Association of current Helicobacter pylori infection and metabolic factors with gastric cancer in 35,519 subjects: A cross-sectional study

Abstract

Background

The effect of current infection of Helicobacter pylori on gastric cancer has rarely been studied in a large population. We investigated the association of current H. pylori infection and metabolic factors with gastric cancer in a large population.

Methods

Persons who made their first visit to the National Cancer Center for a health examination, including endoscopy and H. pylori testing using gastric tissue between 2003 and 2013, were included. The association of H. pylori with gastric cancer was estimated using odds ratios (ORs) and 95% confidence intervals (CIs).

Results

Among 35,519 people, 113 gastric cancer and 158 gastric dysplasia cases were detected. In the adjusted analysis, gastric cancer was associated with current H. pylori infection (OR, 2.39; 95% CI, 1.53–3.74), age (OR, 1.06; 95% CI 1.04–1.08), first-degree relatives with gastric cancer (OR, 2.08; 95% CI, 1.30–3.32) and hyperglycaemia (OR, 1.66; 95% CI, 1.04–2.65), whereas it was inversely associated with high-density lipoprotein (HDL) (OR, 0.49; 95% CI, 0.22–0.94). In the subanalysis, gastric cancer was associated with first-degree relatives with gastric cancer (OR, 3.23; 95% CI, 1.39–7.50) in the absence of H. pylori, whereas it was associated with hyperglycaemia (OR, 1.98; 95% CI, 1.16–3.39) in the presence of H. pylori.

Conclusions

Gastric cancer was associated with current H. pylori infection, hyperglycaemia, and low HDL levels in a large population.

Key points

• What is already known:

  • Even though several previous case-control studies have suggested a positive association between Helicobacter pylori serology and gastric cancer, no study has evaluated the effect of current H. pylori infection on gastric cancer in a large screening population.
  • A small Korean nested case-control study identified no association of serum glucose levels with gastric cancer. However, recent Japanese cohort studies have suggested that high fasting glucose and hemoglobin A1C levels increase the risk of gastric cancer.
• New findings from the study:

  • In 35,519 Korean adults, gastric cancer was associated with current H. pylori infection (odds ratio (OR), 2.39), age (OR, 1.06), first-degree relatives with gastric cancer (OR, 2.08) and hyperglycaemia (OR, 1.66), whereas it was inversely associated with high-density lipoprotein (OR, 0.49).
  • In the subanalysis, gastric cancer was associated with first-degree relatives with gastric cancer (OR, 3.23) in the absence of H. pylori, whereas it was associated with hyperglycaemia (OR, 1.98) in the presence of H. pylori.

Introduction

The International Agency for Research on Cancer has classified Helicobacter pylori as ‘group 1’ based on epidemiological studies.¹ The serological prevalence of H. pylori in developing countries and East Asia exceeded 70% during the 1990s.^2,3 The prevalence in the general population is 50% in Korea.^4,5 Several case-control studies have suggested a positive association between H. pylori serology and gastric cancer.^6–8 A meta-analysis revealed that gastric cancer was associated with a twofold increase in H. pylori seropositivity in case-control studies.⁹ Non-cardiac gastric cancer was higher in persons with positive H. pylori serology in another meta-analysis.¹⁰ Most previous studies have used H. pylori serology to evaluate the effect of H. pylori on gastric cancer. However, positive H. pylori serology does not mean current infection and it may continue after eradication. To our knowledge, no study to date has evaluated the association between current H. pylori infection and gastric cancer in a large screening population.

Although a meta-analysis suggested a positive association between serum glucose levels and the risk of hormonally driven cancer,¹¹ associations between metabolic factors and gastric cancer have rarely been identified. A small Korean nested case-control study identified no association of serum glucose levels with gastric cancer.¹² However, recent Japanese cohort studies have suggested that high fasting glucose and HbA1c levels increase the risk of gastric cancer.^13,14 The association between metabolic factors and gastric cancer has been controversial in previous small studies, and therefore their association in a large population needs to be investigated.

