Analysis of candidate gene polymorphism associations with vibration syndrome

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Background

Vibration syndrome (VS) belongs to occupational diseases. Workers in construction, shipbuilding and aircraft manufacturing, mining, metallurgy, agriculture, and transportation industries are at the highest risk of developing VS. The main cause of VS is prolonged exposure to industrial vibration exceeding permissible levels. VS holds one of the leading positions in the structure of occupational pathology [1]. The disease is characterized by diverse clinical symptoms involving various homeostatic components, multiple organs and systems, with specific course features that often lead to disability. Typical manifestations include changes in the nervous and cardiovascular systems, musculoskeletal apparatus, and metabolic processes. These disorders may occur concomitantly or sequentially, affecting reflex, neurohumoral, and neuroendocrine mechanisms [2, 3].

Genetic predisposition plays a significant role in individual susceptibility to occupational factors, as well as in the development and progression of occupational diseases. Recent studies regularly publish new findings evaluating the contribution of genetic factors to the mechanisms underlying occupational diseases [4–6]. The SOD2 gene, which encodes superoxide dismutase 2 (SOD2), a manganese-containing enzyme belonging to the core antioxidant defense system, is of particular interest. Impaired enzymatic activity of SOD2 leads to increased oxidative stress [7]. Tumor necrosis factor-alpha (TNF-α), a proinflammatory cytokine, plays a crucial role in vascular endothelial activation and immune response regulation. Additionally, it affects type 1 collagen synthesis by fibroblasts, demonstrating antifibrotic properties. Cytokines of the interleukin-1 (IL-1) family participate in inflammatory processes and immune regulation, serving as key mediators of both innate and adaptive immunity. Studies have identified direct effects of IL-1 on bone tissue homeostasis, with regulatory disruptions potentially linked to various bone pathologies [8]. The matrix metalloproteinase-1 (MMP-1) gene, expressed in various cells including chondrocytes, fibroblasts, and epithelial and endothelial cells, also warrants attention. MMP-1 expression levels significantly increase under pathological conditions, leading to abnormal connective tissue degradation. Interleukin-6 (IL-6), a pleiotropic inflammatory cytokine, plays a substantial role in immune response modulation.

Modern methods for identifying markers of high occupational disease risk provide new opportunities for developing timely preventive measures. However, despite significant progress, molecular genetic aspects of many occupational diseases remain poorly studied.

AIM. The study aimed to investigate the associations between polymorphisms in the SOD2, TNF-α, IL-1β, MMP-1, and IL-6 genes and vibration syndrome.

Methods

A cross-sectional case-control study was conducted. The study included patients with VS caused by exposure to whole-body vibration, local vibration, and combined vibration. The patient sample consisted of 71 individuals (22.5% women and 77.5% men) aged 23 to 79 years (mean age 59.9±1.6 years). Patients diagnosed with vibration syndrome were consecutively recruited from those undergoing examination and treatment at the Neurology and Occupational Pathology Department of the clinic of the Ufa Research Institute of Occupational Medicine and Human Ecology between 2022 and 2023. The inclusion criteria for the group were confirmed VS diagnosis, at least three years of work experience at the enterprise, and residence in the Republic of Bashkortostan. All participants were exposed to occupational vibration. The majority in this group were employees of a mining and processing plant.

The control group comprised 76 individuals (17.1% women and 82.9% men) aged 23 to 79 years (mean age 53.0±1.0 years). The inclusion criteria for the control group were excluded VS diagnosis, absence of chronic rheumatoid, cardiovascular, or musculoskeletal diseases, no exposure to vibration, and residence in the Republic of Bashkortostan.

The study protocol was approved by the Biomedical Ethics Committee of the Ufa Research Institute of Occupational Medicine and Human Ecology (Protocol No. 01-01 dated January 22, 2024). All patients provided written informed consent to participate in the study.

