High-Negative Anti–Helicobacter pylori IgG Antibody Titers and Long-Term Risk of Gastric Cancer: Results from a Large-Scale Population-Based Cohort Study in Japan

Manami Inoue; Norie Sawada; Atsushi Goto; Taichi Shimazu; Taiki Yamaji; Motoki Iwasaki; Shoichiro Tsugane

doi:10.1158/1055-9965.EPI-19-0993

DOI: 10.1158/1055-9965.EPI-19-0993 Published February 2020

Article Figures & Data

Tables

Table 1.

Baseline characteristics of study subjects according to anti–H. pylori IgG titer and severity of atrophic gastritis (JPHC Cohort II; n = 19,106).

		Anti–H. pylori IgG titer			Severity of atrophic gastritis
	Number of subjects	Low-negative ≤3 U/mL	High-negative >3 and <10 U/mL	Positive ≥10 U/mL	None	Mild	Moderate	Severe
	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)
Total	19,106 (100.0)	4,244 (22.2)	1,784 (9.3)	13,078 (68.5)	5,429 (28.4)	5,638 (29.5)	7,440 (38.9)	599 (3.1)
Men	6,934	1,339 (19.3)	669 (9.7)	4,926 (71.0)	1,748 (25.2)	2,204 (31.8)	2,722 (39.3)	260 (3.7)
Women	12,172	2,905 (23.9)	1,115 (9.1)	8,152 (67.0)	3,681 (30.2)	3,434 (28.2)	4,718 (38.8)	339 (2.8)
Age (years ± SD)	56.7 (±8.3)	55.2 (±8.7)	57.5 (±8.0)	57.0 (±8.1)	55.7 (±8.4)	56.6 (±8.0)	57.4 (±8.0)	60.9 (±6.7)
Smoking status
Never and former	15,634 (81.8)	3,585 (84.5)	1,372 (76.9)	10,677 (81.6)	9,074 (82.0)	2,344 (85.7)	2,648 (82.0)	1,568 (75.6)
Current	3,472 (18.2)	659 (15.5)	412 (23.1)	2,401 (18.4)	1,993 (18.0)	390 (14.3)	583 (18.0)	506 (24.4)
Men
Never and former	3,976 (57.3)	800 (18.9)	318 (17.8)	2,858 (21.9)	2,281 (57.7)	521 (62.0)	663 (57.3)	511 (51.9)
Current	2,958 (42.7)	539 (12.7)	351 (19.7)	2,068 (15.8)	1,671 (42.3)	319 (38.0)	494 (42.7)	474 (48.1)
Women
Never and former	11,658 (57.3)	2,785 (65.6)	1,054 (59.1)	7,819 (59.8)	6,793 (95.5)	1,823 (96.3)	1,985 (95.7)	1,057 (97.1)
Current	514 (42.7)	120 (2.8)	61 (3.4)	333 (2.5)	322 (4.5)	71 (3.7)	89 (4.3)	32 (2.9)
Family history (parents or siblings)
No	17,836 (93.4)	4,003 (94.3)	1,674 (93.8)	12,159 (93.0)	10,390 (93.9)	2,554 (93.4)	2,994 (92.7)	1,898 (91.5)
Yes	1,270 (6.6)	241 (5.7)	110 (6.2)	919 (7.0)	677 (6.1)	180 (6.6)	237 (7.3)	176 (8.5)
Consumption of highly salted food (fish roe, fish gut)
No	8,460 (44.3)	2,029 (47.8)	832 (46.6)	5,599 (42.8)	5,072 (45.8)	1,182 (43.2)	1,372 (42.5)	834 (40.2)
Yes	10,646 (55.7)	2,215 (52.2)	952 (53.4)	7,479 (57.2)	5,995 (54.2)	1,552 (56.8)	1,859 (57.5)	1240 (59.8)
Atrophic gastritis
Absent	11,067 (57.9)	4,020 (94.7)	1,409 (79.0)	5,638 (43.1)
Mild	2,734 (14.3)	11 (0.3)	53 (3.0)	2,670 (20.4)
Moderate	3,231 (16.9)	92 (2.2)	146 (8.2)	2,994 (22.9)
Severe	2,074 (10.9)	121 (2.9)	176 (9.9)	1,777 (13.6)
Atrophic gastritis
Low-negative ≤3 U/mL	4,244 (22.2)				4,020 (36.3)	11 (0.4)	92 (2.9)	121 (5.8)
High-negative >3 and <10 U/mL	1,784 (9.3)				1,409 (12.7)	53 (1.9)	146 (4.5)	176 (8.5)
Positive ≥10 U/mL	13,078 (68.4)				5,638 (51.0)	2,670 (97.7)	2,993 (92.6)	1,777 (85.7)

Note: Atrophic gastritis: Negative (PG I >70 ng/mL or PG I/II >3.0), positive (PG I ≤70 ng/mL and PG I/II ≤3.0), mild (PG I ≤70 ng/mL and PG I/II ≤3.0 and not moderate/severe), moderate (PG I ≤50 ng/mL and PG I/II ≤3.0 and not severe), severe (PG I ≤30 ng/mL and PG I/II ≤2.0). Sex-specific values are in italic.

