Background
Low back pain (LBP) can have a significant impact on athletes’ performance and may sometimes cause disability [
1‐
3]. LBP has been largely studied in the general population; approximately 50–80% of people have at least one episode during their lifetime [
4‐
7]. Conversely, there are few studies focused on LBP in athletes. In studies were lumbar spine pain is evaluated as a symptom by questionnaire, it had a prevalence of around 30–40% [
1,
2,
8]. Prevalence of LBP seems to vary according to type of sport discipline [
9], rates over 70% were reported for bowling/skittles, canoe, cycling, gymnastics, rowing, shooting, snowboarding, and volleyball [
8]. A recent Iranian study [
10] among college female athletes found a life-time prevalence of LBP of nearly 70% in basketball, karate, and track-and-field athletes.
LBP has a complex etiology and it is often recurrent [
11‐
13]. In the general population many environmental/behavioral risk factors, including age, sex, weight, occupational load, smoking and exposure to vehicle vibration were demonstrated to contribute to spinal degeneration and severe pain [
7,
14,
15]. In athletes, exposure to high exercise load [
16], decreased lumbar flexion and extension, shoulder flexibility, and forward bending have been involved in LBP and disc degeneration processes [
1,
9,
17]. Recently, some epidemiologic and genetic studies [
6,
7,
14,
15,
18‐
20] performed in the general non-athletic population supported the notion that LBP and disc degeneration disorders may be affected by genetic polymorphisms of the vitamin D receptor gene (
VDR) including FokI, BsmI, TaqI and ApaI single nucleotide polymorphisms (SNPs).
Among several SNPs identified in the
VDR gene, only the FokI polymorphism is located in an exon sequence [
21,
22]. The FokI polymorphism (rs2228570) is a C to T transition polymorphic site located in the
VDR start codon, affecting the amino acid sequence and the function of the encoded receptor protein [
21]. The allelic variants of this polymorphism code for structurally different receptor proteins (from a 424 aminoacids wild type encoded by the F allele to a 427 amino acid long protein encoded by the f allele). The short and long protein variants are associated with a different efficiency of
VDR binding with the transcription factor II B (TFIIB) and, thus, to a different ability to induce transcription of VDR-dependent genes (vitamin D response elements, VDREs [
23]). The shorter wild protein (corresponding to the F allele) appears to interact more efficiently with TFIIB showing a higher transcriptional rate [
24,
25]. Consequently, studies concerning the possible association of
VDR-FokI polymorphism with LBP and disc degeneration may be particularly interesting for the potential biological significance.
VDR-FokI is an independent polymorphic site, not in linkage disequilibrium with other
VDR-SNPs [
21]. Distribution of
VDR-FokI polymorphism genotypes and alleles can vary with the genetic backgrounds. Therefore, specific ethnic group focused studies are warranted [
6].
Wide evidence supports the notion that the vitamin D endocrine system, including active vitamin D hormone (1α,25-dihydroxyvitamin D
3), its receptor and the enzymes involved in the generation of the biologically-active forms of vitamin D are implicated in the modulation of different biological processes, including skeletal metabolism, immunological response (in general, vitamin D/VDR action promotes interleukin-1 and innate immune response, while it attenuates adaptive immunity), detoxification, oxidative stress, cancer-related metabolic pathways, proliferation and differentiation of a wide variety of cell types [
26,
27]. Recently, the presence of VDR was evident in skeletal muscle [
28,
29] and also in intervertebral disc cells, more specifically in the nucleus pulposus and annulus fibrosus cells, which constitute the two different major parts of the intervertebral disc [
30]. This highlighted that biological interactions of intervertebral disc cells with the vitamin D metabolites may be crucial to disc health, consequently an altered vitamin D signaling could have a role in the pathophysiology of the disc degeneration and LBP [
6].
To our knowledge, there are no studies investigating the association of the VDR-FokI polymorphism and LBP in athletes. This polymorphism by changing the sequence and activity of the VDR protein could affect the activity of the wide variety of genes modulated by the VDR nuclear receptor. Identification of genetic traits in athletes predisposing to LBP might help clinicians, coaches, sport trainers, and athletes themselves to develop personalized strategies to prevent or reduce LBP, for example, by modification of some lifestyles habits and/or kind of training.
The aims of this study were to evaluate the VDR-FokI genotypic and allelic frequencies distribution in athletes with LBP in comparison with asymptomatic athletes (no-LBP), and to analyze the interplay of genetic and behavioral/environmental factors in the development of LBP in athletes.