It is difficult to discriminate past and current H. pylori infection using serology. We evaluated the relationship of current H. pylori infection and metabolic factors with gastric cancer and dysplasia, a strong precancerous lesion, in a large population undergoing health check-up, close to the general population. The negative current H. pylori infection group was divided into a never had H. pylori eradication group and a previous H. pylori eradication group. We also performed subgroup analysis for the associating factors to gastric cancer according to H. pylori status.

Methods

Study participants

This large cross-sectional study recruited persons who underwent a first health examination at the Center for Cancer Prevention and Detection, National Cancer Center between January 2003 and December 2013.⁴ We excluded subjects who had previously undergone gastric surgery or endoscopic resection of gastric neoplasm, and those who did not undergo gastroscopy or H. pylori testing (Figure 1). The questionnaires included chronic disease, medication, previous surgery, previous H. pylori eradication, family history of cancer, gastrointestinal symptoms, smoking habits and alcohol consumption. Smoking and alcohol consumption status was classified as current or non-current.

Figure 1.

Study flow diagram.

Eligible participants first underwent comprehensive health screening, which included endoscopy and H. pylori testing.

Weight and height were measured (In Body, Biospace Co., Ltd, Seoul, Korea), and body mass index (BMI) was calculated as weight/height² (kg/m²). Serum levels of total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides and glucose were measured after 12 hours of fasting.

Endoscopy and H. pylori testing

Gastroscopy was performed under conscious sedation using a flexible endoscope (GIF-Q260, Olympus Optical Co., Ltd, Tokyo, Japan) on subjects who had fasted overnight.⁴ During endoscopy, gastroenterologists obtained gastric tissues to test for H. pylori infection using a rapid urease test (Pronto Dry, Medical Instruments Corporation, Solothurn, Switzerland).¹⁵

Cancer staging and treatment

After computed tomographic and endoscopic ultrasonographic staging, proper treatment was provided to patients with gastric cancer. A specialized gastric pathologist investigated the resected specimen. The final stage was determined after treatment according to the Union of International Cancer Control staging system. Gastric cancer was also classified as early gastric cancer (EGC) or advanced gastric cancer (AGC). We used the Japanese classification definition that EGC comprises T1 irrespective of lymph node metastasis. Based on differentiation, gastric cancer was categorized as well/moderate differentiation or poor differentiation/signet ring cell types. The National Cancer Center Institutional Review Board approved this study (approval number NCCNCS-2014-0218). Written informed consent was obtained from the subjects before endoscopy.

Statistical analysis

The subjects were classified according to the absence of gastric neoplasm, gastric dysplasia and gastric cancer. We used Pearson’s χ² test or independent Student’s t-tests to assess the differences between the groups with and without gastric neoplasms regarding demographic characteristics, H. pylori status, and serum levels of lipids and glucose. H. pylori status was classified into three groups: (a) the presence of H. pylori group refers to participants with a positive rapid urease test or H. pylori positivity in pathology; (b) the previous H. pylori eradication group refers to subjects who previously received H. pylori eradication and had no current H. pylori infection; and (c) the absence of H. pylori group refers to subjects who had neither current infection nor past eradication.

Significant continuous variables in the Student’s t-tests were classified as categorical variables. BMI was classified as low, normal (18.5 ≤ BMI < 25 kg/m²) and high. The incidence of gastric neoplasm was low in subjects with low and normal BMIs. Therefore, BMI was classified as two groups (<25 kg/m² and ≥ 25 kg/m²). HDL levels were categorized as low (<40 mg/dL), intermediate (40 ≤ HDL < 60 mg/dL) and high (≥60 mg/dL). Hypertension or high blood pressure (BP) was defined as systolic BP > 130 mmHg, diastolic BP > 85 mmHg or a previous diagnosis of hypertension. High glucose was defined as fasting glucose > 110 mg/dL.

