Associations of collagen type 1 α1 gene polymorphisms and musculoskeletal soft tissue injuries: a meta-analysis with trial sequential analysis

Results

Literature identification

A total of 358 items were initially identified. After removing duplicates and reviewing titles and abstracts, 229 irrelevant articles were excluded, leaving 31 articles for full-text review. Ultimately, 16 articles [10–19, 22–27] were deemed eligible for final data analysis (Figure 1).

Figure 1. Flow chart of literature identification.

Main characteristics

Table 1 displays the basic characteristics of the included studies. These 16 articles [10–19, 22–27] published from 2008 to 2023 consisted of one cross-sectional study [15], three cohort studies [10, 12, 17], and remaining case-control studies [11, 13, 14, 16, 18, 19, 22–27]. Geographically, five studies [11, 14, 15, 17, 18] were conducted in Asian populations, two [19, 26] in mixed populations, and the rest in European populations. The injury types studied included anterior cruciate ligament injury (ACLI), shoulder dislocation, musculoskeletal injury, tennis elbow, Achilles tendinopathy (TEN), Achilles tendon rupture, tendinopathy, and patellar tendinopathy. Notably, two studies [15, 16] on the rs1800012 polymorphism and one [18] on the rs1107946 polymorphism deviated from HWE. All studies scored ≥6 points in quality assessment, indicating high quality (Table 2).

Table 1. Main characteristics of included studies.

Study ID	Year	Country	Ethnicity	Gender	Study design	Genotyping methods	Diagnosis	Case			Control			HWE
								TT	TG	GG	TT	TG	GG
Rs1800012
Erduran M	2014	Turkey	Caucasian	Both	Case-control	PCR-RFLP	TE	2	32	69	7	35	61	0.53
Ficek K	2013	Poland	Caucasian	Male	Case-control	PCR	ACLI	0	26	65	6	41	96	0.55
Gibbon A	2020	South Africa, UK	Caucasian	Both	Case-control	PCR	TEN, RUP, ACLI	7	119	299	15	125	326	0.49
Haug KBF	2018	Norway	Caucasian	Both	Cohort	TaqMan assay	PTEN	0	14	19	6	23	64	0.07
Khoschnau S	2008	Sweden	Caucasian	Both	Case-control	PCR	CLR, SD	2	99	257	12	83	230	0.20
Le´znicka K	2021	Poland	Caucasian	Both	Case-control	TaqMan assay	MI	8	13	32	9	9	43	< 0.01
Massidda M	2023	Italy	Caucasian	Both	Case-control	PCR-RFLP	ACLI	6	41	38	4	33	44	0.48
Prabhakar S	2019	India	Asian	Both	Case-control	PCR	ACLI	39	7	1	43	7	0	0.60
Shukla M	2020	India	Asian	Both	Case-control	PCR	ACLI	0	14	76	0	12	64	0.46
Sivertsen EA	2019	Norway, Finland	Caucasian	Female	Cohort	TaqMan assay	ACLI	2	38	79	15	205	512	0.29
Stępień-Słodkowska M	2017	Poland	Caucasian	Male	Case-control	TaqMan assay	ACLI	2	46	90	5	39	139	0.28
Zhao D	2020	China	Asian	Both	Cross-sectional	PCR-RFLP	ACLI	1	2	98	1	2	107	< 0.01
Rs1107946
Ficek K	2013	Poland	Caucasian	Male	Case-control	PCR	ACLI	1	30	60	3	33	107	0.81
Gibbon A	2020	South Africa, UK	Caucasian	Both	Case-control	PCR	TEN, RUP, ACLI	5	97	313	12	112	349	0.41
Lopes LR	2023	Brazil	Mixed	Both	Case-control	TaqMan assay	TEND	7	18	29	14	61	110	0.18
Mirghaderi SP	2022	Iran	Asian	Male	Case-control	TaqMan assay	ACLI	33	43	124	29	57	114	< 0.01
Miyamoto-Mikami E	2021	Japan	Asian	Both	Cohort	TaqMan assay	MI	37	87	67	223	652	498	0.70
Perini JA	2022	Brazil	Mixed	Both	Case-control	TaqMan assay	ACLI	10	43	92	15	65	110	0.23
Prabhakar S	2019	India	Asian	Both	Case-control	PCR	ACLI	23	17	7	23	19	8	0.25
Sivertsen EA	2019	Norway, Finland	Caucasian	Female	Cohort	TaqMan assay	ACLI	3	34	82	15	168	549	0.62
Stępień-Słodkowska M	2017	Poland	Caucasian	Male	Case-control	TaqMan assay	ACLI	1	48	89	4	46	133	0.99
Abbreviations: PCR: Polymerase chain reaction; PCR-RFLP: Polymerase chain reaction–restriction fragment length polymorphism; CLR: cruciate ligament rupture; SD: shoulder dislocation; ACLI: anterior cruciate ligament injury; MI: musculoskeletal injury; TE: tennis elbow; TEN: Achilles tendinopathy; TEND: tendinopathy; RUP: Achilles tendon rupture; PTEN: patellar tendinopathy; HWE: Hardy-Weinberg Equilibrium.

