Maarten Peeters

Growth in peak aerobic power during adolescence.

PURPOSE To model the growth of peak aerobic power during adolescence in both sexes followed longitudinally from 10 to 18 yr. METHODS Peak aerobic power (peak VO2) was measured annually during a maximal treadmill test with the Bruce protocol. Height and weight were measured semiannually. The Preece-Baines Model I growth function was used to fit curves to data for individuals with >/= six observations for peak aerobic power to estimate age at peak velocity (PV) for peak VO2 (age at PVPVO2), PVPVO2 (L x min(-1) x yr(-1)), and value at PVPVO2 (L x min(-1)) for each individual. Curves were successfully fitted for 83 individuals (48 males, 35 females). The model was also fitted to individual data for height and weight to estimate ages at peak height velocity (PHV) and peak weight velocity (PWV). Age at PVPVO2 was compared with ages at PHV and PWV. Pearson correlation coefficients were calculated between ages at PV and PV for peak VO2, height, and weight. RESULTS Mean ages at PVPVO2 are 12.3 +/- 1.2 yr for females and 14.1 +/- 1.2 yr for males. Peak VO2 increases in both sexes throughout adolescence, with males having higher values than females at all ages. Age at PVPVO2 occurs nearly coincident with PHV and before PWV in both sexes. Correlation coefficients among ages at PHV, PWV, and PVPVO2 suggest a general maturity factor for body size and aerobic power. CONCLUSION Growth in peak VO2 exhibits a clear growth spurt in both sexes during adolescence. The growth spurt occurs earlier in females but is of greater magnitude in males.

Heritability of childhood weight gain from birth and risk markers for adult metabolic disease in prepubertal twins.

OBJECTIVE Associations between size at birth, postnatal weight gain, and potential risk for adult disease have been variably explained by in utero exposures or genetic risk that could affect both outcomes. We utilized a twin model to explore these hypotheses. METHODS One hundred pairs of healthy twins aged 8.9 yr (range, 7.2-10.9 yr) had fasting blood samples collected, blood pressure (BP) measured, and anthropometry assessed. All measurements were converted to sd scores (SDS) to adjust for age and sex. RESULTS Mean birth weights in both monozygotic and dizygotic twins were -0.90 SDS lower than the UK reference. In postnatal life, 58% of monozygotic twins and 59% of dizygotic twins showed rapid weight gain (a change of more than +0.67 in weight SDS) from birth. Postnatal weight gain was positively associated with sum of skinfolds (r = 0.51; P < 0.0005), fasting insulin levels (r = 0.35; P < 0.0005), systolic BP (r = 0.30; P < 0.0005), and diastolic BP (r = 0.15; P < 0.05) at follow-up. Heritability estimates (additive genetic components) were calculated using variance components models for: birth weight, 44%; postnatal weight gain, 80%; childhood height, 89%; body mass index, 72%; sum of skinfolds, 89%; waist circumference, 74%; fasting insulin, 65%; systolic BP, 33%; and diastolic BP, 29%. CONCLUSIONS Postnatal weight gain from birth, rather than birth weight, was associated with childhood risk markers for adult metabolic disease. Childhood weight gain was highly heritable, and genetic factors associated with postnatal weight gain are likely to also contribute to risks for adult disease.

Heritability of somatotype components from early adolescence into young adulthood: a multivariate analysis on a longitudinal twin study.

Background : Several studies with different designs have attempted to estimate the heritability of somatotype components. However they often ignore the covariation between the three components as well as possible sex and age effects. Shared environmental factors are not always controlled for. Aim : This study explores the pattern of genetic and environmental determination of the variation in Heath-Carter somatotype components from early adolescence into young adulthood. Subjects and methods : Data from the Leuven Longitudinal Twin Study, a longitudinal sample of Belgian same-aged twins followed from 10 to 18 years ( n = 105 pairs, equally divided over five zygosity groups), is entered into a multivariate path analysis. Thus the covariation between the somatotype components is taken into account, gender heterogeneity can be tested, common environmental influences can be distinguished from genetic effects and age effects are controlled for. Results : Heritability estimates from 10 to 18 years range from 0.21 to 0.88, 0.46 to 0.76 and 0.16 to 0.73 for endomorphy, mesomorphy and ectomorphy in boys. In girls, heritability estimates range from 0.76 to 0.89, 0.36 to 0.57 and 0.57 to 0.76 for the respective somatotype components. Sex differences are significant from 14 years onwards. More than half of the variance in all somatotype components for both sexes at all time points is explained by factors the three components have in common. Conclusions : The finding of substantial genetic influence on the variability of somatotype components is further supported. The need to consider somatotype as a whole is stressed as well as the need for sex- and perhaps age-specific analyses. Further multivariate analyses are needed to confirm the present findings.