Associating factors to gastric neoplasm were investigated using odds ratios (ORs) and 95% confidence intervals (CIs). We investigated the OR of gastric cancer in presence of H. pylori group compared to the absence of H. pylori (excluding negativity by previous eradication) and the OR in the previous eradication group compared to absence of H. pylori. Significant variables in univariate analysis were adjusted in the multivariate analysis. The Breslow–Day test was performed to test the homogeneity OR of hyperglycaemia for gastric cancer by H. pylori presence. The Breslow–Day test for OR between H. pylori presence and H. pylori absence was not statistically significant (P = 0.3), but the association between hyperglycaemia and gastric cancer in the absence of H. pylori was not significant (OR, 1.54; 95% CI, 0.53–4.45), whereas the association in the presence of H. pylori was significant (OR, 2.80; 95% CI, 1.68–4.64). In previous studies, an association was found between H. pylori and several metabolic factors such as glucose and lipids.^4,14 Therefore, we performed subgroup analysis to estimate the contributing factors to gastric cancer according to the H. pylori status. We used STATA software (version 12; College Station, Texas, USA) for all analyses. All statistical tests were two-sided, and P values less than 0.05 were considered statistically significant.

Results

Demographic findings

Among 42,021 subjects who underwent first comprehensive screening, 35,519 people were eligible (Figure 1). Demographic differences between the excluded and included subjects are shown in Supplementary Table 1. The mean age of the participants was 49 years and 19,396 participants were male (55%). Current H. pylori infection was identified in 50% (n = 17,762) of all participants and in 73% (n = 82) of those with gastric cancer. Previous eradication of H. pylori was 5% of all participants and 3% of those with gastric cancer. The prevalence of gastric cancer and dysplasia were 0.32 (n = 113) and 0.44% (n = 158), respectively (Figure 1 and Table 1). EGC comprised 88% of cases and non-cardiac cancer comprised 97%.

Table 1.

Demographic characteristics of participants.

	Absence of gastric neoplasm (n = 35,261)	Gastric dysplasia (n = 158)a	P valuesb	Gastric cancer (n = 113)	P valuesb
Age, mean (SD), years	49 (10)	58 (10)	<0.001	55 (11)	<0.001
Male sex, number (%)	19,223 (54)	109 (69)	<0.001	77 (68)	<0.001
BMI, mean (SD), kg/m2	23.8 (3.1)	24.3 (2.6)	0.02	24.6 (3.0)	0.009
BMI < 18.5, number (%)	1019 (3)	3 (2)	0.001	1 (1)	0.008
18.5 ≤ BMI < 25, number (%)	22,054 (64)	80 (51)		55 (52)
BMI ≥ 25, number (%)	11,375 (33)	73 (47)		49 (47)
Status of H. pylori, number (%)
Absence of H. pylori	15,953 (45)	56 (35)	0.04	28 (25)	<0.001
Presence of H. pylori	17,586 (50)	94 (60)		82 (72)
Previous eradication	1722 (5)	8 (5)		3 (3)
Current smoker, number (%)	9787 (28)	51 (33)	0.26	34 (32)	0.48
Current drinker, number (%)	21,828 (65)	95 (63)	0.54	67 (63)	0.66
Family history of gastric cancer, number (%)c	3989 (11)	32 (20)	<0.001	24 (21)	0.001
Diabetes, number (%)	1867 (5)	14 (9)	0.05	12 (11)	0.01
Hypertension, number (%)	5090 (14)	28 (18)	0.24	25 (22)	0.02
Blood level, mean (SD), mg/dL
Total cholesterol	200 (36)	202 (38)	0.50	195 (41)	0.13
Triglyceride	117 (86)	120 (71)	0.64	130 (89)	0.12
Low density lipoprotein	125 (32)	129 (35)	0.17	123 (35)	0.50
High density lipoprotein	57 (14)	54 (14)	0.02	52 (13)	<0.001
Glucose	90 (20)	93 (23)	0.03	96 (29)	0.004
Diabetes or glucose > 110 mg/dL, number (%)	3554 (10)	22 (14)	0.11	25 (22)	<0.001
Hypertension or high BP, number (%)d	13,050 (37)	75 (48)	0.007	56 (50)	0.006

BMI: body mass index.

^aThirteen persons have both cancer and dysplasia.

^bP values were derived from a χ² test or Student’s t-test between absence of gastric neoplasm and presence of each gastric neoplasm.

^cFirst-degree relatives of gastric cancer (parents, offspring, and brothers and sisters).

