Causal associations between frailty and low back pain: a bidirectional two-sample mendelian randomization study.

BACKGROUND: Previous observational studies have revealed a potentially robust bidirectional relationship between frailty and low back pain (LBP). However, the precise causal relationship remains unclear. METHODS: To examine the potential causal association between frailty and LBP, we conducted bidirectional two-sample Mendelian randomization analysis (MR) study. Genetic data on frailty index (FI) and LBP were acquired from publicly available genome-wide association studies (GWAS). Various MR methodologies were utilized, such as inverse variance weighting (IVW), weighted median, and MR-Egger, to evaluate causality. Additionally, sensitivity analyses were conducted to evaluate the robustness of the findings. RESULTS: Genetically predicted higher FI (IVW, odds ratio [OR] = 1.66, 95% CI 1.17-2.36, p = 4.92E-03) was associated with a higher risk of LBP. As for the reverse direction, genetic liability to LBP showed consistent associations with a higher FI (IVW, OR = 1.13, 95% CI 1.07-1.19, p = 2.67E-05). The outcomes from various MR techniques and sensitivity analyses indicate the robustness of our findings. CONCLUSION: Our research findings provide additional evidence bolstering the bidirectional causal relationship between frailty and LBP.

Lipid levels and low back pain risk: A two-sample mendelian randomization study.

BACKGROUND: Previous observational studies have shown controversial results about the relationship between lipid levels and low back pain (LBP). Herein, we aimed to explore the potential causal relationship between lipid levels and LBP by using the mendelian randomization (MR) analysis. METHODS: In this two-sample MR study, data were extracted from publicly available MRC Integrative Epidemiology Unit database. Three single-nucleotide polymorphisms (SNPs) of lipid levels [high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), and triglycerides (TG)] and two SNPs of LBP risk (LBP and back pain) were retrieved and used as genetic instrumental variables. Inverse-variance weighted (IVW), weighted median, MR-Egger, robust adjusted profile score (MR-RAPS), and MR-PRESSO were used to examine the potential causal association between lipid levels and LBP. RESULTS: IVW (fixed effect) estimation indicated that increased HDL-C level was negatively related to the odds of LBP for European populations. [odds ratio (OR) = 0.923, 95% confidence interval (CI): 0.857-0.993, P = 0.0323]. Similar results were also found in IVW (random effect) (OR = 0.923, 95% CI: 0.866-0.983, P = 0.0134), MR-Egger (OR = 0.858, 95%CI: 0.757-0.973, P = 0.0177), MR-RAPS (OR = 0.932, 95%CI: 0.871-0.997, P = 0.0419), and MR-PRESSO (OR = 0.933, 95%CI: 0.880-0.989, P = 0.0198) analyses. Whereas no causal link was observed between LDL-C/TG and LBP risk (P>0.05). CONCLUSION: This two-sample MR study demonstrated a causal relationship between lipid levels and LBP risk. Further investigations are necessary to elucidate the causal association and specific underlying mechanisms by which lipid levels contribute to the development of LBP.

Association of TaqI (rs731236) Polymorphism of Vitamin D Receptor Gene with Lumbar Degenerative Disc Disease.

