Background
As a consequence of untreated group A streptococcal pharyngitis, as many as 3–6% of individuals may develop acute rheumatic fever (ARF) [
1], and 42–60% of those with ARF will eventually develop rheumatic heart disease (RHD) [
2,
3]. According to the Global Burden of Disease (GBD) Study, it is estimated that there were 34,232,795 cases of RHD and 345,000 deaths from RHD globally in 2010 [
4]. In China, the prevalence of RHD is around 1.86 cases per 1000 adults between 27 and 71 years of age [
5]. Approximately 30–45% of children and young adults with ARF develop RHD due to permanent valvular damage [
6]. The basic pathological change is degradation and remodeling of the extracellular matrix (ECM) [
7], which is characterized by the destruction of glycosaminoglycans, proteoglycans collagen, and elastin [
8,
9].
Matrix metalloproteinases (
MMPs), which are members of the multidomain zinc endopeptidases family, are not only capable of degrading many ECM components associated with valvular remodeling and calcification [
10], but they also can modulate immune responses by processing cytokines and chemokines to change their activity [
11].
McQuibban GA et al. [
12] demonstrated that the N-terminus of monocyte chemoattractant protein 1 (MCP1), MCP2 and MCP4 was cleaved by
MMP1 and 3 to produce antagonist factors which dampen inflammatory processes. Further study has shown that
MMP3 has a dual role in biphasic modulation of inflammatory mediator activity by cleaving Interleukin 1β precursor into active form and degrading the biologically active cytokine [
13]. RHD is an autoimmune disease that is triggered by ARF [
14]. We can speculate that
MMPs may be involved in the pathogenesis of RHD through an immune mechanism. However, there are few reports on the relationship between
MMPs and RHD. In the present study, we will investigate the effect of
MMPs polymorphisms on RHD.
Genetic polymorphisms in the promoter region of
MMPs genes play an important role in the predisposition of patients to various diseases by altering transcriptional activity [
15‐
18]. In the promoter of the
MMP1 gene, an insertion (2G)/deletion (1G) polymorphism was detected at position − 1607 (rs1799750). It has been demonstrated that the 2G promoter processes higher transcriptional activity than the 1G promoter by binding more Ets-1 transcription factor [
16]. This
MMP1 promoter polymorphism has been reported to be associated with oligodendroglioma [
19], coronary artery disease [
20], osteoarthritis [
21], and lumbar disc disease [
22].
Another insertion (6A)/deletion (5A) polymorphism has been reported at position − 1612 (rs3025058) of the
MMP3 promoter. The 6A promoter has a reduced transcription level due to its higher affinity to the repressor binding site [
17]. This
MMP3 promoter polymorphism has been associated with osteoarthritis [
23], lung cancer [
24], and myocardial infarction [
25].
A single nucleotide polymorphism (SNP) in the
MMP12 promoter region has been reported to influence transcriptional activity [
18]. This A to G substitution polymorphism is located at position − 82 (rs2276109) adjacent to the transcription factor activator protein-1 (AP-1). It has been suggested that this SNP may be a risk factor for rheumatoid arthritis [
26], systemic sclerosis [
27], ovarian carcinoma [
28], and ischemic stroke [
29].
Although
MMPs polymorphisms have been associated with various diseases, the role of genetic polymorphisms in
MMPs has not yet been evaluated in patients with RHD. In addition,
MMP1,
3, and
12 are known to be adjacently localized on chromosome 11q22.3 [
15] and these 3 loci are considered to act in cooperation with each other [
30]. In the present study, we evaluated the associations of 3
MMPs polymorphisms, rs1799750 in
MMP1, rs3025058 in
MMP3, and rs2276109 in
MMP12, with RHD in a Han population in Southern China.
Discussion
Twin studies have found that the risk of ARF in monozygotic twins with a history of ARF is increased by more than 6 times compared to that of dizygotic twins [
31]. These findings provide evidence for the involvement of a host of genetic factors in susceptibility to RHD, which is the sequel to ARF in endemic conditions. Genetic association studies have shown that methylenetetrahydrofolate reductase (
MTHFR) C677T polymorphism is associated with RHD [
32] and other studies have suggested genetic associations between promoter polymorphisms in angiotensin-converting enzyme (
ACE) and interleukin 10 (
IL-10) and RHD [
33,
34]. In the present study, we evaluated the associations of 3
MMPs polymorphisms,
MMP1 (rs1799750),
MMP3 (rs3025058), and
MMP12 (rs2276109), with RHD in a Han population in Southern China. Our study is the first to suggest an association between
MMP1 (rs1799750) and RHD (Table
3). We showed that the
MMP1–1607 2G/2G genotype was associated with a significantly higher risk of RHD when compared with the 1G/1G genotype (OR =3.227; 95% CI: 1.118–9.31;
p = 0.03; Table
3), and the frequency of the 2G allele was higher in RHD compared to the controls (69.4% vs. 58.9%;
p = 0.048; Table
3). Studies have shown that
MMP1 is expressed in all heart valves and that the mRNA transcript for
MMP1 is significantly increased in patients with chronic valvular disease [
35,
36]. Further studies have indicated that
MMP1 and its inhibitors play an important role in the development of an abnormal ECM characteristic of RHD and the
MMP1/TIMP-1 ratio correlates positively with the rheumatic mitral valve area [
8,
37].