DNA extraction was performed using the MAGNO-sorb reagent kit (Central Research Institute of Epidemiology of the Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing). The study included the following polymorphic variants: rs4880 of the SOD2 gene, rs361525 of the TNF-α gene, rs16944 of the IL-1β gene, rs1799750 of the MMP-1 gene, and rs1800795 of the IL-6 gene. Polymorphisms were detected using real-time polymerase chain reaction with locus-specific fluorescently labeled oligonucleotide DNA probes and specific oligonucleotide primers synthesized by DNA-Sintez (Moscow, Russia). The Rotor-Gene Q cycler manufactured by Qiagen (Germany) was used for the analysis.

The statistical analysis was conducted using Microsoft Excel and IBM SPSS Statistics v.21 software packages. The chi-square (χ²) test was used to assess the compliance of genotype frequency distributions with Hardy–Weinberg equilibrium. The comparative analysis of allele and genotype frequencies in the samples was performed using the χ² test, Yates correction χ² test, or Fisher exact test. The odds ratio (OR) with 95% confidence intervals (95% CI) were calculated to evaluate the influence of polymorphisms on disease risk. OR > 1 was interpreted as a positive correlation between the disease and the studied genotype or allele (risk factor). Conversely, OR < 1 indicated a negative correlation (protective factor). The statistical significance of differences was set at p < 0.05.

Results

No deviations from Hardy–Weinberg equilibrium were observed for the studied polymorphisms in the control group. In patients with VS, Hardy–Weinberg equilibrium was not maintained for the polymorphic variants rs361525 of the TNF-α gene, rs16944 of the IL-1β gene, and rs1800795 of the IL-6 gene.

The results of the genotype and allele frequency distribution analysis for the studied polymorphic variants are presented in Table 1. When analyzing the genotype frequencies of the rs4880 polymorphic variant of the SOD2 gene, no statistically significant differences were found between the patients with VS and the control group (p > 0.05). However, a trend toward increased frequency of the homozygous T/T genotype was observed compared with the controls. In the patients with VS, the TT genotype was identified in 43.3% of cases, whereas it occurred in 29.7% of the control group (χ² = 2.80, p = 0.135). The analysis of allele frequency distribution for the rs4880 polymorphic variant of the SOD2 gene revealed a statistically significant increase in the frequency of the T allele in the patients with VS (65.7% vs 52.7% in the controls; χ² = 4.88, p = 0.027). The calculated OR indicated that the T allele was associated with a 1.72-fold increased risk of VS (OR = 1.72; 95% CI: 1.06–2.78). Conversely, the C allele showed a significant decrease in frequency in the VS group: 34.3% compared with 47.3% in the controls (χ² = 4.88, p = 0.027). OR = 0.58 suggests a protective role of this allele against VS (OR = 0.58; 95% CI: 0.36–0.94). The analysis of the TNF-α gene rs361525 polymorphic variant revealed no statistically significant differences in the genotype frequency distribution between the patients with VS and the controls. The dominant G/G genotype was observed in 85.9% of patients and 84.0% of the controls (F = 0.82; p = 0.928). The A/A genotype was detected in 2.8% of the patients with VS, but was absent in the controls (F = 0.24; p = 0.470). Similarly, no significant differences in allele frequencies were found between the groups (F = 1.00; p = 0.333). The IL-1β gene rs16944 polymorphic variant showed no significant differences in genotype frequencies between the patients with VS and controls, though a slight increase in A/A homozygotous variant was observed in the patients (χ² = 1.75; p = 0.185). No statistically significant differences in allele frequencies were detected between the patients with VS and controls (χ² = 0.60; p = 0.437). The analysis of the MMP-1 gene rs1799750 polymorphic variant revealed no significant differences in genotype or allele frequencies between the groups (p > 0.05). The 1G/1G, 1G/2G, and 2G/2G genotype frequencies in the patients with VS were 37.0%, 38.9%, and 24.1% respectively, compared with 35.5%, 44.7%, and 19.8% in the controls. The 1G allele frequency was 56.5% vs 43.5%, and 2G allele 57.9% vs 42.1% in the patients with VS and the controls, respectively. The IL-6 gene rs1800795 polymorphic variant also showed no significant differences in the genotype or allele distribution between the groups (p > 0.05). Despite no statistical significance, a non-significant increase in C/C homozygotes was observed in the patients with VS (20.3% vs 12.2% in the controls; χ² = 1.09; p = 0.297), with both groups showing G allele predominance (63.6% vs 68.2%; χ² = 0.64; p = 0.422).