Discussion
At present, the scientific interest in the risk factors for LBP is increasing both for athletic performance and health implications [
9,
10]. Further research is required in this field because discrepancies exist among studies especially regarding LBP prevalence, causes, and therapeutic strategies [
9,
12,
35]. In addition, sex-specific studies are warranted to take into account sex differences in factors potentially modulating LBP [
10,
14]. Some types of exercise seems to increase LBP prevalence rate [
8‐
10], but studies comparing athletes and non-athletes do not always confirm this view [
11,
36]. On the other hand, some evidence suggests that exercise is effective in preventing LBP [
12,
35,
37].
The present observational study is the first to explore the relationship of non-specific LBP in athletes with VDR-FokI genotypes and alleles in a sample of 60 ethnically homogeneous white athletes practicing various sport disciplines. We found that the frequency of the homozygous FF genotype was higher in LBP athletes, with adjusted OR = 5.78. On the contrary, the Ff genotype was protective (adjusted OR = 0.24). Our findings highlighted that carriage of the F allele was a risk factor (adjusted OR = 2.55), whereas carriage of the f allele was protective for the development of LBP in athletes (adjusted OR = 0.39).
Genotype and allele frequencies in our LBP group (FF 58.3, Ff 41.7, ff 0, F allele 79.2%) were different to those reported in a study on 267 non-athletic patients with lumbar spine pathologies (FF 43.8, Ff 44.9, ff 11.2, F allele 66.3%) [
7]. Our current findings in LBP athletes are similar to those found in a study of 64 Italian non-athletic patients who had discopathies (with or without disc herniation) (FF 57.8, Ff 34.4, ff 7.8, F allele 75.0, and f allele 25.0%). That study showed that the FF genotype and the F allele were risk factors (OR = 2.02, 95% CI 1.15–3.55,
P = 0.015, and OR = 1.76, 95% CI 1.13–2.75,
P = 0.012, respectively) by comparison to healthy non-athletic controls [
7]. Moreover, a group of 87 Italian non-athletic patients with a medical diagnosis (by magnetic resonance imaging, MRI) of discopathies and/or osteochondrosis associated with disc herniation had FF rates of 56.3, Ff 36.8, ff 6.9, F allele 74.7, and f allele 25.3%. The odds ratio of FF was OR = 1.90, 95% CI 1.15–3.13,
P = 0.012, and of F allele was OR = 1.74, 95% CI 1.17–2.57,
P = 0.005 [
7]. Unfortunately, the design of our present study was observational and, thus, we could not assess radiologically whether study athletes with the LBP symptom had a discopathy. Interestingly, Sward and colleagues [
38] found that disc degeneration, defined as reduced disc signal intensity, was significantly more common in elite gymnasts athletes (75%) than in non-athletes (31%). There was also a significant correlation between back pain and reduced disc signal intensity. Moreover, a study by Ong and colleagues [
39] examining 31 Olympic athletes of various disciplines with low back pain found disc degeneration (assessed as reduced disc signal intensity by MRI) in 62% of subjects and a prevalence of disc displacement of 58%. The authors suggested the opportunity for a change in the methods of training to minimize disc degeneration, particularly at the elite levels of sport [
39].
Surprisingly, so far only 6 studies [
40‐
45] have assessed
VDR-FokI polymorphism in athletesprior to the current study. However, no previous studies have examined the association of
VDR-FokI polymorphism with LBP in athletes. A study in 125 Italian soccer players determined frequencies of FF 51.2, Ff 34.4, ff 14.4, F allele 68.4, and f allele 31.6% [
40]. In this study, the FF genotype was not related to different athletic performance, but it was associated with higher values of the ratio of body cell mass over fat-free mass (BCM/FFM) [
40]. Similarly, a study in 80 Italian white male gymnasts participating at international competitions found no relationship between the
VDR-FokI polymorphism and athletic performance [
41]. In addition, 2 studies by Massidda and colleagues in male Italian soccer players found no correlation of
VDR-FokI polymorphism with athletic performance [
42], and no association with incidence or severity of musculoskeletal injury [
43]. A study by Nakamura and colleagues [
44] in 44 Japanese male competitive athletes of various sport disciplines found frequencies of FF of 50.0, and Ff 47.7%; FF carries when compared to Ff carriers had 7.7% greater lumbar spine bone mineral content (BMC) [
44]. In contrast, a Brazilian study examining 46 adolescent soccer players (FF 41.3, Ff 47.8, ff 10.9, F allele 65.2, and f allele 34.8%) found higher total body mineral content and density in boys with Ff genotype compared to those with FF genotype [
45].
