The mediating role of the genetically predicted N6, N6, N6-trimethyllysine levels in the association between HLA DR on CD14- CD16+ monocytes and ankylosing spondylitis.

This study explores the hidden connection between HLA DR on CD14- CD16+ monocytes and ankylosing spondylitis (AS), with a particular emphasis on investigating and measuring the impact of 1091 blood metabolites as potential mediators. We harnessed the power of summary-level data extracted from a comprehensive genome-wide association study to delve into the intricate relationship between genetically predicted HLA DR on CD14- CD16+ monocytes (3621 cases) and AS (1193 cases and 374,621 controls). Furthermore, we employed a two-step Mendelian randomization (MR) methodology to elucidate the extent to which blood metabolites contribute to the effects observed in CD14- CD16+ monocytes, ultimately influencing the development of AS. This methodological approach provides a comprehensive and rigorous exploration of the interplay between blood metabolites and AS, shedding light on the underlying mechanisms governing this intricate association. Through MR analysis, our investigation revealed an increase in HLA DR on CD14- CD16+ monocytes within plasma, which correspondingly led to a reduction in the incidence of AS. The primary MR analysis yielded an odds ratio of 0.64 with a 95% confidence interval spanning from 0.53 to 0.78, underscoring the protective effect of elevated HLA DR on CD14- CD16+ monocytes against the development of AS. Furthermore, our study found no compelling evidence to suggest that AS exerts any discernible influence on HLA DR on CD14- CD16+ monocytes. Instead, our investigation identified N6, N6, N6-trimethyllysine levels (TML), a blood metabolite, as the sole mediator in the relationship between HLA DR on CD14- CD16+ monocytes and AS. Notably, the genetic prediction of AS mediated by TML accounted for a substantial -2.98% proportion of the observed variance. Our investigation has delineated a causal association between HLA DR on CD14- CD16+ monocytes and AS. Specifically, HLA DR on CD14- CD16+ monocytes exhibited a protective effect against the development of AS. Conversely, AS mediated by TML emerged as a risk factor, though the precise impact of HLA DR on CD14- CD16+ monocytes on AS pathogenesis remains enigmatic. It is imperative to embark on further investigations into potential mediators. In a clinical setting, it is imperative to carefully monitor the patient's HLA DR on CD14- CD16+ monocytes levels.