This is a novel study that investigated whether TP53 rs1625895 (IVS6 + 62A > G) is associated with the increased risk of sarcopenia and sarcopenic obesity. The results of this study confirmed the outcomes in our previous study. Similarly, we displayed that age, waist circumference, calf circumference, BMI, ALM, FFM, FM, FM %, SMI, HGS, GS, FM/FFM, Albumin, Creatinine was significantly differed between sarcopenic and non-sarcopenic individuals. We also observed a significant difference between sarcopenic obesity and non sarcopenic obesity in the terms of waist circumference, calf circumference, BMI, ALM, FFM, FM, FM %, SMI, HGS, GS, FM/FFM, Creatinine and HDL. The major findings of our study is that G allele is the risk factor of sarcopenic obesity. In addition, carriers of G allele (GG + AG) had higher risk of sarcopenic obesity compared to non-carriers (AA). We also observed a significant association between TP53 rs1625895 polymorphism and BMI and LDL in our studied population. However, no significant association between TP53 rs1625895 polymorphism and the risk of sarcopenia was detected.
In the last decades, some studies investigated the role of various genes and signaling pathways that was susceptible in progression of obesity, osteoporosis, and insulin resistance (28). However, the genetic background of sarcopenia and sarcopenia related obesity in undefined yet.
The TP53 is a human gene that has been studied highly and comprehensively studied human gene since 40 years ago (29). TP53 plays a critical role in inhibiting cancer progress, and is considered as the “guardian of the genome” (30). Previous studies recommended that expression and activation of p53 protein play a role in maintaining muscle homeostasis like myoblasts differentiation (17, 31–33). It was also demonstrated that although p53-defective myoblasts had normal cell cycle but differentiation of these cells into myocytes and myotubes was deceased so that, it could be a possible mechanism underlying the role of p53 in skeletal muscle differentiation (34).
Now, several TP53 polymorphisms like intronic variations have been defined and considered as important regulator of TP53 expression that can stimulate the synthesis of TP53 protein with altered structural and functional characteristics. It is supposed that intronic variations may modify the gene function by interfering with RNA splicing and via the interaction between the DNA strand and protein molecules (35). On of this functional polymorphism is located in the intron 6 of the TP53 gene (rs1625895) and lead to the change of guanine for adenine on the site of the restriction endonuclease MspI. This polymorphism was established to modify the expression of protein p53 (36, 37), however, the exact mechanism is unclear. It was proposed that rs1625895 may influence splicing or transcription factor binding or may be a target site for regulatory miRNAs (35). Mavridou et al (1998) recommended that the impact of rs1625895 on TP53 function is through modifying the secondary structure of the pre-mRNA (38).
The association between TP53 rs1625895 polymorphism (IVS6 + 62A > G) and susceptibility to sarcopenia and sarcopenia-related obesity has not been investigated previously. Here, we detected that G allele increased the risk of sarcopenic obesity of about 1.9 fold higher than A allele. Furthermore, in logistic regression analysis, we observed that when GG genotype was compared to AG/AA genotype, the risk of sarcopenic obesity increased 2.5 and 2.7 fold in unadjusted and adjusted models, respectively, and when GG/AG genotype was compared to AA genotype, the risk of sarcopenic obesity increased about 2.3 and 2.4 fold in unadjusted and adjusted models, respectively. This results revealed that the carriers of G allele independent of age increased the sarcopenic obesity while no significant influence of this polymorphism on the risk of sarcopenia was detected.