 

Table 1. Comparison of the frequencies of polymorphic variant alleles and genotypes in the examined groups

Polymorphisms	Genotypes and alleles	Group with vibration disease		Control group		χ2 or Fisher F-test	p
		n	%	n	%
rs4880 (SOD2 gene)	T/T	29	43.3	22	29.7	2.80*	0.094
	T/C	30	44.8	34	46.0	0.02*	0.889
	C/C	8	11.9	18	24.3	2.81**	0.094
	T	88	65.7	78	52.7	4.88*	0.027
	C	46	34.3	70	47.3
rs361525 (TNF-α gene)	G/G	61	85.9	63	84.0	0.82***	0.928
	G/A	8	11.3	12	16.0	0.48***	0.557
	A/A	2	2.8	0	0.0	0.24***	0.470
	G	130	91.6	138	92.0	1.00***	0.333
	A	12	8.4	12	8.0
rs16944 (IL-1β gene)	A/A	15	25.9	12	16.4	1.75*	0.185
	A/G	20	34.5	32	43.9	1.18*	0.277
	G/G	23	39.6	29	39.7	0.00*	0.993
	A	50	43.1	56	38.4	0.60*	0.437
	G	66	56.9	90	61.6
rs1799750 (MMP-1 gene)	1G/1G	20	37.0	27	35.5	0.03*	0.860
	1G/2G	21	38.9	34	44.7	0.44*	0.506
	2G/2G	13	24.1	15	19.8	0.35*	0.553
	1G	61	56.5	88	57.9	0.05*	0.820
	2G	47	43.5	64	42.1
rs1800795 (IL-6 gene)	C/C	12	20.3	9	12.2	1.09**	0.297
	C/G	19	32.2	29	39.2	0.69*	0.405
	G/G	28	47.5	36	48.6	0.02*	0.891
	C	43	36.4	47	31.8	0.64*	0.422
	G	75	63.6	101	68.2

χ² test; ** Yates correction χ² test; *** Fisher exact test.

 

Discussion

This study evaluated the association between polymorphisms in the SOD2, TNF-α, IL-1β, MMP-1, and IL-6 genes and the risk of VS. An association was found between the rs4880 polymorphic variant of the SOD2 gene and VS. However, no data were obtained indicating associations of the rs361525 (TNF-α), rs16944 (IL-1β), rs1799750 (MMP-1), and rs1800795 (IL-6) polymorphic variants with VS.

The rs4880 single nucleotide polymorphism of the SOD2 gene, characterized by an alanine-to-valine substitution at position 16, plays a significant role in various diseases. It is believed that the T allele induces structural changes in the mitochondrial domain of SOD2, which, in turn, leads to less efficient post-transcriptional transport into mitochondria and reduced superoxide anion neutralization capacity. Our study demonstrated an association between the T allele of the rs4880 SOD2 gene polymorphic variant and VS. This finding partially aligns with the published data indicating this allele’s association with increased risks of ischemic heart disease, stroke, and cardiomyopathy (T allele frequencies in patient cohorts with these diagnoses were 0.577, 0.481, and 0.670, respectively) [7, 9, 10]. A higher frequency of the TT homozygous genotype of the rs4880 SOD2 polymorphic variant was observed in the patients with VS and comorbid arterial hypertension [11]. T allele may reduce resistance to mitochondrial reactive oxygen species and promote oxidative protein damage due to inefficient mitochondrial transport [12].

The studies have shown that finger numbness and other symptoms in hand-arm vibration syndrome may be associated with elevated TNF-α levels [13, 14]. Increased TNF-α levels have been detected in the patients with VS [15, 16]. The TNF-α gene contains several polymorphic sites, including the extensively studied rs361525. Some studies have reported an association between the rs361525 polymorphic variant of the TNF-α gene and susceptibility to rheumatoid arthritis and psoriatic arthritis [17, 18]. The GG genotype and G allele were more frequent in the patients with rheumatoid arthritis compared with the controls (0.931 vs 0.839 and 0.965 vs 0.905, respectively). However, similar results were not observed in our study of the patients with VS.