Detection and prognostic significance of circulating tumour cells in patients with metastatic breast cancer according to immunohistochemical subtypes

Background:The enumeration of circulating tumour cells (CTCs) with the EpCAM-based CellSearch system has prognostic significance in patients with metastatic breast cancer (MBC). The aim of this study was to explore potential differences in the detection and prognostic significance of CTCs in MBC according to immunohistochemical subtypes of breast cancer.Methods:CellSearch CTC counts were obtained from 154 MBC patients before first-line systemic treatment between November 2007 and August 2012. Patients were categorised in five subgroups according to immunohistochemical surrogate definitions of intrinsic subtypes in breast cancer based on hormone receptor status, HER2/neu status and histological grade. Differences in progression-free (PFS) and overall survival (OS) were assessed relative to the cut-off value of ⩾5 CTCs per 7.5 ml blood.Results:No significant differences were observed in the absolute CTC counts (P=0.120) or in CTC positivity rates according to ⩾1 and ⩾5 CTCs per 7.5 ml blood detection thresholds (P=0.165 and P=0.651, respectively) between immunohistochemical subtypes. However, very high CTC counts, defined as ⩾80 CTCs per 7.5 ml, were observed more frequently in patients with Luminal A and triple negative (TN) breast cancer (P=0.024). In the total study population, the presence of ⩾5 CTCs was the single most significant prognostic factor for both PFS and OS in multivariate analysis (P<0.001). A more limited prognostic impact, not reaching statistical significance, was observed in patients with HER2-positive disease as opposed to patients with Luminal A, Luminal B–HER2-negative and TN disease.Conclusion:The detection of EpCAM+CTCs was not clearly associated with any of the immunohistochemical subtypes of breast cancer in patients with MBC before first-line treatment. Potentially clinically relevant differences were however observed at very high CTC counts. Furthermore, our data suggest a lower prognostic significance of CTC evaluation in HER2-positive patients with MBC.

Genetics and sports: an overview of the pre-molecular biology era.

Estimated genetic and environmental contributions to individual differences in physical performance phenotypes, responsiveness to intermittent, aerobic and strength training, and specific skill training protocols are the focus of this chapter. Data are derived primarily from twin and family studies, although methods of analysis vary considerably. Estimates of heritability span a wide range for several performance phenotypes and the responsiveness to training. This is explained, in part, by differences in sample characteristics and analytical strategies. Corresponding data for skill acquisition are very limited. Data dealing with the effects of age, sex, maturation and ethnicity on heritability estimates are lacking, and information on behavioral phenotypes that may be related to performance is not available.

Comprehensive fine mapping of chr12q12-14 and follow-up replication identify activin receptor 1B (ACVR1B) as a muscle strength gene

Muscle strength is important in functional activities of daily living and the prevention of common pathologies. We describe the two-staged fine mapping of a previously identified linkage peak for knee strength on chr12q12-14. First, 209 tagSNPs in/around 74 prioritized genes were genotyped in 500 Caucasian brothers from the Leuven Genes for Muscular Strength study (LGfMS). Combined linkage and family-based association analyses identified activin receptor 1B (ACVR1B) and inhibin β C (INHBC), part of the transforming growth factor β pathway regulating myostatin – a negative regulator of muscle mass – signaling, for follow-up. Second, 33 SNPs, selected in these genes based on their likelihood to functionally affect gene expression/function, were genotyped in an extended sample of 536 LGfMS siblings. Strong associations between ACVR1B genotypes and knee muscle strength (P-values up to 0.00002) were present. Of particular interest was the association with rs2854464, located in a putative miR-24-binding site, as miR-24 was implicated in the inhibition of skeletal muscle differentiation. Rs2854464 AA individuals were ∼2% stronger than G-allele carriers. The strength increasing effect of the A-allele was also observed in an independent replication sample (n=266) selected from the Baltimore Longitudinal Study of Aging and a Flemish Policy Research Centre Sport, Physical Activity and Health study. However, no genotype-related difference in ACVR1B mRNA expression in quadriceps muscle was observed. In conclusion, we applied a two-stage fine mapping approach, and are the first to identify and partially replicate genetic variants in the ACVR1B gene that account for genetic variation in human muscle strength.

Heritability of somatotype components: a multivariate analysis.

Objective:To study the genetic and environmental determination of variation in Heath–Carter somatotype (ST) components (endomorphy, mesomorphy and ectomorphy).Design:Multivariate path analysis on twin data.Subjects:Eight hundred and three members of 424 adult Flemish twin pairs (18–34 years of age).Results:The results indicate the significance of sex differences and the significance of the covariation between the three ST components. After age-regression, variation of the population in ST components and their covariation is explained by additive genetic sources of variance (A), shared (familial) environment (C) and unique environment (E). In men, additive genetic sources of variance explain 28.0% (CI 8.7–50.8%), 86.3% (71.6–90.2%) and 66.5% (37.4–85.1%) for endomorphy, mesomorphy and ectomorphy, respectively. For women, corresponding values are 32.3% (8.9–55.6%), 82.0% (67.7–87.7%) and 70.1% (48.9–81.8%). For all components in men and women, more than 70% of the total variation was explained by sources of variance shared between the three components, emphasising the importance of analysing the ST in a multivariate way.Conclusions:The findings suggest that the high heritabilities for mesomorphy and ectomorphy reported in earlier twin studies in adolescence are maintained in adulthood. For endomorphy, which represents a relative measure of subcutaneous adipose tissue, however, the results suggest heritability may be considerably lower than most values reported in earlier studies on adolescent twins. The heritability is also lower than values reported for, for example, body mass index (BMI), which next to the weight of organs and adipose tissue also includes muscle and bone tissue. Considering the differences in heritability between musculoskeletal robustness (mesomorphy) and subcutaneous adipose tissue (endomorphy) it may be questioned whether studying the genetics of BMI will eventually lead to a better understanding of the genetics of fatness, obesity and overweight.

