Association of miR-499 rs3746444, miR-149 rs2292832 polymorphisms and their expression levels with helicobacter pylori-related gastric diseases and Traditional Chinese Medicine syndromes

doi:10.19852/j.cnki.jtcm.2024.05.009

Abstract

Abstract:

OBJECTIVE: To provide an objective experimental basis for the gastric mucosa pathological evolution and the transformation of different Traditional Chinese Medicine (TCM) syndromes in helicobacter pylori (H. pylori)-related gastric diseases (HPGD) patients, based on the combination of TCM syndrome differentiation, molecular biology and histopathology.

METHODS: A total of 203 participants were enrolled in this study. The expressions of miR-499/miR-149 and H. pylori infection in the gastric tissues from all participants were detected. The genotyping for miR-499 rs3746444 and miR-149 rs2292832 was performed.

RESULTS: In H. pylori positive subjects, the proportion of precancerous gastric lesions (PGL) in liver-stomach disharmony syndrome (LSDS) group was higher than in spleen Qi deficiency syndrome (SQDS) group (P <0.001); The proportion of gastric cancer (GC) in SQDS group was higher than in spleen-stomach damp-heat syndrome (SSDHS) group and LSDS group (all P <0.001). We also found C allele of miR-149 rs2292832 was linked to lower risk of gastric atrophy [miR-149 rs2292832 C vs T: adjusted odds ratio = 0.207; 95% confidence interval (0.043-0.989); P = 0.048]. Compared with healthy control (HC) group, the expression of miR-499 was significantly increased in GC group, while the expression of miR-149 was significantly decreased in chronic inflammation group, PGL group and GC group (all P < 0.05). Test for trend showed that GC risk was on a rising trend with the increasing expression of miR-499 and decreasing expression of miR-149 (both P for trend < 0.05).

CONCLUSION: The C allele of miR-149 rs2292832 may be a protective factor for gastric mucosal atrophy. H. pylori may participate in the evolution of benign to malignant gastric mucosa lesions by inducing the overexpression of miR-499 and down regulation of miR-149. In addition, patients with H. pylori infection combined SQDS or LSDS may have higher risk of gastric mucosal malignant lesions.

Key words: microRNAs, helicobacter pylori, stomach diseases, polymorphism, genetic, syndrome complex

LIU Qi, YU Chang, YE Jintong, ZHANG Ling, LI Danyan, DAI Yunkai, ZHANG Yunzhan, LUO Qi, CHEN Weijing, PAN Huaigeng, LI Ruliu, HU Ling. Association of miR-499 rs3746444, miR-149 rs2292832 polymorphisms and their expression levels with helicobacter pylori-related gastric diseases and Traditional Chinese Medicine syndromes[J]. Journal of Traditional Chinese Medicine, 2024, 44(5): 1024-1034.

Figures/Tables 9

Figure 1 Genotying results of miR-499 rs3746444/miR-149 rs2292832 and detection of the relative expression of miR-499/miR-149 A: 1.0% agarose gel electrophoresis for quality identification of PCR amplification products. A1: amplification of miR-149 rs2292832 locus; A2: amplification of miR-499 rs3746444 locus. 1 and 10 are positive control and negative control, respectively; Lane 2 to 9 represent 8 different individuals. B: Genotyping for miR-149 rs2292832 and miR-499 rs3746444. B1: TT homozygous wild type at miR-149 rs2292832; B2: CT heterozygous mutant type at miR-149 rs2292832; B3: CC homozygous mutant type at miR-149 rs2292832; B4: AA homozygous wild type at miR-499 rs3746444; B5: AG heterozygous mutant type at miR-499 rs3746444; B6: GG homozygous mutant type at miR-499 rs3746444. C: amplification curves of target gene and internal reference gene. C1: internal reference gene U6; C2: miR-149; C3: miR-499. PCR: polymerase chain reaction; bp: base pair; M: Maker; miR: microRNA.