Interleukin-1 beta (IL-1β) participates in various pathological disc degeneration processes, with its expression significantly increased in the cells and tissues of degenerative intervertebral discs [19]. Elevated IL-1β levels have also been identified in the patients with VS [15, 16]. Elevated proinflammatory cytokine levels in the patients with VS indicate activation of inflammatory processes, potentially initiated by altered immune reactivity during prolonged exposure to physical factors [20]. TNF-α and IL-1β are among the first responders to vibration exposure. Inflammatory mediators cross the blood-brain barrier into the bloodstream, inducing glucocorticoid production, which subsequently suppresses the immune system [21]. The IL-1β cytokine is encoded by the IL-1β gene, which is highly polymorphic. The polymorphic variant rs16944 of the IL-1β gene is known to influence susceptibility to intervertebral disc degeneration, with evidence also linking it to predisposition for rheumatoid arthritis [22, 23]. For this polymorphism, the frequency of the C/C genotype was 21.4% in the control group versus 34.7% in the patients with intervertebral disc degeneration; C/T genotype was 50.5% vs 44.4%; and T/T genotype was 28.1% vs 20.9%, respectively [23]. The comparative analysis of genotype frequencies in the patients with rheumatoid arthritis revealed statistically significant increases in T/T homozygotes (13.4%) and C/T heterozygotes (49.2%), along with a decrease in C/C homozygotes (40.4%) compared with the controls (6.6%, 34.6%, and 58.8%, respectively) [22]. However, we found no association between the rs16944 polymorphic variant of the IL-1β gene and VS.

The evaluation of systemic inflammation markers revealed a significant increase in MMP-1 levels in the group of comorbid VS and arterial hypertension model [24]. The key intronic variant of the MMP-1 gene is the rs1799750 polymorphism, which may lead to increased transcriptional activity and MMP-1 expression. The studies of the rs1799750 polymorphism have shown its association with various inflammatory diseases, including rheumatoid arthritis and knee osteoarthritis [25, 26]. The frequency distribution of 1G1G, 1G2G, and 2G2G genotypes in the patients with knee osteoarthritis was 24.7%, 50.0%, and 24.7%, respectively, compared with 34.4%, 49.8%, and 15.1% in the control group [26]. However, we found no association between this polymorphic variant and VS.

The patients with VS combined with arterial hypertension showed elevated levels of pro-inflammatory cytokines, including IL-6 [27]. The authors suggest that alterations in the cytokine profile intensify as VS progresses. Evidence indicates that IL-6 gene polymorphisms may influence blood IL-6 concentrations and functional characteristics. The rs1800795 polymorphic variant, located in the promoter region of this gene, is a factor determining individual susceptibility to inflammatory processes and oxidative stress levels. This polymorphic variant has been associated with susceptibility to intervertebral disc diseases, rheumatoid arthritis, and the onset or progression of knee osteoarthritis [28–31]. Higher frequencies of GC (46.5%), CC (9.1%) genotypes, and the C allele (32.3%) were observed in the patients with rheumatoid arthritis compared with the controls (23.2%, 1%, and 12.6%, respectively) [28]. The CC genotype frequency (15.0%) was also higher in the knee osteoarthritis group than in the controls (4.3%) [30]. Our study revealed no statistically significant association between the IL-6 gene rs1800795 polymorphic variant and VS. When analyzing the data, we compared our results with those from the studies by other authors focusing on VS and conditions significantly influencing VS manifestations.

Study limitations. The main limitations include the small sample size, which may have limited the ability to fully achieve the study aim.

Conclusion

The study revealed an association between the rs4880 polymorphic variant of the SOD2 gene and VS. It can be hypothesized that the T allele serves as a risk factor for VS, while the C allele exerts a protective effect against disease onset. No significant associations were found for polymorphisms in the TNF-α, IL-1β, MMP-1, or IL-6 genes and developing VS. These findings may serve as a basis for developing screening programs aimed at identifying individuals with an increased risk of VS.

