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Original Article · Open access

Causal associations of specific immunoglobulin G N-glycosylation subtypes with osteoporosis: A two-sample Mendelian randomization

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Yu Zhao

Department of Endocrinology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Geriatric Medicine Center, Hangzhou, China

ORCID: 0000-0002-3904-4276

Yimiao Zhu

Department of Gastroenterology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Center for General Practice Medicine, Hangzhou, China

ORCID: 0000-0002-1745-4063

Wei Zhang

Department of Endocrinology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Geriatric Medicine Center, Hangzhou, China

ORCID: 0000-0003-0459-5382

Lijun Wang

Department of Endocrinology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Geriatric Medicine Center, Hangzhou, China

ORCID: 0009-0004-2954-3049

Chenyan Yan

Department of Endocrinology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Geriatric Medicine Center, Hangzhou, China

ORCID: 0000-0002-0328-4964

Chaoyun Yuan

Information Center, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, China

ORCID: 0000-0002-4182-0908

Lijuan Wang

Department of Rheumatology and Immunology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Center for General Practice Medicine, Hangzhou, China

ORCID: 0000-0002-0864-8229

Abstract

Objectives: This study aims to examine whether genetically predicted immunoglobulin G (IgG) N-glycosylation patterns (IGPs) affect osteoporosis risk using a two-sample Mendelian randomization (MR) method.

Materials and methods: In a collaborative effort involving the Medical Research Council (MRC) Human Genetics Unit and the FinnGen consortium, we conducted genome-wide association studies (GWAS) to explore the relationship between 77 IGPs (8,090 samples) and osteoporosis (438,872 samples). Utilizing the inverse-variance weighted (IVW) method as our primary analytical tool, we delved into these complex genetic associations. To further substantiate our findings, we employed additional complementary methods such as MR-Egger, weighted median, and weighted mode. Sensitivity analyses, including MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO), MR-Egger, Cochran’s Q, and leave-one-out methods, were used to test the core MR assumptions and validate the robustness of the results. This multi-faceted approach allowed us to detect underlying causal relationships with greater confidence.

Results: The IGP4 exhibited a protective effect against osteoporosis with an odds ratio (OR) of 0.77 (95% confidence interval [CI]: 0.63-0.95, p=0.012). In contrast, IGP45 demonstrated a modest risk increase with an OR of 1.10 (95% CI: 1.01-1.19, p=0.021). Similarly, the results of the present MR study suggest that IGP56 also showed a protective trend, with an OR of 0.86 (95% CI: 0.78-0.96, p=0.006). To confirm our findings, we conducted rigorous sensitivity analyses utilizing MR-PRESSO, MR-Egger, Cochran’s Q, and leave-one-out methods. These analyses revealed no evidence of heterogeneity or horizontal pleiotropy, thereby reinforcing the robustness and reliability of our findings.

Conclusion: Our study results indicate that IgG45 contributes positively to osteoporosis, whereas IgG4 and IgG56 exhibit a negative correlation. Nonetheless, additional research is crucial to understand their mechanisms and devise broader preventive strategies for osteoporosis.

Declarations

Author Contributions

Carried out the studies, participated in collecting data, and drafted the manuscript: Y.Z., Y.M.Z.; Performed the statistical analysis and participated in its design: C.Y.Y., C.Y.Y.; Participated in acquisition, analysis, or interpretation of data and draft the manuscript: W.Z., L.J.W.; Designed the study, supervised the research and revised the manuscript: L.J.W. All authors read and approved the final manuscript.

Conflict of Interest

The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Financial Disclosure

This study was supported by Medical and Health Science and Technology Project of Zhejiang Province (grant number 2025KY552)--Lijuan Wang; Zhejiang Provincial Department of Education General Project (Y202146105); Medical and Health Science and Technology Project of Zhejiang Province (grant number 2022KY068)-- Wei Zhang.

Data Sharing Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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