Gastric cancer remains a significant global health burden, the leading cause of cancer mortality worldwide [1]. We previously reported associations between metabolic factor and gastric cancer using National Health Insurance Service data [2]. High density lipoprotein cholesterol (HDL-C) has shown some promise in reducing gastric cancer risk in cancer screening cohort [3,4]. Japanese cohort studies have indicated that higher fasting glucose and elevated hemoglobin A1c levels may contribute to an increased risk of gastric cancer [5,6]. Obesity, a well-established risk factor for many cancers, presents a more complex association with gastric cancer. In a meta-analysis, high body mass index (BMI) has been linked to the risk of cardiac gastric cancer but not non-cardiac gastric cancer [7], whereas some studies even suggest an inverse association between high BMI and non-cardiac gastric cancer [8,9] and other studies show no association [10,11]. Although findings remain inconsistent, possibly due to differences in study populations, including factors like sex, age, cancer location, and stage. Notably, patients with early gastric cancer (EGC) are less likely to experience weight loss, while those with advanced gastric cancer (AGC) frequently present with weight loss, adding complexity to the BMI-cancer risk relationship.

In this study, we investigate the association of metabolic factors with gastric cancer in a hospital setting, focusing on BMI, HDL-C, and glucose levels. Additionally, we conducted subgroup analysis by sex and cancer stage.

Study population

Patients who diagnosed with gastric cancer and have the values for HDL-C, glucose, and BMI from 2005 to 2013 in Kyungpook National University Hospital were enrolled. Patients who had other site malignancy or underwent previous gastrectomy, were excluded.

Among 19,827 individuals who underwent upper endoscopy and blood tests as part of health check-ups between 2011 and 2016, we excluded those who were diagnosed with gastric cancer or gastric adenoma during the screening process (Fig. 1). This exclusion ensured that the study population consisted only of individuals without any pre-existing gastric neoplasms at the time of their health examinations, allowing for a more accurate analysis of the target conditions. Patients’ consent was waived because this study reviewed medical records, didn’t include personal identify information, and had no effect on disease course. This study was approved by the Institutional Review Board of the Kyungpook National University Hospital Chilgok (KNUHC 2016-08-024).

Figure 1. Study flow. Patients newly diagnosed with gastric cancer in Kyungpook National University Hospital (KNUH) were enrolled. Healthy screening persons in KNUH were used as controls. BMI, body mass index; HDL, high density lipoprotein.

Statistical analysis

To assess differences between groups with and without gastric cancer across demographic characteristics, BMI, and serum lipid and glucose levels, we employed Pearson chi-square tests or independent t tests, as appropriate. Continuous variables were categorized as follows: BMI was classified per the Asian-Pacific guidelines [12] into low (< 18.5 kg/m²), normal (18.5–22.9 kg/m²), overweight (23–24.9 kg/m²), obesity I (25–29.9 kg/m²), and obesity II (≥ 30 kg/m²). HDL-C levels were defined according to the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) criteria [13] as low (< 40 mg/dl for males, < 50 mg/dl for females) or normal (≥ 40 mg/dl for males, ≥ 50 mg/dl for females). Serum fasting glucose was categorized into normal (< 110 mg/dl), intermediate (110–125 mg/dl), and high (≥ 126 mg/dl or prior diagnosis of diabetes). Age was grouped in 10-year intervals (40–49, 50–59, 60–69, ≥ 70 years), and cancer stage was classified as either EGC or AGC.

To identify factors associated with gastric cancer, we conducted logistic regression analysis to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Additionally, we performed subgroup analyses by sex and cancer stage. All statistical analyses were performed using SAS software (version 9; SAS Institute). Statistical significance was defined as a two-sided p value < 0.05.

Demographic and laboratory findings

A total of 3,382 gastric cancer patients (2,256 male sex) and 19,609 healthy controls (10,966 male sex) were enrolled (Fig. 1, Table 1). The health screening group was younger than the gastric cancer group in this study. Gastric cancers were located in antrum (43%) and middle third (43%), upper third (14%). EGC was 70.8% (n = 2,395), and AGC was 29.2% (n = 986). Gastric cancer was associated with low BMI, high fasting glucose, and low HDL.

Table 1 . Demographic and Laboratory Findings.