BACKGROUND: Lumbar degenerative disc disease (LDDD) significantly contributes to low back pain, with a complicated etiology involving genetic and environmental facts. The aim of study was to investigate the association between the TaqI (rs731236) polymorphism of the vitamin D receptor (VDR) gene with LDDD. METHODS: In total, 248 patients with symptomatic LDDD and 146 control subjects were examined. The evaluation of clinical features of patients with LDDD comprised radiodiagnostic magnetic resonance imaging, neurologic examinations, pain scores including the visual analog scale (VAS), and disability investigation with Oswestry Disability Index (ODI). Genotyping of the VDR gene polymorphism was conducted using polymerase chain reaction-based methods. RESULTS: Individuals of the LDDD group who were VDR TaqI AA genotype carriers were significantly greater than the other group (P = 0.014), whereas those with GG genotype were significantly lower (P = 0.028) in the patient group. In addition, VAS and ODI scores were significantly lower in the GG genotype carrier group, whereas AA genotype carriers had the greatest scores (P = 0.004). Carrying the G allele decreased the risk of LDDD 1.7 times (P = 0.014) and carrying the A allele enhanced the risk 1.8 times (P = 0.028). Moreover, G-allele carriers had significantly lower VAS (P = 0.002) and ODI scores (P < 0.0001). CONCLUSIONS: VDR TaqI (rs731236) GG genotype and G allele have protective potential, whereas the AA genotype and A allele are risk factors for LDDD. The findings reveal a statistically significant association of the TaqI (rs731236) polymorphism of VDR gene polymorphism with LDDD. This result highlights the potential role of genetic factors in developing LDDD and suggests avenues for future research in genetic screening and personalized treatment strategies.

COMT and SCN9A gene variants do not contribute to chronic low back pain in Mexican-Mestizo patients.

BACKGROUND: Chronic low back pain (CLBP) is a complex condition in which genetic factors play a role in its susceptibility. Catechol-O-methyltransferase (COMT) and sodium channel NaV1.7 (SCN9A) genes are implicated in pain perception. The aim is to analyze the association of COMT and SCN9A with CLBP and their interaction, in a Mexican-Mestizo population. METHODS: A case-control study was conducted. Cases corresponded to adults of both sexes with CLBP. Controls were adults with no CLBP. Variants of SCN9A and COMT were genotyped. Allelic and genotypic frequencies and Hardy-Weinberg equilibrium (HWE) were calculated. Association was tested under codominant, dominant, and recessive models. Multifactor dimensionality reduction was developed to detect epistasis. RESULTS: Gene variants were in HWE, and there was no association under different inheritance models in the whole sample. In women, in codominant and dominant models, a trend to a high risk was observed for AA of rs4680 of COMT (OR = 1.7 [0.5-5.3] and 1.6 [0.7-3.4]) and for TT of rs4633 (OR = 1.6 [0.7-3.7] and 1.6 [0.7-3.4]). In men, a trend to low risk was observed for AG genotype of rs4680 in the same models (OR = 0.6 [0.2-1.7] and 0.7 [0.3-1.7]), and for TC genotype of rs4633 in the codominant model (OR = 0.6 [0.2-1.7]). In the interaction analysis, a model of the SCN9A and COMT variants showed a CVC of 10/10; however, the TA was 0.4141. CONCLUSION: COMT and SCN9A variants are not associated with CLBP in the analyzed Mexican-Mestizo population.

Smoking and BMI mediate the causal effect of education on lower back pain: observational and Mendelian randomization analyses.

Objective: Low back pain (LBP) has been associated with education in previous observational studies, but the causality remains unclear. This study aims to assess the impact of education on LBP and to explore mediation by multiple lifestyle factors. Design: Univariable Mendelian randomization (MR) was performed to examine the overall effect of education on LBP. Subsequently, multivariable MR was conducted to assess both the direct effect of education on LBP and the influence of potential mediators. Indirect effects were estimated using either the coefficient product method or the difference method, and the proportion of mediation was calculated by dividing the indirect effect by the total effect. The observational study utilized data from the NHANES database collected between 1999 and 2004, and included 15,580 participants aged 20 years and above. Results: Increasing education by 4.2 years leads to a 48% reduction in the risk of LBP (OR=0.52; 95% CI: 0.46 to 0.59). Compared to individuals with less than a high school education, those with education beyond high school have a 28% lower risk of LBP (OR=0.72; 95% CI: 0.63 to 0.83). In the MR study, smoking accounts for 12.8% (95% CI: 1.04% to 20.8%) of the total effect, while BMI accounts for 5.9% (95% CI: 2.99% to 8.55%). The combined mediation effect of smoking and BMI is 27.6% (95% CI: 23.99% to 32.7%). In the NHANES study, only smoking exhibits a mediating effect, accounting for 34.3% (95% CI: 21.07% to 41.65%) of the effect, while BMI does not demonstrate a mediating role. Conclusions: Higher levels of education provide a protective effect against the risk of LBP. Additionally, implementing interventions to reduce smoking and promote weight loss among individuals with lower levels of education can also decrease this risk.