Table 2. Quality assessment of included studies.

Study ID	Selection				Control for important factor	Exposure
	Adequate definition of cases	Representativeness of cases	Selection of control subjects	Definition of control subjects		Exposure assessment	Same method of ascertainment for all subjects	Non-response rate	Total
Erduran M, 2014	★	★	☆	★	★★	★	★	★	8
Ficek K, 2013	★	☆	☆	★	★★	★	★	★	7
Gibbon A, 2020	★	☆	☆	★	★☆	★	★	★	6
Haug KBF, 2018	★	☆	☆	★	★☆	★	★	★	6
Khoschnau S, 2008	★	☆	★	★	★☆	★	★	★	7
Le´znicka K, 2021	★	☆	☆	★	★☆	★	★	★	6
Lopes LR, 2023	★	☆	☆	★	★★	★	★	★	7
Massidda M, 2023	★	☆	☆	★	★☆	★	★	★	6
Mirghaderi SP, 2022	★	☆	☆	★	★★	★	★	★	7
Miyamoto-Mikami E, 2021	★	☆	☆	★	★☆	★	★	★	6
Perini JA, 2022	★	☆	☆	★	★★	★	★	★	7
Prabhakar S, 2019	★	☆	☆	★	★☆	★	★	★	6
Shukla M, 2020	★	☆	☆	★	★☆	★	★	★	6
Sivertsen EA, 2019	★	☆	★	★	★☆	★	★	★	7
Stępień-Słodkowska M, 2017	★	☆	☆	★	★☆	★	★	★	6
Zhao D, 2020	★	☆	☆	★	★☆	★	★	★	7

Meta-analyses and subgroup analyses

Association of the rs1800012 polymorphism and MSTIs

Twelve studies [10–16, 22–25, 27] analyzed the correlation between the rs1800012 polymorphism and MSTIs, involving 1643 cases and 2423 controls. Low heterogeneity was observed, and the fixed-effects model was applied. The combined data showed that TT genotype carriers had a significantly decreased risk of MSTIs (TT vs. GG, OR = 0.53, 95% CI 0.35–0.82, P = 0.004; TT vs. TG + GG, OR = 0.54, 95% CI 0.36–0.80, P = 0.002; Figure 2).

Figure 2. Forest plot of rs1800012 polymorphism and musculoskeletal soft tissue injuries (TT vs. TG+GG).

Stratified analyses by injury type revealed that TG-genotype carriers tended to have an increased risk of ACLI (TG vs. GG, OR = 1.25, 95% CI 1.02–1.55, P = 0.03). Ethnicity-based analysis indicated that TT genotype individuals had a reduced risk of MSTIs among Caucasians (TT vs. GG, OR = 0.53, 95% CI 0.34–0.83, P = 0.005; TT vs. TG + GG, OR = 0.50, 95% CI 0.32–0.78, P = 0.002; Table 3) but not among Asians.

