Helicobacter pylori and cytokine gene variants as predictors of premalignant gastric lesions

doi:10.3748/wjg.v25.i30.4105

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World J Gastroenterol. Aug 14, 2019; 25(30): 4105-4124
Published online Aug 14, 2019. doi: 10.3748/wjg.v25.i30.4105

Table 1 Statistical methods used in mentioned original research articles that analysed the relationship between cytokine gene variants and premalignant gastric lesions

Ref.	Target population (sample size)	Cytokine SNPs¹	Outcomes	Confounding factors/other covariates	Control for confounding/covariate effect	Statistical methods
[73]	Chinese adult patients (1330)	IL-8-4073, IL-18RAP917997, IL-1Brs1143627, IL-1B rs1143634, IL-1Brs16944, IL-4Rrs2057768, IL-10rs1800896, IL-22rs1179251, IL-32rs2015620	ChAG risk	Age, sex, smoking status, H. pylori	Stratification, adjustment	χ² test, multivariable logistic model with interaction term, Synergy index
			IM risk
			DYS risk
			GC risk
[75]	Slovenian adults (318)	TNF-α -308, IL-1RN, IL-1B -511	ChAG risk	Gender	Adjustment	χ² test, Multivariable logistic model
[75]	Slovenian adults (318)	TNF-α -308, IL-1RN, IL-1B -511	GC risk	Gender	Adjustment	χ² test, Multivariable logistic model
[76]	German older adults (1068)	TNF-α -308, IL10T-819C, IL10A-1082G, IL1AC-889T, IL1B C-511T, IL1RN 9589T, IL8 T-251A	ChAG risk	Age, gender	Adjustment	Multivariable logistic model
[83]	Peruvian Amerindian adults (334)	IL-1B-511, IL-1RN	ChAG risk	Age, gender, H. pylori	Adjustment	χ² test/Fisher’s exact test, multivariable logistic model
[83]	Peruvian Amerindian adults (334)	IL-1B-511, IL-1RN	GCrisk	Age, gender, H. pylori	Adjustment	χ² test/Fisher’s exact test, multivariable logistic model
[84]	Venezuelan adults (109)	IL-1B-31, IL-1B-511, IL-1B+13954, IL-1RN	ChAG risk	H. pylori	Adjustment	χ² test/Fisher’s exact test, univariable logistic model
			GI risk
			LI risk
[87]	Costa Rican adults (223)	IL-1β-511, IL-1β-3954, IL-1RN intron 2, IL-10 -1082, IL-10 -592	AG risk	Sex, age, H. pylori	Adjustment	χ² test/Fisher’s exact test, multivariable logistic model
			CoAG risk
			IM risk
[96]	Venezuelan adults (2033)	IL4 –590, IL4R -3223, IL4R -398, IL10 –1082	AG risk	Age, sex, H. pylori, education, environmental factors	Adjustment	χ² test/Fisher’s exact test, multivariable logistic model
			IM risk
			DYS risk
[101]	Brazilian adults (112)	IL-6	ChG	None	None	χ² test/Fisher’s exact test
[101]	Brazilian adults (112)	IL-6	GC	None	None	χ² test/Fisher’s exact test
[102]	Japanese adults (863)	IL-8 -251, IL-1B -511, IL-1RN	AG	Age, sex, H. pylori	Adjustment	χ² test/Fisher’s exact test, multivariable logistic model
[102]	Japanese adults (863)	IL-8 -251, IL-1B -511, IL-1RN	GC	Age, sex, H. pylori	Adjustment	χ² test/Fisher’s exact test, multivariable logistic model
[103]	Chinese adults (372)	IL-8-251	Severe ChAG risk	Age, gender	Stratification, adjustment	χ² test, multivariable logistic model, Synergy index
[103]	Chinese adults (372)	IL-8-251	IM risk	Age, gender	Stratification, adjustment	χ² test, multivariable logistic model, Synergy index
[106]	Chinese adult patients (556)	IL-10-1082, IL-10-819, IL-10-592	AG risk	Age, sex, H. pylori	Stratification, adjustment	χ² test, multivariable logistic model with interaction term
[106]	Chinese adult patients (556)	IL-10-1082, IL-10-819, IL-10-592	GC risk	Age, sex, H. pylori	Stratification, adjustment	χ² test, multivariable logistic model with interaction term
[108]	Brazilian adults (227)	IL-6-174, IL-8-251, IL-10-819	Gastritis, peptic ulcer, GC	H. pylori infection	Stratification	χ² test/Fisher’s exact test
[111]	Chinese adults H. pylori (302)	IL-1B-511	IM risk	Age	Adjustment	χ² test/Fisher’s exact test, univariable/multivariable logistic model

Only the original research articles containing analysis of cytokines’ genotypes (not haplotypes) were included.