Risk factors	Gastric cancer (n = 3,382)	Control (n = 19,609)	p values*
Male sex	2,256 (66.7)	10,966 (55.9)	< 0.001
Age, yr	61.4 ± 11.1	46.9 ± 11.9	< 0.001
Age group, yr
< 40	120 (3.4)	5,488 (28.0)	< 0.001
40–49	376 (11.1)	5,861 (29.9)
50–59	885 (26.2)	5,421 (27.7)
60–69	1,100 (32.5)	2,165 (11.0)
≥ 70	900 (26.6)	674 (3.4)
Body mass index, kg/m2	23.6 ± 3.1	23.7 ± 3.1	0.016
Body mass index, kg/m2
< 18.5	139 (4.2)	657 (3.4)	0.003
18.5–22.9	1,276 (38.1)	7,622 (38.9)
23–24.9	898 (26.8)	5,044 (25.7)
25–29.9	970 (28.9)	5,695 (29.0)
≥ 30	69 (2.1)	591 (3.0)
HDL, mg/dl	48.4 ± 16.4	56.4 ± 14.9	< 0.001
Low HDL, mg/dl	1,328 (39.3)	3,577 (18.2)	< 0.001
Fasting glucose, mg/dl
< 110	1,843 (60.1)	17,020 (86.8)	< 0.001
110–126	560 (18.3)	1,401 (7.1)
≥ 127 or known DM	664 (21.7)	1,188 (6.1)

Values are presented as number (%) or mean ± standard deviation..

HDL, high density lipoprotein; DM, diabetes mellitus..

*p values were derived from t test or chi-square test..

Contributing factors of gastric cancer

In adjusted analysis, male sex, increasing age, low BMI (OR, 1.44; 95% CI, 1.13–1.84), low HDL (OR, 2.28; 95% CI, 2.07–2.50), and high fasting glucose (OR, 2.94; 95% CI, 2.22–2.99) were associated with gastric cancer, whereas high BMI (OR, 0.61–0.81) was inversely associated with gastric cancer (Table 2).

Table 2 . Contributing Factors of Gastric Cancer by Sex (Multivariable Analysis).

Risk factors	Total			Males			Females
	OR (95% CI)	p values*		OR (95% CI)	p values*		OR (95% CI)	p values*
Male sex	1.65 (1.52–1.81)	< 0.001
Age group, yr	2.55 (2.45–2.65)			2.85 (2.69–3.00)	< 0.001		2.10 (1.97–2.24)	< 0.001
Body mass index, kg/m2
< 18.5	1.44 (1.13–1.84)	< 0.001		1.47 (1.05–2.07)	0.026		1.35 (0.95–1.93)	0.098
18.5–22.9	1			1			1
23–24.9	0.81 (0.73–0.90)	0.003		0.76 (0.66–0.87)	< 0.001		0.92 (0.76–1.10)	0.348
25–29.9	0.71 (0.64–0.79)	< 0.001		0.63 (0.55–0.72)	< 0.001		0.97 (0.81–1.16)	0.763
≥ 30	0.61 (0.46–0.82)	< 0.001		0.50 (0.33–0.75)	0.001		0.83 (0.54–1.29)	0.414
p for trend		< 0.001			< 0.001			NS
Low HDL, mg/dl	2.28 (2.07–2.50)	< 0.001		2.59 (2.28–2.93)	< 0.001		1.96 (1.69–2.27)	< 0.001
Fasting glucose, mg/dl
< 110	1			1			1
110–125	2.21 (1.95–2.50)	< 0.001		1.95 (1.67–2.27)	< 0.001		2.93 (2.38–3.62)	< 0.001
≥ 126 or known DM	2.94 (2.61–3.32)	< 0.001		2.58 (2.22–2.99)	< 0.001		4.02 (3.25–4.97)	< 0.001

Age group refers to 10 year interval of age..

OR, odds ratio; CI, confidence interval; HDL, high density lipoprotein; DM, diabetes mellitus; NS, not significant..

*p values were derived from adjusted regression analysis..

In sex-specific analysis, BMI was inversely associated with gastric cancer in males (p for trend < 0.001), whereas BMI had no association with gastric cancer in females (Fig. 2A). A low serum level of HDL and high fasting glucose was strongly associated with gastric cancer in both males and females (Table 2, Fig. 2B). The effect of high glucose was more prominent in females than in males (OR, 2.58 in males and 4.02 in females).

