DNA Methylation, SERPING1 Expression, and Immune-related Traits in Osteoporosis: A Mendelian Randomization Study And Supportive Ex Vivo Evidence.

Abstract

INTRODUCTION: Osteoporosis (OP) is a major public health burden; however, the role of SERPIN family proteins remains incompletely understood. This study aimed to investigate genetically inferred associations between SERPINs and OP and to explore potential regulatory relationships. METHODS: Genome-wide association study (GWAS) summary statistics were used to perform two-sample Mendelian randomization (MR) and summary-data-based Mendelian randomization (SMR) analyses. Primary MR estimates were derived using inverse-variance-weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode methods. Cancellous bone tissue from the greater trochanter of the femur was collected from three patients with OP and three non-osteoporotic controls. qPCR and WB were used to analyze the whole bone homogenate, IHC was used to detect decalcified bone sections, and mediation analysis was used to explore potential regulatory associations. RESULTS: Among the proteins of the SERPIN family, only SERPING1 had an obvious positive correlation with the risk of osteoporosis (OR = 1.06, P = 0.0012). qPCR, WB, and IHC analyses demonstrated increased SERPING1 mRNA and protein expression in bone tissue from OP patients. Mediation analyses suggested that cg15918732 DNA methylation may serve as an upstream regulatory factor for SERPING1 expression. In addition, the downstream associations also consist of the alteration of immune cell conditions, like the decrease in the quantity of natural killer cells and T cells, and the rise in the level of mononuclear cells, and so forth. DISCUSSION: These findings provide genetic evidence for the possible role of SERPING1 in OP, which may be achieved through epigenetic regulation and immune pathways. Due to the corresponding characteristics of genetic inference and the small sample size, these results are hypothetical and generative. CONCLUSION: This study shows that DNA methylation of cg15918732 may be associated with SERPING1 expression in osteoporosis and immune-related traits. These findings provide new insights into potential epigenetic and immunological pathways in osteoporosis, which may contribute to future mechanistic and translational research.