DataSheet_2_HemoglobinA1c Is a Risk Factor for Changes of Bone Mineral Density: A Mendelian Randomization Study.docx

BackgroundAs 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.
MethodsTake 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.
ResultsGenetically 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.
ConclusionOur study revealed the significant causal effect of HbA1c on eBMD, and this causal link might achieve through non-glycemic pathways (erythrocytic indices).

研究背景
糖化血红蛋白A1c（HemoglobinA1c, HbA1c）作为重要的血糖检测指标，对糖尿病的临床诊疗具有极高价值。然而既往观察性研究中，关于HbA1c对骨密度（Bone Mineral Density, BMD）的影响，所得结论并不一致。本研究旨在采用孟德尔随机化（Mendelian Randomization, MR）方法，评估HbA1c对骨密度及骨折风险的因果效应，并进一步探索该关联是否通过血糖相关或非血糖相关因素介导。

研究方法
本研究以HbA1c作为暴露因素，以定量足跟超声估算的骨密度（estimated BMD, eBMD）及骨折作为结局指标。采用双样本孟德尔随机化分析，评估HbA1c对足跟骨密度及骨折风险的因果效应。随后，我们基于两类遗传变异亚组开展分析：一类与血糖指标相关，另一类与红细胞指标相关。

研究结果
遗传水平升高的HbA1c与足跟eBMD降低显著相关[比值比（OR）=0.91，95%置信区间（CI）：0.87~0.96，每1%单位，逆方差加权（IVW）法P=3×10^-4]。仅使用红细胞相关遗传变异进行分析时，更高的HbA1c水平仍与足跟eBMD降低相关[OR=0.87，95%CI：0.82~0.93，IVW法P=2×10^-5]；但仅使用血糖相关遗传变异时，该因果关联并不成立。在进一步的孟德尔随机化分析中，我们验证了红细胞性状与足跟eBMD的关联。

研究结论
本研究揭示了HbA1c对eBMD存在显著的因果效应，该因果关联可能通过非血糖通路（红细胞指标）介导。