Causal associations between gut microbiota with intervertebral disk degeneration, low back pain, and sciatica: a Mendelian randomization study.

PURPOSE: Although studies have suggested that gut microbiota may be associated with intervertebral disk disease, their causal relationship is unclear. This study aimed to investigate the causal relationship between the gut microbiota and its metabolic pathways with the risk of intervertebral disk degeneration (IVDD), low back pain (LBP), and sciatica. METHODS: Genetic variation data for 211 gut microbiota taxa at the phylum to genus level were obtained from the MiBioGen consortium. Genetic variation data for 105 taxa at the species level and 205 metabolic pathways were obtained from the Dutch Microbiome Project. Genetic variation data for disease outcomes were obtained from the FinnGen consortium. The causal relationships between the gut microbiota and its metabolic pathways and the risk of IVDD, LBP, and sciatica were evaluated via Mendelian randomization (MR). The robustness of the results was assessed through sensitivity analysis. RESULTS: Inverse variance weighting identified 46 taxa and 33 metabolic pathways that were causally related to IVDD, LBP, and sciatica. After correction by weighted median and MR-PRESSO, 15 taxa and nine pathways remained stable. After FDR correction, only the effect of the genus_Eubacterium coprostanoligenes group on IVDD remained stable. Sensitivity analyses showed no evidence of horizontal pleiotropy, heterogeneity, or reverse causation. CONCLUSION: Some microbial taxa and their metabolic pathways are causally related to IVDD, LBP, and sciatica and may serve as potential intervention targets. This study provides new insights into the mechanisms of gut microbiota-mediated development of intervertebral disk disease.

Diet and risk of low back pain: a Mendelian randomization analysis.

PURPOSE: Previous epidemiological and other studies have shown an association between diet and low back pain (LBP). This study aimed to investigate the causal relationship between diet and LBP using a Mendelian randomization (MR) approach. METHODS: The three main methods in this study were weighted median, MR-Egger, and inverse variance weighting (IVW). We utilized MR-PRESSO to eliminate abnormal SNPs. Additionally, tests for pleiotropy and heterogeneity were conducted. Utilizing IVW and MR-Egger's Cochran's Q test, heterogeneity was evaluated. MR-Egger intercepts were used in pleiotropy tests. A leave-one-out analysis was also used to evaluate the stability of the study's findings. RESULTS: The frequency of alcohol intake was associated with an increased risk of LBP. Increased processed meat intake, dried fruit intake, cereal intake, and tea intake were causally associated with a decreased risk of LBP (alcohol intake frequency: odds ratio (OR) = 1.28; 95% confidence interval (CI), 1.11-1.47; P = 0.0006; processed meat intake: OR = 0.60, 95%CI 0.39-0.92, P = 0.019; dried fruit intake: OR = 0.43, 95%CI 0.29-0.66, P = 0.00008; cereal intake: OR = 0.62, 95%CI 0.42-0.92, P = 0.018; tea intake: OR = 0.75, 95%CI 0.58-0.97, P = 0.029). Heterogeneity and pleiotropy were also not found in the sensitivity analysis. The leave-one-out analysis also showed more robust results. Other dietary intakes were not causally associated with LBP. CONCLUSIONS: This two-sample MR study found that frequency of alcohol intake was associated with an increased risk of LBP, and intake of processed meat, dried fruit, cereals, and tea was associated with a decreased risk of LBP. Moreover, no causal relationship was found with LBP in the other 13 diets.

The Genetic Causal Association between Educational Attainment and Risk of 12 Common Musculoskeletal Disorders: A Two-Sample Mendelian Randomization.

