Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and gastric cancer susceptibility

Table 1 Characteristics of eligible studies included in the meta-analysis

Ref.	Country	Ethnicity	Sample size		C677T											A1298C
					Genotypes distribution						Alleles frequency				P	Genotypes distribution						Alleles frequency				P
			Case	Control	Case			Control			Case		Control		HWE	Case			Control			Case		Control		HWE
					CC	CT	TT	CC	CT	TT	C	T	C	T		AA	AC	CC	AA	AC	CC	A	C	A	C
Gao et al[12]	China	Eastern	264	535	115	105	44	277	207	51	335	193	761	309	0.19
Guo et al[13]	China	Eastern	97	114	22	48	27	32	57	25	92	102	121	107	0.97
Saberi et al[14]	Iran	Eastern	405	780	198	172	35	422	308	50	578	242	1152	408	0.54
Yang et al[15]	China	Eastern	139	165	44	80	15	62	75	28	168	110	197	131	0.5
Cui et al[16]	South Korea	Eastern	2213	1700	778	1052	382	540	863	297	2608	1816	1943	1457	0.13
De Re et al[17]	Italy	Western	48	96	12	23	13	37	46	13	47	49	120	72	0.73	24	19	5	33	54	9	67	29	120	72	0.08
Galvan-Portillo et al[18]	Mexico	Western	248	478	37	132	79	89	217	172	216	290	395	561	0.17
Gotze et al[19]	Germany	Western	106	106	46	45	12	41	49	16	137	69	131	81	0.74
Zeybek et al[20]	Turkey	Eastern	35	144	18	12	5	64	65	15	48	22	193	95	0.76
Vollset et al[21]	Europea1	Western	247	631	109	104	32	248	277	94	322	168	773	465	0.27	103	116	25	315	246	53	322	166	876	352	0.61
Mu et al[22]	China	Eastern	196	397	50	106	38	135	199	57	206	182	469	313	0.23	147	49	0	275	112	7	343	49	662	126	0.25
Zhang et al[23]	Poland	Western	305	427	146	116	33	185	178	36	408	182	548	250	0.48	135	125	31	180	179	41	395	187	539	261	0.72
Boccia et al[24]	Italy	Western	102	254	29	51	22	98	115	41	109	95	311	197	0.43	50	43	9	125	107	22	143	61	357	151	0.89
Fu et al[25]	China	Eastern	169	169												96	73	0	125	44	0	265	73	294	44	0.12
Graziano et al[26]	Italy	Western	162	164	34	86	42	67	68	29	154	126	202	126	0.10
Li et al[27]	China	Eastern	170	140	61	78	31	67	56	17	200	140	190	90	0.32	126	42	2	97	41	2	294	46	235	45	0.32
Weng et al[28]	China	Eastern	38	34	14	19	5	15	11	8	47	29	41	27	0.06	26	12	0	22	11	1	64	12	55	13	0.79
Kim et al[29]	South Korea	Eastern	133	445	42	64	27	143	239	63	148	118	525	365	0.022	98	34	1	308	129	8	230	36	745	145	0.19
Si et al[30]	China	Eastern	122	101	58	48	16	49	43	9	164	80	141	61	0.92	73	44	5	58	38	5	190	54	154	48	0.70
Sarbia et al[31]	Germany	Western	332	255	138	153	41	107	115	33	429	235	329	181	0.81
Bi et al[32]	China	Eastern	309	188	139	150	20	97	76	15	428	190	270	106	0.99
Wang et al[33]	China	Eastern	129	315	25	45	59	74	143	98	95	163	291	339	0.12
Stolzenberg-Solomon et al[34]	China	Eastern	90	398	17	36	37	65	209	124	70	110	339	457	0.14	69	21	0	294	104	0	159	21	692	104	0.0032
Miao et al[35]	China	Eastern	217	468	47	107	63	151	217	100	201	233	519	417	0.18	150	64	3	324	139	5	364	70	787	149	0.022
Gao et al[36]	China	Eastern	107	200	22	61	24	63	99	38	105	109	225	175	0.93
Shen et al[37]	China	Eastern	187	166	55	90	42	60	80	26	200	174	200	132	0.96	130	55	2	111	50	5	315	59	272	60	0.83

¹Study involving Denmark, France, Greece, Germany, Italy, the Netherlands, Norway, Spain, Sweden, and United Kingdom;

²Studies with the controls not in Hardy-Weinberg equilibrium (HWE).