¹Only the discussed cytokine SNPs of interest (and not all of SNPs mentioned in the above studies) are described. AG: Atrophic gastritis; CoAG: Corpus atrophic gastritis; ChAG: Chronic atrophic gastritis (the term used in original research); ChG: Chronic gastritis; DYS: Dysplasia; GC: Gastric cancer; GI: Granulocytic infiltration; IM: Intestinal metaplasia; LI: Lymphocytic infiltration; H. pylori: Helicobacter pylori.

Table 2 Frequencies of studied cytokine SNP genotypes and significance of relationships with premalignant gastric lesions in the discussed scientific articles

Ref.	SNP¹	Variant genotypes	Frequency (%) of variant genotypes in premalignant gastric lesions vs control	Premalignant gastric lesions
[73]	IL-8-4073	TA	145 (48.5)/144 (48.6)	ChAG susceptibility
		AA	53 (17.7)/50 (16.9)
		TA	148 (49.5)/144 (48.6)	IM susceptibility
		AA	50 (16.7)/50 (16.9)
		TA	140 (46.4)/144 (48.6)	DYS susceptibility
		AA	48 (15.9)/50 (16.9)
	IL-18RAP917997	AG^a	130 (43.9)/166 (56.3)	ChAG susceptibility
		GG	72 (24.3)/61 (20.7)
		AG	167 (56.4)/166 (56.3)	IM susceptibility
		GG	57 (19.3)/61 (20.7)
		AG	151 (50.0)/166 (56.3)	DYS susceptibility
		GG	66 (21.8)/61 (20.7)
	IL-1Brs1143627	TC	152 (50.9)/144 (48.5)	ChAG susceptibility
		CC	59 (19.7)/66 (22.2)
		TC	148 (49.3)/144 (48.5)	IM susceptibility
		CC	68 (22.7)/66 (22.2)
		TC	158 (52.5)/144 (48.5)	DYS susceptibility
		CC	71 (23.6)/66 (22.2)
	IL-1Brs1143634	CT	15 (5.0)/21 (7.1)	ChAG susceptibility
		TT	0 (0.0)/1 (0.3)
		CT	14 (4.7)/21 (7.1)	IM susceptibility
		TT	0 (0.0)/1 (0.3)
		CT	13 (4.3)/21 (7.1)	DYS susceptibility
		TT	0 (0.0)/1 (0.3)
	IL-1Brs16944	GA	153 (51.2)/143 (48.2)	ChAG susceptibility
		AA	57 (19.0)/66 (22.2)
		GA	147 (49.0)/143 (48.2)	IM susceptibility
		AA	67 (22.3)/66 (22.2)
		GA	156 (51.6)/143 (48.2)	DYS susceptibility
		AA	70 (23.2)/66 (22.2)
	IL-4Rrs2057768	AG	140 (46.8)/150 (50.7)	ChAG susceptibility
		GG	71 (23.8)/61 (20.6)
		AG	129 (43.1)/150 (50.7)	IM susceptibility
		GG	80 (26.8)/61 (20.6)
		AG	154 (51.2)/150 (50.7)	DYS susceptibility
		GG	59 (19.6)/61 (20.6)
	IL-10rs1800896	AG	61 (20.4)/53 (17.9)	ChAG susceptibility
		GG	1 (0.3)/3 (1.0)
		AG	53 (17.6)/53 (17.9)	IM susceptibility
		GG	5 (1.7)/3 (1.0)
		AG	52 (17.3)/53 (17.9)	DYS susceptibility
		GG	2 (0.7)/3 (1.0)
	IL-32rs2015620	AT	135 (45.8)/133 (45.7)	ChAG susceptibility
		TT	78 (26.4)/82 (28.2)
		AT	144 (48.8)/133 (45.7)	IM susceptibility
		TT	73 (24.8)/82 (28.2)
		AT	151 (50.0)/133 (45.7)	DYS susceptibility
		TT	76 (25.2)/82 (28.2)
	IL-22rs1179251	CG^a	82 (27.4)/143 (48.1)	ChAG susceptibility
		GG^a	20 (6.7)/29 (9.8)
		CG^a	47 (15.7)/143 (48.1)	IM susceptibility
		GG^a	12 (4.0)/29 (9.8)
