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  • Open Access
  • Open Peer Review

Association between GDF5 rs143383 genetic polymorphism and musculoskeletal degenerative diseases susceptibility: a meta-analysis

BMC Medical Genetics201819:169

https://doi.org/10.1186/s12881-018-0685-7

  • Received: 18 June 2018
  • Accepted: 9 September 2018
  • Published:
Open Peer Review reports

Abstract

Background

Several studies have assessed the association between GDF5 rs143383 polymorphism and the susceptibility of musculoskeletal degenerative diseases, such as intervertebral disc degeneration (IDD) and osteoarthritis (OA), but the results are inconsistent. The aim of our study was to evaluate the association between them comprehensively.

Methods

A systematical search was conducted on PubMed, Scopus, Web of Science (WOS), Embase, and the Cochrane Library databases updated to April 20, 2018. Eligible studies about polymorphisms in GDF5 gene and risk of IDD or OA were included. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were utilized.

Results

Fifteen studies with a total of 5915 cases and 12,252 controls were finally included in our study. Meta-analysis of GDF5 rs143383 polymorphism was statistically associated with increased risk of musculoskeletal degenerative diseases under each genetic model (allele model: OR = 1.32, 95% CI 1.19–1.48, P = 0.000; homozygote model: OR = 1.80, 95%CI 1.49–2.16, P = 0.000; heterozygote model: OR = 1.37, 95%CI 1.21–1.55, P = 0.000; dominant model: OR = 1.56, 95%CI 1.39–1.75, P = 0.000; recessive model: OR = 1.39, 95%CI 1.20–1.60, P = 0.000). Stratified analyses based on disease type showed a significant association between the GDF5 rs143383 polymorphism and increased risk of IDD and OA under all genetic models studied. When stratified with ethnicity, pooled outcomes revealed that this polymorphism was significantly related with increased risk of musculoskeletal degenerative diseases in both Asian and Caucasian populations under all genetic models studied.

Conclusions

The present study suggested that GDF5 rs143383 polymorphism was significantly associated with susceptibility to musculoskeletal degenerative diseases.

Keywords

  • GDF5 gene
  • Polymorphisms
  • Musculoskeletal degenerative diseases
  • Meta-analysis

Background

Intervertebral disc degeneration (IDD) and osteoarthritis (OA) are two major musculoskeletal degenerative diseases that bring about pain, physical limitations and disability of patients. IDD has been one of the important causes to low back pain (LBP) and motor deficiency. Lumbar disc herniation (LDH) is caused mainly by IDD because the degeneration and herniation of nucleus pulposus exist in the lumbar intervertebral disc [1]. OA is a chronic age-associated disease resulted from articular cartilage degeneration [2, 3], which has a profound influence on the functioning of synovial joints, primarily the knee, hip, and hands [3]. Apart from aging, hormonal, environmental and behavioral factors, genetic factor has been implicated in the etiology and pathogenesis of musculoskeletal degenerative diseases [46].

Growth differentiation factor 5 (GDF5) is a member of the transforming growth factor-β (TGF-β) superfamily with high articular cartilage specificity [7]. Studies have revealed the significant value of GDF5 gene in musculoskeletal processes including endochondral ossification, synovial joint formation, tendon repair and bone production [810]. It is also suggested that GDF5 is effective in enhancing the proliferation and matrix anabolism of intervertebral disc cells [1113]. The + 104 T/C polymorphism (rs143383) in the 5′-untranslated region (UTR) of GDF5 gene influences transcriptional activity in the gene core promoter, and lower GDF5 expression has been detected in individuals carrying T alleles.

Although several meta-analyses have revealed a possible relationship between the GDF5 rs143383 and knee OA and other common phenotypes OA [6, 1416], several new studies have also reported an association between rs143383 and the risk of IDD [1719] and other phenotypes of OA [5, 2023]. Therefore, the data needs to be updated and more reliable studies are warranted to conclude whether the association varies by disease type and ethnicity. Our study conducted a meta-analysis to shed some light on the relationship between GDF5 rs143383 polymorphism and the susceptibility of IDD and OA using all published case–control association studies.

