et al[106]	2003	NUD	448	234	177	37	-
+396 T/G						T/T	T/G	G/G
	GC	Kamangar et al[83]	2006	GC	111	42	55	14	NS
				NUD	208	72	112	24
	GCC	Savage et al[101]	2004	GC	86	29	33	24	GG: 2.1 (1.1-3.9)
				NUD	402	152	181	69
+781 C/T						C/C	C/T	T/T
	GC	Kamangar et al[83]	2006	GC	111	47	52	12	NS
				NUD	208	81	105	22
	GCC	Savage et al[101]	2004	GC	85	28	41	16	NS
				NUD	406	167	177	62

Although Seno et al[55] investigated six SNPs (IL-4-352, 289, 294, 680, 2217 and 2670), data were not described in detail. IM: Intestinal metaplasia.

Table 5 ORs for gastric non-cardia cancer and peptic ulcer development in IL-2-330 polymorphism

	Genotype	1NUD (n)	Cancer (n)	OR	95% CI	P value	Ulcer (n)	OR	95% CI	P value
IL-2-330	T/T	870	258	-			159	-
	G/T	755	209	0.93	0.76-1.15	0.51	45	0.33	0.23-0.46	< 0.01
	G/G	153	35	0.77	0.52-1.14	0.20	16	0.57	0.33-0.98	0.04
	G carrier	908	244	0.91	0.74-1.11	0.33	61	0.37	0.27-0.50	< 0.01

¹NUD includes gastritis without gastric cancer and peptic ulcer, and atrophic gastritis patients. Because we deleted a number of gastric cardia cancer patients, a number of cancer patients shown in this Table do not match that in Table 1.

Table 6 ORs for gastric non-cardia cancer and peptic ulcer development with IL-4-168 and -590 polymorphisms

	Genotype	1NUD (n)	Cancer (n)	OR	95% CI	P value	Ulcer (n)	OR	95% CI	P value
IL-4-168	T/T	743	744	-
	T/C	332	271	0.81	0.67-0.98	0.03
	C/C	24	27	1.12	0.64-2.00	0.70
	C carrier	356	298	0.81	0.69-1.00	0.05
IL-4-590	C/C	1716	591	-			46	-
	C/T	1039	242	0.68	0.57-0.80	< 0.01	18	0.65	0.37-1.10	0.12
	T/T	229	28	0.36	0.24-0.53	< 0.01	2	0.33	0.08-1.35	0.12
	T carrier	1268	270	0.61	0.53-0.73	< 0.01	20	0.58	0.34-0.99	0.05

¹NUD includes patients with gastritis without gastric cancer and peptic ulcer, and atrophic gastritis. Because we deleted a number of gastric cardia cancer patients, the number of cancer patients in this Table does not match that in Table 2.

Table 7 Prevalence of inflammatory cytokine gene genotypes in East Asian and Western populations

Gene	Population	NUD			GC			PU
IL-2-330		T/T	T/G	G/G	T/T	T/G	G/G	T/T	T/G	G/G
	Asian	870	755	153	258	209	35	159	45	16
	Western
IL-4-590		C/C	C/T	T/T	C/C	C/T	T/T	C/C	C/T	T/T
	Asian	268	105	19	229	107	7
	Western	1448	934	210	362	135	21
IL-6-174		C/C	C/G	G/G	C/C	C/G	G/G	C/C	C/G	G/G
	Asian				0	0	30	0	0	30
	Western	126	310	261	34	82	112	1	26	94
IL-6-572		C/C	C/G	G/G	C/C	C/G	G/G	C/C	C/G	G/G
	Asian	140	123	15	170	126	18	165	170	19
	Western	37	20	5	3	16	11	62	34	25
IL-6-597		G/G	G/A	A/A	G/G	G/A	A/A	G/G	G/A	A/A
	Asian				30	0	0	30	0	0
	Western	102	102	61	45	67	28	75	37	10
IL-8-251		T/T	T/A	A/A	T/T	T/A	A/A	T/T	T/A	A/A
	Asian	1324	1425	443	735	826	233	294	350	86
	Western	676	1093	449	243	418	168	76	182	77
IL-8+396		T/T	T/G	G/G	T/T	T/G	G/G	T/T	T/G	G/G
	Asian	152	181	69
	Western	72	112	24	27	43	12
IL-8+781		C/C	C/T	T/T	C/C	C/T	T/T	C/C	C/T	T/T
	Asian	167	177	62
	Western	81	105	22	29	41	11

Table 8 Comparison of the incidence of gastric non-cardia cancer and peptic ulcer in Asian and Western populations

