COX7A2L genetic variants determine cardiorespiratory fitness in mice and human

Benegiamo et al. identify genetic variants of the mitochondrial supercomplex assembly factor COX7A2L in the skeletal muscle of mice and humans that promote cardiorespiratory fitness.Mitochondrial respiratory complexes form superassembled structures called supercomplexes. COX7A2L is a supercomplex-specific assembly factor in mammals, although its implication for supercomplex formation and cellular metabolism remains controversial. Here we identify a role for COX7A2L for mitochondrial supercomplex formation in humans. By using human cis-expression quantitative trait loci data, we highlight genetic variants in the COX7A2L gene that affect its skeletal muscle expression specifically. The most significant cis-expression quantitative trait locus is a 10-bp insertion in the COX7A2L 3 ' untranslated region that increases messenger RNA stability and expression. Human myotubes harboring this insertion have more supercomplexes and increased respiration. Notably, increased COX7A2L expression in the muscle is associated with lower body fat and improved cardiorespiratory fitness in humans. Accordingly, specific reconstitution of Cox7a2l expression in C57BL/6J mice leads to higher maximal oxygen consumption, increased lean mass and increased energy expenditure. Furthermore, Cox7a2l expression in mice is induced specifically in the muscle upon exercise. These findings elucidate the genetic basis of mitochondrial supercomplex formation and function in humans and show that COX7A2L plays an important role in cardiorespiratory fitness, which could have broad therapeutic implications in reducing cardiovascular mortality.Peer reviewe

COX7A2L genetic variants determine cardiorespiratory fitness in mice and human

Benegiamo et al. identify genetic variants of the mitochondrial supercomplex assembly factor COX7A2L in the skeletal muscle of mice and humans that promote cardiorespiratory fitness.Mitochondrial respiratory complexes form superassembled structures called supercomplexes. COX7A2L is a supercomplex-specific assembly factor in mammals, although its implication for supercomplex formation and cellular metabolism remains controversial. Here we identify a role for COX7A2L for mitochondrial supercomplex formation in humans. By using human cis-expression quantitative trait loci data, we highlight genetic variants in the COX7A2L gene that affect its skeletal muscle expression specifically. The most significant cis-expression quantitative trait locus is a 10-bp insertion in the COX7A2L 3 ' untranslated region that increases messenger RNA stability and expression. Human myotubes harboring this insertion have more supercomplexes and increased respiration. Notably, increased COX7A2L expression in the muscle is associated with lower body fat and improved cardiorespiratory fitness in humans. Accordingly, specific reconstitution of Cox7a2l expression in C57BL/6J mice leads to higher maximal oxygen consumption, increased lean mass and increased energy expenditure. Furthermore, Cox7a2l expression in mice is induced specifically in the muscle upon exercise. These findings elucidate the genetic basis of mitochondrial supercomplex formation and function in humans and show that COX7A2L plays an important role in cardiorespiratory fitness, which could have broad therapeutic implications in reducing cardiovascular mortality

A multi-country test of brief reappraisal interventions on emotions during the COVID-19 pandemic.

The COVID-19 pandemic has increased negative emotions and decreased positive emotions globally. Left unchecked, these emotional changes might have a wide array of adverse impacts. To reduce negative emotions and increase positive emotions, we tested the effectiveness of reappraisal, an emotion-regulation strategy that modifies how one thinks about a situation. Participants from 87 countries and regions (n = 21,644) were randomly assigned to one of two brief reappraisal interventions (reconstrual or repurposing) or one of two control conditions (active or passive). Results revealed that both reappraisal interventions (vesus both control conditions) consistently reduced negative emotions and increased positive emotions across different measures. Reconstrual and repurposing interventions had similar effects. Importantly, planned exploratory analyses indicated that reappraisal interventions did not reduce intentions to practice preventive health behaviours. The findings demonstrate the viability of creating scalable, low-cost interventions for use around the world

Circulating lipoprotein subfractions and their association with aerobic fitness level