Methods

Search strategy

A computerized literature search was conducted in the PubMed, Scopus, Web of Science (WOS), Embase, and the Cochrane Library databases up to April 20, 2018. The search method of our study followed the terms such as: (“IDD” or “LDD” or “LDH” or “LBP” or “Intervertebral Disc Degeneration” or “OA” or “osteoarthritis”) and (“GDF5” or “rs143383” or “GDF5 + 104 T/C”) and (“polymorphisms” or “variants” or “variation” or “SNP”). Eligible articles that matched the inclusion criteria were included. Moreover, the references of articles were examined one by one to avoid missing any eligible studies. When the important data were not available, we tried to contact researchers of some articles.

Inclusion and exclusion criteria

A study that is eligible for inclusion must meet the following criteria: (1) case–control study or cohort study including both case and control groups, (2) detection of GDF5 polymorphisms and IDD or OA risk, (3) having an accessible genotype frequency for calculating an odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (95% CI), (4) genotype frequencies in controls must conform to Hardy-Weinberg equilibrium (HWE). Whereas, reviews, case reports or serious, or similar works were all eliminated. We also eliminated the studies with genotype frequencies not in HWE [24].

Data extraction and quality assessment

Two investigators (Xin Huang, Weiyue Zhang) were assigned to assess the eligibility of all studies. And the relevant data for analysis were extracted on their own. Moreover, a third investigator (Zengwu Shao) resolved the disagreements when necessary. The important data were collected as follows: name of first author, year, countries, ethnicity, sample size, disease, sex, age, genotyping methods, and allele frequencies of GDF5 rs143383. The study quality was assessed in accordance with the Newcastle-Ottawa Scale (NOS). The study was considered high quality with the scores were ≥ 7.

Statistical analysis

The statistical data was analyzed by Stata version 14.0. Outcomes were calculated by odds ratios (ORs) and 95% confidence intervals (CIs). Genotype frequencies of GDF5 rs143383 polymorphism for HWE were calculated using the chi-square test, and P < 0.05 was regarded as significant disequilibrium. The chi-square test and the I2 statistic were utilized to assess the between-study heterogeneity. If an I2 value of < 50%, it was considered that no significant heterogeneity existed [25]. A random effects model was utilized when there was a significant heterogeneity. On the contrary, the fixed effects model was utilized. Moreover, we further made subgroup analyses to evaluate the source of heterogeneity. Begg’s and Egger’s methods were mainly utilized to assess publication bias. And sensitivity analyses were to evaluate the stability of major outcomes and possible source of heterogeneity.

Results

Search results

The study search is shown in the flow diagram (Fig. 1). 108 relevant articles were collected during the databases search. Furthermore, 75 were eliminated during abstract review, and 33 for further review. During the full-text review, 18 articles were eliminated for the following reasons: seven were neither case–control study or cohort study, five were not associated with IDD or OA, four were not GDF5 polymorphisms on IDD or OA risk, two was not consistent with HWE. To sum up, 15 studies with 5915 cases and 12,252 controls were included in the present study.
Fig. 1
Fig. 1

Flowchart of the study selection process

Study selection and characteristics

The main features of each eligible study are summarized in details (Table 1). Among these eligible studies, three articles investigated value of GDF5 rs143383 in IDD risk in seven independent populations. In addition, twelve articles examined effects of GDF5 rs143383 on the risk of OA in fifteen independent populations. Ten in the included studies had been made among Asian populations, and twelve were in Caucasian populations. The years for publication ranged from 2007 to 2017. In all these articles, genotype frequencies in controls conformed to HWE (Table 2). According to NOS, the quality scores of all eligible articles ranged from 7 to 8, which indicated a good quality (Additional file 1: Table S1). Furthermore, the definitions of diseases, inclusions, and exclusions of patients in each study are also shown (Additional file 1: Table S2).
Table 1

