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Lipid Metabolism, Methylation Aberrant, and Osteoporosis: A Multi-omics Study Based on Mendelian Randomization

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Abstract

Background

Observational studies have shown a causal association between dyslipidemia and osteoporosis, but the genetic causation and complete mechanism of which are uncertain. The disadvantage of previous observational studies is that they are susceptible to confounding factors and bias, that makes it difficult to infer a causal link between those two diseases. Abnormal epigenetic modifications, represented by DNA methylation, are important causes of many diseases. However, there are no studies showing a bridging role for methylation modifications in blood lipid metabolism and osteoporosis.

Methods

SNPs for lipid profile (Blood VLDL cholesterol (VLDL-C), blood LDL cholesterol (LDL-C), blood HDL cholesterol (HDL-C), blood triglycerides (TG), diagnosed pure hypercholesterolaemia, blood apolipoprotein B (Apo B), blood apolipoprotein A1(Apo A1)), and bone mineral density (BMD) in different body parts (Heel BMD, lumbar BMD, whole-body BMD, femoral neck BMD) were obtained from large meta-analyses of genome-wide association studies as instrumental variables for two-sample Mendelian randomization. Assessment of the genetic effects of lipid profile-associated methylation sites and bone mineral density was carried out using the summary-data-based Mendelian randomization (SMR) method.

Results

Two-sample Mendelian randomization showed that there was a negative causal association between hypercholesterolaemia and heel BMD (p = 0.0103, OR = 0.4590), and total body BMD (p = 0.0002, OR = 0.2826). LDL-C had a negative causal association with heel BMD (p = 8.68E-05, OR = 0.9586). VLDL-C had a negative causal association with heel BMD (p = 0.035, OR = 0.9484), lumbar BMD (p = 0.0316, OR = 0.9356), and total body BMD (p = 0.0035, OR = 0.9484). HDL-C had a negative causal association with heel BMD (p = 1.25E-05, OR = 0.9548), lumbar BMD (p = 0.0129, OR = 0.9358), and total body BMD (p = 0.0399, OR = 0.9644). Apo B had a negative causal association with heel BMD (p = 0.0001, OR = 0.9647). Apo A1 had a negative causal association with heel BMD (p = 0.0132, OR = 0.9746) and lumbar BMD (p = 0.0058, OR = 0.9261). The p-values of all positive results corrected by the FDR method remained significant and sensitivity analysis showed that there was no horizontal pleiotropy in the results despite the heterogeneity in some results. SMR identified 3 methylation sites associated with lipid profiles in the presence of genetic effects on BMD: cg15707428(GREB1), cg16000331(SREBF2), cg14364472(NOTCH1).

Conclusion

Our study provides insights into the potential causal links and co-pathogenesis between dyslipidemia and osteoporosis. The genetic effects of dyslipidaemia on osteoporosis may be related to certain aberrant methylation genetic modifications.

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Data Availability

GWAS summary data are from IEU OpenGWAS project (mrcieu.ac.uk). Data for all individuals have been uploaded to Tables 1–10 of Supplementary material.

Abbreviations

GWAS:

Genome-wide association study

BMD:

Bone mineral density

MR:

Mendelian randomization

Total.Body.BMD:

Whole-body bone mineral density

Heel.BMD:

Heel bone mineral density

Lumbar.BMD:

Lumbar bone mineral density

SMR:

Summary-data-based mendelian randomization

LDL-C:

Blood low-density lipoprotein cholesterol

VLDL-C:

Blood very low-density lipoprotein cholesterol

HDL-C:

Blood high-density lipoprotein cholesterol

TC:

Total cholesterol

TG:

Triglycerides

SNPs:

Single nucleotide polymorphism

IVW:

Inverse-variance weighted

GLGC:

Global Lipids Genetics Consortium

GEFOs:

GEnetic Factors for OSteoporosis Consortium

IV:

Instrumental variable

Apo B:

Apolipoprotein B

Apo A1:

Apolipoprotein A1

meQTL:

Methylation quantitative trait loci

MAF:

Minor allele frequency

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Acknowledgements

We thank all the researchers who provided publicly open GWAS summary data.

Funding

This work was supported by ShanXi Applied Basic Research Programme (Nos.201901D111409), Key Research and Development (R&D) Projects of Shanxi Province (No.201803D31134) and Taiyuan Science and Technology Programme (No.202201). All of the funding were gratefully acknowledged.

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Authors and Affiliations

  1. Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China

    ZhaoLiang Zhang & YuChen Duan

  2. Taiyuan Central Hospital, Ninth Hospital of Shanxi Medical University, Southern Fendong Road 256, Taiyuan, 030009, Shanxi, China

    JianZhong Huo

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Contributions

ZZ was responsible for the methodological design and data collation and visualisation of the figures. YD was responsible for the writing of the draft and grammatical touch-ups. JH provided the conceptualisation, revision and review of the draft and the financial support for the study. ZZ and YD contributed equally to the article.

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Correspondence to JianZhong Huo.

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Conflict of interest

Zhaoliang Zhang, Yuchen Duan and Jianzhong Huo declare that they have no conflict of interest.

Ethical Approval

This study was conducted in accordance with the Declaration of Helsinki. All cited GWAS and other data have been approved by the relevant review boards.

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All Human and Animal Rights and Informed Consent statements can be found from the original GWAS.

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Zhang, Z., Duan, Y. & Huo, J. Lipid Metabolism, Methylation Aberrant, and Osteoporosis: A Multi-omics Study Based on Mendelian Randomization. Calcif Tissue Int 114, 147–156 (2024). https://doi.org/10.1007/s00223-023-01160-6

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