Table 1 The baseline characteristics of participants (n)

Variable	HC (n = 35)	CI (n = 23)	GA (n = 11)	PGL (n = 79)	APL (n = 10)	GC (n = 45)	χ²value	P value
Age (years)							2.46	0.782^a
≤40	11	8	3	21	1	12
>40	24	15	8	58	9	33
Gender							5.93	0.313^a
Male	18	11	6	52	6	32
Female	17	12	5	27	4	13
H. pylori							29.52	<0.001^b
Positive	19	15	11	73	10	39
Negative	16	8	0	6	0	6

Table 2 Association of miR-499 rs3746444 (A > G) with gastric pathological features and TCM syndromes

Group		Genotype [n (%)]			Adjusted^a OR (95% CI), P value
Group		AA	AG	GG	AG vs AA	AG+GG vs AA	G vs A
Pathological groups	HC	28 (80.0)	7 (20.0)	0 (0.0)	Reference	Reference	Reference
	CI	19 (82.6)	4 (17.4)	0 (0.0)	0.814 (0.207-3.201), 0.768	0.815 (0.208-3.200), 0.770	0.834 (0.229-3.041), 0.783
	GA	9 (81.8)	2 (18.2)	0 (0.0)	0.871 (0.143-5.304), 0.881	0.862 (0.142-5.238), 0.872	0.865 (0.158-4.733), 0.867
	PGL	61 (77.2)	17 (21.5)	1 (1.3)	1.157 (0.400-3.343), 0.788	1.186 (0.414-3.398), 0.751	1.189 (0.447-3.162), 0.729
	APL	9 (90.0)	1 (10.0)	0 (0.0)	0.481 (0.049-4.757), 0.531	0.492 (0.050-4.861), 0.544	0.531 (0.058-4.839), 0.575
	GC	35 (77.8)	9 (20.0)	1 (2.2)	1.125 (0.349-3.633), 0.843	1.266 (0.401-3.998), 0.688	1.379 (0.479-3.969), 0.551
TCM syndromes	NON	9 (81.8)	2 (18.2)	0 (0.0)	Reference	Reference	Reference
	SSDHS	69 (77.5)	19 (21.4)	1 (1.1)	1.312 (0.240-7.186), 0.754	1.314 (0.242-7.141), 0.752	1.275 (0.259-6.282), 0.765
	LSDS	52 (78.8)	14 (21.2)	0 (0.0)	1.192 (0.203-6.997), 0.846	1.098 (0.188-6.400), 0.917	1.002 (0.190-5.279), 0.998
	SQDS	27 (84.4)	4 (12.5)	1 (3.1)	0.649 (0.095-4.413), 0.658	0.807 (0.125-5.196), 0.807	0.986 (0.175-5.545), 0.987
	IBSBS	4 (80.0)	1 (20.0)	0 (0.0)	1.052 (0.065-17.030), 0.971	1.022 (0.063-16.471), 0.988	0.991 (0.073-13.520), 0.994

Figure 2 representative images of H. pylori infection and different gastric mucosal pathological changes A: H. pylori infection in gastric mucosa (methylene blue staining, ×400). A1: H. pylori negative; A2: mild H. pylori infection; A3: moderate H. pylori infection; A4: severe H. pylori infection. B: histopathological changes of gastric mucosa (hematoxylin-eosin staining, ×200). B1: normal gastric mucosa; B2: gastric mucosa with moderate inflammation; B3: moderate atrophic gastric mucosa with severe inflammation; B4: moderate dysplasia of gastric mucosa with mild atrophy, intestinal metaplasia, inflammation; B5: severe dysplasia of gastric mucosa with moderate intestinal metaplasia; B6: gastric mucosal carcinogenesis. H. pylori: Helicobacter pylori.

Figure 3 Comparison between different TCM syndrome groups A: comparison among all subjects (n = 203); B: comparison among H. pylori-positive subjects (n = 167); C: comparison among H. pylori-negative subjects (n = 36). NON group: subjects without obvious symptoms; SSDHS group: subjects diagnosed with SSDHS; LSDS group: subjects diagnosed with LSDS; SQDS group: subjects diagnosed with SQDS; IBSBS group: subjects diagnosed with IBSBS. TCM: Traditional Chinese Medicine; H. pylori: Helicobacter pylori; HC: healthy control; CI: chronic inflammation; GA: gastric atrophy; PGL: precancerous gastric lesions; APL: advanced precancerous lesions; GC: gastric cancer; SSDHS: spleen-stomach damp-heat syndrome; LSDS: liver-stomach disharmony syndrome; SQDS: spleen Qi deficiency syndrome; IBSBS: internal block of static blood syndrome; NON: non-symptomatic. The count data was compared by χ2 test and Fisher’s exact test. aP ﹤0.001 and cP ﹤0.01, compared with the NON group. bP ﹤0.001 and eP ﹤0.001, compared with the SQDS group. dP ﹤0.01, compared with the SQDS group.