Main characteristics of the studies included in this meta-analysis

First author

Year

Country

Ethnicity

Sample size

Disease

Sex

Age (y)

Genotyping method

Quality

Citation

Case

Control

Mu J

2014

China

Asian

231

370

LDH

Both

21.9

DNA analyzers

Y

[17]

Mu J

2013

China

Asian

305

587

LBP

Both

48.4

DNA analyzers

Y

[18]

Williams FMK a

2011

UK

Caucasian

194

1268

LDD

Both

65.7

KASPar chemistry

Y

[19]

Williams FMK b

2011

UK

Caucasian

33

539

LDD

Both

54.7

KASPar chemistry

Y

[19]

Williams FMK c

2011

UK

Caucasian

54

704

LDD

Both

62.9

KASPar chemistry

Y

[19]

Williams FMK d

2011

UK

Caucasian

18

574

LDD

Both

53.6

KASPar chemistry

Y

[19]

Williams FMK e

2011

UK

Caucasian

14

116

LDD

Both

65.8

KASPar chemistry

Y

[19]

Tülüce Y

2017

Turkey

Caucasian

95

77

OA

Both

62.5

PCR-RFLP

Y

[20]

Abd Elazeem MI

2017

Egypt

Caucasian

50

50

Primary knee OA

Both

56.5

TaqMan

Y

[21]

Sabah-Ozcan S

2016

Turkey

Caucasian

94

279

Knee OA

Both

58.4

PCR-RFLP

Y

[22]

Xiao JL

2015

China

Asian

114

126

Temporomandibular joint OA

Both

33.6

PCR-RFLP

Y

[23]

Mishra A

2013

India

Asian

300

300

Knee OA

Both

54.0

PCR-RFLP

Y

[5]

Tawonsawatruk T

2011

Thailand

Asian

90

103

Knee OA

Both

68.5

PCR-RFLP

Y

[29]

Cao Z

2010

Korea

Asian

276

298

Knee OA

Both

63.0

PCR-RFLP

Y

[30]

Valdes AM

2009

UK

Caucasian

259

509

Knee OA

Both

68.5

Allele-specific PCR

Y

[31]

Tsezou A

2007

Greece

Caucasian

251

268

Knee OA

Both

67.9

Direct sequence

Y

[32]

Miyamoto Y a

2007

Japan

Asian

718

861

Knee OA

Both

71.9

TaqMan

Y

[33]

Miyamoto Y b

2007

China

Asian

313

485

Knee OA

Both

58.8

TaqMan

Y

[33]

Miyamoto Y c

2007

Japan

Asian

998

983

Hip OA

Both

71.9

TaqMan

Y

[33]

Southam L a

2007

UK

Caucasian

509

822

Knee OA

Both

65.0

PCR-RFLP

Y

[34]

Southam L b

2007

Spain

Caucasian

274

1196

Knee OA

Both

65.0

TaqMan

Y

[34]

Shin MH

2012

Korea

Asian

725

1737

Knee OA

Both

67.4

High resolution melting analysis

Y

[35]

a,b,c,dand e denote an independent study in one article, respectively; LDD lumbar disc degeneration, LDH lumbar disc herniation, LBP low-back pain, OA osteoarthritis, RT-PCR real-time polymerase chain reaction, PCR-RFLP polymerase chain reaction-restriction fragment-length polymorphism, Y yes

Table 2

Genotype distribution of the studies included in this meta-analysis

Study ID

Year

Ethnicity

Disease

Case group

Control group

P for HWE

GDF5 rs143383

   

CC

CT

TT

CC

CT

TT

 