Table 2 Distribution of MTHFR C677T and A1298C genotypes and alleles frequency in gastric cardia cancer, non-cardia cancer and controls

Ref.	Sample size			Genotypes distribution									Alleles frequency
	Cardia	Non-cardia	Control	Cardia			Non-cardia			Control			Cardia		Non-cardia		Control
MTHFR C677T polymorphism				CC	CT	TT	CC	CT	TT	CC	CT	TT	C	T	C	T	C	T
Saberi et al[14]	152	210	780	77	60	15	99	98	13	422	308	50	214	90	296	124	1152	408
Gotze et al[19]	27	76	106	13	13	1	33	32	11	41	49	16	39	15	98	54	131	81
Graziano et al[26]	43	119	164	7	25	11	27	61	31	67	68	29	39	47	115	123	202	126
Weng et al[28]	NA	38	34	NA			14	19	5	15	11	8	NA		47	29	41	27
Sarbia et al[31]	119	213	255	65	45	9	73	108	32	107	115	33	175	63	254	172	329	181
Si et al[30]	29	93	101	21	7	1	37	41	15	49	43	9	49	9	115	71	141	61
Bi et al[32]	155	154	188	74	73	8	65	77	12	97	76	15	211	89	207	101	270	106
Wang et al[33]	129	NA	315	25	45	59	NA			74	143	98	95	163	NA		291	339
Stolzenberg-Solomon et al[34]	90	NA	398	17	36	37	NA			65	209	124	70	110	NA		339	457
Miao et al[35]	217	NA	468	47	107	63	NA			151	217	100	201	233	NA		519	417
Shen et al[37]	82	105	166	22	38	22	33	52	20	60	80	26	82	82	118	92	200	132
MTHFR A1298C polymorphism				AA	AC	CC	AA	AC	CC	AA	AC	CC	A	C	A	C	A	C
Weng et al[28]	NA	38	34	NA			26	12	0	22	11	1	NA		64	12	55	13
Si et al[30]	29	93	101	15	12	2	58	32	3	58	38	5	42	16	148	38	154	48
Shen et al[37]	82	105	166	64	17	1	66	38	1	111	50	5	145	19	170	40	272	60

NA: Not available.

Table 3 Distribution of MTHFR C677T and A1298C genotypes and alleles frequency in intestinal, diffuse gastric cancer and controls

Ref.	Sample size			Genotypes distribution									Alleles frequency
	Intestinal	Diffuse	Control	Intestinal			Diffuse			Control			Intestinal		Diffuse		Control
				CC	CT	TT	CC	CT	TT	CC	CT	TT	C	T	C	T	C	T
MTHFR C677T polymorphism
Saberi et al[14]	142	80	780	69	59	14	39	34	7	422	308	50	197	87	112	48	1152	408
Galvan-Portillo et al[18]	88	152	454	50		38	113		39	291		163	NA		NA		NA
Gotze et al[19]	53	37	106	21	24	8	18	15	4	41	49	16	66	40	51	23	131	81
Graziano et al[26]	91	71	164	19	47	25	15	39	17	67	68	29	85	97	69	73	202	126

NA: Not available.

Table 4 Comparisons of MTHFR C677T and A1298C polymorphisms for whole and stratified analysis

