Identification of novel genetic variants associated with cardiorespiratory fitness

Bye, Anja; Klevjer, Marie; Ryeng, Einar; Silva, Gustavo José Justo da; Moreira, José Bianco Nascimento; Stensvold, Dorthe; Wisløff, Ulrik

doi:10.1016/j.pcad.2020.02.001

Cited by 26 publications

(24 citation statements)

References 46 publications

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“…Cardiorespiratory fitness is largely modified by physical activity and exercise, but even though these concepts are closely related, they are considered two distinct components of cardiovascular health [7,9,[14][15][16]. To a large degree, cardiorespiratory fitness is also determined by genetic factors, and the trainability of cardiorespiratory fitness varies greatly between individuals [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Association between Cardiorespiratory Fitness and Circulating Proteins in 50-Year-Old Swedish Men and Women: a Cross-Sectional Study

et al. 2021

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Background and Aims A strong cardiorespiratory fitness is suggested to have beneficial effects on cardiovascular risk; the exact mechanisms underlying the cardioprotective effects of fitness remain uncertain. Our aim was to investigate associations between cardiorespiratory fitness and multiple plasma proteins, in order to obtain insights about physiological pathways associated with the effects of exercise on cardiovascular health. Methods In the Prospective investigation of Obesity, Energy and Metabolism (POEM) study (n=444 adults aged 50 years, 50% women), cardiorespiratory fitness was measured by a maximal exercise test on bicycle ergometer with gas exchange (VO2peak) normalized for body lean mass (dual-energy X-ray absorptiometry (DXA)). We measured 82 cardiovascular proteins associated with cardiovascular pathology and inflammation in plasma samples with a proximity extension assay. Results In sex-adjusted linear regression, VO2peak was associated with 18 proteins after Bonferroni correction for multiple testing (p<0.0006). Following additional adjustment for fat mass (DXA), fasting glucose (mmol/L), low-density lipoprotein (LDL, mmol/L), smoking status, waist/hip ratio, blood pressure (mmHg), education level, and lpnr (lab sequence number), higher VO2peak was significantly associated with lower levels of 6 proteins: fatty-acid binding protein-4 (FABP4), interleukin-6 (IL-6), leptin, cystatin-B (CSTB), interleukin-1 receptor antagonist (IL-1RA), and growth differentiation factor 15 (GDF-15), and higher levels of 3 proteins: galanin, kallikrein-6 (KLK6), and heparin-binding EGF-like growth factor (HB-EGF), at nominal p-values (p<0.05). Conclusions We identified multiple novel associations between cardiorespiratory fitness and plasma proteins involved in several atherosclerotic processes and key cellular mechanisms such as inflammation, energy homeostasis, and protease activity, which shed new light on how exercise asserts its beneficial effects on cardiovascular health. Our findings encourage additional studies in order to understand the underlying causal mechanisms for these associations.

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Section: Introductionmentioning

confidence: 99%

Association between Cardiorespiratory Fitness and Circulating Proteins in 50-Year-Old Swedish Men and Women: a Cross-Sectional Study

et al. 2021

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“…Also, the best model obtained through multiple regression analyses could only explaiñ 2.2% of the interindividual variance in VO 2peak . As in the study by Bye et al [14], we created a polygenic score to determine whether those individuals with a higher number of alleles associated with VO 2peak did indeed present with higher values of this parameter. The only differences found between our findings and those of the Bye et al study were the number of SNPs included in the polygenic score (7 vs 3, respectively) and the use of an intermediate genotype score for heterozygotes, which was not included by Bye et al Interestingly, in both studies, participants with the theoretically lowest (or 'less favorable') genotype scores had the lowest VO 2peak (22-24 mL/kg/min), which was significantly lower than for those with the theoretically highest (or 'most favorable') genotype score (~32 mL/kg/min).…”

Section: Discussionmentioning

confidence: 99%

“…It has also been reported that twins with similar VO 2peak values present with comparable levels of a variety of PA indices [13], suggesting that part of the heritability of VO 2peak in twins might be due to the similarity of their PA levels. In fact, in a recent analysis of 123,545 single nucleotide polymorphisms (SNPs), only nine were associated with VO 2peak [14]. The authors of this study found that those individuals whose genotype was associated with a high VO 2peak value had a lower CVD risk (e.g., less visceral fat or lower total blood cholesterol), but they did not calculate the additive effect that the nine SNPs had on the interindividual variability of VO 2peak .…”

Section: Introductionmentioning

confidence: 87%

Interindividual Variation in Cardiorespiratory Fitness: A Candidate Gene Study in Han Chinese People

