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BMC Neurology

, 19:67 | Cite as

Association of the MMP-9 polymorphism and ischemic stroke risk in southern Chinese Han population

  • Ning Gao
  • Tie Guo
  • Han Luo
  • Guolong Tu
  • Fanglin Niu
  • Mengdan Yan
  • Ying XiaEmail author
Open Access
Research article
  • 95 Downloads
Part of the following topical collections:
  1. Cerebrovascular disease and stroke

Abstract

Background

Stroke is a serious cardiovascular disease and is also the leading cause of long-term disability in developing and developed countries. Because matrix metalloproteinase-9 (MMP-9) is associated with the risk of many cardiovascular diseases, we investigated the relationship between single nucleotide polymorphisms (SNPs) in MMP-9 and the risk of Ischemic stroke (IS) in a southern Chinese Han population.

Methods

This study included 250 stroke patients and 250 healthy controls. Genotyping was performed using the Agena MassARRAY system, and chi-squared tests and genetic models were used to evaluate the associations between MMP-9 SNPs and the risk of IS. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression adjusted for age.

Results

Polymorphism rs3787268 was associated with increased the risk of IS. Specifically, the genotype “G/A” significantly correlated with IS risk in the co-dominant model [odds ratio (OR) = 1.62; 95% confidence interval (CI) = 1.10–2.41; p = 0.035)], while genotypes “G/A” and “A/A” may increase the risk of IS based on the dominant model (OR = 1.62; 95% CI = 1.12–2.35; p = 0.0097). This SNP was also significantly associated with IS risk in the log-additive model (OR = 1.33; 95% CI = 1.03–1.70; p = 0.026). Conversely, haplotype “C/G” appears to reduce the risk of IS (OR = 0.71; 95% CI = 0.54–0.95; p = 0.019).

Conclusions

Our study showed that the rs3787268 locus in the MMP-9 gene may increase risk of IS in a southern Chinese Han population and thus provide insight into the IS pathogenesis.

Keywords

Ischemic stroke MMP-9 Case-control study Single nucleotide polymorphism 

Abbreviations

CIs

95% confidence intervals

IS

Ischemic stroke

MMP-9

Matrix metalloproteinase-9

OR

Odds ratio

SNPs

Single nucleotide polymorphisms

Background

Stroke is a serious cardiovascular disease with an estimated global mortality of 4.7 million per year [1], and is also the leading cause of long-term disability in developing and developed countries [2]. It occurs when the brain tissue does not get enough oxygen and nutrients [3]. Ischemic stroke (IS) is the most common type of stroke, accounting for about 72–86% of cases [4]. The specific pathogenesis of IS remains unclear, but increasing evidence indicates that both environmental and genetic factors play a crucial role in its etiology. Observational studies have shown that hypertension [5], diabetes [6], smoking [7], drinking [8], hypercholesterolemia [9], lack of exercise among young people [10] may be clinically relevant risk factors for IS. Nevertheless, a large body of scientific research have indicated that IS was greatly affected by genetic factors [11], and gene polymorphisms may regulate the pathophysiological process of IS and confer a small to moderate risk [12].

Matrix metalloproteinases (MMPs) are a family of zinc- and calcium-dependent enzymes with proteolytic activity and can be adjusted by tissue inhibitors [13]. MMP-9 plays an important part in various cardiovascular diseases [14] and can degrade components of the extracellular matrix, leading to weakening of the fibrous cap [15] and development of cardiovascular and cerebrovascular diseases, including IS, atherosclerosis [16], and neuroinflammation [17]. The research of Zhong et al. showed that certain MMP-9 polymorphisms may increase the risk of IS in western Guangdong Province, China [18], although Buraczynska et al. did not observe associations between MMP-9 polymorphisms and IS in a Polish population [19]. However, it is unknown if MMP-9 polymorphisms are significantly related to IS risk in a southern Chinese Han population.

Therefore, the purpose of this study is to determine if susceptible single nucleotide polymorphisms (SNPs) in the MMP9 gene are associated with increased risk of IS in a southern Chinese Han population. These results may contribute to further clarify their potential role in IS and provide basis for the early prevention and targeted treatment of IS in a southern Chinese Han population.