^dHigh blood pressure means resting systolic blood pressure > 130 mmHg or diastolic blood pressure > 85 mmHg.

Gastric cancer was associated with increasing age, male sex, H. pylori infection (0.17 and 0.46% in the H. pylori-negative and H. pylori-positive groups, respectively), family history of gastric cancer, diabetes, hypertension, high glucose and low HDL (Table 1). Gastric dysplasia was associated with increasing age, male sex, high BMI, H. pylori infection, family history of gastric cancer, diabetes, high glucose, low HDL and high BP (Table 1).

Host characteristics according to H. pylori status

Current infection with H. pylori was associated with male sex, increasing age, higher BMI, current smoking, current drinking, family history of gastric cancer, low serum HDL, high serum level of cholesterol, triglycerides, LDL and fasting glucose (Supplementary Table 2).

Although H. pylori infection was higher in men in the total population, no gender difference was observed in patients with gastric cancer (Table 2). Patients with H. pylori-positive gastric cancer were younger than those with H. pylori-negative gastric cancer (54 years vs. 58 years, P = 0.05). Differentiation, tumour site, stage and the proportion of EGC cases had no association with H. pylori (Table 2). The H. pylori infection rate had no difference between non-cardiac and cardiac cancer (72 vs. 100%, P = 0.28).

Table 2.

Characteristics of gastric cancer patients characterized by H. pylori status.

	H. pylori-positive gastric cancer (n = 82)	H. pylori-negative gastric cancer (n = 31)	P values
Age, years, mean (SD)	54 (10)	58 (11)	0.05
Male sex, number (%)	56 (68)	21 (68)	0.96
Body mass index, kg/m2, mean (SD)	24.9 (2.9)	23.9 (3.3)	0.11
Family history of gastric cancer, number (%)	14 (17)	10 (32)	0.08
Differentiation, number (%)
Well/moderate	48 (59)	20 (65)	0.56
Poor/signet ring cell	34 (42)	11 (36)
Site, number (%)a
Proximal	13 (16)	3 (10)	0.63
Middle	19 (23)	9 (29)
Distal	50 (61)	19 (61)
Site, number (%)
Cardiac	3 (4)	0 (0)	0.28
Non-cardiac	79 (96)	31 (100)
Stage
I	74 (90)	29 (94)
II/III	8 (10)	2 (6)
Morphologic type, number (%)
Early gastric cancer	72 (88)	27 (87)	0.92
Advanced gastric cancer	10 (12)	4 (13)

^aSites of gastric cancer were classified as distal stomach (antrum or angle), middle stomach (mid body or lower body) and proximal stomach (high body, fundus or cardiac).

Associated factors for gastric cancer

In the adjusted analysis, gastric cancer was associated with increasing age (OR, 1.06; 95% CI, 1.04–1.08), current H. pylori infection (OR, 2.39; 95% CI, 1.53–3.74), family history of gastric cancer (OR, 2.08; 95% CI, 1.30–3.32) and hyperglycaemia (OR, 1.66; 95% CI, 1.04–2.65), whereas it was inversely associated with high HDL (OR, 0.49; 95% CI, 0.22–0.94) (Table 3).

Table 3.

Associated factors of gastric cancer.

	Unadjusted analysis		Adjusted analysisa
	OR (95% CI)	P valuesb	OR (95% CI)	P valuesb
Age, years	1.06 (1.04–1.08)	<0.001	1.06 (1.04–1.08)	<0.001
Male sex	1.79 (1.20–2.65)	0.004	1.11 (0.60–2.02)	0.74
BMI ≥ 25 kg/m2	1.77 (1.21–2.61)	0.003	1.36 (0.90–2.03)	0.14
Status of H. pylori
Absence of H. pylori	1		1
Presence of H. pylori	2.66 (1.53–3.50)	<0.001	2.39 (1.53–3.74)	<0.001
Previous eradication	0.90 (0.27–2.94)	0.86	0.86 (0.26–2.86)	0.81
Family history of gastric cancerc	2.11 (1.34–3.32)	0.001	2.08 (1.30–3.32)	0.002
Diabetes or glucose > 110 mg/dL	2.53 (1.62–3.95)	<0.001	1.66 (1.04–2.65)	0.03
Hypertension or high BPd	1.67 (1.15–2.42)	0.006	1.19 (0.79–1.79)	0.42
High-density lipoprotein
Low (<40 mg/dL)	1		1
Intermediate (40–60 mg/dL)	0.76 (0.44–1.31)	0.33	0.97 (0.55–1.75)	0.94
High (≥60 mg/dL)	0.30 (0.15–0.58)	<0.001	0.49 (0.22–0.94)	0.03

BMI: body mass index; BP: blood pressure; CI: confidence interval; OR: odds ratio.