By examining demographic and lifestyle characteristics, we observed that daily exposure for 2 or more hours to vehicle vibrations and family history of lumbar spine pathologies were risk factors for LBP in athletes. Similar results were previously observed for non-athletic patients with lumbar pathologies, especially those with discopathies and/or osteochondrosis associated with disc herniation [
7,
14]. We have shown in this study that athletes with LBP were not older, were not more frequently males, had no higher BMI, were not more frequently smokers, and had no a more physically intense job than no-LBP controls. On the contrary of previous findings evidenced in non-athletic patients [
7,
14]. Interestingly, hours of physical exercise did not differ between LBP and no-LBP athletes, conversely, non-athletic patients with lumbar pathologies did less leisure physical activity than healthy controls [
7,
14].
In our study, BMI was not a risk factor for LBP. A study in elite junior divers [
1] found that a higher BMI was a LBP risk factor for male but not female athletes. A recent comprehensive review on risk factors of non-specific LBP in athletes [
9] found that there is moderate evidence for high body weight as a risk factor.
Interestingly, Moradi and colleagues [
9] reported that there is insufficient evidence that amount of training per week, active years in sport, age, and sex are associated with LBP. We found that amount of weekly physical exercise, age and sex were not risk factors for LBP in athletes. Thus, our present findings seem to concur with most accumulated evidence of risk factors for LBP in athletes.
The effect of smoking on LBP in athletes was poorly investigated in previous studies [
9], however, smoking in athletes is much less frequent and intense than in non-athletes [
46].
Mechanisms leading to LBP in athletes still need to be clarified. Further studies with increased number of subjects, and also “ex vivo” research will be necessary to evaluate the biochemical pathways relating the vitamin D endocrine system to LBP.
Some evidence showed that FF genotype is associated with increased lumbar spine bone mineral density (BMD) [
24,
44,
47]. Whether increased risk of LBP in athletes due to carriage of F allele is mediated by higher transcriptional activity of VDR and thus, higher biological efficacy of vitamin D in subjects with a specific genetic background needs further investigations. Future studies are warranted to assess if the observed increased frequency of FF genotype and F allele in LBP athletes is associated with up-regulation (or down-regulation) of specific genes responsive to VDR action and associated with lumbar spine pain. Interestingly recent studies showed that a wide variety of hundreds of genes can be affected by vitamin D [
23,
26,
48]. Genome-wide studies indicated the existence of up to 2776 VDR binding sites in human genome [
48]. Bioinformatic analysis has found 14,548 putative VDR binding sites; 16–21% of these sites are located at gene promoters [
23]. VDR binding at VDREs may up- and down-regulate transcription of genes in a tissue specific manner, this is also modulated by epigenetic changes [
23,
26].
Deeper understanding of biological pathways of vitamin D related to LBP may indicate whether vitamin D rich diet and/or supplementation should be recommended according to
VDR-FokI polymorphism. Recently, dietary and vitamin supplementation were proposed to athletes having LBP [
9]. To our knowledge none so far suggested specifically vitamin D supplementation to athletes with LBP. Future studies will be necessary to assess this issue of personalized medicine [
28,
49,
50].
It is generally recognized that LBP can negatively affect athletic performance and recovery. Assessing the predisposing and protective factors for LBP in athletes may be complicated by several confounding factors, among these VDR-FokI polymorphism may constitute a major confounder as shown by our present findings.
There are limitations in our study. We studied adult athletes, and thus, we cannot generalize these results to younger or older athletes or athletes with different ethnic backgrounds. Sport activities of athletes were heterogeneous ranging from aerobic to mixed aerobic-anaerobic and to anaerobic activity, and from elite to non-elite competing level. We included several types of sport disciplines but some other disciplines like tennis, skiing, golf etc. were not assessed. However, we did not prove a LBP association with elite status and hours of physical exercise per week. In our study we examined non-specific LBP thus our results cannot address other kinds of LBP in athletes. In our study the confidence intervals were somewhat large; however, significant results were obtained after multivariate adjustments including several confounders. Finally, we evaluated LBP by a questionnaire and we did performed radiological investigations.
Strengths of the present study include assessment of LBP and VDR-FokI polymorphism in a homogeneous ethnic group of competitive athletes, evaluation of demographic, social, lifestyle characteristics and family history, and stringent inclusion and exclusion criteria.
Further studies have to be carried out to expand our observations including larger numbers of athlete practising different sport disciplines and to better assess biochemical pathways related to vitamin D’s effects on LBP in athletes.
Acknowledgements
We are grateful to Dionisio Cauci for help in enrolment of participant athletes. We thank Alberto Degrassi for critical reading of the manuscript.