Methods

Study participants

Our study consisted of 250 stroke patients, who were consecutively recruited between January 2015 and January 2018 at the Haikou Hospital affiliated to Xiangya Medical College of Central South University, with no age or gender restrictions. Controls identified through the annual health assessment were recruited from the same hospital physical examination center between January 2015 and October 2017. They are healthy individuals had no history of cerebrovascular disease or MI, tumor, hypertension, diabetes, etc. All study participants were Han Chinese individuals living in the Hainan province and provided written informed consent. The Ethic Committee of the Haikou Hospital affiliated to Xiangya Medical College of Central South University approved the use of human blood samples for this study.

According to the World Health Organization’s diagnostic criteria, all participants’ IS was confirmed by at least two independent neurologists using computed tomography (CT) scans and/or magnetic resonance imaging (MRI) along with standardized blood tests. Patients with IS were excluded from the study if they had history of transient ischemic attack, coronary artery disease, autoimmune disease, systemic inflammatory disease, malignant tumor and.

Single nucleotide polymorphisms (SNPs) selection and genotyping

The professional technicians professional technicians collected about 5 mL of peripheral blood samples of each participant into the test tube containing ethylenediamine tetraacetic acid (EDTA) for anticoagulation in a freezer, at − 80 °C.Subsequently, genomic DNA was then extracted from blood samples using the Gold-Mag nanoparticles method (Gold Mag Co. Ltd., Xi’an City, China) according to the manufacturer’s instructions, and the DNA concentration and purity were measured by NanoDrop 2000C (Thermo Scientifc, Waltham, Massachusetts, USA), and finally stored at − 80 °C until analysis. Blood was taken within 5 h after the patient was initial diagnosed with a IS.

In our study, four SNPs rs3787268, rs3918249, rs2274755 and rs3918254 in MMP-9 were selected for genotyping. Based on the research, it is found that rs3787268 has no correlation with IS in the Polish population [19], but it will increase the risk of IS in the western Guangdong region [18], indicating that the correlation between this site and IS was different in different populations, and it is still different. It is unclear whether the MMP-9 polymorphism is significantly associated with the IS risk of the southern Chinese Han population, so it was chosen. The choice of rs3918249, rs2274755, and rs3918254 based on the fact that their effects on IS has not been studied. Data management and analysis were performed with Agena MassARRAY Assay Design software v4.0 [10, 11].

Statistical analyses

All statistical analyses were performed using SPSS v19.0 (IBM Analytics, Chicago, IL, USA) and Microsoft Excel. Allele and genotype frequencies were obtained by direct counts and analyzed with Chi-squared and Fisher’s exact tests. Hardy-Weinberg equilibrium (HWE) for each SNP was determined using an exact test to compare the expected frequencies of genotypes in controls. Association between MMP-9 polymorphisms and the risk of IS were estimated by computing odds ratios (OR) and 95% confidence intervals (CIs) with unconditional logistic regression analysis. Four models (co-dominant, dominant, recessive, and log-additive) were used to assess these relationships [12]. Linkage disequilibrium (LD) analysis was performed using genotype data from IS patients and controls. All p values were two- sided, and p < 0.05 indicated statistical significance [13].

Results

Our study included 250 IS cases (167 males, 83 females; median age at diagnosis: 64.13 years) and 250 controls (152 males, 98 females; median age 48.31 years). As shown in Table 1, we detected no significant difference in the distribution of age or gender between cases and healthy controls (p >  0.001).
Table 1

Characteristics of patients with ischemic stroke and the control individuals

Variable(s)

Case

(n = 250)

Control

(n = 250)

p value

Sex N (%)

  

>  0.001a

 Male

167

152

 

 Female

83

98

 

Age, year (mean ± SD)