Table 3 Association of miR-149 rs2292832 (T > C) with gastric pathological features and TCM syndromes

Group	Genotype [n (%)]			Adjusted^aOR (95% CI), P value
Group	TT	CT	CC	CT vs TT	CT + CC vs TT	C vs T
Pathological
HC	15 (42.8)	17 (48.6)	3 (8.6)	Reference	Reference	Reference
CI	10 (43.5)	10 (43.5)	3 (13.0)	0.920 (0.296-2.854), 0.885	1.012 (0.346-2.957), 0.983	1.105 (0.502-2.436), 0.804
GA	9 (81.8)	2 (18.2)	0 (0.0)	0.245 (0.043-1.386), 0.112	0.192 (0.035-1.063), 0.059	0.207 (0.043-0.989), 0.048
PGL	32 (40.5)	42 (53.2)	5 (6.3)	1.472 (0.593-3.651), 0.405	1.266 (0.531-3.019), 0.595	1.001 (0.524-1.912), 0.997
APL	4 (40.0)	6 (60.0)	0 (0.0)	1.665 (0.364-7.605), 0.511	1.294 (0.290-5.778), 0.735	0.890 (0.288-2.744), 0.839
GC	21 (46.7)	17 (37.8)	7 (15.5)	0.871 (0.319-2.378), 0.787	0.982 (0.381-2.533), 0.970	1.102 (0.543-2.235), 0.789
TCM syndromes
NON	3 (27.3)	8 (72.7)	0 (0.0)	Reference	Reference	Reference
SSDHS	38 (42.7)	39 (43.8)	12 (13.5)	0.376 (0.087-1.632), 0.192	0.467 (0.108-2.019), 0.308	0.878 (0.333-2.320), 0.794
LSDS	31 (47.0)	30 (45.4)	5 (7.6)	0.351 (0.077-1.601), 0.176	0.387 (0.085-1.762), 0.220	0.694 (0.251-1.915), 0.480
SQDS	14 (43.8)	17 (53.1)	1 (3.1)	0.436 (0.092-2.069), 0.296	0.447 (0.094-2.119), 0.310	0.693 (0.241-1.998), 0.498
IBSBS	5 (100.0)	0 (0.0)	0 (0.0)	-	-	-

Table 4 Distribution of combined genotypes of miR-499 and miR-149 among pathological groups [n (%)]

Genotype	HC (n = 35)	CI (n = 23)	P, OR (95% CI)	GA (n = 11)	P, OR (95% CI)	PGL (n = 79)	P, OR (95% CI)	APL (n = 10)	P, OR (95% CI)	GC (n = 45)	P, OR (95% CI)
AA/TT	13 (37.1)	8 (34.8)	0.855, 1.108 (0.369-3.323)	7 (63.6)	0.169, 0.338 (0.083-1.379)	26 (32.9)	0.660, 1.205 (0.525-2.765)	3 (30.0)	1.000, 1.379 (0.303-6.281)	18 (40.0)	0.795, 0.886 (0.357-2.199)
AA/CT	13 (37.1)	8 (34.8)	0.855, 1.108 (0.369-3.323)	2 (18.2)	0.296, 2.659 (0.496-14.247)	31 (39.2)	0.832, 0.915 (0.403-2.080)	6 (60.0)	0.281, 0.394 (0.093-1.661)	11 (24.4)	0.219, 1.826 (0.695-4.797)
AA/CC	2 (5.7)	3 (13.0)	0.376, 0.404 (0.062-2.631)	0 (0.0)	1.000, -	4 (5.1)	1.000, 1.136 (0.198-6.514)	0 (0.0)	1.000, -	6 (13.4)	0.455, 0.394 (0.074-2.085)
AG/TT	2 (5.7)	2 (8.7)	1.000, 0.636 (0.083-4.896)	2 (18.2)	0.238, 0.273 (0.034-2.214)	5 (6.3)	1.000, 0.897 (0.165-4.863)	1 (10.0)	0.539, 0.545 (0.044-6.719)	3 (6.7)	1.000, 0.848 (0.134-5.377)
AG/CT	4 (11.4)	2 (8.7)	1.000, 1.355 (0.227-8.078)	0 (0.0)	0.559, -	11 (13.9)	1.000, 0.798 (0.235-2.704)	0 (0.0)	0.561, -	5 (11.1)	1.000, 1.032 (0.256-4.169)
AG/CC	1 (3.0)	0 (0.0)	-	0 (0.0)	1.000, -	1 (1.3)	0.522, 2.294 (0.139-37.761)	0 (0.0)	1.000, -	1 (2.2)	1.000, 1.294 (0.078-21.446)
GG/TT	0 (0.0)	0 (0.0)	-	0 (0.0)	-	1 (1.3)	1.000, -	0 (0.0)	-	0 (0.0)	-
GG/CT	0 (0.0)	0 (0.0)	-	0 (0.0)	-	0 (0.0)	-	0 (0.0)	-	1 (2.2)	1.000, -
GG/CC	0 (0.0)	0 (0.0)	-	0 (0.0)	-	0 (0.0)	-	0 (0.0)	-	0 (0.0)	-

