No abstract

The etiology of common complex diseases is multifactorial, involving both genetic, and environmental factors. A role for mitochondrial dysfunction and mitochondrial DNA (mtDNA) variation has been suggested in the pathogenesis of common complex traits. The aim of this study was to investigate a potential role of mtDNA variants in the development of obesity, diabetes, and atherosclerosis in the Polish population. Whole mtDNA sequences from 415 Polish individuals representing three disease cohorts and a control group were obtained using high-throughput sequencing. Two approaches for the assessment of mtDNA variation were applied, traditional mitochondrial haplogroup association analysis and the mutational or variant load model using the MutPred pathogenicity prediction algorithm for amino acid substitutions in humans. We present a possible association between mildly deleterious mtDNA variant load and atherosclerosis that might be due to having more than one likely mildly deleterious non-synonymous substitution. Moreover, it seems largely dependent upon a few common haplogroup associated variants with MutPred score above 0.5.

Leber hereditary optic neuropathy (LHON) is a mitochondrial disorder with symptoms limited to a single tissue, optic nerve, resulting in vision loss. In the majority of cases it is caused by one of three point mutations in mitochondrial DNA (mtDNA) but their presence is not sufficient for disease development, since ~50% of men and ~10% women who carry them are affected. Thus additional modifying factors must exist. In this study, we use next generation sequencing to investigate the role of whole mtDNA variation in male Polish patients with LHON and m.11778G > A, the most frequent LHON mutation. We present a possible association between mtDNA haplogroup K and variants in its background, a combination of m.3480A > G, m.9055G > A, m.11299 T > C and m.14167C > T, and LHON mutation. These variants may have a negative effect on m.11778G > A increasing its penetrance and the risk of LHON in the Polish population. Surprisingly, we did not observe associations previously reported for m.11778G > A and LHON in European populations, particularly for haplogroup J as a risk factor, implying that mtDNA variation is much more complex. Our results indicate possible contribution of novel combination of mtDNA genetic factors to the LHON phenotype.

This comprehensive case analysis aimed to identify the features enabling a runner to achieve championship in 24-h ultramarathon (UM) races. A 36-year-old, multiple medalist of the World Championships in 24-h running, was assessed before, one and 10 days after a 24-h run. Results of his extensive laboratory and cardiological diagnostics with transthoracic echocardiography (TTE) and a one-time cardiopulmonary exercise test (CPET) were analyzed. After 12 h of running (approximately 130 km), the athlete experienced an increasing pain in the right knee. His baseline clinical data were within the normal range. High physical efficiency in CPET (VO2max 63 mL/kg/min) was similar to the average achieved by other ultramarathoners who had significantly worse results. Thus, we also performed genetic tests and assessed his psychological profile, body composition, and markers of physical and mental stress (serotonin, cortisol, epinephrine, prolactin, testosterone, and luteinizing hormone). The athlete had a mtDNA haplogroup H (HV0a1 subgroup, belonging to the HV cluster), characteristic of athletes with the highest endurance. Psychological studies have shown high and very high intensity of the properties of individual scales of the tools used mental resilience (62–100% depending on the scale), openness to experience (10th sten), coherence (10th sten), positive perfectionism (100%) and overall hope for success score (10th sten). The athlete himself considers the commitment and mental support of his team to be a significant factor of his success. Body composition assessment (%fat 13.9) and the level of stress markers were unremarkable. The tested athlete showed a number of features of the champions of ultramarathon runs, such as: inborn predispositions, mental traits, level of training, and resistance to pain. However, none of these features are reserved exclusively for “champions”. Team support’s participation cannot be underestimated. The factors that guarantee the success of this elite 24-h UM runner go far beyond physiological and psychological explanations. Further studies are needed to identify individual elements of the putative “mosaic theory of being a champion”.