Effects of Sex and Obesity on LEP Variant and Leptin Level Associations in Intervertebral Disc Degeneration

Abstract

Intervertebral disc degeneration (IVDD), for which obesity and genetics are known risk factors, is a chronic process that alters the structure and function of the intervertebral discs (IVD). Circulating leptin is positively correlated with body weight and is often measured to elucidate the pathogenesis of IVD degeneration. In this study, we examined the associations of LEP single nucleotide polymorphisms (SNPs) genetic and environmental effects with IVDD. A total of 303 Taiwanese patients with IVDD (mean age, 58.6 ± 12.7 years) undergoing cervical discectomy for neck pain or lumbar discectomy for back pain were enrolled. Commercially available enzyme-linked immunosorbent assay (ELISA) kits measured the circulating plasma leptin levels. TaqMan SNP genotyping assays genotyped the LEP SNPs rs2167270 and rs7799039. Leptin levels were significantly increased in obese individuals (p < 0.001) and non-obese or obese women (p < 0.001). In the dominant model, recoded minor alleles of rs2167270 and rs7799039 were associated with higher leptin levels in all individuals (p = 0.011, p = 0.012). Further, the association between these LEP SNPs and leptin levels was significant only in obese women (p = 0.025 and p = 0.008, respectively). There was an interaction effect between sex and obesity, particularly among obese women (interaction p = 0.04 and 0.02, respectively). Our findings demonstrate that these SNPs have sex-specific associations with BMI in IVDD patients, and that obesity and sex, particularly among obese women, may modify the LEP transcription effect.

Comparative histopathological analysis of age‐associated intervertebral disc degeneration in CD‐1 and C57BL/6 mice: Anatomical and sex‐based differences

“…Sex‐related differences have likewise been reported in rat models of IVD degeneration, demonstrating increased AF degeneration in females compared to males following annular puncture, 48 as well as sex‐based differences in the relationship between degeneration and pain 49 . Interestingly, recent studies in humans have begun to explore the associations between risk factors for IVD degeneration, highlighting the interaction between sex and factors including genetic polymorphisms and obesity and the role of sex hormones 50,51 . Taken together, these findings further underscore the importance of evaluating sex as a biological factor for the development of age‐associated IVD degeneration in the identification of disease‐associated factors or the assessment of potential therapeutic interventions in murine models.…”

“…49 Interestingly, recent studies in humans have begun to explore the associations between risk factors for IVD degeneration, highlighting the interaction between sex and factors including genetic polymorphisms and obesity and the role of sex hormones. 50,51 Taken together, these findings further underscore the importance of evalu- Despite the design of a longitudinal study that evaluated four groups of mice at four time points each from a total of over 80 mice and approximately 2400 IVDs, our study was associated with a number of limitations. First, our analysis was limited to that of two mouse strains commonly used for the generation of gene-modified mice but did not include additional strains that have been previously investigated in the context of IVD degeneration such as the SM/J or LG/J mice which demonstrate differences in regenerative capacities.…”

Leptin in Relation to Degenerative orthopaedic diseases: A Two-Sample Mendelian Randomization Study

“…Nonetheless, after adjusting body mass index (BMI) and other BMD-related factors, the results showed that the differences were not statistically significant. The same is true for leptin and KOA, LDH studies [28][29][30][31][32][33] . Obviously, the available evidence from epidemiological studies has the limitations of small sample size, variable population selection, and many confounding factors.…”

Assessing the causal relationship between CRP,IL-1α, IL-1β, and IL-6 levels and intervertebral discdegeneration: a two-sample Mendelianrandomization study

“…Then, the MR Pleiotropy RESidual Sum andOutlier (MR-PRESSO) method were used to eliminate potential outliers before each MR analysis 26 . Finally, in order to satisfy the second key assumption of MR (independence from confounders), we scanned each of the SNPs used as IVs for their potential secondary phenotypes using the GWAS Catalog ( https://www.ebi.ac.uk/gwas), then the significant associations of the selected SNPs with IVDD (P < 5e − 8) were excluded, including BMI, obesity and serum leptin levels 27,28 . After a thorough screening, the remaining SNPs were used for subsequent analyses.…”