^aOdds ratios were adjusted for age, sex, body mass index, H. pylori status, family history of gastric cancer, glucose, blood pressure and high-density lipoprotein.

^bP values were derived from logistic regression analysis.

^cFirst-degree relatives of gastric cancer (parents, offspring, and brothers and sisters).

^dHigh blood pressure means resting systolic BP > 130 mmHg or diastolic blood pressure > 85 mmHg.

In subgroup analysis according to the H. pylori status, gastric cancer was associated with increasing age for both non-infected and infected groups (Table 4). Gastric cancer was associated with family history in the absence of H. pylori infection (OR, 3.23; 95% CI, 1.39–7.50). Gastric cancer was associated with hyperglycaemia in the presence of H. pylori infection (OR, 1.98; 95% CI, 1.16–3.39), but was not associated with hyperglycaemia in the absence of H. pylori (OR, 0.91; 95% CI, 0.30–2.72). However, the Wald test was not statistically significant (P = 0.2 by Wald test) between OR = 1.98 and OR = 0.91.

Table 4.

Associated factors of gastric cancer according to H. pylori status.

	Absence of H. pylori		Presence of H. pylori
	OR (95% CI)	P valuesa	OR (95% CI)	P valuesa
Age, years	1.11 (1.07–1.15)	<0.001	1.04 (1.01–1.07)	0.001
Male sex	1.00 (0.44–2.69)	0.99	1.35 (0.81–2.27)	0.26
BMI ≥ 25 kg/m2	1.13 (0.49–2.59)	0.77	1.35 (0.84–2.16)	0.21
Family history of gastric cancerb	3.23 (1.39–7.50)	<0.001	1.62 (0.90–2.91)	0.11
Diabetes or glucose > 110 mg/dL	0.91 (0.30–2.72)	0.87	1.98 (1.16–3.39)	0.01
Hypertension or high BPc	0.65 (0.28–1.51)	0.32	1.34 (0.82–2.16)	0.24
High-density lipoprotein
Low (<40 mg/dL)	1		1
Intermediate (40–60 mg/dL)	0.73 (0.24–2.24)	0.59	1.10 (0.56–2.19)	0.78
High (≥60 mg/dL)	0.39 (0.10–1.49)	0.17	0.49 (0.20–1.17)	0.11

BMI: body mass index; BP: blood pressure; CI: confidence interval; OR: odds ratio.

^aP values and odds ratios were derived from logistic regression analysis, and were adjusted for age, sex, body mass index, family history of gastric cancer, glucose, blood pressure and high-density lipoprotein.

^bFirst-degree relatives of gastric cancer (parents, off springs, brothers, and sisters).

^cHigh blood pressure means resting systolic blood pressure > 130 mmHg or diastolic blood pressure > 85 mmHg.

Factors associated with gastric dysplasia

In the unadjusted analysis, gastric dysplasia was associated with increasing age, male sex, higher BMI, current H. pylori infection, family history of gastric cancer, diabetes and hypertension, whereas it was inversely associated with high HDL (Table 5). In the adjusted analysis, increasing age (OR, 1.09; 95% CI, 1.07–1.10), male sex (OR 1.61; 95% CI, 1.13–2.28), higher BMI (OR, 1.52; 95% CI, 1.10–2.12), current H. pylori infection (OR, 1.43; 95% CI, 1.01–2.01) and family history of gastric cancer (OR, 1.78; 95% CI, 1.19–2.65) were associated with gastric dysplasia (Table 5).

Table 5.

Associated factors of gastric dysplasia.