	n	Case/control	OR (95%CI)	P	PHeterogeneity	OR (95%CI)	P	PHeterogeneity	OR (95%CI)	P	PHeterogeneity	OR (95%CI)	P	PHeterogeneity
			(TT + CT)/CC			T/C			TT/CC			TT/(CT + CC)
C677T
Total	24	6266/8250	1.23 (1.08, 1.40)	0.002	< 0.0001	1.15 (1.06, 1.25)	0.001	0.0004	1.37 (1.15, 1.63)	0.0005	0.0005	1.17 (1.07, 1.28)	0.0008	0.01
Eastern	16	4716/5839	1.26 (1.08, 1.47)	0.003	0.002	1.21 (1.08, 1.34)	0.0005	0.002	1.42 (1.15, 1.76)	0.001	0.005	1.22 (1.09, 1.35)	0.0003	0.03
Western	8	1550/2411	1.20 (0.92, 1.56)	0.180	0.002	1.05 (0.91, 1.21)	0.53	0.05	1.28 (0.91, 1.82)	0.16	0.009	1.05 (0.88, 1.25)	0.55	0.11
Tumor site
Cardia
Total	10	1043/2941	1.09 (0.81, 1.48)	0.560	0.0005	1.16 (0.95, 1.41)	0.14	0.002	1.28 (0.85, 1.95)	0.24	0.003	1.38 (1.15, 1.67)	0.0006	0.05
Eastern	7	854/2416	1.16 (0.89, 1.52)	0.280	0.05	1.24 (1.04, 1.48)	0.02	0.06	1.57(1.23, 2.00)	0.0003	0.16	1.53 (1.25, 1.87)	< 0.0001	0.31
Western	3	189/525	1.09 (0.38, 3.12)	0.870	0.001	1.00 (0.52, 1.91)	1.00	0.004	0.78 (0.15, 4.16)	0.77	0.003	0.73 (0.27, 1.99)	0.54	0.07
Non-cardia
Total	8	1008/1794	1.38 (1.18, 1.63)	< 0.0001	0.42	1.24 (1.10, 1.40)	0.0003	0.42	1.44 (1.09, 1.91)	0.01	0.31	1.19 (0.93, 1.52)	0.16	0.61
Eastern	5	600/1269	1.35 (1.10, 1.66)	0.004	0.99	1.21 (1.04, 1.41)	0.01	0.87	1.30 (0.87, 1.95)	0.20	0.48	1.10 (0.79, 1.55)	0.57	0.44
Western	3	408/525	1.41 (0.83, 2.38)	0.400	0.03	1.26 (0.91, 1.76)	0.16	0.06	1.55 (0.86, 2.78)	0.14	0.12	1.29 (0.91, 1.83)	0.16	0.53
Lauren’s classification
Intestinal
Total	4	374/1504	1.46 (0.86, 2.47)	0.160	0.05	1.33 (0.97, 1.84)	0.08	0.10	1.88 (1.22, 2.89)	0.004	0.19	1.45 (1.07, 1.95)	0.02	0.76
Eastern	1	142/780	1.25 (0.87,1.87)	0.230	NA	1.25 (0.95, 1.64)	0.12	NA	1.71 (0.90, 3.26)	0.10	NA	1.60 (0.86, 2.97)	0.14	NA
Western	3	232/724	1.61 (0.60,4.29)	0.340	0.03	1.37 (0.74, 2.52)	0.32	0.04	2.01 (1.13, 3.59)	0.02	0.07	1.41 (1.00, 1.98)	0.05	0.58
Diffuse
Total	4	340/1504	1.31 (0.66,2.58)	0.440	0.03	1.19 (0.78, 1.82)	0.42	0.06	1.46 (0.66, 3.21)	0.35	0.13	0.94 (0.56, 1.58)	0.82	0.09
Eastern	1	80/780	1.24 (0.78,1.96)	0.360	NA	1.21 (0.85, 1.73)	0.29	NA	1.51 (0.64, 3.57)	0.34	NA	1.40 (0.61, 3.20)	0.80	NA
Western	3	260/724	1.33 (0.35,5.01)	0.670	0.008	1.14 (0.50, 2.60)	0.76	0.02	1.31 (0.29, 5.83)	0.72	0.04	0.85 (0.46, 1.55)	0.59	0.1
A1298C			(CC + AC)/AA			C/A			CC/AA			CC/(AC + AA)
Total	11	2007/3679	0.98 (0.79, 1.21)	0.840	0.008	0.97 (0.83, 1.14)	0.73	0.03	0.95 (0.71, 1.28)	0.76	0.60	0.95 (0.72, 1.27)	0.75	0.78
Eastern	7	1015/1452	0.96 (0.72, 1.29)	0.790	0.02	0.93 (0.73, 1.19)	0.56	0.04	0.44 (0.21, 0.93)	0.03	0.84	0.46 (0.22, 0.96)	0.04	0
Western	4	702/1408	1.00 (0.71, 1.41)	0.990	0.04	1.07 (0.93, 1.23)	0.36	0.15	1.13 (0.82, 1.57)	0.46	0.69	1.11 (0.81, 1.51)	0.53	0.98
Tumor site
Cardia
Total	2	111/267	0.80 (0.37, 1.74)	0.240	0.13	0.83 (0.41, 1.69)	0.61	0.10	0.76 (0.21, 2.83)	0.69	0.28	0.80 (0.22, 2.93)	0.73	0.36
Eastern	2	111/267	0.80 (0.37, 1.74)	0.240	0.13	0.83 (0.41, 1.69)	0.61	0.10	0.76 (0.21, 2.83)	0.69	0.28	0.80 (0.22, 2.93)	0.73	0.36
Western	0	0	NA			NA			NA			NA
Non-cardia
Total	3	236/301	0.98 (0.69, 1.41)	0.930	0.59	0.93 (0.68, 1.26)	0.62	0.69	0.45 (0.15, 1.40)	0.17	0.86	0.46 (0.15, 1.40)	0.17	0.82
Eastern	3	236/301	0.98 (0.69, 1.41)	0.930	0.59	0.93 (0.68, 1.26)	0.62	0.69	0.45 (0.15, 1.40)	0.17	0.86	0.46 (0.15, 1.40)	0.17	0.82
Western	0	0	NA			NA			NA			NA