64.13 ± 10.82

48.31 ± 13.31

>  0.001b

aTwo-sided Chi-squared test

bIndependent samples t test

Table 2 summarizes the allele frequencies of tested SNPs among individuals in both case and control groups. All SNP call rates exceeded 98.5%, which were high enough to perform association analyses. In addition to SNP rs2274755 locus (p-HWE >  0.05), all tested loci followed HWE at the 5% level. Chi-squared tests indicated rs3787268 was significantly associated with increased IS risk (OR = 1.34, 95% CI = 1.04–1.73; p = 0.022).
Table 2

Allele frequencies in cases and controls and odds ratio estimates for IS risk

SNP

Gene(s)

Band

Alleles A/B

MAF

HWE a p value

OR (95% CI)

b p value

Case

Control

rs3918249

MMP9

20q13.12

T/C

0.212

0.251

0.09

0.80 (0.59–1.07)

0.142

rs2274755

MMP9

20q13.12

T/G

0.116

0.131

0.011

0.88 (0.60–1.28)

0.500

rs3918254

MMP9

20q13.12

T/C

0.221

0.227

0.277

0.97 (0.72–1.30)

0.820

rs3787268

MMP9

20q13.12

A/G

0.442

0.371

0.134

1.34 (1.04–1.73)

0.022*

SNP: single nucleotide polymorphism, Alleles A/B: Minor/Major alleles, MAF: minor allele frequency, OR: odds ratio, CI: confidence interval, HWE: Hardy–Weinberg equilibrium

* p ≤ 0.05 indicates statistical significance

a p was calculated by exact test

b p was calculated by Pearson Chi-squared test

We used four genetic models to analyze the association between the tested SNPs and risk of IS (Table 3). In the co-dominant model, genotype “G/A” of rs3787268 increased the risk of IS 1.62-fold (OR = 1.62; 95% CI = 1.10–2.41; p = 0.035). In the dominant model, genotype “G/A - A/A” was associated with a 1.62-fold increase in IS risk (OR = 1.62; 95% CI = 1.12–2.35; p = 0.010). The log-additive model indicated rs3787268 increased the risk of IS 1.33-fold (OR = 1.33, 95% CI = 1.03–1.70; p = 0.026).
Table 3

Relationship between MMP-9 polymorphism and IS risk

SNP

Model

Genotype

control

case

OR (95% CI)

P-value

AIC

BIC

rs3787268

Codominant

G/G

104 (41.9%)

77 (30.8%)

1.00

0.035*

689.7

702.3

G/A

104 (41.9%)

125 (50%)

1.62 (1.10–2.41)

A/A

40 (16.1%)

48 (19.2%)

1.62 (0.97–2.71)

Dominant

G/G

104 (41.9%)

77 (30.8%)

1.00

0.009*

687.7

696.1

G/A-A/A

144 (58.1%)

173 (69.2%)

1.62 (1.12–2.35)

Recessive

G/G-G/A

208 (83.9%)

202 (80.8%)

1.00

0.370

693.6

702

A/A

40 (16.1%)

48 (19.2%)

1.24 (0.78–1.96)

Overdominant

G/G-A/A

144 (58.1%)

125 (50%)

1.00

0.071

691.1

699.5

G/A

104 (41.9%)

125 (50%)

1.38 (0.97–1.97)

Log-additive

1.33 (1.03–1.70)

0.026*

689.4

697.8

rs3918249

Co-dominant

C/C

145 (58.2%)

155 (62.5%)

1.00

0.240

692.1

704.8

T/C

83 (33.3%)

81 (32.7%)

0.91 (0.62–1.34)

T/T

21 (8.4%)

12 (4.8%)

0.53 (0.25–1.13)

Dominant

C/C

145 (58.2%)

155 (62.5%)

1.00

0.330

692

700.5

T/C-T/T

104 (41.8%)

93 (37.5%)

0.84 (0.58–1.20)

Recessive

C/C-T/C

228 (91.6%)

236 (95.2%)

1.00

0.110

690.4

698.8

T/T

21 (8.4%)

12 (4.8%)

0.55 (0.27–1.15)

Over-dominant

C/C-T/T

166 (66.7%)

167 (67.3%)

