This study is the first to investigate the causal relationship between MetS and LBP in a European population using two-sample MR analysis, incorporating components of MetS such as WC, FBG, hypertension, TG, and HDL-C. Our analysis revealed no genetic evidence supporting an association between MetS and the risk of LBP. This suggests that previously reported epidemiological associations may be attributed to residual confounding and detection bias. Considering our MR results across various consistency models and methods, we are confident that our MR analysis yields compelling evidence.
LBP is commonly defined as pain, muscle tension, or stiffness below the rib edges and above the lower buttock folds, with or without leg pain (sciatica) (Koes et al. 2006; Lv et al. 2022). In a cross-sectional study using data from the fourth Korean National Health and Nutrition Examination Survey (KNHANES IV), it was found that MetS was prevalent in Korean patients with chronic LBP. The prevalence of MetS in patients with chronic LBP was 36.2% (30.2% in males and 38.6% in females) (Ha 2011). To our knowledge, several recent studies have investigated risk or protective factors for LBP using MR methods (Zhou et al. 2021; Liu et al. 2023; Zhu et al. 2023). However, limited research has explored the association between MetS and LBP. Leveraging the newly updated genetic data from GWAS, our study, in contrast to previous research, conclusively establishes the absence of statistical causality between MetS and LBP.
In the absence of directional pleiotropy, the IVW model can offer a relatively robust and precise evaluation of causality by integrating the Wald ratio of each SNP through a meta-analysis approach (Burgess and Thompson 2017; Bowden and Holmes 2019). Consequently, it was chosen as the primary analytical method in this study, with other models utilized to assess result stability. Despite the IVW method indicating a statistically significant association at the genetic level (OR = 1.003, 95%CI = 1.002–1.004, P = 3.47×10− 6), we advocate caution when interpreting the causal relationship between MetS and LBP. On one hand, its OR value is approximately equal to one, implying that MetS has a minimal impact on causing LBP. On the other hand, both the MR-Egger method (OR = 1.001, 95%CI = 0.997–1.005, P = 0.644) and weighted median method (OR = 1.002, 95%CI = 0.999–1.004, P = 0.148) support our conclusion. Nevertheless, further analysis in future prospective studies with a larger sample size is warranted.
To enhance our understanding of the causal relationship between the individual components of MetS and LBP, we conducted a component analysis examining the causal relationship between WC, FBG, HT, TG, HDL-C and LBP. Our findings do not provide support for the presence of a genetic-level causal relationship between FBG, HT, TG, HDL-C and LBP in the European population, and no statistically significant associations were evident in several methods.
In the MR analysis, we employed the weighted median method and the MR-PRESSO method to assess result robustness and detect potential pleiotropic effects. The weighted median method tolerates < 50% invalid instruments, while the MR-PRESSO test identifies and corrects estimates for outliers related to horizontal pleiotropy. We concluded that there was no directional pleiotropy between these IVs, as all P values of MR-Egger regression intercept test and MR-PRESSO test exceeded 0.05, and no abnormal values were identified concurrently. Additionally, considering the variability across study conditions and populations, two-sample MR analyses may exhibit heterogeneity, potentially introducing bias to the causal effect results. Hence, we employed Cochran's Q test for IVW analysis method and MR-Egger regression were used in this study.
This study has both strengths and limitations. This two-sample MR study, utilizing genetic variation as IVs, is effective in mitigating the impact of unknown confounding factors and addressing reverse causality measurement errors. Moreover, all F-statistics values exceeded 50, indicating high instrument strength for MetS and its component IVs, with minimal susceptibility to weak instrumental bias. Nevertheless, we must acknowledge several limitations. Firstly, the exposure and outcome dataset in this study only includes information for Europeans, thereby restricting the generalizability of our findings. However, it is important to note that this limitation mitigates the potential for bias arising from population stratification. Secondly, we did not conduct external validation of the results. We hope that in future studies, external data can be employed for validation to enhance the robustness of the evidence. Despite presenting evidence contrary to previous studies, the exact mechanism remains unclear. Lastly, the nature of the MR study constrained us from conducting a sex-stratified analysis. A question arises as to whether the same conclusions can be drawn for both males and females. Consequently, we advocate for further prospective studies to elucidate causality in the future.
In conclusion, our findings do not support that susceptibility to MetS and its components influences the risk of LBP in Europeans. Instead, the observed correlations may arise from shared genetic effects or environmental confounders.