Linkage of myostatin pathway genes with knee strength in humans.

This study was the first to explore the potential role of the myostatin (GDF8) pathway in relation to muscle strength and estimated muscle cross-sectional area in humans using linkage analysis with a candidate gene approach. In young male sibs (n = 329) 11 polymorphic markers in or near 10 candidate genes from the myostatin pathway were genotyped. Muscle mass was estimated by anthropometric measurements, and maximal knee strength was evaluated using isokinetic dynamometers (Cybex NORM). Single-point nonparametric variance components and linear quantitative trait locus regression linkage analysis methods were used. Linkage patterns were observed between knee extension and flexion peak torque with markers D2S118 (GDF8), D6S1051 (CDKN1A), and D11S4138 (MYOD1), and a maximum LOD score of 2.63 (P = 0.0002) was observed with D2S118. The ratios of peak torque over muscle and bone area of the midthigh of the lower contraction velocity (60 degrees/s) showed more frequently significant LOD scores than the torques at high velocity (240 degrees/s). Although myostatin is physiologically more related to muscle mass through possible effects of hyperplasia and hypertrophy than it is to strength, only two estimated muscle cross-sectional areas were marginally linked (LOD 1.06 and 1.07, P = 0.01) with marker D2S118 near GDF8 (2q32.2). The present results gave suggestive evidence that the myostatin pathway might be important for strength phenotypes, and GDF8, CDKN1A, and MYOD1 are potential candidate regions for a further and denser mapping with respect to these phenotypes.

Screening for marasmus: a discriminant analysis as a guide to choose the anthropometric variables.

In a cross-sectional study, children 0-6 yr of age from eight different population groups in Africa and Asia were examined. Clinical assessment defined 8750 children as being well nourished and 194 as having marasmus. Height, weight, arm circumference (AC), and triceps skinfold thickness were measured; the latter two measurements and the clinical assessment were done by the same observer. Based on data from normal children, local growth curves were computed for each group. Each child's growth was expressed in standard deviation scores (SDS) of his own group. On the basis of the results of a discriminant analysis, all variables were ranked by their decreasing power to discriminate between normal and marasmic children. For 83% of the children one measurement (AC/age) is sufficient to classify them definitely; for the others several variables are needed. This strategy yields an overall sensitivity of 80%, a specificity of 97%, and a positive predictive value of 38%.

PIP: The definition of a malnourished child is commonly based on anthropometric measurements. In order to define an optimal selection procedure, this study uses a discriminant analysis to choose the most appropriate anthropometric variables for distinguishing clinically defined marasmic children from clinically normal children. This selection procedure would be a better alternative for routine practice in health clinics than the commonly used procedures of weight for age or weight for height. In a cross-sectional study, children 0-6 years of age from 8 different population groups in Africa and Asia were examined. Clinical assessment defined 8750 children as being well nourished and 194 as having marasmus. Height, weight, arm circumference, and triceps skinfold thickness were measured; the latter 2 measurements and the clinical assessment were done by the same observer. Based on data from normal children, local growth curves were computed for each group. Each child's growth expressed in standard deviation scores of his own group. On the basis of the results of a discriminant analysis, all variables were ranked by their decreasing power to discriminate between normal and marasmic children. For 83% of the children 1 measurement (arm circumference/age) is sufficient to classify them definitely; for the others, several variables are needed. This strategy yields an overall sensitivity of 80%, a specificity of 97%, and a positive predictive value of 38%. Developing countries, where scarcity of resources is a daily reality, need uniformly efficient selection procedures in order to tackle their very common problem: marasmus. Using the clinical definition of marasmus as a substitute for morbidity and mortality, the proposed selection procedure is able to select children at risk with high sensitivity and a very low number of false positives.

Genetic modelling of dizygotic twinning in pedigrees of spontaneous dizygotic twins.