Figure 2. Effect of BMI and HDL on gastric cancer. (A) Effect of BMI on gastric cancer stratified by sex. (B) Effect of low HDL on gastric cancer stratified by sex. (C) Effect of BMI on gastric cancer stratified by stage. (D) Effect of low HDL on gastric cancer stratified by stage. ***p < 0.001. Thick solid line is aOR and thin solid line is 95% CI. BMI, body mass index; HDL, high density lipoprotein; EGC, early gastric cancer; AGC, advanced gastric cancer; aOR, adjusted odd ratio; CI, confidence interval.

Sub-analysis by gastric cancer stage

Even if BMI was inversely associated with both AGC (p for trend < 0.001) and EGC (p for trend = 0.001), low BMI strongly associated with AGC (OR, 2.09; 95% CI, 1.70–2.56) but not with EGC (Table 3). However, high BMI was associated with reduced gastric cancer in both EGC and AGC (Fig. 2C). A low serum level of HDL and high fasting glucose was strongly associated with gastric cancer in both EGC and AGC (Table 3, Fig. 2D).

Table 3 . Contributing Factors of Gastric Cancer by Stage (Multivariable Analysis).

Risk factors	Early gastric cancer			Advanced gastric cancer
	OR (95% CI)	p values*		OR (95% CI)	p values*
Male sex	1.58 (1.42–1.76)	< 0.001		1.96 (1.68–2.28)	< 0.001
Age group, yr	2.54 (2.13–2.67)	< 0.001		2.62 (2.45–2.79)	< 0.001
Body mass index, kg/m2
< 18.5	1.14 (0.84–1.55)	0.408		1.99 (1.44–2.75)	< 0.001
18.5–22.9	1			1
23–24.9	0.89 (0.78–1.01)	0.069		0.68 (0.57–0.81)	< 0.001
25–29.9	0.82 (0.72–0.93)	0.002		0.51 (0.43–0.61)	< 0.001
≥ 30	0.63 (0.44–0.88)	0.008		0.62 (0.39–0.99)	0.047
p for trend		0.001			< 0.001
Low HDL, mg/dl	2.31 (2.07–2.57)	< 0.001		2.34 (2.00–2.72)	< 0.001
Fasting glucose, mg/dl
< 110	1			1
110–125	2.36 (2.05–2.70)	< 0.001		1.84 (1.49–2.25)	< 0.001
≥ 126 or known DM	2.98 (2.59–3.41)	< 0.001		2.82 (2.34–3.40)	< 0.001

Age group refers to 10 year interval of age..

OR, odds ratio; CI, confidence interval; HDL, high density lipoprotein; DM, diabetes mellitus..

*p values were derived from logistic regression analysis..

This study demonstrates a strong association of low BMI, low HDL-C, and hyperglycemia with gastric cancer. In analyses stratified by sex, low BMI was associated with gastric cancer in males but not in females. Stage-specific analysis revealed that low BMI was strongly associated with AGC but BMI effect on EGC was markedly attenuated. However, low HDL was strongly associated with gastric cancer across of sex and stage.

Our findings highlight that low HDL-C is linked to a higher risk of gastric cancer in both males (OR, 2.59) and females (OR, 1.96). These findings are consistent with our previous report using the National Health Insurance Sharing Service (NHISS) data [2]. A meta-analysis suggested an inverse association of HDL with overall cancer risk [14]. A cross-sectional study previously found that high HDL (≥ 60 mg/dl) was associated with a reduced incidence of gastric cancer (OR, 0.49) [15], and a small cohort study similarly indicated that low HDL-C increased gastric cancer risk [16]. However, these hospital based studies were limited by sample size, preventing detailed analysis by sex and stage. In this study, low HDL-C was strongly associated with both EGC (OR, 2.31) and AGC (OR, 2.34). We previously showed the similar sex- and stage-specific association of HDL with gastric cancer [2]. Antioxidant properties of HDL-C, which protect DNA from oxidative damage, and its anti-inflammatory effects, such as macrophage reprogramming [17], may underlie its protective role.