Table 3. Association of COL1A1 gene polymorphisms and musculoskeletal soft tissue injuries.

Polymorphism/ genetic models	Association			No. of cohorts	Heterogeneity		Statistical model
	OR	95% CI	P		I2 (%)	P
Rs1800012
Overall
T vs. G	0.98	0.86–1.12	0.79	12	2	0.43	F
TT vs. GG	0.53	0.35–0.82	0.004	12	9	0.36	F
TG vs. GG	1.16	0.99–1.35	0.07	12	0	0.54	F
TT+TG vs. GG	1.05	0.90–1.22	0.53	12	0	0.56	F
TT vs. TG+GG	0.54	0.36–0.80	0.002	12	0	0.45	F
ACLI
T vs. G	1.09	0.91–1.30	0.34	8	0	0.61	F
TT vs. GG	0.66	0.34–1.26	0.20	8	0	0.63	F
TG vs. GG	1.25	1.02–1.55	0.03	8	0	0.72	F
TT+TG vs. GG	1.19	0.97–1.46	0.10	8	0	0.65	F
TT vs. TG+GG	0.88	0.73–1.06	0.18	8	0	0.64	F
Caucasian
T vs. G	0.99	0.87–1.13	0.84	9	26	0.21	F
TT vs. GG	0.53	0.34–0.83	0.005	9	25	0.22	F
TG vs. GG	1.17	1.00–1.36	0.05	9	13	0.33	F
TT+TG vs. GG	1.05	0.91–1.23	0.50	9	12	0.33	F
TT vs. TG+GG	0.50	0.32–0.78	0.002	9	15	0.31	F
Asian
T vs. G	0.90	0.51–1.61	0.73	3	0	0.85	F
TT vs. GG	0.60	0.08–4.58	0.63	3	0	0.55	F
TG vs. GG	0.94	0.44–1.98	0.86	3	0	0.82	F
TT+TG vs. GG	0.93	0.45–1.92	0.85	3	0	0.78	F
TT vs. TG+GG	0.83	0.30–2.31	0.72	3	0	0.84	F
Rs1107946
Overall
T vs. G	1.05	0.94–1.18	0.40	9	0	0.45	F
TT vs. GG	1.05	0.80–1.37	0.73	9	0	0.67	F
TG vs. GG	1.05	0.90–1.22	0.57	9	26	0.22	F
TT+TG vs. GG	1.05	0.91–1.21	0.51	9	13	0.33	F
TT vs. TG+GG	1.09	0.85–1.40	0.50	9	0	0.65	F
ACLI
T vs. G	1.04	0.89–1.21	0.61	7	0	0.45	F
TT vs. GG	0.92	0.63–1.37	0.69	7	0	0.88	F
TG vs. GG	1.07	0.89–1.30	0.47	7	42	0.11	F
TT+TG vs. GG	1.06	0.88–1.27	0.53	7	28	0.21	F
TT vs. TG+GG	0.99	0.69–1.42	0.96	7	0	0.83	F
Caucasian
T vs. G	1.09	0.91–1.31	0.36	4	31	0.22	F
TT vs. GG	0.63	0.30–1.30	0.21	4	0	0.59	F
TG vs. GG	1.22	0.99–1.50	0.07	4	30	0.23	F
TT+TG vs. GG	1.17	0.95–1.43	0.14	4	35	0.20	F
TT vs. TG+GG	0.60	0.29–1.24	0.17	4	0	0.62	F
Asian
T vs. G	1.04	0.88–1.23	0.65	3	0	0.69	F
TT vs. GG	1.16	0.83–1.61	0.38	3	0	0.90	F
TG vs. GG	0.88	0.68–1.15	0.37	3	0	0.47	F
TT+TG vs. GG	0.96	0.75–1.22	0.74	3	0	0.59	F
TT vs. TG+GG	1.20	0.89–1.61	0.22	3	0	0.97	F
Abbreviations: OR: odds ratios; CI: confidence interval; F: fixed-effects model; R: random-effects model; ACLI: anterior cruciate ligament injury.