Mu J

2014

Asian

LDH

8

79

144

39

158

173

0.743

Mu J

2013

Asian

LBP

10

89

206

58

254

275

0.953

Williams FMK a

2011

Caucasian

LDD

21

103

70

218

586

464

0.159

Williams FMK b

2011

Caucasian

LDD

4

14

15

94

252

193

0.453

Williams FMK c

2011

Caucasian

LDD

6

23

25

119

312

273

0.067

Williams FMK d

2011

Caucasian

LDD

2

7

9

72

256

246

0.671

Williams FMK e

2011

Caucasian

LDD

1

8

5

16

42

58

0.073

Tülüce Y

2017

Caucasian

OA

24

39

32

8

39

30

0.366

Abd Elazeem MI

2017

Caucasian

OA

14

16

20

13

25

12

0.998

Sabah-Ozcan S

2016

Caucasian

OA

14

43

37

52

153

74

0.083

Xiao JL

2015

Asian

OA

5

47

62

19

54

53

0.396

Mishra

2013

Asian

OA

46

130

124

56

160

84

0.188

Tawonsawatruk T

2011

Asian

OA

11

41

38

23

47

33

0.424

Cao Z

2010

Asian

OA

11

115

150

26

113

159

0.397

Valdes AM

2009

Caucasian

OA

35

98

126

84

244

181

0.908

Tsezou A

2007

Caucasian

OA

30

126

95

44

125

99

0.669

Miyamoto Y a

2007

Asian

OA

31

243

444

58

330

473

0.966

Miyamoto Y b

2007

Asian

OA

19

97

197

48

193

244

0.283

Miyamoto Y c

2007

Asian

OA

31

266

701

70

371

542

0.552

Southam L a

2007

Caucasian

OA

52

238

219

126

372

324

0.262

Southam L b

2007

Caucasian

OA

36

136

102

194

563

439

0.549

Shin MH

2012

Asian

OA

38

305

382

106

689

942

0.176

a,b,c,d and e denote an independent study in one article, respectively, HWE Hardy-Weinberg equilibrium, LDD lumbar disc degeneration, LDH lumbar disc herniation, LBP low-back pain, OA osteoarthritis

Association between GDF5 rs143383 and musculoskeletal degenerative diseases

A total of 5915 patients and 12,252 controls were included in our study on GDF5 rs143383 polymorphism. There was a significant relationship between GDF5 rs143383 polymorphism and increased risk of musculoskeletal degenerative diseases under each genetic model (allele model: OR = 1.32, 95% CI 1.19–1.48, P = 0.000; homozygote model: OR = 1.80, 95%CI 1.49–2.16, P = 0.000; heterozygote model: OR = 1.37, 95%CI 1.21–1.55, P = 0.000; dominant model: OR = 1.56, 95%CI 1.39–1.75, P = 0.000; recessive model: OR = 1.39, 95%CI 1.20–1.60, P = 0.000) (Fig. 2 and Table 3). The heterogeneity of studies on this polymorphism was< 50%, under homozygote, heterozygote and dominant models.
Fig. 2
Fig. 2

(a) Meta-analysis for GDF5 rs143383 polymorphism under allele model; (b) Meta-analysis for GDF5 rs143383 polymorphism under homozygote model; (c) Meta-analysis for GDF5 rs143383 polymorphism under dominant model; (d) Meta-analysis for GDF5 rs143383 polymorphism under recessive model

Table 3

Meta-analysis of the association between GDF5 rs143383 and musculoskeletal degenerative diseases

GDF5 rs143383

Subgroup

Assessment of association

Assessment of heterogeneity

OR

95% CI

P

Pooling model

I2 (%)