MMP1 is located on chromosome 11q22 and produced by stromal fibroblast cells, macrophages, endothelial, and epithelial cells [
38]. The level of
MMP1 expression can be influenced by an insertion/deletion of guanine at position − 1607 in the promoter region; a core-binding site (5′-GGA-3′) for the Ets family of transcription factors is created when 2 guanines are present instead of 1 guanine, leading to a higher expression of
MMP1 [
16]. Our findings were in accordance with those of previous studies that suggested that patients who carry the 2G allele are predisposed to the development of several types of cancers, periodontitis, coronary artery disease, and peripheral arterial occlusive disease [
39]. We hypothesized that the 2G allele in the
MMP1 polymorphism might potentially increase the level of protein expression and accelerate the degradation of ECM, which provides the molecular basis for valvular tissue remodeling and repair during the development of RHD.
This
MMP3 promoter polymorphism has been associated with osteoarthritis [
22], lung cancer [
24], and myocardial infarction [
25]. The
MMP3 gene is located in the same chromosome region as
MMP1. The
MMP3–1612 polymorphism has been associated with serum
MMP3 titer in rheumatoid arthritis patients and congestive heart failure associated with RHD [
40,
41]. Ye et al. first reported that the
MMP3–1612 polymorphism was involved in the regulation of transcription by binding the transcriptional repressor protein [
17,
42]. These findings suggest that this functional polymorphism could be involved in the pathogenesis of RHD; however, we did not find a significant association between the
MMP3–1612 polymorphism and RHD in this study, possibly due to the limited sample size. In addition, we observed in the present study that the 5A homozygote was very rare (2.8%) in the Yunnan population (Southern China), which is consistent with the results from previous investigations in the Guangdong population (1.8%, Southern China) and the Hebei population (2.5%, Northern China) [
43,
44]. However, in other studies from British, Iranian, and Lithuanian populations, the frequency of the 5A homozygote was 25.5, 35.5, and 26.2%, respectively [
45‐
47]. These findings suggest an ethnic difference in the
MMP3 gene polymorphism.
The
MMP12 gene,
MMP1, and
MMP3 are located near each other on the same chromosome. In addition, the
MMP12 expression has been reported to be upregulated in human heart valve disease [
48]. Accordingly, we postulated that the
MMP12 polymorphism might play an important role in the pathogenesis process of RHD; however, the present study did not show a significant association between the
MMP12 polymorphism and RHD. The lack of a significant association of the
MMP12 polymorphism with RHD could indicate that the
MMP12 polymorphism might not be a major risk factor for RHD.
Although our study did not reveal correlation between
MMP3–1612 6A/5A,
MMP12 -82A/G polymorphisms and RHD in Han population, studies have shown a combined effect of
MMP1–1607 1G/2G,
MMP3–1612 6A/5A and
MMP12-82A/G polymorphisms associated with esophageal adenocarcinoma (EA) risk in Caucasian [
30]. The cause of the different conclusions may be difference in study population, low sample size or poor control-patient matching. In addition, the expression level of other
MMPs members were found elevated in patients with RHD, such as
MMP2 and
MMP9 [
49,
50]. Elevated
MMP2 levels in patients with RHD may be involved in atrial remodeling and atrial fibrosis by modulating the balance between B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (BAX). Increased
MMP-9 may facilitate cardiac remodeling in RHD by playing a compensatory role for the decreased insulin-like growth factor (IGF)-I levels. Thus other
MMPs members should be included in the polymorphism study due to their different pathogenic mechanisms in RHD.
There were several limitations in the present study. First, this case-control study had a relatively small sample size that might limit the statistical power to detect potential real genetic associations even though the controls were matched to the cases for age and sex. Further studies with larger samples are necessary to confirm our results. Second, our study subjects were confined to the Han population in Southern China. Additional studies in other ethnic populations are warranted to confirm our findings. Third, we only assessed the association between single polymorphisms of MMP1, 3, and 12 and RHD. Investigations into other polymorphisms in MMP1, 3, and 12 or other MMPs genes are required to elucidate the roles of MMPs genes in the development of RHD. Fourth, we did not use different methods to validate our results, such as RT-PCR, ELISA and/or immunohistochemical analysis.