TT genotype is more frequent among younger AG patients without Helicobacter pylori infection
The study group consisted of 128 AG patients (50.00% men, age range 27–80 years, mean age 55.1±10.2 years). The clinical characteristics of patients are shown in Table 1. The genotypes and frequencies observed in our population were TT in 21.88% (28/128) of patients, CT in 53.91% (69/128), and CC in 24.22% (31/128). This distribution followed the Hardy-Weinberg equilibrium (P=0.817). Generally, the allele frequencies of the MTHFR C677T genotypes should be stable for people of all age groups. However, in patients 44 years or younger (≤44 years), the frequency of the TT genotype was significantly higher than that in older patients greater than 44 years (41.18% vs. 18.92%; P=0.039; Figure 1). For the 17 patients aged 27–44 years, the MTHFR C677T genotypes and frequencies were TT in 41.18% (7/17), CT in 29.41% (5/17), and CC in 29.41% (5/17). In the 111 patients older than 44 years, the genotypes and frequencies were TT in 18.92% (21/111), CT in 57.66% (64/111), and CC in 23.42% (26/111). In addition, the pepsinogen I to pepsinogen II ratio (PGR) was significantly higher among patients aged 44 years and older compared to that among patients older than 44 years (13.0±4.2 vs. 10.9±3.9; P=0.045).
The analyzed factors were age; gender; presence of peptic ulcers; smoking and drinking habits; body mass index; Hcy; BMI; family history; MTHFR C677T genotype. The mean ± SD or the number of each variable (age, gender, etc.), odd ratio, 95% confidence interval, and P-value are listed in Table 2. MTHFR C677T genotype and aging remained independent risk factors.
AG may be main cause of hyperhomocysteinemia in AG patients without Helicobacter pylori infection rather than MTHFR polymorphism
As shown in Table 3, the mean levels of Hcy in patients with the CC, CT, and TT genotypes were 11.7±5.4 μmol/L, 12.9±5.6 μmol/L and 13.5±6.0 μmol/L, respectively. The highest levels of Hcy were observed in patients with the TT genotype followed by those with the CT and CC genotypes (P>0.05). Also, no statistical difference was observed in the incidence of hyperhomocysteinemia (>15 μmol/L) among patients with the different MTHFR C677T genotypes (P=0.82). However, folic acid deficiency (≤6 ng/mL, as defined in ref ) was observed more often in patients with the TT genotype compared with the CT and CC genotypes (P=0.001).
As shown in Table 4, in our population, 29.69% (38/128) of AG patients had hyperhomocysteinemia and 16.41% (21/128) of AG patients had folic acid deficiency. We found that patients with folic acid deficiency had a significantly higher incidence of hyperhomocysteinemia compared with patients without folic acid deficiency (52.38% [11/21] vs. 25.23% [27/107], P=0.013).
Association between high-risk OLGA/OLGIM stages III-Ⅳ and MTHFR C677T polymorphism
The results regarding the influence of the MTHFR C677T polymorphism on lesion status in the gastric mucosa of AG patients are presented in Table 5. The antrum region showed the highest frequency of atrophy or IM (86.72%, 111/128), followed by the incisura (37.50%, 48/128) and corpus (8.59%, 11/128). No association was observed between the MTHFR C677T polymorphism and lesions in the corpus and antrum (P>0.05). However, in the incisura part of the stomach, patients with the TT genotype showed a higher susceptibility to develop lesions including atrophy or IM (CC+CT vs. TT: 40.00% [40/100] vs. 64.29% [18/28], P=0.02). OLGA and OLGIM stages III-IV were observed more frequently in patients with TT genotype compared with the CC+CT genotypes (for OLGA: CC+CT vs. TT: 16.50% [17/103] vs. 44.00% [11/25], P=0.003; for OLGIM: CC+CT vs. TT: 16.05% [13/81] vs. 31.91% [15/47], P=0.036).
For moderate-to-severe lesions (moderate-to-severe IM, moderate-to-severe atrophy or low-grade intraepithelial neoplasia in any one location), TT homozygous patients were at an increased risk compared with CC+CT patients (P=0.01). In addition, TT homozygous patients had an increased risk of IM at any location compared with CC+CT patients (P=0.01). Although not statistically significant (P=0.07), a trend towards a higher frequency of more severe atrophy at any location was observed in those with the TT genotype (CC+CT vs. TT: 38.00% vs. 57.14%).
The MTHFR C677T polymorphism was an independent predictor of the severity of lesions as shown in Table 5 (TT vs. CC+CT for atrophy: odds ratio [OR]=2.18; 95% confidence interval [CI], 0.93–5.09; P=0.07; for IM: OR=3.39; 95% CI, 1.27–9.06; P=0.02; for moderate-to-severe lesions: OR=3.84; 95% CI, 1.24–11.90; P=0.02; for OLGA: OR=3.98; 95% CI, 1.54–10.23; P=0 .004; and for OLGIM: OR=2.45; 95% CI, 1.05–5.76; P=0.039).
Weak correlation between C-1/C-2 of endoscopic atrophy and OLGA stages I-II
The Kimura-Takemoto endoscopic classification (C-1, C-2, C-3, O-1, O-2, O-3) has been widely used in some Eastern countries for the assessment and grading of AG. In our study, the MTHFR C677T polymorphism was an independent predictor of the severity of lesions in patients stratified according to the OLGA and OLGIM systems. However, there was no statistical difference in the severity of endoscopic gastric atrophy between those with the TT and CT+CC genotypes according to the Kimura-Takemoto endoscopic classification (P=0.40, Figure 2). In our study, based on the Kimura-Takemoto endoscopic classification, 92.59% patients were C-1 or C-2 and 80.47% patients of patients stratified according to the OLGA system were stages I-II. Based on these classifications, the strength of agreement between the C-1 or C-2 levels on endoscopic atrophy and OLGA stages I-II for the histological atrophy was fair, with a kappa value of 0.29 (95% CI, 0.06–0.50). In addition, correlations of C-1 or C-2 levels on endoscopic atrophy and stages I-II of OLGA were observed (Spearman’s rho=0.31, P=0.014).