Strong evidence demonstrated the fundamental importance of p53 in metabolic diseases for example cardiovascular disease, obesity, and type 2 diabetes (39, 40). p53 is known as a negative regulator of adipogenesis in vitro, and also it was reported that p53 levels in white adipose tissue are augmented in diet-induced and genetic obesity mouse models and in obese humans (41). Elevated expression and activity of p53 was proven to occurs in the adipose tissue of obese mice (42). In 2019, Sabir et al. observed that p53 rs1042522 mutant allele is more frequent among obese individuals in Saudi population and suggested that p53 may be considered as genetic modifier for obesity development (43). The p53 rs1042522 polymorphism ( Pro72Arg) impression on body metabolism was also inspected in humanized p53 mice (44). It was revealed that under high fat diet, mice carrying the p53 rs1042522 mutant allele exhibited higher weight gain, associated with higher fat mass, adipose tissue immune cell infiltration, hepatic steatosis and fibrosis, and insulin resistance (41). In another study, Shafiee et al. 2018 reported that P53 besides Neurotrophic Receptor Tyrosine Kinase 1 (NTRK1) and Cullin 3 (CUL3) in the protein-protein interaction (PPI) network involved in lipid storage in older women (17). Wang et al. 2009 found that PPAR pathway activate P53 through accretion of PLINs and additional fatty acids as toxic lipid intermediates, and decline the muscle volume in older people (45).
Wu et al. (2002) in a functional in vitro study suggested that mutant variant in the TP53 rs1625895 significantly reduced the ability of TP53 to regulate DNA repair processes (27). One explanation for the link between TP53 rs1625895 and the increased risk of sarcopenia related obesity in our study is that mutation in TP53 rs1625895 like p53 rs1042522 results in impaired function of TP53 as a negative regulator of adipogenesis, however the exact mechanism is unclear. Since it was reported that elevated expression and activity of p53 is well known to occur in the adipocytes [42], decreased expression and activity of P53 as a result of functional mutation may lead to increased rate of adipogenesis. In addition, aging beside calorie overload, cellular senescence, or cardiac dysfunction is believed as metabolic stressors which could induce p53 expression in visceral WAT (41). So that, it may be concluded that individuals with mutation in the p53 gene have defects in protection against aging-induce adipogenesis.
In addition, we found the individuals carrying TP53 rs1625895 mutant allele had higher BMI compared to non-carriers. Di Renzo et al. 2014 reported that according to BMI, 4.54% of individuals in studied population were obese and sarcopenic. They also suggested that up to 20% of sarcopenia frequency might be declined by appropriate approaches for managing obesity. Similar to our results, a genome-wide association study indicated a strong association of the TP53 mutant variant (rs1042522 R72) with higher BMI (46). Furthermore, Gloria-Bottini et al. described that p53 variant Arg72 is accompanying with elevated risk of BMI and diabetes (47). Also, a latest cohort study of over 2,500 Dutch and Finnish individuals informed a significant association between R72 and higher waist circumference (14).
In the current study, we also displayed a significant difference in the case of LDL level between genotype groups. Subjects with GG genotype had lower LDL level compared to AG/AA genotype. According to our best knowledge, there is no study on association betweenTP53 rs1625895 and lipid levels. Sabir et al. 2019 reported that Arg72 variant of TP53 increased BMI, W/H ratio, cholesterol, LDL level, and insulin levels (43). Although mutations in p53 could interrupt the fatty acid oxidation function (48, 49), the exact mechanism between LDL level and TP53 rs1625895 is unclear.
As a limitation of our study we can point to the relatively small sample size that may affect the statistical power of associations of TP53 rs1625895 polymorphism with the risk of sarcopenia and sarcopenic obesity. Persons enrolled in the current study were nominated from a cohort study from the South of Iran and may not be considered as the general population of Iranian old adults. As a strength, this is a former study on association of TP53 rs1625895 polymorphism with risk of sarcopenia and sarcopenic obesity. Since, Race and ethnicity may clarify some of the high variation of occurrence frequency for sarcopenia and sarcopenic obesity, and it is confirmed that body composition differs between major races (50), finding the genetic factor that influence the susceptibility to these two traits in different populations is crucial. So that, as another strength, in this study for the first time the association of a polymorphism with the risk of sarcopenia and sarcopenic obesity in Iranian population was investigated.