1.00

0.870

693

701.4

T/C

83 (33.3%)

81 (32.7%)

0.97 (0.67–1.41)

Log-additive

0.81 (0.61–1.08)

0.160

691

699.4

rs2274755

G/G

184 (73.9%)

191 (76.7%)

1.00

0.470

693.8

702.3

G/T

65 (26.1%)

58 (23.3%)

0.86 (0.57–1.29)

rs3918254

Co-dominant

C/C

152 (61%)

152 (61%)

1.00

0.830

696

708.6

T/C

81 (32.5%)

84 (33.7%)

1.04 (0.71–1.52)

T/T

16 (6.4%)

13 (5.2%)

0.81 (0.38–1.75)

Dominant

C/C

152 (61%)

152 (61%)

1.00

NA

694.4

702.8

T/C-T/T

97 (39%)

97 (39%)

1.00 (0.70–1.43)

Recessive

C/C-T/C

233 (93.6%)

236 (94.8%)

1.00

0.570

694

702.5

T/T

16 (6.4%)

13 (5.2%)

0.80 (0.38–1.70)

Over-dominant

C/C-T/T

168 (67.5%)

165 (66.3%)

1.00

0.780

694.3

702.7

T/C

81 (32.5%)

84 (33.7%)

1.06 (0.73–1.53)

Log-additive

0.97 (0.72–1.29)

0.820

694.3

702.7

ORs, odds ratios; CI: confidence interval; AIC: Akaike’s Information criterion; BIC: Bayesian Information criterion

*p value ≤0.05 indicates statistical significance

We further evaluated the association between MMP-9 haplotype and risk of developing IS. Figure 1 shows the LD of rs3918254 and rs3787268 in MMP-9. Haplotype “CG” was significantly associated with decreased risk of IS (OR = 0.71; 95% CI = 0.54–0.95; p = 0.019) (Table 4).
Fig. 1

Haplotype block map for the four MMP-9 single nucleotide polymorphisms explored in our study

Table 4

MMP-9 haplotype frequencies and the association with the IS risk

Haplotype

rs3918254

rs3787268

Freq

OR(95%CI)

p

1

C

A

0.404

1.00

2

C

G

0.373

0.71 (0.54–0.95)

0.019*

3

T

G

0.221

0.82 (0.60–1.14)

0.240

rare

*

*

0.003

0.80 (0.05–13.09)

0.870

* p value ≤ 0.05 indicates statistical significance

Freq frequency, ORs odds ratios, CI confidence interval

We used HaploReg (version 4.1) to identify the rs3787268 tagged variants using the LD information from the 1000 Genomes Project (EUR) with r 2 ≥ 0.8, and we got 13 genetic variants tagged by rs3787268 variant with r 2 ≥ 0.8. These 13 genetic variants were located around the 18kb 5' of MMP9, MMP9, RP11-465L10.7 and SLC12A5. The detailed information including the LD information about these variants was provided in Table 5.
Table 5

rs3787268 and variants with r2 ≥ 0.8

SNP

chr

pos (hg38)

LD (r2)

LD (D’)

Ref

Alt

Gene

Functional annotation

rs25610751

20

45,991,015

0.87

0.94

C

G

18 kb 5′ of MMP9

 

rs6073980

20

45,991,065

0.86

0.94

G

A

18 kb 5′ of MMP9

 

rs6073983

20

46,001,252

0.89

0.98

A

T

18 kb 5′ of MMP9

 

rs3761157

20

46,006,183

98

0.99

C

T

18 kb 5′ of MMP9

 

rs3787268

20

46,013,092

1

1

G

A

MMP9

intronic

rs3918262

20

46,015,131

1

1

A

G

MMP9

intronic

rs6073989

20

46,022,571

0.95

0.98

G

T

RP11-465 L10.7

intronic

rs16991010

20

46,023,675

0.95

0.98

A

C

RP11-465 L10.7

intronic

rs6130998

20

46,024,480

0.95

0.98

C

T

RP11-465 L10.7

intronic

rs6130999

20

46,026,853

0.95

0.98

G

A

RP11-465 L10.7

intronic

rs6073991

20

46,027,473

0.95

0.98

A

G

RP11-465 L10.7

intronic

rs13039389

20

46,031,067

0.91

0.97

G

C

SLC12A5

intronic

rs6131001

20

46,032,717

0.94

0.98

C

T

SLC12A5

intronic

LD linkage disequilibrium, SNP single nucleotide polymorphism, Ref reference allele, Alt altered allele