Kondisnivå, målt som maksimalt oksygenopptak (VO2max), er en sterk markør for hjertehelse. Basert på dette kan serum profiler fra friske individ med stor differanse i VO2max nivå brukes til å identifisere sirkulerende biomarkører som representerer tidlig risiko for hjerte- og karsykdom . Målet med denne studien vår å identifisere sirkulerende lipoprotein subfraksjoner som uttykkes forskjellige hos individer med store forskjeller i VO2max nivå. 218 individer (40-59 år) fra Helseundersøkelsen i Nord-Trøndelag (HUNT3) utførte en gullstandard VO2max-test og avga serumprøver. Individene ble utvalgt parvis med hvert par bestående av en lav VO2max person og en høy VO2max person (valgt ut fra enten top 15 eller bunn 15 av personer i den aktuelle aldersgruppen). Individene ble matchet for kjønn, alder, fysisk aktivitetsnivå og fastestatus. NMR lipidomics analyser ble utført på serumprøvene, som ga data på 105 lipoprotein subfraksjoner. Resultatene viste signifikant negativ korrelasjon mellom VO2max-nivå og flere lipoprotein subfraksjoner, inkludert både LDL og HDL subfraksjoner. Konsentrasjonsnedgangen i LDL subfraksjoner som følge av økende VO2max omfattet de største LDL subfraksjonen (LDL-1, LDL-2 og LDL-3). Spesielt triglyseridnivåene i disse subfraksjonene korrelerte negativt med VO2max nivå (LDL1-TG, LDL2-TG and LDL3-TG). I tillegg til dette var syv av HDL subfraksjonene signifikant økt i individer med lav VO2max, hvor av fire av syv var fra HDL-3 gruppen og to av syv var fra HDL-2 gruppen. Videre var også konsentrasjonen av 12 VLDL subfraksjoner, da spesielt de store subfraksjonen, signifikant høyerei individer med lav VO2max. Interessant nok er lipoprotein profilen til de med lav VO2max veldig lik på lipoprotein profilen sett hos individer med insulinresistens. Dette kan indikere at denne økte risikoen for hjerte- og karsykdom man har hos dem med lav VO2max og de med insulin resistens kan skyldes samme endring i lipidprofil. Konklusjonen er at vi fant signifikante forskjeller i flere lipoprotein subfraksjoner når vi sammenlignet individer med store forskjeller i VO2max. Lipoprotein profilen til individer med lav VO2max ligner den profilen vi ser hos individer med insulinresistens. Flere studier er nødvendige for å teste om noen av disse lipoprotein subfraksjonene kan utgjøre viktige risikomarkører for hjerte- og karsykdom

Impact of a FTO gene risk variant on variables of energy metabolism in adults with obesity class 2 and 3

Purpose The metabolic consequences of carrying a FTO obesity-promoting risk allele have not been fully elucidated and may be confounded by obesity per se. Against this background, we investigated the impact of FTO allele (SNP rs9939609) on fasting and postprandial energy expenditure and fasting substrate expenditure in a study population of uniformly and similarly obese individuals. Procedures We studied a similar number of participants with BMI classes 2–3 (median BMI 42.8 kg/m2) who were either homozygote for the non-risk allele TT (n = 33, numbers increased by enrichment), heterozygote (AT) (n = 32), or homozygote for the risk allele AA (n = 35). Major findings Basal metabolic rate and postprandial energy expenditure did not differ between FTO-groups. However, fasting respiratory quotient (RQ) was increased in those carrying ≥1 risk allele (p = 0.008), whereas postprandial RQ was not. Conclusion In this study population, the FTO-risk allele associates with fasting reduced fat and increased carbohydrate oxidation

Identification of novel genetic variants associated with cardiorespiratory fitness