NA: Not available; P_{Heterogeneity}: P value of Q test for heterogeneity test.

Table 5 Comparisons of MTHFR C677T and A1298C polymorphisms for gastric cardia and non-cardia cancers, intestinal-type and diffuse-type gastric cancers

	n	Case/control	OR (95%CI)	P	PHeterogeneity	OR (95%CI)	P	PHeterogeneity	OR (95%CI)	P	PHeterogeneity	OR (95%CI)	P	PHeterogeneity
C677T			(TT + CT)/CC			T/C			TT/CC			TT/(CT + CC)
Cardia and non-cardia
Total	7	607/970	0.74 (0.51, 1.08)	0.12	0.01	0.80 (0.59, 1.09)	0.2	0.002	0.82 (0.49, 1.38)	0.46	0.01	0.71 (0.36, 1.39)	0.31	0.06
Eastern	4	418/562	0.76 (0.47, 1.21)	0.24	0.04	0.85 (0.56, 1.27)	0.4	0.01	1.04 (0.52, 2.06)	0.91	0.05	0.89 (0.39, 2.03)	0.78	0.10
Western	3	189/408	0.75 (0.35, 1.61)	0.46	0.04	0.73 (0.45, 1.20)	0.2	0.05	0.59 (0.35, 1.00)	0.05	0.08	0.52 (0.17, 1.59)	0.25	0.26
Intestinal-type and diffuse-type
Total	4	374/340	1.09 (0.74, 1.62)	0.67	0.76	1.10 (0.84, 1.45)	0.5	0.78	1.60 (1.09, 2.35)	0.02	0.87	1.24 (0.68, 2.27)	0.48	0.50
Eastern	1	142/80	1.01 (0.58, 1.74)	0.98	NA	1.03 (0.68, 1.57)	0.9	NA	1.14 (0.44, 2.95)	0.79	NA	1.13 (0.42, 3.04)	0.81	NA
Western	3	232/260	1.19 (0.68, 2.09)	0.55	0.54	1.16 (0.81, 1.66)	0.4	0.57	1.71 (1.13, 2.59)	0.01	0.64	1.32 (0.62, 2.80)	0.48	0.41
A1298C			(CC + AC)/AA			C/A			CC/AA			CC/(AC + AA)
Cardia and non-cardia
Total	2	111/198	0.83 (0.26, 2.64)	0.75	0.03	0.90 (0.34, 2.34)	0.8	0.03	1.87 (0.39, 9.03)	0.44	0.59	1.85 (0.39, 8.69)	0.43	0.75
Eastern	2	111/199	0.83 (0.26, 2.64)	0.75	0.03	0.90 (0.34, 2.34)	0.8	0.03	1.87 (0.39, 9.03)	0.44	0.59	1.85 (0.39, 8.69)	0.43	0.75
Western	0	0	NA			NA			NA			NA

NA: Not available; P_{Heterogeneity}: P value of Q test for heterogeneity test.