The MDM2 SNP309 differentially impacts cardiorespiratory fitness in young healthy women and men

Abstract

PURPOSE: Maximal oxygen consumption (VO2max), the predominant index of cardiorespiratory fitness (CRF), is a predictor of whole-body function and longevity in humans. Central cardiac function and the skeletal muscle’s capacity to use oxygen are key determinants of VO2max. Murine Double Minute 2 (MDM2), mainly known as an oncogene, could regulate myocardial hypertrophy, skeletal muscle angiogenesis and oxidative phosphorylation. A prevalent single nucleotide polymorphism in the MDM2 promoter (SNP309) substitutes a T for a G, supporting a greater transcriptional activity. We aim to assess whether SNP309 impacts intrinsic CRF. METHODS: 82 young healthy nonathletic male and female adults aged 23±2 years performed cardiorespiratory exercise testing to determine their VO2max (mL∙kg-1∙min-1). Genomic DNAs isolated from saliva were genotyped using Taqman-based qPCR. RESULTS: A one-way ANOVA showed that SNP309 influenced relative VO2max in the whole cohort (p=0.044) and in men (p=0.009), remaining non-significant in women (p=0.133). VO2max was higher in TT homozygotes than in GT heterozygotes (whole cohort, 47±12 vs. 42±6 mL∙kg-1∙min-1, p=0.030; men, 53±8 vs. 45±6 mL∙kg-1∙min-1, p=0.011). A contingency analysis revealed a positive association between SNP309 in men in which the TT genotype was more frequent in the high VO2max group (p=0.006). When considering G as the dominant allele, men bearing a G allele had lower relative VO2max than TT homozygotes (47±7 vs. 53±8, GG/GT vs. TT, p=0.010). Conversely, women bearing a G allele had a higher relative VO2max than TT homozygotes (39±5 vs. 34±7, GG/GT vs. TT, p=0.047). CONCLUSION: SNP309 impacts VO2max in a sex-dependent manner in our cohort.