Introduction Low maximal oxygen uptake (VO2max) is a strong and independent risk factor for all-cause and cardiovascular disease (CVD) mortality. For other CVD risk factors, numerous genetic association studies have been performed, revealing promising risk markers and new therapeutic targets. However, large genomic association studies on VO2max are still lacking, despite the fact that VO2max has a large genetic component. Methods We performed a genetic association study on 123.545 single-nucleotide polymorphisms (SNPs) and directly measured VO2max in 3470 individuals (exploration cohort). Candidate SNPs from the exploration cohort were analyzed in a validation cohort of 718 individuals, in addition to 7 wild-card SNPs. Sub-analyses were performed for each gender. Validated SNPs were used to create a genetic score for VO2max. In silico analyses and genotype-phenotype databases were used to predict physiological function of the SNPs. Results In the exploration cohort, 41 SNPs were associated with VO2max (p < 5.0 ∗ 10−4). Six of the candidate SNPs were associated with VO2max also in the validation cohort, in addition to three wild-card SNPs (p < 0.05, in men, women or both). The cumulative number of high-VO2max-SNPs correlated negatively with CVD risk factors, e.g. waist-circumference, visceral fat, fat %, cholesterol levels and BMI. In silico analysis indicated that several of the VO2max-SNPs influence gene expression in adipose tissue, skeletal muscle and heart. Conclusion We discovered and validated new SNPs associated with VO2max and proposed possible links between VO2max and CVD. Studies combining several large cohorts with directly measured VO2max are needed to identify more SNPs associated with this phenotype

Lipoprotein subfraction profiling in the search of new risk markers for myocardial infarction: The HUNT study.

BackgroundTraditional biomarkers used to measure risk of myocardial infarction (MI) only explain a modest proportion of the incidence. Lipoprotein subfractions have the potential to improve risk prediction of MI.AimWe aimed to identify lipoprotein subfractions that were associated with imminent MI risk.MethodsWe identified apparently healthy participants with a predicted low 10-year risk of MI from The Trøndelag Health Survey 3 (HUNT3) that developed MI within 5 years after inclusion (cases, n = 50) and 100 matched controls. Lipoprotein subfractions were analyzed in serum by nuclear magnetic resonance spectroscopy at time of inclusion in HUNT3. Lipoprotein subfractions were compared between cases and controls in the full population (N = 150), and in subgroups of males (n = 90) and females (n = 60). In addition, a sub analysis was performed in participants that experienced MI within two years and their matched controls (n = 56).ResultsNone of the lipoprotein subfractions were significantly associated with future MI when adjusting for multiple testing (pConclusionNone of the investigated lipoprotein subfractions were associated with future MI after adjustment for multiple testing. However, our findings suggests that HDL subfractions may be of interest in relation to risk prediction for MI, especially in males. This need to be further investigated in future studies

Identification of novel genetic variants associated with cardiorespiratory fitness

Introduction: Low maximal oxygen uptake (VO) is a strong and independent risk factor for all-cause and cardiovascular disease (CVD) mortality. For other CVD risk factors, numerous genetic association studies have been performed, revealing promising risk markers and new therapeutic targets. However, large genomic association studies on VO are still lacking, despite the fact that VO has a large genetic component. Methods: We performed a genetic association study on 123.545 single-nucleotide polymorphisms (SNPs) and directly measured VO in 3470 individuals (exploration cohort). Candidate SNPs from the exploration cohort were analyzed in a validation cohort of 718 individuals, in addition to 7 wild-card SNPs. Sub-analyses were performed for each gender. Validated SNPs were used to create a genetic score for VO. In silico analyses and genotype-phenotype databases were used to predict physiological function of the SNPs. Results: In the exploration cohort, 41 SNPs were associated with VO (p < 5.0 ∗ 10). Six of the candidate SNPs were associated with VO also in the validation cohort, in addition to three wild-card SNPs (p < 0.05, in men, women or both). The cumulative number of high-VO SNPs correlated negatively with CVD risk factors, e.g. waist-circumference, visceral fat, fat %, cholesterol levels and BMI. In silico analysis indicated that several of the VO-SNPs influence gene expression in adipose tissue, skeletal muscle and heart. Conclusion: We discovered and validated new SNPs associated with VO and proposed possible links between VO and CVD. Studies combining several large cohorts with directly measured VO are needed to identify more SNPs associated with this phenotype

Associations of polygenic inheritance of physical activity with aerobic fitness, cardiometabolic risk factors and diseases : the HUNT study

