Pilot Study on Genetic Associations With Age-Related Sarcopenia

Abstract

Despite strong evidence of an inheritable component of muscle phenotypes, little progress has been made in identifying the specific genetic factors involved in the development of sarcopenia. Even rarer are studies that focus on predicting the risk of sarcopenia based on a genetic risk score. In the present study, we tested the single and combined effect of seven candidate gene variants on the risk of sarcopenia. Single nucleotide polymorphisms in candidate genes were genotyped using the KASP assay. We examined 190 older adults that were classified as non-sarcopenic or sarcopenic according to the diagnostic criteria of the European Working Group on Sarcopenia in Older People. Sarcopenia was associated with Methylenetetrahydrofolate reductase, Alpha-actinin-3, and Nuclear respiratory factor 2 genotypes. The combined effect of all three polymorphisms explained 39% of the interindividual variation in sarcopenia risk. Our results suggest that the single and combined effect of Methylenetetrahydrofolate reductase, Alpha-actinin-3, and Nuclear respiratory factor 2 polymorphism is associated with sarcopenia risk in older adults. Nowadays, as the population is getting older and older, great efforts are being made to research the etiology, diagnosis and treatment of sarcopenia. At the same time, small progress has been made in understanding the genetic etiology of sarcopenia. Given the importance of research on this disease, further genetic studies are needed to better understand the genetic risk underlying sarcopenia. We believe that this small-scale study will help to demonstrate that there is still much to be discovered in this field.

Keywords: ACTN3; MTHFR; NRF2; genetic factors; sarcopenia.

FIGURE 1

The representative images show the result of three single nucleotide polymorphisms (SNPs) associated with sarcopenia in older adults. Each image represents two groups of participants – non-sarcopenic and sarcopenic. (A) The study identifies the C allele of polymorphic variants (rs1801131 A/C) of the MTHFR gene as a risk factor for sarcopenia in older adults. The Chi-square association test showed significantly higher frequencies of the C allele in sarcopenic participants than in controls (57% vs. 28%, p < 0.001). The C-allele carriers had 3.3 increased odds ratios for the likelihood of being sarcopenic compared to the A-allele carriers. (B) The X allele of ACTN3 R577X (rs1815739 R/X) was associated with sarcopenia risk in older adults. The Chi-square association test showed significantly higher frequencies of the X allele in sarcopenic participants than in controls (60.0 vs. 42%, p = 0.003). The X allele carriers had 2.0 increased odds ratios for the likelihood of being sarcopenic compared to R allele carriers. (C) The C allele of NRF2 (rs12594956 A/C) was identified as a risk factor for sarcopenia in older adults. The Chi-square association test demonstrated significantly higher frequencies of the C allele in sarcopenic participants than in controls (65 vs. 49%, p = 0.009). The C-allele carriers had 1.9 increased odds ratios for the likelihood of being sarcopenic compared to carriers of the A allele.

FIGURE 2

The representative images reveal the result of risk prediction based on a total genetic risk score for sarcopenia with the combined effect of all three (MTHFR, ACTN3, and NRF2) gene polymorphisms associated with sarcopenia in older adults. Each image represents a group of participants - non-sarcopenic and sarcopenic. We found a significantly higher total genetic risk score in sarcopenic participants compared to controls (62% vs. 39%, p < 0.001). Older adults with a genetic risk score of ≥58.3% had 1.9 increased odds ratios for the likelihood of being sarcopenic compared to those with a lower total sarcopenia genetic risk score.

FIGURE 3

The image shows the identified genetic factors in individuals with sarcopenia compared to controls. The single and combined effect of MTHFR C (rs1801131 A/C), ACTN3 X (rs1815739 R/X), and NRF2 C (rs12594956 A/C) polymorphisms is associated with sarcopenia risk in older adults (Figure created using BioRender).