OBJECTIVE: In numerous observational studies, there has been an indication that educational attainment (EA) can impact the intensity of pain and disability resulting from chronic musculoskeletal disorders. Nonetheless, the association observed in these studies is not entirely conclusive. The aim of this study was to investigate the genetic causal relationship between educational attainment and 12 musculoskeletal disorders using Mendelian randomization (MR). METHODS: The meta-analysis of genome-wide association studies (GWAS) identified 3952 single-nucleotide polymorphisms (SNPs) associated with educational attainment (EA) from the Social Science Genetic Association Consortium (SSGAC). Genetic data for 12 musculoskeletal disorders, including osteonecrosis, osteoporosis, osteomyelitis, low back pain, gout, spinal stenosis, rheumatoid arthritis, meniscus derangement, rotator cuff syndrome, ankylosing spondylitis, cervicobrachial syndrome, and lateral epicondylitis, were obtained from the FinnGen consortium. We conducted a two-sample Mendelian randomization analysis to examine the causal effect of EA on the risk of these musculoskeletal disorders using the TwoSampleMR package in R. RESULTS: Based on the inverse-variance weighted (IVW) method, we found that a genetically predicted per standard deviation (SD) increase in EA was inversely associated with low back pain [odds ratio (OR) 0.46, 95% confidence interval (Cl) 0.51-0.61, p < 0.001], spinal stenosis (OR 0.62, 95% Cl 0.54-0.71, p < 0.001), rheumatoid arthritis (OR 0.65, 95% Cl 0.55-0.76, p < 0.001), meniscus derangement (OR 0.73, 95% Cl 0.65-0.82, p < 0.001), rotator cuff syndrome (OR 0.55, 95% Cl 0.49-0.61, p < 0.001), cervicobrachial syndrome (OR 0.50, 95% Cl 0.42-0.60, p < 0.001), and lateral epicondylitis (OR 0.30, 95% Cl 0.24-0.37, p < 0.001). There was no causal association between EA and osteonecrosis (OR 1.11, 95% CI 0.76-1.72, p = 0.60), osteoporosis (OR 0.91, 95% CI 0.65-1.27, p = 0.59), or osteomyelitis (OR 0.90, 95% CI 0.75-1.01, p = 0.22). Genetic predisposition to EA had a suggestive causal association with gout (OR 0.80, 95% CI 0.68-0.95, p = 0.01) and ankylosing spondylitis (OR 0.64, 95% CI 0.45-0.91, p = 0.01) after Bonferroni correction. None of the analyses revealed any horizontal pleiotropy or heterogeneity. CONCLUSION: In our investigation, we have uncovered evidence supporting a causal relationship between low level of EA and the incidence of certain musculoskeletal disorders. In the future, it is imperative to ascertain risk factors such as lifestyle patterns linked with EA to uncover the underlying causal relationship and offer informed interventions for individuals.

Occupational factors and low back pain: a Mendelian randomization study.

Background: Low back pain (LBP) is a common condition and a leading cause of health function loss worldwide. This study assessed the impact of occupational factors on LBP using Mendelian Randomization (MR) method, controlling for confounding variables. Methods: Based on publicly available genome-wide association studies (GWAS), two-sample univariate and multivariate MR analyses were performed to assess the causal effect of occupational factors on LBP. We used the inverse variance weighted (IVW) method and sensitivity analyses to generate the total results for the univariate MR analysis. Furthermore, we performed multivariate MR analysis to assess the direct causal association between occupational factors and LBP after accounting for potential confounding variables. Results: The total causal effect of genetically predicted job involves heavy manual or physical work on LBP was found to be significant (IVW OR, 2.117; 95% CI, 1,288-3.479; p = 0.003). Upon adjusting for potential confounding variables, the direct effect of job involves heavy manual or physical work on LBP remained statistically significant. Similarly, the total causal effect of genetically predicted job involves mainly walking or standing on LBP was also found to be significant (IVW OR, 1.429; 95% CI, 1,035-1.975; p = 0.030). However, upon adjusting for potential confounding variables, the direct effect of job involves mainly walking or standing on LBP became insignificant. In contrast, the findings from the MR analysis indicated a lack of association between work/job satisfaction and LBP. Sensitivity analysis consistently supported these trends. Conclusion: Our results supported a causal link between job involves heavy manual or physical work and increased risk of LBP, while finding no significant associations between prolonged walking/standing at work, job satisfaction, and LBP, providing valuable insights for the development of targeted prevention and intervention strategies for LBP.