P

Allelic model

Overall

1.32

1.19–1.48

0.000

Random

72.8

0.000

Disease

IDD

1.45

1.13–1.86

0.004

Random

67.6

0.005

OA

1.28

1.14–1.44

0.000

Random

73.4

0.000

Ethnicity

Asian

1.49

1.25–1.77

0.000

Random

83.2

0.000

Caucasian

1.18

1.09–1.28

0.000

Fixed

17.1

0.276

Homozygote model

Overall

1.80

1.49–2.16

0.000

Fixed

47.5

0.007

Disease

IDD

2.33

1.55–3.51

0.000

Fixed

29.5

0.203

OA

1.67

1.36–2.05

0.000

Random

50.1

0.014

Ethnicity

Asian

2.28

1.71–3.05

0.000

Random

58.9

0.009

Caucasian

1.46

1.23–1.74

0.000

Fixed

0.0

0.460

Heterozygote model

Overall

1.37

1.21–1.55

0.000

Fixed

26.7

0.122

Disease

IDD

1.84

1.34–2.52

0.000

Fixed

0.0

0.926

OA

1.29

1.13–1.48

0.000

Fixed

38.4

0.065

Ethnicity

Asian

1.49

1.25–1.78

0.000

Fixed

15.5

0.300

Caucasian

1.27

1.07–1.51

0.006

Fixed

33.8

0.120

Dominant model

Overall

1.56

1.39–1.75

0.000

Fixed

40.5

0.026

Disease

IDD

2.11

1.57–2.86

0.000

Fixed

0.0

0.569

OA

1.46

1.29–1.66

0.000

Fixed

46.2

0.026

Ethnicity

Asian

1.82

1.54–2.16

0.000

Fixed

47.8

0.045

Caucasian

1.35

1.15–1.58

0.000

Fixed

14.9

0.299

Recessive model

Overall

1.39

1.20–1.60

0.000

Random

73.3

0.000

Disease

IDD

1.44

1.02–2.04

0.037

Random

71.4

0.002

OA

1.35

1.16–1.59

0.000

Random

74.0

0.000

Ethnicity

Asian

1.55

1.25–1.92

0.000

Random

83.2

0.000

Caucasian

1.21

1.03–1.42

0.019

Fixed

36.2

0.101

IDD intervertebral disc degeneration, OA osteoarthritis, OR odds ratio, CI confidence interval

Subgroup analysis

Because of heterogeneity, we conducted stratified analyses based on different disease types and ethnicity. Stratified analyses based on disease type revealed a significant relationship between the GDF5 rs143383 polymorphism and increased risk of IDD under all genetic models studied (allele model: OR = 1.45, 95% CI 1.13–1.86, P = 0.004; homozygote model: OR = 2.33, 95%CI 1.55–3.51, P = 0.000; heterozygote model: OR = 1.84, 95%CI 1.34–2.52, P = 0.000; dominant model: OR = 2.11, 95%CI 1.57–2.86, P = 0.000; recessive model: OR = 1.44, 95%CI 1.02–2.04, P = 0.037). Additionally, rs143383 polymorphism was related with increased OA risk in all genetic models (allele model: OR = 1.28, 95% CI 1.28 1.14–1.44, P = 0.000; homozygote model: OR = 1.67, 95%CI 1.36–2.05, P = 0.000; heterozygote model: OR = 1.29, 95%CI 1.13–1.48, P = 0.000; dominant model: OR = 1.46, 95%CI 1.29–1.66, P = 0.000; recessive model: OR = 1.35, 95%CI 1.16–1.59, P = 0.000) (Table 3).

When stratified with ethnicity, the outcomes revealed that this polymorphism was statistically related with increased risk of musculoskeletal degenerative diseases in Asian populations under all genetic models studied (allele model: OR = 1.49, 95% CI 1.25–1.77, P = 0.000; homozygote model: OR = 2.28, 95%CI 1.71–3.05, P = 0.000; heterozygote model: OR = 1.49, 95%CI 1.25–1.78, P = 0.000; dominant model: OR = 1.82, 95%CI 1.54–2.16, P = 0.000; recessive model: OR = 1.55, 95%CI 1.25–1.92, P = 0.000). In the Caucasian subgroup, a significant relationship between rs143383 polymorphism and increased risk of musculoskeletal degenerative diseases under all genetic models was also observed in our study (allele model: OR = 1.18, 95% CI 1.09–1.28, P = 0.000; homozygote model: OR = 1.46, 95%CI 1.23–1.74, P = 0.000; heterozygote model: OR = 1.27, 95%CI 1.07–1.51, P = 0.006; dominant model: OR = 1.35 95%CI 1.15–1.58, P = 0.000; recessive model: OR = 1.21, 95%CI 1.03–1.42, P = 0.019) (Table 3).