Association of the rs1107946 polymorphism and MSTIs

Nine studies [11–13, 17–19, 23, 25, 26] examined the association of the rs1107946 polymorphism with MSTIs, involving 1400 cases and 3529 controls. As minimal between-study heterogeneity was detected, the fixed-effects model was used. The pooled data did not show any significant association between the rs1107946 polymorphism and MSTIs (TT vs. TG + GG, OR = 1.09, 95% CI 0.85–1.40, P = 0.50; Figure 3). Subgroup analyses by injury type and ethnicity also revealed no significant association (Table 3).

Figure 3. Forest plot of rs1107946 polymorphism and musculoskeletal soft tissue injuries (TT vs. TG+GG).

Sensitivity analysis and publication bias

Sequential removal of each study did not result in significant fluctuations in the re-pooled ORs and 95% CIs, indicating the stability and robustness of the results. Funnel plots displayed symmetrical patterns, suggesting no significant publication bias (Figure 4). Egger’s and Begg’s linear regression tests did not find significant publication bias (Supplementary Table 1).

Figure 4. Funnel plot of rs1800012 polymorphism and musculoskeletal soft tissue injuries (TT vs. TG+GG).

Trial sequential analysis

For the rs1800012 polymorphism, the cumulative Z-curves did not surpass the TSA monitoring boundaries or the RIS line under five genetic models, indicating insufficient evidence and the need for further studies (Figure 5). In contrast, for the rs1107946 polymorphism, the cumulative Z-curves exceeded the RIS line but did not surpass the TSA monitoring boundaries under the allele, heterozygote, and dominant models, suggesting sufficient evidence. However, the cumulative Z-curves did not cross the TSA monitoring boundaries or the RIS line under the homozygote and recessive models, indicating the need for additional studies to obtain definitive outcomes.

Figure 5. Trial sequential analysis of rs1800012 polymorphism and musculoskeletal soft tissue injuries (TT vs. TG+GG).

Discussion

Understanding the etiology of MSTIs is crucial for risk reduction and improved prognosis. However, the causative mechanisms of MSTIs are complex and not fully understood. Genetic factors play a significant role in MSTIs, as indicated by mounting evidence and the postulation of familial predisposition by researchers [28, 29]. Over 80 loci have been associated with MSTIs [30]. The association of COL1A1 polymorphisms with MSTIs has been extensively studied but with inconsistent findings. Therefore, this meta-analysis was conducted to synthesize existing evidence and clarify this association. Our findings support a protective role of the TT genotype of the rs1800012 polymorphism in MSTIs, particularly among Caucasians. However, the rs1107946 polymorphism showed no association with MSTIs across different ethnicities and injury types.

Tendons and ligaments are vital components of the musculoskeletal system, with COL1 playing a crucial role. COL1, also known as fibril-forming collagen, is abundant and widely used in tissue engineering due to its structural properties. Although COL1 fibers have high tensile strength and are resistant to most proteases, abnormal accumulation can lead to fibrotic diseases. COL1 is encoded by the COL1A1 and COL1A2 genes, which are respectively translated into α1 and α2 polypeptide chains in a coordinated pattern. Two α1 chains interplay with one α2 to form a triple-helical structure. The genetic aspects of the synthesis, function, and degradation of COL1 fibers and its association with diseases are under active studies [31]. In human genome, the COL1A1 gene is mapped to chromosome 17q21.33, which is 18 kb in length and consists of 52 exons.

COL1A1 gene variants are associated with various musculoskeletal disorders, including intervertebral disc degeneration [32], osteoporosis [33], osteoarthritis [34], and osteogenesis imperfecta [35]. The rs1800012 polymorphism is a guanine (G) to thymine (T) transversion within an Sp1 binding element in intron 1 (position +1245) of the COL1A1 gene [36]. Mann et al. [37] found that the T allele of rs1800012 is associated with stronger transcriptional activity and higher α1 to α2 chain ratio, which was reflected by the increased mRNA ratio of COL1A1 to COL1A2. Ireland et al. [38] observed elevated levels of COL1 and COL3 mRNAs in samples from individuals with TEN.