Gaowa

Coso

et al. 2020

Genes

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Cardiorespiratory fitness, as assessed through peak oxygen uptake (VO2peak), is a powerful health indicator. We aimed to evaluate the influence of several candidate causal genetic variants on VO2peak level in untrained Han Chinese people. A total of 1009 participants (566 women; age [mean ± SD] 40 ± 14 years, VO2peak 29.9 ± 7.1 mL/kg/min) performed a maximal incremental cycling test for VO2peak determination. Genomic DNA was extracted from peripheral whole blood, and genotyping analysis was performed on 125 gene variants. Using age, sex, and body mass as covariates, and setting a stringent threshold p-value of 0.0004, only one single nucleotide polymorphism (SNP), located in the gene encoding angiotensin-converting enzyme (rs4295), was associated with VO2peak (β = 0.87; p < 2.9 × 10−4). Stepwise multiple regression analysis identified a panel of three SNPs (rs4295 = 1.1%, angiotensin II receptor type 1 rs275652 = 0.6%, and myostatin rs7570532 = 0.5%) that together accounted for 2.2% (p = 0.0007) of the interindividual variance in VO2peak. Participants carrying six ‘favorable’ alleles had a higher VO2peak (32.3 ± 8.1 mL/kg/min) than those carrying only one favorable allele (24.6 ± 5.2 mL/kg/min, p < 0.0001). In summary, VO2peak at the pre-trained state is partly influenced by several polymorphic variations in candidate genes, but they represent a minor portion of the variance.

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“…Although we did not detect significant interactions for most SNPs, which might be due to limited sample sizes, some significant SNPs may provide new insights into potential mechanisms. For example, rs3757354 at MYLIP is associated with the expression of MYLIP, which could stimulate the ubiquitination of the LDL receptor and direct its degradation, thereby inhibiting the uptake of LDL-C from the circulation and increasing circulating LDL-C cholesterol levels (44,45). MAFB encodes a transcription factor that upregulates the expression of ABCA1 and ABCG1, two genes involved in cholesterol efflux (46).…”

Section: Discussionmentioning

confidence: 99%

Genetic susceptibility, dietary cholesterol intake, and plasma cholesterol levels in a Chinese population

Huo

Sun

Zong

et al. 2020

Journal of Lipid Research

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Accompanied with nutrition transition, non-HDL-cholesterol (HDL-C) levels of Asian countries increased rapidly, which has caused the global epicenter of non-optimal cholesterol to shift from Western countries to Asian countries. Thus, it is critical to underline major genetic and dietary determinants. In the current study of 2,330 Chinese individuals, genetic risk scores (GRSs) were calculated for total cholesterol (TC; GRSTC, 57 SNPs), LDL-cholesterol (LDL-C; GRSLDL-C, 45 SNPs) and HDL-C (GRSHDL-C, 65 SNPs) based on SNPs from the Global Lipid Genetics Consortium study. Cholesterol intake was estimated by a 74-item food frequency questionnaire. Associations of dietary cholesterol intake with plasma TC and LDL-C strengthened across quartiles of the GRSTC (effect sizes = -0.29, 0.34, 2.45 and 6.47; Pinteraction = 0.002) and GRSLDL-C (effect sizes = -1.35, 0.17, 5.45 and 6.07; Pinteraction = 0.001), respectively. Similar interactions on non-HDL-C were observed between dietary cholesterol and GRSTC (Pinteraction = 0.001) and GRSLDL-C (Pinteraction = 0.004). The adverse effects of GRSTC on TC (effect sizes across dietary cholesterol quartiles: 0.51, 0.82, 1.21 and 1.31; Pinteraction = 0.023) and GRSLDL-C on LDL-C (effect sizes across dietary cholesterol quartiles: 0.66, 0.52, 1.12 and 1.56; Pinteraction = 0.020) were more profound in those having higher cholesterol intake compared to those with lower intake. Our findings suggest significant interactions between genetic susceptibility and dietary cholesterol intake on plasma cholesterol profiles in a Chinese population.

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Identification of novel genetic variants associated with cardiorespiratory fitness

Cited by 26 publications

References 46 publications

Association between Cardiorespiratory Fitness and Circulating Proteins in 50-Year-Old Swedish Men and Women: a Cross-Sectional Study

Association between Cardiorespiratory Fitness and Circulating Proteins in 50-Year-Old Swedish Men and Women: a Cross-Sectional Study

Interindividual Variation in Cardiorespiratory Fitness: A Candidate Gene Study in Han Chinese People

Genetic susceptibility, dietary cholesterol intake, and plasma cholesterol levels in a Chinese population

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