DataSheet_7_Causality between sarcopenia and diabetic nephropathy: a bidirectional Mendelian randomization study.csv

Background and purposeObservational studies have shown that sarcopenia and diabetic nephropathy (DN), are closely related; however, the causal relationship is unclear. This study aims to address this issue using a bidirectional Mendelian randomization (MR) study.
MethodologyWe data from genome-wide association studies including appendicular lean mass (n = 244,730), grip strength (right: n = 461,089, left: n = 461026), walking speed (n = 459,915), and DN (3283 cases and 181,704 controls) to conduct a bidirectional MR study. First, we conducted a Forward MR analysis to evaluate the causality of sarcopenia on the risk of DN from the genetic perspective with appendicular lean mass, grip strength, and walking speed as exposure and DN as the outcome. Then, DN as the exposure, we performed a Reverse MR analysis to determine whether DN impacted the appendicular lean mass, grip strength, and walking speed of the appendices. Finally, a series of sensitivity studies, such as heterogeneity tests, pleiotropy evaluations, and Leave-one-out analyses, were conducted to assess the MR analysis’s accuracy further.
ResultsAccording to a forward MR analysis, a genetically predicted decrease in appendicular lean mass is associated with an increased risk of developing DN risk (inverse variance weighting[IVW]: odd ratio [OR] = 0.863, 95% confidence interval [CI] 0.767-0.971; P = 0.014). According to reverse MR results, grip strength decreased as DN progressed (IVW: right β = 0.003, 95% CI: - 0.021 to - 0.009, P = 5.116e-06; left β = 0.003, 95% CI: - 0.024 to - 0.012, P = 7.035e-09). However, the results of the other MR analyses were not statistically different.
ConclusionNotably, our findings suggest that the causal relationship between sarcopenia and DN cannot be generalized. According to analysis of the individual characteristic factors of sarcopenia, reducing in appendicular lean mass increases the risk of developing DN and DN is linked to reduced grip strength. But overall, there is no causal relationship between sarcopenia and DN, because the diagnosis of sarcopenia cannot be determined by one of these factors alone.

研究背景与目的：观察性研究已表明，肌肉减少症（sarcopenia）与糖尿病肾病（diabetic nephropathy, DN）密切相关，但二者的因果关联尚不明确。本研究拟采用双向孟德尔随机化（bidirectional Mendelian randomization, MR）研究方法，对这一问题展开探讨。
研究方法：本研究从全基因组关联研究（genome-wide association studies）中获取数据，涵盖四肢瘦体重（appendicular lean mass, n=244730）、握力（右侧：n=461089，左侧：n=461026）、步行速度（n=459915）以及糖尿病肾病（3283例病例及181704例对照），以此开展双向孟德尔随机化研究。首先，我们进行正向孟德尔随机化分析，以四肢瘦体重、握力及步行速度作为暴露因素，以糖尿病肾病作为结局指标，从遗传学视角评估肌肉减少症对糖尿病肾病发病风险的因果效应。随后，以糖尿病肾病作为暴露因素，我们开展反向孟德尔随机化分析，以明确糖尿病肾病是否会对四肢瘦体重、握力及步行速度产生影响。最后，通过异质性检验、多效性评估、留一法分析等一系列敏感性研究，进一步验证孟德尔随机化分析结果的可靠性。
研究结果：正向孟德尔随机化分析结果显示，遗传预测的四肢瘦体重降低与糖尿病肾病发病风险升高存在显著关联（逆方差加权[IVW]分析：比值比[OR]=0.863，95%置信区间[CI]：0.767~0.971；P=0.014）。反向孟德尔随机化分析结果表明，随着糖尿病肾病进展，握力出现显著下降（IVW分析：右侧β=0.003，95%CI：-0.021~-0.009，P=5.116×10^-6；左侧β=0.003，95%CI：-0.024~-0.012，P=7.035×10^-9）。但其余孟德尔随机化分析结果未达到统计学显著性差异。
研究结论：值得注意的是，本研究结果提示，肌肉减少症与糖尿病肾病之间的因果关联并不能一概而论。针对肌肉减少症的各项特征性指标分析显示，四肢瘦体重降低会升高糖尿病肾病的发病风险，而糖尿病肾病与握力下降存在关联。但总体而言，肌肉减少症与糖尿病肾病之间并不存在明确的因果关联，这是因为肌肉减少症的临床诊断无法仅通过单一指标进行判定。