		CG	111 (36.7)/143 (48.1)	DYS susceptibility
		GG	28 (9.3)/29 (9.8)
[75]	TNF-α -308	GA	15 (29.4)/22 (20.4)	ChAG susceptibility
		AA	0 (0)/3 (2.8)
	IL-1B -511	CT	18 (35.3)/53 (49.1)	ChAG susceptibility
		TT	3 (5.9)/13 (12.0)
	IL-1RN	L/2	15 (29.4)/32 (29.6)	ChAG susceptibility
		2/2	2 (3.9)/13 (12.0)
[76]	TNF-α -308	GA	125 (23.4)/129 (24.2)	ChAG susceptibility
		AA	13 (2.4)/8 (1.5)
	IL10T-819C	TC	200 (37.5)/199 (37.3)	ChAG susceptibility
		CC^a	44 (8.2)/28 (5.2)
	IL10 A-1082G	AG	246 (46.1)/262 (49.1)	ChAG susceptibility
		GG	109 (20.4)/116 (21.7)
	IL1A C-889T	CT	213 (39.9)/203 (38.0)	ChAG susceptibility
		TT	37 (6.9)/43 (8.1)
	IL1B C-511T	CT	205 (38.4)/230 (43.1)	ChAG susceptibility
		TT	59 (11.0)/52 (9.7)
	IL1RN	AT	212 (39.7)/219 (41.0)	ChAG susceptibility
		TT	39 (7.3)/35 (6.6)
	IL8T-251A	TA	273 (51.1)/254 (47.6)	ChAG susceptibility
		AA	100 (18.7)/114 (21.3)
[83]	IL-1B-511	CT^a	21 (48.8)/28 (32.6)	ChAG risk
		CC^a	7 (16.3)/3 (3.5)
	IL-1RN	2/L	21 (50.0)/46 (53.5)	ChAG risk
		2/2	8 (19.0)/10 (11.6)
[84]	IL-1B 31C	CC+CT	70 (84.3)/21 (80.8)	ChAG risk
	IL-1B 31C	CC+CT	18 (100)/73 (80.2)	moderate/severe GI risk
	IL-1B 31C	CC+CT	22 (91.7)/69 (81.2)	moderate/severe LI risk
	IL-1B 511T	TT+CT	71 (85.5)/20 (76.9)	ChAG risk
	IL-1B 511T	TT+CT	18 (100)/73 (80.2)	Moderate/severe GI risk
	IL-1B 511T	TT+CT	22 (91.7)/69 (81.2)	Moderate/severe LI risk
	IL-1RN*2	1/ 2+2/ 2	40 (48.2)/10 (38.5)	ChAG risk
	IL-1RN*2	1/ 2+2/ 2	7 (38.9)/43 (51.8)	Moderate/severe GI risk
	IL-1RN*2	1/ 2+2/ 2	12 (50.0)/38 (44.7)	Moderate/severe LI risk
[87]	IL-1β-511	TT	16 (27.6)/26 (15.8)	AG risk
		TC	30 (51.7)/88 (53.3)
		TT	8 (25.8)/34 (17.7)	CoAG risk
		TC	16 (51.6)/102 (53.1)
		TT	8 (34.8)/34 (15.2)	IM risk
		TC	12 (52.2)/106 (47.5)
	IL-1β+3954	TT	1 (1.7)/2 (1.2)	AG risk
		TC	33 (56.9)/77 (46.7)
		TT	0 (0.0)/3 (1.6)	CoAG risk
		TC	19 (61.3)/91 (47.4)
		TT^a	0 (0.0)/3 (1.3)	IM risk
		TC^a	18 (78.2)/92 (41.2)
	IL-1RN intron2	2/2	13 (22.4)/20 (12.1)	AG risk
		2/L	18 (31.0)/49 (29.7)
		2/2	9 (29.0)/24 (12.5)	CoAG risk
		2/L	8 (25.8)/59 (30.7)
		2/2^a	8 (34.8)/25 (11.2)	IM risk
		2/L	5 (21.7)/62 (27.8)
	IL-10 -1082	AA	35 (60.3)/81 (49.1)	AG risk
		GA	17 (29.3)/56 (33.9)
		AA	17 (54.8)/99 (51.6)	CoAG risk
		GA	10 (32.3)/63 (32.8)
		AA	12 (52.2)/104 (46/6)	IM risk
		GA	10 (43.5)/63 (28.3)
	IL-10 -592	AA	8 (13.8)/12 (7.3)	AG risk
		CA	19 (32.8)/58 (35.1)
		AA	4 (12.9)/16 (8.3)	CoAG risk
		CA	10 (32.3)/67 (34.9)
		AA	4 (17.4)/16 (7.2)	IM risk
		CA	8 (34.8)/69 (30.9)
[96]	IL4–590	CT	111 (38.4)/414 (38.2)	AG risk
		CC	134 (46.3)/506 (46.7)
	IL4–590	CT	197 (36.2)/414 (38.2)	IM risk
		CC	264 (48.6)/506 (46.7)
	IL4–590	CT	48 (40.7)/414 (38.2)	DYS risk