Physical activity (PA), aerobic fitness, and cardiometabolic diseases (CMD) are highly heritable multifactorial phenotypes. Shared genetic factors may underlie the associations between higher levels of PA and better aerobic fitness and a lower risk for CMDs. We aimed to study how PA genotype associates with self-reported PA, aerobic fitness, cardiometabolic risk factors and diseases. PA genotype, which combined variation in over one million of gene variants, was composed using the SBayesR polygenic scoring methodology. First, we constructed a polygenic risk score for PA in the Trondelag Health Study (N = 47,148) using UK Biobank single nucleotide polymorphism-specific weights (N = 400,124). The associations of the PA PRS and continuous variables were analysed using linear regression models and with CMD incidences using Cox proportional hazard models. The results showed that genotypes predisposing to higher amount of PA were associated with greater self-reported PA (Beta [B] = 0.282 MET-h/wk per SD of PRS for PA, 95% confidence interval [CI] = 0.211, 0.354) but not with aerobic fitness. These genotypes were also associated with healthier cardiometabolic profile (waist circumference [B = -0.003 cm, 95% CI = -0.004, -0.002], body mass index [B = -0.002 kg/m(2), 95% CI = -0.004, -0.001], high-density lipoprotein cholesterol [B = 0.004 mmol/L, 95% CI = 0.002, 0.006]) and lower incidence of hypertensive diseases (Hazard Ratio [HR] = 0.97, 95% CI = 0.951, 0.990), stroke (HR = 0.94, 95% CI = 0.903, 0.978) and type 2 diabetes (HR = 0.94, 95 % CI = 0.902, 0.970). Observed associations were independent of self-reported PA. These results support earlier findings suggesting small pleiotropic effects between PA and CMDs and provide new evidence about associations of polygenic inheritance of PA and intermediate cardiometabolic risk factors.Peer reviewe

Shared genetic factors may partly explain the associations between physical activity and cardiometabolic diseases

Shared genetic factors may contribute to the associations between higher levels of physical activity (PA) and lower risk for cardiometabolic diseases (CMDs), and may partially explain these associations observed in cohort studies. To explore this, we used novel methodology to calculate PA genotypes (polygenic risk score, PRS) and validated them against measured or reported PA in three independent cohorts. We then investigated the associations between polygenic inheritance of PA and cardiometabolic risk factors and diseases in two large population-based biobank datasets, and examined whether selected associations were independent of self-reported PA. Our study utilized the UK Biobank as a base dataset (N = 400,124) and constructed genomewide PRSs for both self-reported and device-measured PA using single nucleotide polymorphism (SNP)-specific weights and SBayesR methodology. Both PRSs for PA included over one million SNPs. PRSs were constructed in the Finnish Twin cohort (N = 759–11,528), the Northern Finland Birth Cohort 1966 (N = 3,263–4,061), the Trøndelag Health Study cohort (HUNT, N = 47,148), and the FinnGen (N = 218,792). Cardiometabolic risk factors were measured in laboratory conditions, and CMD outcomes were derived from national health registers (ICD codes). We utilized linear, logistic, and cox regression methods for analysis. Our results showed that genotypes predisposing to higher PA were associated with higher levels of PA in independent datasets, but PRSs accounted for only a limited amount of variation (0.13-1.44%). Genotypes supporting higher PA were associated with lower body mass index [B=-0.002 in HUNT and B=-0.025 in FinnGen] and favorable cardiometabolic health in HUNT (waist circumference [B=-0.003] and HDL cholesterol [B = 0.004]). Genotypes supporting higher PA volumes were associated with lower incidence of CMDs in both HUNT and FinnGen. The strongest associations were found in hypertensive diseases and Type 2 Diabetes. In HUNT, the observed associations were not materially changed after accounting for self-reported PA. Higher PRS for PA was also associated with lower risk of mortality in FinnGen. Our findings suggest small pleiotropic effects between PA and CMDs. This means that same genetic variation may explain both physical activity behaviour and risk of diseases. PRSs provide new tools for genetic studies in sport science, but they currently have substantial practical limitations.nonPeerReviewe