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. 2022 Jul 18:13:942878.
doi: 10.3389/fendo.2022.942878. eCollection 2022.

HemoglobinA1c Is a Risk Factor for Changes of Bone Mineral Density: A Mendelian Randomization Study

Xiaoxiao Ji  1   2   3 , Jianqiao Hong  4   2   3 , Zihao Qu  4   2   3 , Weinan Yang  4   2   3 , Yibo Wang  4   2   3 , Jiyan Lin  4   2   3 , Congsun Li  4   2   3 , Jie Wang  1   2   3 , Haochen Mou  4   2   3 , Mingmin Shi  4   2   3 , Chenhe Zhou  4   2   3 , Wei Wang  4   2   3 , Changjian Lin  4   2   3 , Shigui Yan  4   2   3 , Haobo Wu  4   2   3
Affiliations

HemoglobinA1c Is a Risk Factor for Changes of Bone Mineral Density: A Mendelian Randomization Study

Xiaoxiao Ji et al. Front Endocrinol (Lausanne). .

Abstract

Background: As a valuable blood glucose measurement, HemoglobinA1c (HbA1c) is of great clinical value for diabetes. However, in previous observational studies, studies on its effect on bone mineral density (BMD) have different results. This study aimed to use Mendelian randomization (MR) to assess the effect of HbA1c on bone mineral density and fracture risk, and try to further explore whether this association was achieved through glycemic or non-glycemic factors.

Methods: Take HbA1c measurement as exposure, and BMD estimated from quantitative heel ultrasounds (eBMD) and bone fractures as outcomes. Two-Sample MR Analysis was conducted to assess the causal effect of HbA1C on heel BMD and risk fracture. Then, we performed the analysis using two subsets of these variants, one related to glycemic measurement and the other to erythrocyte indices.

Results: Genetically increased HbA1C was associated with the lower heel eBMD [odds ratio (OR) 0.91 (95% CI 0.87, 0.96) per %-unit, P = 3 × 10-4(IVW)]. Higher HbA1C was associated with lower heel eBMD when using only erythrocytic variants [OR 0.87 (0.82, 0.93), P=2× 10-5(IVW)]; However, when using only glycemic variants, this casual association does not hold. In further MR analysis, we test the association of erythrocytic traits with heel eBMD.

Conclusion: Our study revealed the significant causal effect of HbA1c on eBMD, and this causal link might achieve through non-glycemic pathways (erythrocytic indices).

Keywords: bone mineral density; hemoglobin; hemoglobinA1c; mendelian randomization; osteoporosis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Causal effect on eBMD in UKBB of increased A1C instrumented by all A1C-associated genetic variants, glycemic-only A1C variants, and erythrocytic-only A1C variants. MR analysis were performed by the IVW and WM methods. Effect estimates are OR of eBMD per %-unit increase in A1C.
Figure 2
Figure 2
Causal effect on Bone fracture in UKBB of increased A1C instrumented by all A1C-associated genetic variants, glycemic-only A1C variants, and erythrocytic-only A1C variants. MR analysis were performed by the IVW and WM methods. Effect estimates are OR of Bone fracture per %-unit increase in A1C.
Figure 3
Figure 3
Causal effect on eBMD in UKBB of increased erythrocytic traits, including genetic variants of Hb, HCT and MCV. MR analysis were performed by the IVW and WM methods. Effect estimates are OR of eBMD per %-unit increase in erythrocytic traits.
Figure 4
Figure 4
The genetic casual effect of HbA1c on eBMD is represented by an MR diagram of glycemic and erythrocytic factors. Generally, increased HbA1C when instrumented by all HbA1c genetic variants was associated with lower heel eBMD; Increased HbA1c when instrumented by erythrocytic HbA1c variants was associated with lower heel eBMD. Moreover, decreased hemoglobin was associated with lower heel eBMD. The causal association of lower Hb with higher HbA1c has been shown in the literature (25), so the MR analysis was not performed.
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