	Unadjusted analysis		Adjusted analysisa
	OR (95% CI)	P valuesb	OR (95% CI)	P valuesb
Age, years	1.09 (1.07–1.10)	<0.001	1.09 (1.07–1.10)	<0.001
Male sex	1.86 (1.32–2.60)	<0.001	1.61 (1.13–2.28)	0.009
BMI ≥ 25 kg/m2	1.78 (1.30–2.45)	<0.001	1.52 (1.10–2.12)	0.01
Presence of H. pylori
Absence of H. pylori	1		1
Presence of H. pylori	1.52 (1.09–2.12)	0.01	1.43 (1.01–2.01)	0.04
Previous eradication	1.32 (0.63–2.78)	0.46	1.08 (0.51–2.28)	0.84
Family history of gastric cancerc	1.99 (1.35–2.94)	0.001	1.78 (1.19–2.65)	0.005
Diabetes	1.74 (1.00–3.01)	0.05	0.83 (0.61–1.20)	0.42
Hypertension or high BPd	1.54 (1.12–2.10)	0.007	0.86 (0.88–2.03)	0.39
High-density lipoprotein
Low (<40 mg/dL)	1		1
Intermediate (40–60 mg/dL)	0.79 (0.48–1.28)	0.33	0.92 (0.55–1.31)	0.74
High (≥60 mg/dL)	0.54 (0.32–0.91)	0.02	0.81 (0.46–1.43)	0.47

BMI: body mass index; BP: blood pressure; CI: confidence interval; OR: odds ratio.

^aOdds ratios were adjusted for age, sex, body mass index, H. pylori status, family history of gastric cancer, glucose, blood pressure and high-density lipoprotein.

^bP values were derived from logistic regression analysis.

^cFirst-degree relatives of gastric cancer (parents, offspring, and brothers and sisters).

^dHigh blood pressure means resting systolic blood pressure > 130 mmHg or diastolic blood pressure > 85 mmHg.

Discussion

To our knowledge, this is the first study to evaluate the relationship of current H. pylori infection and metabolic factors with gastric cancer in a large health check-up population. In the adjusted analysis, gastric cancer was associated with increasing age, current H. pylori infection, family history of gastric cancer and hyperglycaemia, whereas it had an inverse relationship with high HDL. Interestingly, the effect of the presence of gastric cancer in the previous H. pylori eradication group and the non-infected group did not differ. In the subgroup analysis, gastric cancer was associated with family history in H. pylori non-infected subjects, whereas it was associated with hyperglycaemia in H. pylori-infected subjects.

This large study showed that current infection with H. pylori was associated with gastric cancer with an adjusted OR of 2.39. In a meta-analysis of 19 studies (2491 patients with gastric cancer and 3959 controls), the ORs for gastric cancer in H. pylori-seropositive patients was 2.24 for cohort studies and 1.81 for case-control studies.⁹ Serological positivity include both current and past infection. Serological negativity include never being infected and past infection. Therefore, the OR for gastric cancer using serology may be underestimated or overestimated by population characteristics. However, studies for the association of current H. pylori infection with gastric cancer in an asymptomatic population are extremely rare. A study from Japanese patients with peptic ulcers (1246 H. pylori-infected and 280 uninfected persons) showed that gastric cancer developed in subjects infected with H. pylori but did not develop in uninfected subjects over 7.8 years.¹⁶ The number of non-infected subjects in the Japanese study was too small to evaluate gastric cancer risk. Therefore, our study, which evaluated the association between current H. pylori infection and gastric cancer in a large population can provide more insight into the role of H. pylori in gastric cancer compared to results in serological studies.

A recent meta-analysis of 15 case-control studies (2722 people with EGC, 13976 controls and 1130 people with AGC) suggested that H. pylori infection was more frequent among patients with EGC than controls (OR, 3.38) or patients with AGC (OR, 2.13).¹⁷ In the current study, H. pylori infection rates did not differ between EGC and AGC cases. In previous studies, the low prevalence of H. pylori infection in AGC compared to that in EGC has been assumed to be associated with older age, and the progression to mucosal atrophy and metaplasia in AGC. In the current study, the patients were younger (49 years) than those in previous studies.

