Sex hormones and neuromyelitis optica spectrum disorder: a bidirectional Mendelian randomization study

Yaxian Hu; Fei Zou; Wei Lu

doi:10.1007/s10072-024-07501-z

Sex hormones and neuromyelitis optica spectrum disorder: a bidirectional Mendelian randomization study

Neurol Sci. 2024 Apr 2. doi: 10.1007/s10072-024-07501-z. Online ahead of print.

Authors

Yaxian Hu^#¹, Fei Zou^#^{2

3

4}, Wei Lu⁵

Affiliations

¹ Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
² Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
³ Research Center of Digestive Disease, Central South University, Changsha, 410011, China.
⁴ Clinical Research Center for Digestive Disease in Hunan Province, Changsha, 410011, China.
⁵ Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China. luwei0338@csu.edu.cn.

^# Contributed equally.

PMID: 38565746
DOI: 10.1007/s10072-024-07501-z

Abstract

Background: Females are considered to have an increased susceptibility to neuromyelitis optica spectrum disorder (NMOSD) than males, especially aquaporin-4 (AQP4) antibody positive NMOSD, indicating that sex hormones may be involved in the NMOSD pathogenesis. However, the causality between sex hormones and NMOSD still remains unclear.

Methods: Based on the genome-wide association study (GWAS) data of three sex hormones (estradiol (E2), progesterone (PROG) and bioavailable testosterone (BAT)), sex hormone-binding globulin (SHBG), age of menarche, age of menopause, and NMOSD (total, AQP4 + and AQP4 -), we performed a two-sample bidirectional Mendelian randomization (MR) study. Sex-stratified GWAS data of E2, PROG, BAT, and SHBG was obtained for gender-specific MR analysis. Causal inferences were based on the inverse variance weighted method, MR-Egger regression, and weighted median method. The reverse MR analysis was also performed to assess the impact of NMOSD on hormone levels.

Results: PROG in females had aggravative effects on NMOSD (P < 0.001), especially AQP4 - NMOSD (P < 0.001). In the reverse MR analysis, total NMOSD was found to decrease the level of BAT (P < 0.001) and increase the level of SHBG (P = 0.001) in females.

Conclusion: Findings of this MR analysis revealed mutual causal associations between sex hormones and NMOSD, which provided novel perspectives about the gender-related pathogenesis of NMOSD.

Keywords: Mendelian randomization; Neuromyelitis optica spectrum disorder; Progesterone; Sex hormone; Testosterone.