Complex metabolic diseases such as Obesity and Type 2 Diabetes (2TD) and physical activity levels have long been recognised as being closely-related. For instance, it has been shown that elite athletes or former elite athletes tend to have longer life expectancies, and lower risks of complex metabolic diseases such as obesity and T2D, than matched sedentary controls [1-3]. Genetic factors seem to play a role in elite athlete development, on one hand [4,5], and the predisposing for complex metabolic diseases, on the other hand [6]. Recently, we [6] and others [7,8] hypothesised that genetic Single Nucleotide Polymorphisms (SNPs), including SNPs identified in Genome Wide Association Studies (GWAS) that have been associated with increased risk for complex metabolic diseases, would also be candidates to influence athletic performance/physical activity levels.

The A/T polymorphism (rs9939609) in the fat mass and obesity associated (FTO) gene, was discovered in two separate GWAS [9,10], and is an example of specific variant associated with obesity, 2TD, and physical activity levels. Recent meta-analysis combining data from adults and children, and an adolescent population (overall 54 studies of n = 218,166 and n = 19,268, respectively) have shown that physically active people with the FTO risk allele are 30% less likely to be obese compared to their inactive counterparts [11]. Visfatin, a recently discovered adipokine that contributes to glucose and obesity-related conditions, is another gene that potentially influences both exercise-related phenotypes and complex metabolic diseases. rs4730153 within the Visfatin was associated with aerobic exercise training-induced changes in glucose and obesity-related phenotypes [12]. The peroxisome proliferator-activated receptor gamma coactivator1α (PPARGC1A) Gly482Ser SNP was also associated with increased risk of obesity and type 2 diabetes [13] on one hand, and with elite athletic performance [14-17], on the other hand.

The outcomes of the abovementioned studies assist with understanding the genomic link between complex metabolic diseases and athletic performance; however the widely accepted hypothesis is that there are likely to be many other uncovered variants with dual effects. In that sense, elite athletes represent the end point of the human physical activity continuum with a “rare” and distinguished phenotype, and hence are an excellent model to study.

Potential obesity and T2D-related genetic variants that may influence athletic performance as well are located in the IGF2BP2, LPL, KCJN, and MTHFR genes. IGF2BP2 rs4402960 G > T variant is associated with predisposition to T2D and obesity. GWAS studies have indicated that the risk allele for T2D and obesity is the T allele. Animal model and human studies implicate this variant with reduced beta-cell function, insulin secretion and sensitivity and with raised fasting glucose levels [18-20]. Importantly, recent studies suggest a potential role for IGF2BP2 in skeletal muscle cell proliferation and differentiation [21]. LPL rs320 and rs328 SNPs have been associated with plasma lipids levels, through the protein’s role in the uptake of Free Fatty Acids (FFA) from the plasma to tissues, including muscle cells [22-24]. Thus, it has been hypothesised that these SNPs may alter the availability of FFA to muscle cells and to the utilization of fat by muscles. The obesity risk allele/genotype for both rs320 and rs328 are G allele and the GG genotype. KCNJ11 is an ATP-sensitive K+ (KATP) channel, which couples cell metabolism with membrane excitability in various cell types, including muscle cells. The protein’s known function is mainly related to diabetes phenotypes [25]. However, it was also found to be association with impaired exercise stress response in several models. The E23K SNP at codon 23 of the KCNJ11 gene (rs5219) results in substitution of glutamic acid to lysine, and may cause modest reductions in ATP sensitivity, which could influence muscle response to exercise. The metabolic risk allele/genotype in rs5219 is T/TT. MTHFR is a key enzyme in one carbon cycle. MTHFR C677T SNP results in elevated plasma homocysteine, which has been linked to reduced mobility and muscle functioning in the elderly (women) and has been associated with T2D. The risk allele/genotype in rs1801133 is T/TT [26,27].

Therefore, we studied the association between these five genetic variants associated with both obesity and obesity co-morbidities (IGF2BP2 rs4402960, LPL rs320, LPL rs328, KCJN rs5219, and MTHFR rs1801133) and elite athletic status in a relatively-large cohort (n = 929, from Poland and Russia) of sprint/power and endurance athletes. We also examined the association between these variants and athletic status according to the athletes’ level of competition (‘elite’ and ‘national’ level). We hypothesised that the obesity and/or co-morbidities risk allele/genotype in each of these variants would be underrepresented in elite athletes compared to controls.