Rs1107946 is a frequently studied variant located in the proximal promoter of the COL1A1 gene, specifically at position-1997 in intron 1. In contrast to the rs1800012 polymorphism, the G allele of rs1107946 exhibits higher transcriptional activity than the T allele. Individuals with the TT genotype for the rs1107946 polymorphism have a significantly lower proportion of α1 chain homotrimers, potentially leading to increased resistance against injury [17]. Furthermore, rs1107946 is strongly linked with the rs1800012 polymorphism [39]. Ficek et al. [23] reported that while the rs1800012 and rs1107946 polymorphisms were not directly associated with ACLI, the COL1A1 G-T haplotype demonstrated a protective effect against ACLI among professional soccer players [23]. Additionally, Jin et al. [40] observed that COLIA1 variants regulate transcription through DNA-protein interactions. They suggested that the G-del-T haplotype (rs1107946-rs2412298-rs1800012) leads to higher transcriptional activity of COL1A1, resulting in increased production of the α1 chain, disruption of the α1 and α2 chain ratio, and generation of mature COL1 with an altered structure. Perini et al. [19] found that a separate polymorphism in the COL1A1 and COL1A2 genes was not directly associated with ACLI, but the cumulative effects of COL1A1 and COL1A2 variants might contribute to the risk of ACLI among athletes.

Wang et al. [41] conducted a meta-analysis involving 933 cases and 1381 controls to investigate the relationship between rs1800012 and tendon-ligament injuries. Compared with Wang et al.’s study, the present study has several advantages. First, new evidence was incorporated into this study, leading to an increase in the sample size and enhancement of statistical power. Moreover, while Wang et al.’s study focused solely on Caucasian participants, our study included subjects from Asian and Brazilian populations. Ethnicity stratification was performed to assess potential differences among variant ethnicities. Furthermore, the rs1107946 polymorphism, a crucial locus within the COL1A1 gene, was examined in this meta-analysis. Additionally, TSA was conducted to evaluate the adequacy of the current data to achieve positive outcomes.

Several limitations should be acknowledged in this study. First, most of the included studies had small sample sizes, which may have limited statistical power, as also indicated by TSA results. Second, the majority of research focused on Caucasians and Asians, necessitating the replication of findings in other ancestral groups to ensure generalizability. Third, all studies were observational, indicating a lower level of evidence. Fourth, due to limited data availability, adjustments for confounding factors such as gender, age, body mass index, occupation, and exercise intensity were not feasible. Fifth, the participant group in this study was heterogeneous, encompassing various injuries and occupations. Lastly, the meta-analysis only analyzed two loci within the COL1A1 gene, whereas MSTIs are complex and likely influenced by multiple genes interacting synergistically. The interaction network of COL1A1 and its related genes, including ADAMTS2, COL1A2, COL5A2, and RUNX2, is illustrated in Figure 6, suggesting a potential role of COL1A1 in the pathogenesis of MSTIs.

Figure 6. Network of COL1A1 with its potentially functional partners.

In conclusion, this study supports the protective effect of the TT genotype of the rs1800012 polymorphism against MSTIs, particularly among Caucasians. However, the rs1107946 polymorphism does not show an association with MSTIs. Given the limitations outlined, larger-scale prospective studies across diverse ethnic backgrounds are warranted to validate these findings and provide a more comprehensive understanding of genetic influences on MSTIs.

Abbreviations

NOS: Newcastle-Ottawa Scale; OR: Odds ratio; 95% CI: 95% confidence interval; COL1A1: collagen type I α1; MSTIs: musculoskeletal soft tissue injuries.

Author Contributions

ZW designed this study. RG, and SG performed the literature search and selection, data extraction, and data analysis. NS, AA, HW, XF drafted the manuscript. All authors reviewed and approved the final manuscript.

Conflicts of Interest

The authors declare no conflicts of interest related to this study.

Funding

This study was supported by the Graduate's Innovation Foundation of Xinjiang Medical University (XJ2022G159).

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