Causal Relationship of Genetically Predicted Serum Micronutrients Levels With Sarcopenia: A Mendelian Randomization Study

Abstract

ObjectivesPrevious observational studies have suggested associations between concentrations of several circulating micronutrients and sarcopenia. However, the causality inferred from those studies was subjected to residual confounding and reverse causation. Therefore, we aimed to examine the causal effects of the levels of genetically predicted serum micronutrients on sarcopenia.MethodsSingle nucleotide polymorphisms (SNPs) were chosen from large-scale genome-wide association studies of participants only with European descent and were used as genetic instruments for the levels of 10 serum micronutrients (calcium, magnesium, selenium, copper, iron, zinc, Vitamin A, Vitamin B12, Vitamin D, and Vitamin E). Sarcopenia was defined by referencing to the 2019 definition given by the European Working Group on Sarcopenia in Older People (EWGSOP). A two-sample Mendelian randomization (MR) analysis was carried out to examine the associations between the levels of genetically predicted serum micronutrients and the risk of sarcopenia. Then, sensitivity analyses (including weighted median, MR-Egger and leave-one-out sensitivity analyses) were performed to evaluate the robustness of study findings. The estimates were presented as odds ratio (OR) with their 95% confidence intervals (CIs) per one standard deviation (SD) increase in the exposures.ResultsA total of 378,635 UK Biobank participants, including 572 participants who were identified with sarcopenia, were included in this study. The iron status was shown to have a clear effect on the risk of sarcopenia based on MR analyses. The per one SD increment in the genetically-determined serum iron level corresponded to a 53% increase in the risk of sarcopenia (OR = 1.53, 95% CI: 1.31–1.78, P = 0.001). The exclusion of SNPs of the circulating iron level (i.e., rs1799945 SNP, rs1800562 SNP or rs855791 SNP) did not attenuate the magnitude of the signal in MR analysis. There was little evidence supporting the associations between other remaining micronutrients and sarcopenia.ConclusionsAn increased risk of sarcopenia was observed with a genetically higher concentration of iron, suggesting that iron may play a role in the occurrence or development of sarcopenia.

Assessing the causal association between human blood metabolites and grip strength：a mendelian randomization analysis

“…Our study revealed that the in uence of 3-dehydrocarnitine and hyodeoxycholate on grip strength disappeared after correcting for obesity and type 2 diabetes. A recent MR study also analyzed the causal relationship between blood metabolites and grip strength, and the results were similar to our study [33]. Univariate MR analysis revealed that 3-dehydrocarnitine and hyodeoxycholate were causally related to grip strength, but a previous study did not perform multivariate MR analysis to correct for the impact of obesity and diabetes.…”

Genetic Variants, Serum 25-Hydroxyvitamin D Levels, and Sarcopenia

“…The association of vitamin D levels with sarcopenia or its related indices has previously been investigated in 4 MR studies . Three of them used the standard MR analysis .…”

“…The association of vitamin D levels with sarcopenia or its related indices has previously been investigated in 4 MR studies. 37 , 38 , 39 , 40 Three of them used the standard MR analysis. 38 , 39 , 40 One study reported a null association between 25(OH)D and sarcopenia risk, 38 and the other 2 showed a beneficial effect of 25(OH)D on grip strength 39 and lean mass.…”

“… 37 , 38 , 39 , 40 Three of them used the standard MR analysis. 38 , 39 , 40 One study reported a null association between 25(OH)D and sarcopenia risk, 38 and the other 2 showed a beneficial effect of 25(OH)D on grip strength 39 and lean mass. 40 However, these studies only used 6 SNVs as instruments to infer serum 25(OH)D levels, which might be hindered by the low power to predict low serum 25(OH)D concentration.…”

The syndromic triad of COVID-19, type 2 diabetes, and malnutrition

“…Likewise, branched-chain amino acids, polyunsaturated fatty acids, selenium, vitamin D, and zinc can reduce oxidative stress, support mitochondrial homeostasis, and mitigate low-grade inflammation, thus suggesting their potential roles in the treatment of sarcopenia ( 128 ). To the contrary, however, a Mendelian randomization analysis shows little effect from these nutrients with the exception of a genetically high concentration of serum iron, which increased sarcopenia risk ( 129 ).…”