This study, utilizing MR analysis based on data from the IEU open GWAS database and the FinnGen Biobank, explored the causal relationship between trunk and lower limb fat mass and IVDDs. The results indicated that an increase in both trunk fat mass and lower limb fat mass elevated the risk of IVDDs, identifying both as risk factors for the condition. This conclusion provided empirical support for the association between trunk and lower limb fat mass and IVDDs, offering insights for clinical prevention and treatment strategies.
Obesity is recognized as one of the pathogenic factors in spinal degenerative changes, primarily influencing IVDDs through adipokines released by fat and mechanical stress. BMI and fat mass are common metrics used to assess obesity, with localized fat mass proving more reliable for evaluating the degree of IVDDs in patients.
This study showed that increased trunk fat mass elevated the risk of IVDDs, primarily through two mechanisms: the release of adipose-derived substances and the mechanical stress exerted by additional body weight [31]. The mechanism by which obesity induces osteoarticular diseases may involve lipotoxicity, defined as the accumulation of free fatty acids in non-adipose tissues [32, 33]. In pathological states, adipose tissue releases adipocytokines that not only participate in energy metabolism but also induce the liver to produce pro-inflammatory factors. These inflammation-related factors may lead to a change in the spinal inflammatory environment, causing localized pain similar to that observed in diabetic patients [34, 35]. Beyond the release of adipocytokines, the impact of trunk fat mass on IVDDs might also be linked to fat infiltration. The multifidus muscle, crucial for lumbar spine stability and resisting spinal movements like rotation, may have its function compromised when infiltrated by adipose tissue, leading to reduced control over external loads, such as shear and sliding forces, thereby failing to maintain structural stability of the disc and causing IVDDs [36].
Similarly, the study noted that increased fat mass in the lower limbs also heightened the risk of IVDDs, affecting two main aspects: strength balance and support, and movement coordination. With the rise in fat mass, there could be a corresponding decrease in muscle mass or activity, as adipose tissue, while increasing body weight, does not contribute to muscular support. This reduction in muscle strength can place greater pressure on the lumbar spine, particularly affecting key muscles like the gluteus maximus and quadriceps, which are vital for pelvic stability and reducing lumbar stress. Additionally, an increase in fat can alter an individual’s gait and movement patterns, leading to uncoordinated actions that hinder the maintenance of the spine's natural curvature and alleviate lumbar load, thereby increasing the risk of IVDD. Previous research on the link between lower limb fat and IVDD is scarce, but including it as a risk factor in the assessment of obesity's impact on IVDD could propose new hypotheses and directions for research, offering better strategies for treatment and prevention.
Relying solely on observational studies to conclusively determine how fat mass and its distribution increase the risk of IVDDs and become a risk factor is impractical. This study employed MR as a novel epidemiological method, which offered several advantages: (1) Genetic variants used as instrumental variables were free from confounding factors such as social and lifestyle influences, making the results more reliable; (2) These genetic variants, based on Mendel's laws, preceded both exposure factors and outcome variables, thereby minimizing the possibility of reverse causation; (3) MR data came from publicly accessible research literature and databases, allowing for large sample sizes without ethical issues and achieving a level of randomness comparable to RCTs, thus lowering research costs while maintaining credible results.
However, the study had its limitations. Primarily, the data from the IEU GWAS database and the FinnGen Biobank database represented European populations, which might limit the generalizability of the conclusions to other ethnic groups. The reliance on European population data in GWAS databases was a major limiting factor for the external validity of the results, as data from Asian populations and other regions were insufficient for large-scale analysis. The proliferation of DNA sequencing and human genome technologies may help fill the gap in genetic variation data from other regions, potentially improving the prevention and treatment of human diseases. Moreover, the study did not differentiate between gender differences in abdominal and gluteal fat accumulation, which affected the shear forces the lumbar spine endures[37]. Fat mass was only categorized into trunk and lower limb without specific distinctions between abdominal and lower back areas, limited by the lack of individual-level data in the IEU GWAS database. Strict selection of instrumental variables minimized sample selection bias, ensuring robust and reliable results. Finally, the validation part of the study indicated heterogeneity, yet a significant number of SNPs were maintained after rigorous filtering. An excess number of SNPs may be a major source of heterogeneity, but this did not detract from the interpretation of the study results. Future research would focus on further refining data sources and optimizing analytical tools to provide more reliable evidence for epidemiological studies.
In summary, this study using two-sample MR revealed a positive causal association between trunk fat mass and IVDDs, as well as between lower limb fat mass and IVDDs. Previously, obesity assessments for disc degeneration primarily focused on BMI. This study's genetic-level analysis around fat volume and its primary distribution offered a new perspective on how obesity impacts IVDDs, suggesting that future clinical interventions and prevention of IVDDs should pay closer attention to fat mass and distribution.