Circulating tumour cells in the central and the peripheral venous compartment in patients with metastatic breast cancer

Background:The enumeration of circulating tumour cells (CTC) has prognostic significance in patients with metastatic breast cancer (MBC) and monitoring of CTC levels over time has considerable potential to guide treatment decisions. However, little is known on CTC kinetics in the human bloodstream.Methods:In this study, we compared the number of CTC in both 7.5 ml central venous blood (CVB) and 7.5 ml peripheral venous blood (PVB) from 30 patients with MBC starting with a new line of chemotherapy.Results:The number of CTC was found to be significantly higher in CVB (median: 43.5; range: 0–4036) than in PVB (median: 33; range: 0–4013) (P=0.001). When analysing samples pairwise, CTC counts were found to be significantly higher in CVB than in PVB in 12 out of 26 patients with detectable CTC. In contrast, only 2 out of 26 patients had higher CTC counts in PVB as compared with CVB, whereas in 12 remaining patients no significant difference was seen. The pattern of CTC distribution was independent of the sites of metastatic involvement.Conclusion:A substantial difference in the number of CTC was observed between CVB and PVB of patients with MBC. Registration of the site of blood collection is warranted in studies evaluating the role of CTC assessment in these patients.

Genome-wide linkage scan for contraction velocity characteristics of knee musculature in the Leuven Genes for Muscular Strength Study

The torque-velocity relationship is known to be affected by ageing, decreasing its protective role in the prevention of falls. Interindividual variability in this torque-velocity relationship is partly determined by genetic factors (h(2): 44-67%). As a first attempt, this genome-wide linkage study aimed to identify chromosomal regions linked to the torque-velocity relationship of the knee flexors and extensors. A selection of 283 informative male siblings (17-36 yr), belonging to 105 families, was used to conduct a genome-wide SNP-based (Illumina Linkage IVb panel) multipoint linkage analysis for the torque-velocity relationship of the knee flexors and extensors. The strongest evidence for linkage was found at 15q23 for the torque-velocity slope of the knee extensors (TVSE). Other interesting linkage regions with LOD scores >2 were found at 7p12.3 [logarithm of the odds ratio (LOD) = 2.03, P = 0.0011] for the torque-velocity ratio of the knee flexors (TVRF), at 2q14.3 (LOD = 2.25, P = 0.0006) for TVSE, and at 4p14 and 18q23 for the torque-velocity ratio of the knee extensors TVRE (LOD = 2.23 and 2.08; P = 0.0007 and 0.001, respectively). We conclude that many small contributing genes are involved in causing variation in the torque-velocity relationship of the knee flexor and extensor muscles. Several earlier reported candidate genes for muscle strength and muscle mass and new candidates are harbored within or in close vicinity of the linkage regions reported in the present study.

Genome-wide linkage scan for maximum and length-dependent knee muscle strength in young men: significant evidence for linkage at chromosome 14q24.3

Background: Maintenance of high muscular fitness is positively related to bone health, functionality in daily life and increasing insulin sensitivity, and negatively related to falls and fractures, morbidity and mortality. Heritability of muscle strength phenotypes ranges between 31% and 95%, but little is known about the identity of the genes underlying this complex trait. As a first attempt, this genome-wide linkage study aimed to identify chromosomal regions linked to muscle and bone cross-sectional area, isometric knee flexion and extension torque, and torque–length relationship for knee flexors and extensors. Methods: In total, 283 informative male siblings (17–36 years old), belonging to 105 families, were used to conduct a genome-wide SNP-based multipoint linkage analysis. Results: The strongest evidence for linkage was found for the torque–length relationship of the knee flexors at 14q24.3 (LOD  = 4.09; p<10−5). Suggestive evidence for linkage was found at 14q32.2 (LOD  = 3.00; P = 0.005) for muscle and bone cross-sectional area, at 2p24.2 (LOD  = 2.57; p = 0.01) for isometric knee torque at 30° flexion, at 1q21.3, 2p23.3 and 18q11.2 (LOD  = 2.33, 2.69 and 2.21; p<10−4 for all) for the torque–length relationship of the knee extensors and at 18p11.31 (LOD  = 2.39; p = 0.0004) for muscle-mass adjusted isometric knee extension torque. Conclusions: We conclude that many small contributing genes rather than a few important genes are involved in causing variation in different underlying phenotypes of muscle strength. Furthermore, some overlap in promising genomic regions were identified among different strength phenotypes.