Table 2.

Anti–H. pylori IgG titer and risk of gastric cancer in combination with atrophic gastritis status (19,106 subjects: 6,934 men, 12,172 women; 18 years of follow-up).

Category	Number of participants	Person-years	Number of cases	HR (95%CI)	Number of cases	HR (95%CI)	Number of cases	HR (95%CI)
	19,106	344,441	Both sexes (n = 595)		Men (n = 370)		Women (n = 225)
H. pylori
Negative	6,028	109,304	53	1.00	28	1.00	25	1.00
Positive	13,078	235,136	542	3.96 (2.98–5.27)	342	4.35 (2.96–6.42)	200	3.53 (2.33–5.36)
Low-negative	4,244	77,583	21	1.00	7	1.00	14	1.00
High-negative	1,784	31,721	32	2.81 (1.62–4.89)	21	4.67 (1.98–11.01)	11	1.82 (0.83–4.02)
Positive	13,078	235,136	542	6.51 (4.20–10.09)	342	10.64 (5.02–22.53)	200	4.41 (2.56–7.59)
P_trend (categorical)				<0.001		<0.001		<0.001
Anti–H. pylori-IgG titer (increase per 1 U/mL)				1.01 (1.00–1.01)		1.01 (1.00–1.01)		1.01 (1.00–1.01)
Anti–H. pylori-IgG titer (increase per 10 U/mL)				1.07 (1.04–1.10)		1.06 (1.02–1.10)		1.09 (1.05–1.13)
AG
Negative	11,067	201,857	164	1.00	91	1.00	73	1.00
Positive	8,039	142,584	431	3.06 (2.55–3.68)	279	3.48 (2.73–4.43)	152	2.56 (1.93–3.39)
Mild	2,734	49,639	103	2.45 (1.91–3.14)	53	2.52 (1.79–3.55)	50	2.34 (1.63–3.36)
Moderate	3,231	57,590	176	3.32 (2.68–4.12)	119	4.05 (3.07–5.33)	57	2.44 (1.73–3.46)
Severe	2,074	35,354	152	3.38 (2.68–4.24)	107	3.63 (2.72–4.86)	45	3.11 (2.13–4.55)
P_trend (categorical)				<0.001		<0.001		<0.001
H. pylori detail and AG (negative/mild, moderate/severe)
H. pylori low-negative and AG negative/mild	4,031	73,989	10	1.00	2	1.00	8	1.00
H. pylori high-negative and AG negative/mild	1,462	26,474	10	2.24 (0.93–5.40)	6	5.99 (1.21–29.75)	4	1.29 (0.39–4.30)
H. pylori positive and AG negative/mild	8,308	151,044	247	10.08 (5.35–18.99)	83	24.83 (6.14–100.40)	61	6.53 (3.18–13.40)
H. pylori low-negative and AG moderate/severe	213	3,604	11	17.31 (7.33–40.89)	5	37.76 (7.30–195.44)	6	12.76 (4.41–36.93)
H. pylori high-negative and AG moderate/severe	322	5,247	22	18.73 (8.83–39.70)	15	45.90 (10.46–201.30)	7	13.24 (4.78–36.68)
H. pylori positive and AG moderate/severe	4,770	84,093	295	17.75 (9.42–33.42)	259	52.17 (12.92–210.58)	139	8.65 (4.19–17.89)
P_interaction				<0.001		<0.001		<0.001

Note: H. pylori: Negative (IgG titer <10 U/mL), positive (IgG titer ≥10 U/mL), low-negative (IgG titer ≤3 U/mL), high-negative (3 U/mL <IgG titer <10 U/mL). Atrophic gastritis: Negative (PG I >70 ng/mL or PG I/II >3.0), positive (PG I ≤70 ng/mL and PG I/II ≤3.0), mild (PG I ≤70 ng/mL and PG I/II ≤3.0 and not moderate/severe), moderate (PG I ≤50 ng/mL and PG I/II ≤3.0 and not severe), severe (PG I ≤30 ng/mL and PG I/II ≤2.0). HR: Estimated by a Cox proportional hazards model, including sex (strata), age at baseline (strata, 5-year age categories), study area (strata, 6 PHC areas), smoking status (never or former, current), family history of gastric cancer (no, yes), consumption of highly salted food (no, yes). Point estimate and P values for trend are in italic.
Abbreviation: AG, atrophic gastritis.

Table 3.