Figure 4 Comparison of miR-499 and miR-149 expression levels between different pathological groups and TCM syndromes A: comparison of miR-499 expression level between pathological groups among all subjects (n = 203); B: comparison of miR-499 expression level between pathological groups among H. pylori positive subjects (n = 167); C: comparison of miR-499 expression level between pathological groups among negative subjects (n = 36); D: comparison of miR-149 expression level between pathological groups among all subjects (n = 203); E: comparison of miR-149 expression level between pathological groups among H. pylori positive subjects (n = 167); F: comparison of miR-149 expression level between pathological groups among negative subjects (n = 36); G: comparison of miR-499 expression level between different TCM syndromes among all subjects (n = 203); H: comparison of miR-499 expression level between different TCM syndromes among H. pylori positive subjects (n = 167); I: comparison of miR-499 expression level between different TCM syndromes among negative subjects (n = 36); J: comparison of miR-149 expression level between different TCM syndromes among all subjects (n = 203); K: comparison of miR-149 expression level between different TCM syndromes among H. pylori positive subjects (n = 167); L: comparison of miR-149 expression level between different TCM syndromes among negative subjects (n = 36). The column height represents the median expression levels of miRNAs and the error bars represent the interquartile range. HC group includes healthy individuals subjected to routine physical examination; CI group includes patients with moderate to severe gastric mucosal inflammation; GA group contains patients only suffering from gastric mucosal atrophy; PGL group involves patients with gastric atrophy accompanied by intestinal metaplasia or dysplasia. APL group comprises patients with severe dysplasia; GC group includes patients diagnosed with gastric cancer. NON group: subjects without obvious symptoms; SSDHS group: subjects diagnosed with SSDHS; LSDS group: subjects diagnosed with LSDS; SQDS group: subjects diagnosed with SQDS; IBSBS group: subjects diagnosed with IBSBS. HC: healthy control; CI: chronic inflammation; GA: gastric atrophy; PGL: precancerous gastric lesions; APL: advanced precancerous lesions; GC: gastric cancer. SSDHS: spleen-stomach damp-heat syndrome; LSDS: liver-stomach disharmony syndrome; SQDS: spleen Qi deficiency syndrome; IBSBS: internal block of static blood syndrome; NON: non-symptomatic; H. pylori: Helicobacter pylori. The measurement data was compared by Kruskal-Wallis test. aP ﹤0.01 and cP ﹤0.05, compared with the GC group. bP ﹤0.05 and dP ﹤0.01, compared with the HC group.

Table 5 ORsa of GC by quartiles of expression levels of miR-499/miR-149

Relative expression level	Median	GC	HC	Crude OR (95% CI)	Adjusted^bOR (95% CI)
miR-499
Q1 (≤0.38)	0.15	7	13	1.000 (reference)	1.000 (reference)
Q2 (0.39-1.02)	0.67	11	9	2.270 (0.636-8.106)	1.816 (0.414-7.962)
Q3 (1.03-2.18)	1.48	12	8	2.786 (0.773-10.043)	3.230 (0.728-14.327)
Q4 (≥2.19)	6.23	15	5	5.571 (1.420-21.860)	6.482 (1.283-32.752)
P for trend	-	-	-	0.032	0.035
miR-149
Q1 (≤0.21)	0.10	17	3	1.000 (reference)	1.000 (reference)
Q2 (0.22-0.64)	0.34	10	11	0.160 (0.036-0.717)	0.166 (0.031-0.881)
Q3 (0.65-1.35)	1.01	13	6	0.382 (0.080-1.825)	0.467 (0.083-2.607)
Q4 (≥1.36)	2.39	5	15	0.059 (0.012-0.289)	0.075 (0.012-0.463)
P for trend	-	-	-	0.002	0.028

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