The inheritance of spontaneous dizygotic (DZ) twinning was investigated in 1,422 three-generation pedigrees ascertained through mothers of spontaneous DZ proband twins. DZ twinning was modelled as a trait expressed only in women. The penetrance was modelled first as a parity independent and secondly as parity dependent. The observed frequencies of maternal and paternal grandmothers with DZ twins differed significantly from the expectations under an X-linked mode of inheritance. Complex segregation analysis showed that the parity-independent phenotype of "having DZ twins" was consistent with an autosomal monogenic dominant model, with a gene frequency of 0.035 and a female-specific lifetime penetrance of 0.10. Recessive, polygenic, and sporadic models were rejected. The autosomal dominant model revealed a strong robustness against a changing population prevalence and the loss of information due to the presence of same-sexed twin pairs of unknown zygosity. When DZ twinning was modelled as a parity dependent trait, the data were compatible with an autosomal dominant model with a gene frequency of 0.306 and a penetrance of 0.03 per birth for female gene carriers.

Multivariate genetic analysis of maximal isometric muscle force at different elbow angles.

The maximal isometric moment at five different elbow joint angles was measured in 25 monozygotic and 16 dizygotic male adult twin pairs (22.4 +/- 3.7 yr). Genetic model fitting was used to quantify the genetic and environmental contributions to individual differences in isometric strength. Additive genetic factors explained 66-78% of the variance in maximal torque at 170-140-110 and 80 degrees flexion (extension = 180 degrees). At 50 degrees flexion, common and subject-specific environmental factors contributed equally to the variation. The contribution of unique environmental factors concurs with the level of variability in muscle activation and (dis)-comfort of torque production in the specific angle. The relative contribution of lever arm and force-length relationship in torque varies according to the angle. Because these factors might be genetic, this variability is reflected in the genetic contribution at the extreme angles of 170 and 50 degrees. Multivariate analyses suggested a general set of genes that control muscle area and isometric strength, together with a more specific strength factor. Genetic correlations were high (0.82-0.99). Genes responsible for arm-segment lengths did not contribute to muscle area nor to isometric strength.

Inheritance of physical fitness in 10-yr-old twins and their parents.

This study focuses on the quantification of genetic and environmental sources of variation in physical fitness components in 105 10-yr-old twin pairs and their parents. Nine motor tests and six skinfold measures were administered. Motor tests can be divided into those that are performance-related: static strength, explosive strength, running speed, speed of limb movement, and balance; and those that are health-related: trunk strength, functional strength, maximum oxygen uptake, and flexibility. The significance and contribution of genetic and environmental factors to variation in physical fitness were tested with model fitting. Performance-related fitness characteristics were moderately to highly heritable. The heritability estimates were slightly higher for health-related fitness characteristics. For most variables a simple model including genetic and specific environmental factors fitted the observed phenotypic variance well. Common environmental factors explained a significant part of the variation in speed components and flexibility. Assortative mating was significant and positive for speed components, balance, trunk strength, and cardiorespiratory fitness, but negative for adiposity. Static strength, explosive strength, functional strength, and cardiorespiratory fitness showed evidence for reduced genetic transmission or dominance. The hypothesis that performance-related fitness characteristics are more determined by genetic factors than health-related fitness was not supported. At this prepubertal age, genetic factors have the predominant effect on fitness.

Strength training: importance of genetic factors.

PURPOSE: This study focuses on the quantification of genetic and environmental factors in arm strength after high-resistance strength training. METHODS: Male monozygotic (MZ, N = 25) and dizygotic (DZ, N = 16) twins (22.4 +/- 3.7 yr) participated in a 10-wk resistance training program for the elbow flexors. The evidence for genotype*training interaction, or association of interindividual differences in training effects with the genotype, was tested by a two-way ANOVA in the MZ twins and using a bivariate model-fitting approach on pre- and post-training phenotypes in MZ and DZ twins. One repetition maximum (1RM), isometric strength, and concentric and eccentric moments in 110 degree arm flexion at velocities of 30 degrees x s(-1), 60 degrees x s(-1), and 12 degrees x s(-1) were evaluated as well as arm muscle cross-sectional area (MCSA). RESULTS: Results indicated significant positive training effects for all measures except for maximal eccentric moments. Evidence for genotype*training interaction was found for 1RM and isometric strength, with MZ intra-pair correlations of 0.46 and 0.30, respectively. Bivariate model-fitting indicated that about 20% of the variation in post-training 1RM, isometric strength, and concentric moment at 120 degrees x s(-1) was explained by training-specific genetic factors that were independent from genetic factors that explained variation in the pretraining phenotype (30-77%). CONCLUSIONS: Genetic correlations between measures of pre- and post-training strength were indicative for high pleiotropic gene action and minor activation of training-specific genes during training.

