No abstract

Genome-wide association studies (GWAS) have identified >100 loci of chronic kidney disease-defining traits (CKD-dt). Molecular mechanisms underlying these associations remain elusive. Using 280 kidney transcriptomes and 9958 gene expression profiles from 44 non-renal tissues we uncover gene expression partners (eGenes) for 88.9% of CKD-dt GWAS loci. Through epigenomic chromatin segmentation analysis and variant effect prediction we annotate functional consequences to 74% of these loci. Our colocalisation analysis and Mendelian randomisation in >130,000 subjects demonstrate causal effects of three eGenes (NAT8B, CASP9 and MUC1) on estimated glomerular filtration rate. We identify a common alternative splice variant in MUC1 (a gene responsible for rare Mendelian form of kidney disease) and observe increased renal expression of a specific MUC1 mRNA isoform as a plausible molecular mechanism of the GWAS association signal. These data highlight the variants and genes underpinning the associations uncovered in GWAS of CKD-dt.

Leukocyte telomeres shorten with age, and excessive shortening is associated with age-related cardiometabolic diseases. Exercise training may prevent disease through telomere length maintenance although the optimal amount of exercise that attenuates telomere attrition is unknown. Furthermore, the underlying molecular mechanisms responsible for the enhanced telomere maintenance observed in endurance athletes is poorly understood. We quantified the leukocyte telomere length and analyzed the expression of telomere-regulating genes in endurance athletes and healthy controls (both n = 61), using quantitative PCR. We found endurance athletes have significantly longer (7.1%, 208-416 nt) leukocyte telomeres and upregulated TERT (2.0-fold) and TPP1 (1.3-fold) mRNA expression compared with controls in age-adjusted analysis. The telomere length and telomere-regulating gene expression differences were no longer statistically significant after adjustment for resting heart rate and relative V̇O(2 max) (all P > 0.05). Resting heart rate emerged as an independent predictor of leukocyte telomere length and TERT and TPP1 mRNA expression in stepwise regression models. To gauge whether volume of exercise was associated with leukocyte telomere length, we divided subjects into running and cycling tertiles (distance covered per week) and found individuals in the middle and highest tertiles had longer telomeres than individuals in the lowest tertile. These data emphasize the importance of cardiorespiratory fitness and exercise training in the prevention of biological aging. They also support the concept that moderate amounts of exercise training protects against biological aging, while higher amounts may not elicit additional benefits.

MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression post-transcriptionally. Evidence indicating miRNAs influence exercise-induced health and performance adaptations is mounting. Circulating miRNAs are responsible for intercellular communication and could serve as biomarkers for disease and exercise-related traits. Such biomarkers would contribute to exercise screening, monitoring, and the development of personalized exercise prescription. Accordingly, we investigated the impact of long-term strenuous aerobic exercise training and a single bout of maximal aerobic exercise on five muscle-enriched miRNAs implicated in exercise adaptations (miR-1, miR-133a, miR-181a, miR-486, and miR-494). We also determined linear correlations between miRNAs, resting heart rate, and maximum oxygen uptake (O2 max). We used TaqMan assay quantitative polymerase chain reaction to analyze the abundance of miR-1, miR-133a, miR-181a, miR-486, and miR-494 in resting whole blood of 67 endurance athletes and 61 healthy controls. Relative to controls, endurance athletes exhibited increased miR-1, miR-486, and miR-494 content (1.26- to 1.58-fold change, all p < 0.05). miR-1, miR-133a, and miR-486 were decreased immediately after maximal aerobic exercise (0.64- to 0.76-fold change, all p < 0.01) performed by 19 healthy, young men (20.7 ± 2.4 years). Finally, we observed positive correlations between miRNA abundance and O2 max (miR-1 and miR-486) and an inverse correlation between miR-486 and resting heart rate. Therefore, muscle-enriched miRNAs isolated from whole blood are regulated by acute and long-term aerobic exercise training and could serve as biomarkers of cardiorespiratory fitness.