Discussion

In this case-control study, we investigated four SNPs (rs3787268, rs3918249, rs2274755, rs3918254) of MMP-9 to determine if they are significantly associated with the risk of IS in a southern Chinese Han population. Our results suggested SNP rs3787268 correlated with an increased risk of stroke; although, no significant relationship was found between IS and SNPs rs3918249, rs2274755, and rs3918254.

SNP rs378726 is located within MMP-9 on chromosome 20q13.12 and may affect the development and progression of various diseases. For example, Ho et al. [20] found that rs378726 was associated with susceptibility to spontaneous deep cerebral hemorrhage in a Taiwanese population, while the minor allele of rs3787268 may exert a critical protective effect against diabetes [21]. In addition, rs3787268 has been used to predict the survival rate of breast cancer in a Chinese population [22]. However, the potential association between SNP rs378726 and IS has not been well studied. Currently, only the study of Zhong et al. [18] has suggested that rs3787268 may be a risk factors for IS in a Guangdong Chinese population. Similarly, we found that this polymorphism may promote the occurrence of IS in a southern Chinese Han population, although the effect of rs3787268 polymorphism on IS in other groups needs to be investigated.

The other loci we explored (rs3918249, rs2274755, rs3918254) also correlate with various diseases. For example, rs2274755 is associated with asthma [22] and steroid-induced osteonecrosis of the femoral head [23], while rs3918249 is related to childhood asthma and glaucoma. The rs3918254 locus may confer susceptibility to primary angle-closure glaucoma [24]. However, prior to our current study, their impact on the risk of IS had not been explored, although we found no significant relationship between them. For the first time, we found no significant relationship between them and the risk of IS in a southern Chinese Han population.

Our results suggest that certain polymorphisms in MMP-9 can affect the risk of IS in a southern Chinese Han population, but further research is merited. First, because our sample size was relatively small, large-sample studies are needed to confirm these findings. In addition, we need to conduct functional studies to determine the relevant mechanism(s) of MMP-9 polymorphisms and their effect on IS risk [25].

Conclusion

In conclusion, we found that polymorphisms of MMP-9 are significantly associated to the risk of IS in a southern Chinese Han population, providing foundational data for additional investigations of the relationship between MMP-9 and IS risk in different populations. Our results also provide new insight for future explorations of IS pathogenesis. This may provide clues for the evaluation of individual susceptibility to IS and enable IS patients to receive early prevention and treatment, thus reducing the harm of IS.

Notes

Acknowledgments

We thank all patients and controls for their participation in this study. We also thank the clinicians and hospital staff who contributed to the sample and data collection.

Funding

This study was supported by National Natural Science Foundation, People s Republic of China (No. 81760234).

Availability of data and materials

The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

Authors’ contributions

NG: conceived and designed the experiments. TG: revision of the article. HL: performed the experiments. GLT and FLN: analyzed the data. MDY and YX: contributed reagents/materials/analysis tools. All authors contributed significantly to the final draft of the paper and agreed to submit the manuscript for publication.

Ethics approval and consent to participate

The Ethic Committee of the Haikou Hospital affiliated to Xiangya Medical College of Central South University approved the use of human blood samples for this study. The purpose of this study was well informed to the subjects and written informed consent was obtained from each of them.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Authors and Affiliations

  1. 1.Department of NeurosurgeryAffiliated Haikou Hospital of Xiangya Medical College in Central South UniversityHaikouChina
  2. 2.The First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
  3. 3.Key Laboratory of Resource Biology and Biotechnology in Western ChinaNorthwest University, Ministry of EducationXi’anChina

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