In this study, gastric cancer was associated with low BMI, with overweight and obesity showing an inverse association. In sex-specific analysis, the effect of BMI in males aligned with the overall gastric cancer findings, while low BMI showed no significant association in females. Our findings in a hospital-based population were consistent with results in previous NHISS data [2]. High BMI reduced the risk of non-cardiac gastric cancer (NCGC) in several studies [8,9], whereas some research has found no association with gastric cancer [10,11]. Our results align with recent large-scale population studies [18,19]. A cohort study involving 5.24 million adults in the United Kingdom reported that low BMI increased gastric cancer risk [18] and a Chinese cohort study of 29,584 participants indicated that those in the highest BMI quartile had a lower risk of NCGC (hazard ratio, 0.65) compared to the lowest quartile [19]. Although the mechanisms underlying the inverse relationship between BMI and NCGC remain unclear, patients with NCGC are often heavy users of tobacco and alcohol, are malnourished, and experience significant weight loss as the disease progresses [20]. In this study, BMI was inversely associated with AGC, while its association with EGC was weaker. This weaker inverse relationship with EGC may represent a genuine effect of BMI on gastric cancer, whereas the strong inverse association with AGC likely reflects weight loss as a consequence of disease progression.

In this study, hyperglycemia showed a strong association with gastric cancer in both males (OR, 2.58) and females (OR, 4.02). The higher OR observed here compared to previous NHISS findings [2], may be influenced by age distribution differences between cases and controls. While the mean age of gastric cancer patients was similar between the NHISS (62.2 years) and our study (61.4 years), the control group in our study was younger (mean age 46.9 years) than that in the NHISS (55.7 years), resulting in a lower prevalence of hyperglycemia among controls in this study. A prospective cohort study (Me-Can) also reported a significant association between hyperglycemia and gastric cancer risk in females (1.58-fold increase), though not in males [21]. Hyperglycemia was strongly associated with both EGC and AGC. This study confirms the stage-specific association between hyperglycemia and gastric cancer previously noted in NHISS study [2]. Mechanistically, hyperglycemia may act as a direct carcinogen by causing DNA damage; high glucose levels have been linked to increased oxidative DNA damage [22] and the generation of reactive oxygen species [23], which are known contributors to carcinogenesis. Additionally, hyperglycemia may increase cancer risk by promoting insulin resistance and elevating levels of insulin and insulin-like growth factor 1 (IGF-1). Insulin has been shown to stimulate cell proliferation in colorectal cancer models [24], while IGF-1 inhibits apoptosis, potentially facilitating cancer development [25].

The large size allowed for an in-depth investigation into the sex- and stage-specific association of HDL-C and BMI with gastric cancer, with findings that align with previous NHISS results. This study has certain limitations. First, we did not consider Helicobacter pylori and dietary factors. However, previous small studies considering H. pylori and metabolic factors [15,16] have reported similar associations of HDL-C and hyperglycemia with gastric cancer risk. Second, the health screening group was younger than the gastric cancer group. This age difference is likely due to the higher incidence of gastric cancer in older individuals. Given that diabetes prevalence increases with age, the significant age disparity between the two groups could exaggerate the relationship with hyperglycemia. Therefore, caution is warranted when interpreting these findings.

In conclusion, low BMI, low HDL-C, and hyperglycemia were associated with gastric cancer in a large hospital-based study. Sex-specific analysis revealed an inverse association between BMI and gastric cancer in males, with no significant association in females. BMI was notably inversely associated with AGC, though this association was weaker for EGC. In contrast, low HDL-C and hyperglycemia consistently correlated with increased gastric cancer risk, irrespective of sex or stage. The persistent positive association of low HDL-C with gastric cancer suggests its potential role as an independent risk factor.

This work was supported by the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (1631100) and the National Research Foundation, Republic of Korea (NRF-2015R1D1A1A01059219) (SY Nam). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript.

No potential conflict of interest relevant to this article was reported.

Conceptualization: Su Youn Nam. Data curation: Su Youn Nam. Formal analysis: Su Youn Nam. Funding acquisition: Su Youn Nam. Investigation: Su Youn Nam, Oh Kyoung Kwon, Seong Woo Jeon. Methodology: Su Youn Nam. Project administration: Su Youn Nam. Supervision: Su Youn Nam, Oh Kyoung Kwon, Seong Woo Jeon. Validation: Su Youn Nam. Visualization: Su Youn Nam. Writing—original draft: Su Youn Nam. Writing—review & editing: Su Youn Nam, Oh Kyoung Kwon, Seong Woo Jeon.