Assessing the causal relationship between genetically determined inflammatory biomarkers and low back pain risk: a bidirectional two-sample Mendelian randomization study.

Background: Observational studies have suggested an association between inflammatory markers and low back pain (LBP), but the causal relationship between these factors remains uncertain. Methods: We conducted a bidirectional two-sample Mendelian randomization analysis (MR) study to investigate whether there is a causal relationship between inflammatory markers and low back pain. We obtained genetic data for CRP, along with its upstream inflammatory markers IL-6, IL-8, and IL-10, as well as low back pain from publicly available genome-wide association studies (GWAS). We applied several MR methods, including inverse variance weighting, weighted median, MR-Egger, Wald Ratio, and MR-PRESSO, to test for causal relationships. Sensitivity analyses were also conducted to assess the robustness of the results. Results: Our analyses utilizing the Inverse Variance Weighted (IVW) method, the MR-Egger method, and the weighted median method indicated that IL-6 may be associated with an increased risk of LBP (Effect Size: -0.009, 95% Confidence Interval: -0.013-0.006, p = 9.16e-08); however, in the reverse direction, there was no significant causal effect of LBP on inflammatory markers. Conclusion: Our study used a Mendelian randomization approach and found that elevated IL-6 levels may reduce the risk of LBP.

Causal relationship between leisure sedentary behaviors and low back pain risk: a Mendelian randomization study.

PURPOSE: This study aims to assess the causal associations of leisure sedentary behaviors with low back pain (LBP). METHODS: A Mendelian randomization (MR) study was carried out utilizing genetic instruments to determine whether leisure sedentary behaviors (including leisure television watching, leisure computer use, and driving) are causally associated with LBP. All instrumental variables were selected from publicly available genetic summary data. The inverse variance weighted (IVW) was used as the main method to conduct univariable MR analyses. Further sensitivity analyses were utilized to test the stability of the results. Moreover, multivariable MR was performed to evaluate the independent causal relationship between leisure sedentary behaviors and LBP when body mass index (BMI), waist circumference, smoking initiation, and vigorous physical activity were taken into account. RESULTS: The MR analyses showed evidence that television watching increased the risk for LBP (OR: 1.97, 95% CI 1.45, 2.66; P = 1.19 × 10-5). Genetically determined computer use is causally associated with a decreased risk of LBP (OR: 0.53, 95% CI 0.41, 0.68; P = 4.79 × 10-7). However, no evidence was found of a causal relationship between driving and LBP (OR: 2.27, 95% CI 0.75, 6.81; P = 0.145). After adjusting for BMI, waist circumference, smoking initiation, and vigorous physical activity, only television maintained its causal effect on LBP. CONCLUSIONS: This study indicated that genetically predicted television watching was a risk factor for LBP independent of BMI, waist circumference, smoking initiation, and vigorous physical activity. This finding may be helpful for the diagnosis and management of LBP.

Colonization of intervertebral discs by Cutibacterium acnes in patients with low back pain: Protocol for an analytical study with microbiological, phenotypic, genotypic, and multiomic techniques.

