Effect of L-Carnitine Level on the Risk of Neuromyelitis Optica Spectrum Disorders: A Two-Sample Mendelian Randomization Study

Abstract

Abstract Background and Objectives Previous research has often focused on studying the CNS damage in neuromyelitis optica spectrum disorders (NMOSD), while the role of the peripheral blood in the development of NMOSD is also of significant importance. The relationship between metabolites in blood and cerebrospinal fluid (CSF) with neuroimmune is receiving increasing attention. A study showed that the level of L-carnitine, a metabolite involved in the metabolism of fatty acid, in the plasma of NMOSD patients was lower than that of the healthy control group. Another study showed that L-carnitine, whose astrocytic accumulation is associated with neurodegeneration and neuroinflammation, may participate in the pathogenesis of NMOSD. However, whether circulating L-carnitine level has a causal effect on NMOSD risk needs elucidation. With large data sets now available, we used two-sample Mendelian randomization (MR) to determine whether circulating L-carnitine level is causally associated with the risk of NMOSD. Methods We used genetic variants from one distinct genome-wide association study (GWAS) for circulating L-carnitine level in up to 7,797 individuals in TwinsUK and KORA F4 and for combined NMOSD (1,459, 215 cases and 1,244 controls), AQP4-IgG-seropositive NMOSD (1,376, 132 cases and 1,244 controls) and AQP4-IgG-seronegative NMOSD (1,327, 83 cases and 1,244 controls) from a GWAS in 1,459 individuals in United States dataset. Applying two-sample MR, we examined associations of circulating L-carnitine level and the risk of NMOSD, AQP4-IgG-seropositive NMOSD and AQP4-IgG-seronegative NMOSD. Results 16 SNPs were significantly associated with circulating L-carnitine level (P < 5×10− 8), all of which were independent and available in the NMOSD dataset, after 1 SNP removed for being palindromic with intermediate allele frequencies in harmonization. Finally, a high circulating L-carnitine level conferred a protective effect against combined NMOSD (OR = 2.216×10− 4, 95% confidence interval [CI] = 2.335×10− 7 − 2.104×10− 1, P = 0.0161) as well as AQP4-IgG-seronegative NMOSD (OR = 7.678×10− 7, 95%CI = 2.233×10− 11 − 2.640×10− 2, P = 0.0082). There is no causal effect on AQP4-IgG-seropositive NMOSD risk (OR = 5.471×10 − 3, CI = 1.090×10 − 6–27.465, P = 0.2798) by circulating L-carnitine. Results remained positive and robust after the horizontal pleiotropy test, heterogeneity test and Bonferroni test. Conclusion Our study demonstrates that circulating L-carnitine level may decrease the risk of NMOSD, particularly in AQP4-IgG-seronegative NMOSD. The circulating L-carnitine level appears to be a candidate biomarker and a new drug target for NMOSD. Given limited biomarkers to discriminate AQP4-IgG-seronegative NMOSD from AQP4-IgG-seropositive NMOSD and interventions to prevent NMOSD prevalence, this could have significant implications for global public health because of the increasing burden of NMOSD worldwide. It also provides a potential treatment strategy for NMOSD and AQP4-IgG-seronegative NMOSD. This study provides genetic evidence supporting the potential therapeutic benefits of targeting the three druggable genes for AD treatment, which will be useful for prioritizing AD drug development.