Genetic factors associated with changes in muscle strength and mass during corticosteroid therapy

BACKGROUND: Corticosteroid use is associated with loss of muscle mass and strength, which is associated with an unfavorable prognosis of the underlying disease, as well as an increased risk of cardiovascular disease. Patients with multiple sclerosis (MS) have a higher baseline susceptibility to cardiovascular disease and a higher risk of adverse effects due to corticosteroid use. In clinical practice, different degrees of severity of side effects of corticosteroids are reported. This may be related to the presence of a genetic predisposition, the identification of which should allow a personalized approach to therapy.

AIM: To evaluate the association of polymorphic variants of the glucocorticoid receptor gene NR3C1, the FTO gene, and the melatonin receptor genes MTNR1A, MTNR1B with the development of changes in muscle mass and strength in the context of corticosteroid use in patients with MS.

MATERIALS AND METHODS: The study included 80 patients (mean age 36.3±10.0 years) with MS receiving pulse corticosteroid therapy: 4 (3; 4) g methylprednisolone. Patients were enrolled over the course of one year. To assess the primary endpoint (reduction in muscle mass and strength), muscle strength and mass were monitored before and after therapy using wrist dynamometry, the time-up-and-go test, and bioimpedancemetry. Polymorphic variants of the glucocorticoid receptor gene NR3C1, the FTO gene, and the melatonin receptor genes MTNR1A and MTNR1B were identified by real-time polymerase chain reaction. Intergenic interactions were evaluated using the multifactor dimensionality reduction (MDR) method. R (v. 3.2, R Foundation for Statistical Computing, Austria) was used for statistical analysis.

RESULTS: In women with loss of muscle mass after corticosteroid therapy, there was an increased incidence of depression (p=0.01) for polymorphic variant BclI (rs41423247) of the NR3C1 gene (p=0.005). Reduced dominant arm strength in women was associated with a variant of the BclI gene (rs41423247) (p=0.02), genotypes including BclI (rs41423247) and N363S (rs56149945) (p=0.03). Men with decreased strength in the non-dominant arm were more likely to be smokers (p=0.03). Combinations of genotypes of the NR3C1, FTO, MTNR1B genes were identified with increased and decreased risk of muscle mass loss in women after corticosteroid therapy. Analysis of intergenic interactions showed a strong synergism between the polymorphic variant rs993960 of the FTO gene and rs10830963 of the MTNR1B gene.

CONCLUSION: The presence of polymorphic variants BclI (rs41423247), N363S (rs56149945) of the glucocorticoid receptor gene NR3C1 is associated with loss of muscle strength and mass in women receiving corticosteroid therapy for MS. Combinations of genotypes of the NR3C1, FTO, MTNR1B genes have been identified with an increased risk of muscle mass loss in women after corticosteroid therapy. Modifiable factors associated with loss of muscle mass and strength and cardiovascular risk (depression, smoking) were identified. The data obtained can be used to personalize corticosteroid therapy and prevent cardiovascular and metabolic disorders.