Lumbar disc degeneration (LDD) and low back pain (LBP) are two conditions that are closely related. Several studies have shown Cutibacterium acnes colonization of degenerated discs, but whether and how these finding correlates with LBP is unknown. A prospective study was planned to identify molecules present in lumbar intervertebral discs (LLIVD) colonized by C. acnes in patients with LDD and LBP and correlate them with their clinical, radiological, and demographic profiles. The clinical manifestations, risk factors, and demographic characteristics of participants undergoing surgical microdiscectomy will be tracked. Samples will be isolated and pathogens found in LLIVD will be characterized phenotypically and genotypically. Whole genome sequencing (WGS) of isolated species will be used to phylotype and detect genes associated with virulence, resistance, and oxidative stress. Multiomic analyses of LLIVD colonized and non-colonized will be carried out to explain not only the pathogen's role in LDD, but also its involvement in the pathophysiology of LBP. This study was approved by the Institutional Review Board (CAAE 50077521.0.0000.5258). All patients who agree to participate in the study will sign an informed consent form. Regardless of the study's findings, the results will be published in a peer-reviewed medical journal. Trials registration number NCT05090553; pre-results.

Epigenetic Factors Related to Low Back Pain: A Systematic Review of the Current Literature.

Low back pain (LBP) is one of the most common causes of pain and disability. At present, treatment and interventions for acute and chronic low back pain often fail to provide sufficient levels of pain relief, and full functional restoration can be challenging. Considering the significant socio-economic burden and risk-to-benefit ratio of medical and surgical intervention in low back pain patients, the identification of reliable biomarkers such as epigenetic factors associated with low back pain could be useful in clinical practice. The aim of this study was to review the available literature regarding the epigenetic factors associated with low back pain. This review was carried out in accordance with Preferential Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search was carried out in October 2022. Only peer-reviewed articles were considered for inclusion. Fourteen studies were included and showed promising results in terms of reliable markers. Epigenetic markers for LBP have the potential to significantly modify disease management. Most recent evidence suggests that epigenetics is a more promising field for the identification of factors associated with LBP, offering a rationale for further investigation in this field with the long-term goal of finding epigenetic biomarkers that could constitute biological targets for disease management and treatment.

Association between single-nucleotide polymorphism rs145497186 related to NDUFV2 and lumbar disc degeneration: a pilot case-control study.

OBJECTIVE: The association between the single-nucleotide polymorphisms (SNPs) rs28742109, rs12955018, rs987850, rs8093805, rs12965084 and rs145497186 related to gene named NADH dehydrogenase [ubiquinone] flavoprotein 2 (NDUFV2) and lumbar disc degeneration (LDD) was preliminary investigated in a small sample size. METHODS: A total of 46 patients with LDD and 45 controls were recruited at Qilu Hospital of Shandong University, and each participant provided 5 mL peripheral venous blood. NA was extracted from the blood of each participant for further genotyping. The frequency of different genotypes in the case group and control group was determined, and analysis of the risk of LDD associated with different SNP genotypes was performed. The visual analogue scale (VAS) scores of the patients' degree of chronic low back pain were calculated, and the relationship between VAS scores and SNPs was analysed. RESULTS: After excluding the influence of sex, age, height, and weight on LDD, a significant association between SNP rs145497186 related to NDUFV2 and LDD persisted (P = 0.006). Simultaneously, rs145497186 was found to be associated with chronic low back pain in LDD populations. CONCLUSION: NDUFV2 rs145497186 SNP could be associated with susceptibility to LDD and the degree of chronic low back pain.

Network Pharmacology-Based Dissection of the Mechanism of Drynariae Rhizoma for Low Back Pain.

