Abstract
BACKGROUND/OBJECTIVES: Frailty is a complex geriatric syndrome resulting in decreased physiological reserve. While genetics plays a role, the underlying mechanisms remain unsolved. Metallothioneins (MTs), metal-binding proteins with high affinity for zinc, an essential mineral for many physiological functions, are involved in processes including oxidative stress and inflammation. We investigated the impact of genetic variations in MTs on frailty. METHODS: 448 subjects (235 females and 213 males, median age of 76 years) were categorized into three frailty groups (non-frail/pre-frail/frail), by hierarchical cluster analysis based on cognitive status (MMSE), functional capacity (ADL), and physical strength (HGS). Subjects were analyzed for selected SNPs in MT1A, MT1B, MT2A, and MT3 genes by PCR-RFLP. RESULTS: An association was found between the rs8052394-A/G (Lys51Arg) polymorphism in the MT1A gene and frailty in females both in binary (OR = 0.345, p = 0.037) and multinomial logistic regression (OR = 0.343, p = 0.036) corrected for age and sex, with carriers of the minor G-allele less likely to transition from non-frail to pre-frail status. Additionally, a significant association with albumin levels (beta = 0.231; p = 0.027) and a trend of association with CRP levels (beta = -1.563; p = 0.097) were observed for this SNP in non-frail females, both indicative of a low inflammatory status. However, Bonferroni correction for multiple SNPs and physiological parameters tested renders these results statistically non-significant. CONCLUSIONS: Although its associations do not survive Bonferroni correction, this exploratory study suggests a sex-specific influence of MT1A variability in frailty, likely affecting zinc availability, aligning with ongoing research on sex differences in frailty risk and progression. Larger studies are needed to validate these findings and clarify the mechanisms behind MTs' variability in frailty progression.