		CC	51 (43.2)/506 (46.7)
	IL4R–3223	CT	96 (33.2)/362 (33.4)	AG risk
		CC	22 (7.6)/74 (6.8)
	IL4R–3223	CT	175 (32.2)/362 (33.4)	IM risk
		CC	36 (6.6)/74 (6.8)
	IL4R–3223	CT	42 (35.6)/362 (33.4)	DYS risk
		CC	6 (5.1)/74 (6.8)
	IL4R-398	AG	128 (44.3)/488 (45.1)	AG risk
		GG^a	71 (24.6)/201 (18.6)
		AG	243 (44.8)/488 (45.1)	IM risk
		GG	106 (19.5)/201 (18.6)
		AG	49 (41.5)/488 (45.1)	DYS risk
		GG	26 (22.0)/201 (18.6)
	IL10–1082	AG	102 (35.3)/406 (37.5)	AG risk
		AA	142 (49.1)/508 (46.9)
		AG	201 (37.0)/406 (37.5)	IM risk
		AA	274 (50.5)/508 (46.9)
		AG^a	51 (43.2)/406 (37.5)	DYS risk
		AA^a	60 (50.8)/508 (46.9)
[101]	IL-6	GC	26 (46%)/27 (48%)	ChG⁹
		CC	5 (9%)/6 (11%)
[102]	IL-8 -251	AA^a	26 (12.1%)/22 (8.7%)	AG risk
		AT	99 (46.0%)/105 (41.7%)
	IL-1B -511	TT	46 (21.4%)/49 (19.6%)	AG risk
		CT	104 (48.4%)/133 (53.2%)
	IL-1RN	2/2	0 (40%)/2 (0.8%)	AG risk
		2/L	17 (8.2%)/21 (8.8%)
[103]	IL-8-251	TA	70 (52.2)/64 (46.7)	Severe ChAG risk
		AA^a	25 (18.7)/14 (10.2)
		TA^a	65 (64.4)/64 (46.7)	IM susceptibility
		AA	11 (10.9)/14 (10.2)
[106]	IL-10-1082	AG	15 (12.9)/18 (7.8)	AG susceptibility
	IL-10-1082	GG	0 (0)/1 (0.4)
	IL-10-819	CT	47 (40.5)/104 (44.8)	AG susceptibility
	IL-10-819	CC	28 (24.1)/36 (15.5)
	IL-10-592	AC	46 (39.7)/96 (41.4)	AG susceptibility
	IL-10-592	CC	31 (26.7)/52 (22.4)
[108]	IL-6-174	GC	47 (35.9)/13 (34.2)	Gastritis
	IL-6-174	CC	14 (10.7)/2 (5.3)
	IL-8-251	TA	67 (51.1)/20 (52.6)	Gastritis
	IL-8-251	AA	29 (22.1)/7 (18.4)
	IL-10-819	CT	55 (41.9)/21 (55.3)	Gastritis
	IL-10-819	TT	10 (7.6)/6 (15.8)
	IL-6-174	GC	22 (44.9)/13 (34.2)	Peptic ulcer
		CC	3 (6.1)/2 (5.3)
	IL-8-251	TA	27 (55.1)/20 (52.6)	Peptic ulcer
		AA	15 (30.6)/7 (18.4)
	IL-10-819	CT	21 (42.9)/21 (55.3)
		TT	5 (10.2)/6 (15.8)
		TT	5 (10.2)/6 (15.8)
[111]	IL-1B-511	CT	67 (54.5)/88 (49.2)	IM susceptibility
		TT	34 (27.6)/40 (22.3)

¹Only the cytokine SNPs of interest (mentioned in the above studies) are described; relative frequencies (%) are described in relation to the size of each of the two groups (cases and control group);

^aP < 0.05. AG: Atrophic gastritis; CoAG: Corpus atrophic gastritis; ChAG: Chronic atrophic gastritis (the term used in original research); ChG: Chronic gastritis; DYS: Dysplasia; GC: Gastric cancer; GI: Granulocytic infiltration; IM: Intestinal metaplasia; LI: Lymphocytic infiltration.

Citation: Negovan A, Iancu M, Fülöp E, Bănescu C. Helicobacter pylori and cytokine gene variants as predictors of premalignant gastric lesions. World J Gastroenterol 2019; 25(30): 4105-4124
URL: https://www.wjgnet.com/1007-9327/full/v25/i30/4105.htm
DOI: https://dx.doi.org/10.3748/wjg.v25.i30.4105