Anti–H. pylori IgG titer and risk of gastric cancer in combination with atrophic gastritis status by subsite and histologic type (19,106 subjects: 6,934 men, 12,172 women; 18 years of follow-up).

Category	Number of participants	Person-years	Number of cases	HR (95%CI)	Number of cases	HR (95%CI)	Number of cases	HR (95%CI)	Number of cases	HR (95%CI)
	19,106	344,441	Proximal (n = 50)		Distal (n = 383)		Differentiated type (n = 240)		Nondifferentiated type (n = 133)
H. pylori
Negative	6,028	109,304	5	1.00	31	1.00	17	1.00	7	1.00
Positive	13,078	235,136	45	3.39 (1.34–8.58)	352	4.38 (3.03–6.33)	223	4.78 (2.91–7.84)	126	7.55 (3.52–16.20)
Low-negative	4,244	77,583	0	—	16	1.00	8	1.00	0
High-negative	1,784	31,721	5	—	15	1.70 (0.84–3.45)	9	1.97 (0.76–5.13)	7	—
Positive	13,078	235,136	45	—	352	5.48 (3.31–9.06)	223	6.48 (3.19–13.15)	126	—
P_trend (categorical)				0.005		<0.001		<0.001		<0.001
Anti–H. pylori-IgG titer (increase per 1 U/mL)				1.00 (0.99–1.01)		1.01 (1.00–1.01)		1.00 (1.00–1.01)		1.01 (1.01–1.02)
Anti–H. pylori-IgG titer (increase per 10 U/mL)				1.03 (0.94–1.13)		1.07 (1.03–1.10)		1.05 (1.01–1.09)		1.11 (1.05–1.17)
AG
Negative	11,067	201,857	12	1.00	110	1.00	60	1.00	44	1.00
Positive	8,039	142,584	38	3.60 (1.86–6.95)	272	2.84 (2.27–3.56)	180	3.27 (2.43–4.39)	89	2.55 (1.76–3.68)
Negative	11,067	201,857	12	1.00	111	1.00	60	1.00	44	1.00
Mild	2,734	49,639	10	3.31 (1.43–7.71)	59	2.08 (1.52–2.86)	32	2.01 (1.31–3.10)	36	3.21 (2.05–5.00)
Moderate	3,231	57,590	14	3.58 (1.64–7.78)	119	3.30 (2.54–4.29)	79	3.91 (2.79–5.49)	32	2.32 (1.46–3.67)
Severe	2,074	35,354	14	3.90 (1.76–8.63)	94	3.05 (2.29–4.06)	69	3.72 (2.60–5.32)	21	2.08 (1.22–3.56)
P_trend (categorical)				<0.001		<0.001		<0.001		<0.001
H. pylori detail and AG (negative/mild, moderate/severe)
H. pylori low-negative and AG negative/mild	4,031	73,989	0	1.00	7	1.00	4	1.00	0	1.00
H. pylori high-negative and AG negative/mild	1,462	26,474	2	—	5	1.59 (0.50–5.00)	2	1.08 (0.20–5.91)	2	—
H. pylori positive and AG negative/mild	8,308	151,044	20	—	158	9.14 (4.28–19.51)	86	8.30 (3.04–22.67)	78	—
H. pylori low-negative and AG moderate/severe	213	3,604	0	—	9	20.41 (7.57–55.04)	4	14.84 (3.69–59.67)	0	—
H. pylori high-negative and AG moderate/severe	322	5,247	3	—	10	11.99 (4.54–31.65)	7	13.97 (4.06–48.07)	5	—
H. pylori positive and AG moderate/severe	4,770	84,093	25	—	194	16.48 (7.72–35.15)	137	18.38 (6.77–49.90)	45	—
P_interaction						<0.01		<0.01

Note: H. pylori: Negative (IgG titer <10 U/mL), positive (IgG titer ≥10 U/mL), low-negative (IgG titer ≤3 U/mL), high-negative (3 U/mL <IgG titer <10 U/mL). Atrophic gastritis: Negative (PG I >70 ng/mL or PG I/II >3.0), positive (PG I ≤70 ng/mL and PG I/II ≤3.0), mild (PG I ≤70 ng/mL and PG I/II ≤3.0 and not moderate/severe), moderate (PG I ≤50 ng/mL and PG I/II ≤3.0 and not severe), severe (PG I ≤30 ng/mL and PG I/II ≤2.0). HR: Estimated by a Cox proportional hazards model, including sex (strata), age at baseline (strata, 5-year age categories), study area (strata, 6 PHC areas), smoking status (never or former, current), family history of gastric cancer (no, yes), consumption of highly salted food (no, yes), H. pylori status, and atrophic gastritis status. Point estimate and P values for trend are in italic.
Abbreviation: AG, atrophic gastritis.