Association between antibody-mediated immune responses of herpesvirus and osteoporosis: Mendelian randomization study

Recently, several cohort studies and case-control studies have revealed an association between herpesvirus (HV) and osteoporosis (OP), while the underlying mechanisms remain unclear. The HV-triggered immune responses may be significant in this relationship. Elucidating the contribution and mechanisms of HV-triggered immune responses in OP provides novel insights into the pathogenesis of this condition and promising therapeutic or preventive strategies for OP. We performed a 2-sample Mendelian randomization (MR) analysis using publicly available genome-wide association studies statistics. The inverse-variance weighted (IVW) method, MR-Egger regression, simple mode, weighted median, and weighted mode were applied in this MR analysis. Subsequently, we conducted leave-one-out sensitivity analysis, MR-Egger regression, and Cochran's Q test to assess the stability, horizontal pleiotropy and heterogeneity within the MR framework, respectively. The IVW MR analysis showed significant effects of HV phenotypes on OP (anti-herpes simplex virus 1 IgG seropositivity: IVW odds ratio (OR) = 1.06, P = .04287; varicella zoster virus glycoproteins E and I antibody levels: IVW OR = 1.10, P = .00210; Epstein-Barr virus EA-D antibody levels: IVW OR = 0.86, P = .00016; Epstein-Barr virus EBNA-1 antibody levels: IVW OR = 0.92, P = .00548; human herpesvirus 6 IE1A antibody levels: IVW OR = 0.90, P = .02745). Importantly, the results of other MR analysis except MR-Egger regression were consistent with IVW results. Our analysis indicated that 3 distinct HV antibodies were independently associated with OP in a causal manner, providing new insights into the involvement of viral infections in OP progression via affecting bone density and strength.