Disease	Gene	Reference	Genotype	Western			Asian
				OR	95% CI	P value	OR	95% CI	P value
GC	IL-4-590	C/C	C/T	0.57	0.41-0.72	< 0.01	1.12	0.87-1.65	0.28
			T/T	0.40	0.25-0.64	< 0.01	0.43	0.18-1.04	0.06
			T carrier	0.55	0.46-0.67	< 0.01	1.08	0.79-1.45	0.17
	IL-6-572	C/C	C/G	9.87	2.56-37.98	< 0.01	0.85	0.61-1.19	0.34
			G/G	21.13	5.56-131.98	< 0.01	0.99	0.48-2.03	0.97
			G carrier	13.32	3.64-48.69	< 0.01	0.87	0.63-1.20	0.38
	IL-8-251	T/T	T/A	1.04	0.86-1.25	0.69	1.06	0.93-1.20	0.38
			A/A	1.04	0.83-1.31	0.73	0.95	0.79-1.14	0.56
			A carrier	1.04	0.87-1.24	0.67	1.03	0.92-1.16	0.61
GU	IL-4-590	C/C	C/T	0.61	0.35-1.05	0.08
			T/T	0.30	0.07-1.24	0.10
			T carrier	0.55	0.32-0.94	0.03
	IL-6-572	C/C	C/G	1.31	0.07-2.56	0.42	0.77	0.55-1.05	0.07
			G/G	2.98	1.05-8.47	0.04	0.67	0.33-1.34	2.66
			G carrier	1.65	0.89-3.04	1.65	0.74	0.55-1.01	0.06
	IL-8-251	T/T	T/A	1.48	1.12-1.97	< 0.01	1.11	0.93-1.31	0.25
			A/A	1.53	1.09-2.14	0.01	0.87	0.67-1.14	0.31
			A carrier	1.49	1.14-1.96	< 0.01	1.05	0.89-1.24	0.55

Table 9 ORs for the development of gastric non-cardia cancer with the IL-6-174, +572, +597 and +634 polymorphisms

	Genotype	1NUD (n)	Cancer (n)	OR	95% CI	P value	Ulcer (n)	OR	95% CI	P value
IL-6-174	C/C	126	34	-			1
	C/G	310	82	0.98	0.63-1.54	0.93	26	10.57	1.42-78.73	0.02
	G/G	261	142	2.02	1.31-3.10	< 0.01	124	59.86	8.27-433.4	< 0.01
	G carrier	571	224	1.45	0.97-2.19	0.06	150	33.10	4.59-238.8	< 0.01
IL-6+572	C/C	177	173	-			327	-
	C/G	143	143	1.02	0.75-1.40	0.89	214	0.81	0.61-1.07	0.15
	G/G	20	29	1.48	0.81-2.72	0.20	44	1.19	0.68-2.08	0.54
	G carrier	163	172	1.08	0.80-1.46	0.61	258	0.86	0.66-1.12	0.26
IL-6+597	G/G	102	75	-				-
	G/A	102	67	0.89	0.58-1.37	0.61
	A/A	61	28	0.62	0.37-1.07	0.09
	A carrier	163	95	0.79	0.54-1.17	0.24
IL-6+634	C/C	118	96	-
	C/T	84	55	0.81	0.52-1.24	0.33
	T/T	9	4	0.45	0.16-1.83	0.32
	T carrier	93	59	0.78	0.51-1.12	0.25

¹NUD includes patients with gastritis without gastric cancer and peptic ulcer, and atrophic gastritis. Because we deleted a number of gastric cardia cancer patients, the number of cancer patients shown in this Table does not match that in Table 3.

Table 10 ORs for the development of gastric non-cardia cancer with IL-8-251, +396 and +781 polymorphisms

	Genotype	NUD (n)	Cancer (n)	OR	95% CI	P value	Ulcer (n)	OR	95% CI	P value
IL-8-251	T/T	2000	978	-			370
	T/A	2518	1244	1.01	0.91-1.12	0.38	532	1.14	0.99-1.32	0.07
	A/A	892	401	0.92	0.80-1.06	0.24	163	0.99	0.81-1.21	0.90
	A carrier	3410	1645	0.99	0.90-1.09	0.18	695	1.10	0.96-1.26	0.17
IL-8+396	T/T	224	27	-
	T/G	293	43	1.22	0.73-2.03	0.44
	G/G	93	12	1.07	0.52-2.20	0.85
	G carrier	385	55	1.18	0.73-1.93	0.50
IL-8+781	C/C	248	29	-
	C/T	282	41	1.24	0.75-2.06	0.39
	T/T	84	11	1.12	0.54-2.34	0.76
	T carrier	366	52	1.22	0.75-1.97	0.43

NUD includes patients with gastritis without gastric cancer and peptic ulcer, and atrophic gastritis. Because we deleted a number of gastric cardia cancer patients, the number of cancer patients shown in this Table does not match that in Table 4.

Table 11 Summary of association with inflammatory cytokine genotypes and gastroduodenal diseases in East Asian and Western populations

Gene		Western		Asian
		PU	GC	PU	GC
IL-2-330	G carrier (vs T)	-	-	↓	NS
IL-4-590	T carrier (vs C)	↓	↓	NS	-
IL-6-174	G carrier (vs C)	↑	↑	-	-
IL-6-572	G carrier (vs C)	NS	↑	NS	NS
IL-6-597	A carrier (vs G)	NS	NS	-	-
IL-8-251	A carrier (vs T)	↑	NS	NS	NS
IL-8+396	G carrier (vs T)	-	NS	-	-
IL-8+781	T carrier (vs C)	-	NS	-	-

↓ decrease in risk of disease; ↑ increase in risk of disease.