The Association Between Low Back Pain and Composition of IgG Glycome

Abstract

Low back pain (LBP) is a common debilitating condition which aetiology and pathogenesis are poorly understood. We carried out a first so far analysis of associations between LBP and plasma IgG N-glycome in a sample of 4511 twins from TwinsUK database assessed for LBP, lumbar disc degeneration (LDD) as its possible cause, and IgG-glycan levels. Using weighted correlation network analysis, we established a correlation between LBP and glycan modules featured by glycans that either promote or block antibody-dependent cell-mediated cytotoxicity (ADCC). The levels of four glycan traits representing two of those modules were statistically significantly different in monozygotic twins discordant for LBP. Also, the trend to higher prevalence of systemic inflammatory disorders was shown for twins with low level of fucosylated glycans and high level of non-fucosylated glycans. Core fucosylation of IgG is a "safety switch" reducing ADCC, thus our results suggest the involvement of ADCC and associated inflammation in pathogenesis of LBP. No correlation between LDD scores and glycans was found assuming that the inflammation may not be a part of LDD. These data provide a new insight into understanding the complex pathophysiology of LBP and suggest glycan levels as a possible biomarker for inflammation-related subtypes of LBP.

Figure 1. P-values (−log10) for the analysis of associations between glycan levels and low back pain.

Linear mixed models were used to estimate the associations using LBP status, BMI, sex, and major inflammatory disease status as fixed factors and family status as a random factor.

Figure 2. Modules of correlated glycans obtained using WGCNA methodology.

Figure 3. Relationships between modules of correlated glycans.

Figure 4. Correlations between module eigenvalues and pain phenotypes.

Correlations were calculated between module eigenvalues (vector of first principal component of glycans in a module) and low back pain (LBP) using point-biserial correlation coefficient and summary score for magnetic resonance imaging signs for lumbar spine (LSUM) using Pearson correlation coefficients. Corresponding p-values are provided in brackets.

Figure 5. Average glycan significance across modules for LBP.

Glycan significance was defined as the average coefficient of correlation between a trait and glycan levels in a module; p-value is given for Kruskal-Wallis test for the difference of glycan significance across the modules.

Figure 6. P-values (−log10) for comparisons of mean glycan levels in MZ twins discordant for LBP phenotype by paired t-test.

Red line corresponds to p = 0.0027 which was taken as the significance threshold based on the 19 effective independent tests with Sidak’s correction for multiple testing.

Figure 7. Glycan levels in MZ twins discordant for LBP phenotype.

Figure 8. The prevalence of systemic inflammatory disorders (rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, and Crohn’s disease) in twins with high and low levels of glycans and discordant for LBP.

The cut off points for glycans levels were set at 25% and 75% quintile for the corresponding distribution.