Objective: To explain the potential mechanisms of Drynariae Rhizoma (DR) in the treatment of low back pain (LBP). Design: Network pharmacology was used to reveal the potential mechanisms including collecting the active ingredients of DR, analyzing the common gene targets of LBP and DR, constructing protein-protein interaction (PPI) network, collecting protein classification, performing Gene Ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and verifying significant gene targets. Results: 234 different gene targets and 18 active compounds altogether were obtained. AKT1, VEGFA, and HIF1A were deemed to be major gene targets based on the degree values. According to GO analysis, steroid metabolic process involved 42 (18.10%) potential therapeutic LBP targets, neuronal cell body involved 24 (10.30%) potential therapeutic LBP targets, and protein serine/threonine kinase activity involved 28 (12.02%) potential therapeutic LBP targets in biological process (BP), cellular component (CC), and molecular function (MF), respectively. According to KEGG and pathway interaction analyses, the PI3K-Akt signaling pathway involved 34 (15.89%) potential therapeutic LBP targets, and PI3K-Akt signaling pathway played a significant role in the treatment of LBP. The mRNA expression levels of AKT1 and HIF1A were upregulated in healthy nucleus pulposus (NP) tissue than in degenerative NP tissue. In contrast, the mRNA expression level of VEGFA was downregulated in healthy NP tissue than in degenerative NP tissue. Conclusions: In this study, we identified a potential relationship between LBP and DR in this work, as well as a synergistic mechanism of DR in the treatment of LBP, which serves as a benchmark for further in vivo and in vitro research.

Smoking, alcohol and coffee consumption and risk of low back pain: a Mendelian randomization study.

PURPOSE: Low back pain (LBP) is a common health problem in the global population. This study aims to assess whether smoking initiation, alcohol consumption, and coffee consumption are causally with an increased risk of LBP. METHODS: A two-sample Mendelian Randomization (MR) study was designed, based on summary-level data from the largest published genome-wide association studies. Single nucleotide polymorphisms with genome-wide significance level (P < 5.0 × 10-8) were selected as instrumental variables for each exposure. Standard inverse-variance weighted (IVW) method was used as the primary statistical method. The weighted median, MR-Egger regression, and MR-PRESSO methods, which relax some IV assumptions, were used for sensitivity analysis. RESULTS: Genetically predicted smoking initiation was causally associated with higher odds of LBP. The pooled OR of LBP using IVW method was 1.36 (95%CI 1.22 1.52; P = 6.0 × 10-8) for one SD increase in the prevalence of smoking initiation, which was supported by the weighted median method (OR: 1.41, 95%CI 1.22, 1.64; P = 5.7 × 10-6). Sensitivity analysis confirmed the robustness of pooled OR of LBP. There was no evidence to suggest a causal effect of alcohol and coffee consumption on LBP. The pooled ORs of LBP were 1.36 (95%CI 0.94, 1.97; P = 0.10) for alcohol consumption and 1.00 (95%CI 0.99, 1.00; P = 0.17) for coffee consumption, respectively. CONCLUSION: Smoking is casually associated with an increased risk of LBP. Smoking control should be recommended in LBP patients to avoid worsening the disease. The safety of LBP with moderate alcohol and coffee consumption merits more study.

Nature and nurture. Genetic and environmental factors on the relationship between back pain and sleep quality.

BACKGROUND: Chronic low back pain (LBP), neck pain (NP), and sleep quality (SQ) are genetically influenced. All three conditions frequently co-occur and shared genetic aetiology on a pairwise base has been reported. However, to our knowledge, no study has yet investigated if these three conditions are influenced by the same genetic and environmental factors and the extent and pattern of genetic overlap between them, hence the current research. METHODS: The sample included 2134 participants. Lifetime prevalence of NP and LBP were assessed through a dichotomous self-reported question derived from the Spanish National Health Survey. SQ was measured using the Pittsburgh Sleep Quality Index Questionnaire. A common pathway model with sleep quality and back pain as latent factors was fitted. RESULTS: Our results highlight that a latent back pain factor, including both NP and LBP, is explained by both genetic (41%) and environmental (59%) factors. There are also significant unique environmental factors for NP (33%) and LBP (37%) respectively. Yet, specific genetic factors were scant (9%) for NP and negligible for LBP (0%). Genetic and environmental factors affecting SQ only contribute with 3% and 5% of the variance, respectively, to the common latent back pain variable. CONCLUSIONS: NP and LBP share most of their genetic variance, while environmental effects show greater specificity for each of the back pain locations. Associations with SQ were of a limited magnitude. SIGNIFICANCE: Our results confirm a significant association between both chronic NP and LBP and sleep quality. Such relationship comprises both genetic and environmental factors, with a greater relative weight of the latter. A large part of the individual variance for chronic LBP and chronic NP can be accounted for by a latent common factor of 'back pain'. Genetic influences for LBP and NP were mainly shared. However, environmental influences were common for both problems and specific for each of them in similar magnitudes.