The results that current H. pylori infection accounted for 50% of the total population and 73% of patients with gastric cancer in this study are similar to those of previous Korean studies.⁵ This cross-sectional study consisted of people without warning symptoms, therefore the portion of EGC was high (88%). Non-cardiac cancer comprised 97% of gastric cancer cases. The portion of cardiac cancer cases among subjects with gastric cancer who visited gastroenterology clinics was 9% in a previous Korean study.¹⁸

The OR for gastric cancer in the previous H. pylori eradicated group was similar to that in the non-infected group. This result is clinically important. It may suggest that early H. pylori eradication reduces the risk of gastric cancer to a similar level as that observed for the H. pylori non-infected group. Although the effect of H. pylori eradication on gastric cancer has been controversial, a recent meta-analysis showed that H. pylori eradication reduced the incidence of gastric cancer compared to that in the non-eradicated group with a relative risk of 0.53.¹⁹

Gastric cancer in first-degree relatives was associated with a 2.1-fold increased risk of gastric cancer in this study. This result is similar to ORs in previous studies.^20–22 An American study of 695 patients with gastric cancer and 629 controls estimated the effect of family history on gastric cancer, with an adjusted OR of 2.2.²⁰ Case-control studies from Italy estimated the ORs of family history to be 1.8 and 2.6, respectively.^21,22 Japanese case-control studies suggested that family history was associated with gastric cancer, with ORs ranging from 2.1 to 3.7.^23,24 A Korean study (428 gastric cancers and 368 controls) estimated the OR of first-degree relatives with gastric cancer to be 2.85.²⁵ The ORs for gastric cancer associated with family history ranged between 1.8 and 3.7 in most case-control studies. In a recent prospective cohort study from Finland (20,720 male smokers), gastric cancer was associated with first-degree relatives of gastric cancer patients (hazard ratio (HR), 1.56).²⁶ Their associations were significant for non-cardiac (HR, 1.83) but not cardiac cancers. The proportion of first-degree relatives in gastric cancer patients (22%) in this study was very similar to that in a previous Korean study, which reported that 22% of people with gastric cancer had first-degree relatives with gastric cancer.²⁷ In our study, 11% of people in the control group and 22% of patients with gastric cancer had first-degree relatives with gastric cancer.

Current infection with H. pylori was associated with male sex, older age, higher BMI, current smoking, current drinking, family history of gastric cancer, high serum levels of cholesterol, triglycerides, LDL, fasting glucose, low serum HDL levels and hypertension. These findings were similar to those in a previous Korean study.⁴ The metabolic changes in H. pylori-infected subjects may affect gastric cancer risk.^13,14 Hyperglycaemia was associated with a 1.7-fold increased risk of gastric cancer in our study. In the subgroup analysis by H. pylori status, this association occurs only in the H. pylori-positive population with an OR of 1.98. A 3.23-fold increased risk of gastric cancer was also associated with family history of gastric cancer in non-infected group. These results suggest that hyperglycaemia may be a cofactor that increases the risk of gastric cancer in the presence of H. pylori infection. A small Korean nested case-control study (64 patients with gastric cancer and 236 controls) showed no association of serum glucose levels with gastric cancer.¹² A previous large Korean cohort study evaluated the age-adjusted incidence for various cancers associated with fasting serum glucose levels using data from the National Health Insurance Service (NHIS).²⁸ Fasting glucose had no association with gastric cancer incidence, but diabetes slightly increased the gastric cancer incidence (HR, 1.11) in men. In women, fasting glucose and diabetes had no association with gastric cancer incidence. However, the study did not exclude baseline gastric cancer because NHIS data used in that study did not include baseline upper endoscopy. Therefore, the effect of fasting glucose on gastric cancer may be underevaluated. Two Japanese cohort studies (2400–2600 subjects) previously suggested that high fasting glucose and HbA1c levels increase the risk of gastric cancer,^13,14 and these results are similar to our results.