Publication bias and sensitivity analysis

No obvious publication bias was shown in the funnel plot. In addition, there was no obvious publication bias according to Begg’s test (P = 0.338) and Egger’s test (P = 0.246). Therefore, we could exclude the possibility of publication bias. The sensitivity analysis revealed that the main outcomes of our study did not alter greatly when deleting studies one by one (Additional file 2).

Discussion

Musculoskeletal degenerative diseases including IDD and OA are multifactorial diseases that bring about physical and functional limitations in patients. Various genetic risk factors may be responsible for the leading causes of IDD or OA [26, 27]. Previous studies have revealed that GDF5 polymorphism to be related with IDD, but with inconsistent results. Therefore, our study was made to assess the association between GDF5 rs143383 polymorphism and the susceptibility of IDD and OA. 15 articles with 915 patients and 12,252 controls were in our study. Eligible articles contained three studies in seven independent populations about IDD risk, and twelve studies assessed outcomes of GDF5 rs143383 on the risk of OA in fifteen independent populations.

GDF5 (+ 104 T/C; rs143383) is supposed to bring out a reduced transcription activity [28]. Our study revealed that GDF5 rs143383 polymorphism was significantly related with susceptibility to musculoskeletal degenerative diseases under all genetic models studied. Stratified analyses based on disease type showed a significant relationship between GDF5 rs143383 T allele and increased risk of IDD and OA. When stratified with ethnicity, the outcomes revealed that GDF5 rs143383 was statistically related with susceptibility to musculoskeletal degenerative diseases in both Asians and Caucasians.

Relatively obvious heterogeneities existed under all five genetic models in our study. With the aim of detecting the source of heterogeneity, we conducted sensitivity analysis and found that none articles altered the pooled OR significantly. Furthermore, we predicted that disease type and ethnicity may account for the heterogeneity and stratified analyses were then conducted. Neither the Egger test nor the Begg’s funnel plot revealed obvious publication bias for the IDD or OA risk related with GDF5 polymorphism. Even though the outcomes are reliable, additional studies are warranted to further confirm the findings.

Taken all these data in consideration, our study has several strengths. First, we utilized a comprehensive search method with well-defined inclusion and exclusion criteria. Second, two investigators accessed the eligibility of articles and selected related data separately. Third, we assessed the quality of included studies by well-defined criteria and the scores here were high. Finally, stratified analyses based on disease type and ethnicity were conducted to get a generalized conclusion.

Whereas, several limitations still existed in our study. First, the sample sizes in our study are relatively limited, which might bring about the insufficiency of statistical power. Second, the majority of articles included merely assessed the relationship between the gene polymorphism with IDD or OA risk, and more precise OR adjusted for other covariates such as age, sex, and environmental factors were not accessible. Finally, we concluded merely one representative SNP and articles including other GDF5 polymorphisms are needed.

Conclusion

Our study demonstrated that GDF5 rs143383 polymorphism was significantly related with susceptibility to musculoskeletal degenerative. More studies are warranted to investigate the value of GDF5 polymorphisms and variations in other genes for years to come.

Declarations

Acknowledgements

This study was supported by the National Key Research and Development Program of China (2016YFC1100100) and the Major Research Plan of National Natural Science Foundation of China (No. 91649204).

Funding

This study was funded by the National Key Research and Development Program of China (2016YFC1100100) and the Major Research Plan of National Natural Science Foundation of China (No. 91649204).

Availability of data and materials

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Authors’ contributions

XH: study design, data extraction and analysis, manuscript writing; ZWS: study design, and final approval of the manuscript; WYZ: data extraction, manuscript writing and critical appraisal. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Authors’ Affiliations

(1)
Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
(2)
Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

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