Additional information

Authors’ contribution. G.F. Mukhammadiyeva — data collection, analysis and interpretation of results, literature review, preparation and writing of the article; E.R. Shaikhlislamova — study conception and design, literature review, editing the article; D.D. Karimov — data collection, analysis and interpretation of results; D.O. Karimov — study conception and design, literature review, editing the article; T.G. Yakuрova — data collection, analysis and interpretation of results; Ya.V. Valova — data collection, analysis and interpretation of results; A.A. Gizatullina — data collection, analysis and interpretation of results. All authors confirm that their authorship meets the international ICMJE criteria (all authors have made a significant contribution to the development of the concept, research and preparation of the article, read and approved the final version before publication).

Ethical expertise. The study protocol was approved by the Committee on Biomedical Ethics of the Ufa Research Institute of Occupational Medicine and Human Ecology (Protocol No. 01-01 dated 01/22/2024). All patients signed an informed consent to participate in the study.

Funding sources. The work was carried out within the framework of the industry research program of the Federal Service for Supervision of Consumer Rights Protection and Human Welfare for 2021–2025. “Scientific justification for the national system for ensuring sanitary and epidemiological well-being, managing health risks and improving the quality of life of the Russian population” clause 2.2.9.

Disclosure of interests. The authors have no relationships, activities or interests for the last three years related with for-profit or not-for-profit third parties whose interests may be affected by the content of the article.

Statement of originality. In creating this work, the authors did not use previously published information (text, illustrations, data).

Data availability statement. The editorial policy regarding data sharing does not apply to this work, and no new data was collected or created.

Generative AI. Generative AI technologies were not used for this article creation.

Provenance and peer-review. This paper was submitted to the journal on an unsolicited basis and reviewed according to the usual procedure. Two external reviewers, a member of the editorial board, and the scientific editor of the publication participated in the review.

About the authors

Guzel F. Mukhammadiyeva

Ufa Research Institute of Occupational Health and Human Ecology

Author for correspondence.
Email: ufniimt@mail.ru
ORCID iD: 0000-0002-7456-4787
SPIN-code: 7695-2514

Cand. Sci. (Biology)

Russian Federation, 94 Stepan Kuvykin st, Ufa, 450106

Elmira R. Shaikhlislamova

Ufa Research Institute of Occupational Health and Human Ecology; Bashkir State Medical University Ufa

Email: fbun@uniimtech.ru
ORCID iD: 0000-0002-6127-7703
SPIN-code: 1041-3862

MD, Cand. Sci. (Medicine)

Russian Federation, Ufa; Ufa

Denis D. Karimov

Ufa Research Institute of Occupational Health and Human Ecology

Email: lich-tsar@mail.ru
ORCID iD: 0000-0002-1962-2323
SPIN-code: 8205-7220

Cand. Sci. (Biology)

Russian Federation, Ufa

Denis O. Karimov

Ufa Research Institute of Occupational Health and Human Ecology; N.A. Semashko National Research Institute of Public Health

Email: karimovdo@gmail.com
ORCID iD: 0000-0003-0039-6757
SPIN-code: 8063-3531

MD, Cand. Sci. (Medicine)

Russian Federation, Ufa; Moscow

Tatyana G. Yakupova

Ufa Research Institute of Occupational Health and Human Ecology

Email: tanya.kutlina.92@mail.ru
ORCID iD: 0000-0002-1236-8246
SPIN-code: 8191-2085
Russian Federation, Ufa

Yana V. Valova

Ufa Research Institute of Occupational Health and Human Ecology

Email: q.juk@ya.ru
ORCID iD: 0000-0001-6605-9994
SPIN-code: 8821-9591

Cand. Sci. (Biology)

Russian Federation, Ufa

Alina A. Gizatullina

Ufa Research Institute of Occupational Health and Human Ecology

Email: alinagisa@yandex.ru
ORCID iD: 0000-0002-7321-0864
SPIN-code: 6820-8953
Russian Federation, Ufa

References

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