In this study, the incidence of gastric dysplasia (0.44%) is slightly lower than that in Western countries (0.5–3.75%).²⁹ Because of the high rate of cancer progression (60–85%) from high grade dysplasia³⁰ and high synchronous gastric cancer (30% in gastric dysplasia),³¹ studies evaluating the risk factors for gastric dysplasia may provide a strategy to prevent gastric cancer. However, only a few studies have evaluated risk factors of gastric dysplasia to date.^32,33 In this study, current infection with H. pylori was associated with increased gastric dysplasia by 1.4-fold. In previous studies, the prevalence of H. pylori serology was higher in patients with gastric dysplasia than in controls.³² In our adjusted analysis, increasing age, male sex, higher BMI and family history of gastric cancer were associated with gastric dysplasia. A previous study showed no association between gastric dysplasia and a family history of gastric cancer.³³

This study has several strengths. First, we evaluated the effect of current H. pylori infection on gastric cancer. H. pylori immunoglobulin G was detected in 20% of patients 24 months after successful H. pylori eradication.³⁴ Therefore, serological H. pylori analysis has limitations in evaluating the effect of H. pylori on gastric cancer. Second, we separately analysed the absence of infection, past eradication and current positive infection. Therefore, we could evaluate the effect of H. pylori infection on gastric cancer compared to the absence of H. pylori, excluding negativity by previous treatment. Third, because this study consisted of people undergoing health examinations, close to the general population, the selection bias was lower compared to that in hospital-based case-control studies. Fourth, the large sample size allowed us to evaluate the contributing factors to gastric cancer development according to H. pylori status. The different contributing factors for gastric cancer development according to H. pylori status suggest that different approaches are needed for the prevention of gastric cancer according to H. pylori status. Fifth, this study evaluated the effects of metabolic factors on gastric cancer. Gastric cancer was inversely associated with high HDL levels and hyperglycaemia was associated with a twofold increase in its incidence. Lastly, we evaluated the contributing factors for gastric dysplasia. Although gastric dysplasia is a precursor for gastric cancer, studies examining the contributing factors for gastric dysplasia are rare. In this study, we showed many associated factors of gastric dysplasia.

Nevertheless, this study has several limitations. First, we did not consider dietary factors. Dietary factors, such as high salt and low fruit consumption, have moderate associations with gastric cancer. Second, the rapid urease test could produce a false-negative result even if its sensitivity exceeded 95%.¹⁵ Third, this study population consisted of homogenous Koreans despite its large size. Thus, the result requires validation in other ethnicities to ensure generalizability. Lastly, this was a cross-sectional study. A large population-based cohort study is needed to estimate the long-term effect of H. pylori infection on the risk of gastric cancer. However, H. pylori infection generally occurs in childhood and adolescence, and dietary habits and demographic factors rarely change. Gastric cancer is the result of prolonged exposure to H. pylori, dietary habits and demographic factors. Therefore, a cross-sectional study in the general screening population would be helpful to estimate the associated factors of gastric cancer.

In conclusion, current infection with H. pylori was associated with a twofold increase in gastric cancer development. Gastric cancer was associated with family history, hyperglycaemia and increasing age, and inversely related with high HDL levels. Gastric cancer was strongly associated with family history in the H. pylori non-infected group and with hyperglycaemia in the H. pylori-infected group. In the future, we need to evaluate the effects of H. pylori eradication, and control of the hyperglycaemia and HDL on gastric cancer in a prospective cohort study.

Author contributions

SY Nam contributed to the study design. SY Nam, BJ Park and JH Nam contributed to the acquisition of data, and the implementation and supervision of the study. SY Nam, BJ Park, JH Nam, KH Ryu and J Kim contributed to collection and assembly of data. M-C Kook investigated the pathological slides. SY Nam analysed the data took responsibility for the accuracy of the data analysis. SY Nam had full access to the data in the study. All authors participated in the writing of the manuscript and approved the final version of the manuscript.

Declaration of conflicting interests

All authors declare that they have no potential conflicts including financial interests, activities, relationships and affiliations.

Ethics approval

The National Cancer Center Institutional Review Board approved this study (approval number is NCCNCS-2014-0218). The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution's human research committee

Funding

No funding was received.

Informed consent

Written informed consents were obtained from the subjects before endoscopy.