Epigenome-wide DNA methylation profiling of conditioned pain modulation in individuals with non-specific chronic low back pain.

BACKGROUND: The pathoanatomic cause of chronic low back pain (cLBP) cannot be identified for up to 90% of individuals. However, dysfunctional processing of endogenous nociceptive input, measured as conditioned pain modulation (CPM), has been associated with cLBP and may involve changes in neuronal gene expression. Epigenetic-induced changes such as DNA methylation (DNAm) have been associated with cLBP. METHODS: In the present study, the relationship between CPM and DNAm changes in a sample of community-dwelling adults with nonspecific cLBP (n = 48) and pain-free controls (PFC; n = 50) was examined using reduced representation bisulfite sequencing. Gene ontology (GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were applied to identify key pathways involved in efficient versus deficient CPM. RESULTS: Based on CPM efficiency, we identified 6006 and 18,305 differentially methylated CpG sites (DMCs) with q values < 0.01 among individuals with cLBP and PFCs, respectively. Most of the DMCs were hypomethylated and annotated to genes of relevance to pain, including OPRM1, ADRB2, CACNA2D3, GNA12, LPL, NAXD, and ASPHD1. In both cLBP and PFC groups, the DMCs annotated genes enriched many GO terms relevant to pain processing, including transcription regulation by RNA polymerase II, nervous system development, generation of neurons, neuron differentiation, and neurogenesis. Both groups also enriched the pathways involved in Rap1-signaling, cancer, and dopaminergic neurogenesis. However, MAPK-Ras signaling pathways were enriched in the cLBP, not the PFC group. CONCLUSIONS: This is the first study to investigate the genome-scale DNA methylation profiles of CPM phenotype in adults with cLBP and PFCs. Based on CPM efficiency, fewer DMC enrichment pathways were unique to the cLBP than the PFCs group. Our results suggest that epigenetically induced modification of neuronal development/differentiation pathways may affect CPM efficiency, suggesting novel potential therapeutic targets for central sensitization. However, CPM efficiency and the experience of nonspecific cLBP may be independent. Further mechanistic studies are required to confirm the relationship between CPM, central sensitization, and nonspecific cLBP.

Differentially Expressed Circular RNAs in Degenerative Diseases Related to Low Back Pain: Potential of Circular RNAs as Biomarkers.

Low back pain (LBP) is a major cause of disability worldwide. Nevertheless, given the complex pathophysiology of LBP, its etiological diagnosis remains a challenging process. Thus, identifying appropriate biomarkers and/or therapeutic targets is crucial for LBP research. Recently, circular RNAs (circRNAs) which are both abundant and sphysiologically stable have received a great deal of attention as potential molecular biomarkers. This is part because they can serve as microRNA (miRNA) sponges, inhibit normal miRNA activity. Indeed, it has been reported that circulating and/or tissue-specific circRNAs can be used for diagnosing multiple human diseases, including cancers, neurological diseases, and inflammatory diseases. Since 2015, research on circRNAs involved in LBP-related diseases has been a very active endeavor. Moreover, specific roles for some of the differentially expressed circRNAs have been demonstrated. Thus, the involvement of circRNAs in LBP-related diseases suggests that some of the dysregulated ones may have the potential to serve as therapeutic targets and/or diagnostic biomarkers. This review summarizes the current progress on differentially expressed circRNAs in diseases related to LBP.