A novel stepwise analysis procedure of genome-wide expression profiles identifies transcript signatures of thiamine genes as classifiers of mitochondrial mutants.

To extract functional information on genes and processes from large expression datasets, analysis methods are required that can computationally deal with these amounts of data, are tunable to specific research questions, and construct classifiers that are not overspecific to the dataset at hand. To satisfy these requirements, a stepwise procedure that combines elements from principal component analysis and discriminant analysis, was developed to specifically retrieve genes involved in processes of interest and classify samples based upon those genes. In a global expression dataset of 300 gene knock-outs in Saccharomyces cerevisiae, the procedure successfully classified samples with similar 'cellular component' Gene Ontology annotations of the knock-out gene by expression signatures of limited numbers of genes. The genes discriminating 'mitochondrion' from the other subgroups were evaluated in more detail. The thiamine pathway turned out to be one of the processes involved and was successfully evaluated in a logistic model to predict whether yeast knock-outs were mitochondrial or not. Further, this pathway is biologically related to the mitochondrial system. Hence, this strongly indicates that our approach is effective and efficient in extracting meaningful information from large microarray experiments and assigning functions to yet uncharacterized genes.

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.

Nutritional anthropometry in children from 0 to 6 years of age in different geographical areas.

Anthropometric data of 12,769 clinically normal children 0-6 years of age from 12 different geographical areas in Africa and Asia are presented. Height, weight, arm circumference and triceps skinfold thickness were measured and presented for age. Derived variables, as muscle circumference, muscle area and muscle proportion-for-age were computed. Weight, arm circumference and muscle area-for-height were calculated. Comparison of these 12 cross-sectional growth patterns shows important differences between groups. The observed differences show that height-for-age, weight-for-age, arm circumference-for-age and weight-for-height are not sufficient to describe adequately and to interpret the variations in nutritional status.

Estimation of glomerular filtration rate from beta 2-microglobulin serum levels in children.

In order to evaluate the usefulness of serum beta 2-microglobulin levels (SBM) in predicting the glomerular filtration rate (GFR) in children, SBM values were plotted against Cr51 EDTA clearance values in 34 children, age 18 months or older (49 determinations). A linear correlation was obtained when SBM values were logarithmically transformed. This relationship was significantly better than that between serum creatinine corrected for body height (Ht/SCR) and Cr51 EDTA clearance. The scatter around the regression line, especially for the lower log SBM values was, however, too large to permit an acceptable prediction of the GFR. Correction of the SBM values for height did not significantly alter this relationship. We conclude from our findings that, although there is a good linear correlation between log SBM and GFR, the latter cannot be predicted within acceptable limits from SBM values in children.

Local versus universal growth standards: the effect of using NCHS as universal reference.

Lack of local references has brought many fieldworkers to use the NCHS reference or other Western standards to assess the nutritional status of children in different developing countries. Cross-sectional data from 6631 children between 0 and 6 years of age, without signs of protein-energy malnutrition, were collected by the same observer in four different geographical areas in Africa and Asia. For each of the four geographical areas, local growth curves were drawn and compared with the NCHS reference. The local curves shows clear heterogeneity, and the values at different ages are not a constant proportion of the NCHS. These observations are in favour of using local standards in the nutritional screening of children in order to develop efficient and effective nutritional programmes.

Genetic control over fragile X chromosome expression.

The cytogenetic expression of fragile sites is highly variable. Sites are seen in differing proportions of cells. To determine if part of this variability is genetic, the proportions of lymphocytes manifesting the fragile X were examined in a large cohort of males with the fragile X chromosome. The number of fragile X cells was solely determined by genetic factors: the heritability as determined from the correlation between brothers as well as between cousins was 99.6% and 94.4%, respectively, as compared with 0% in unrelated males with the fragile X. This is consistent with pure genetic determination without any environmental influence over the expression of the fragile X chromosome in males.

EEC Concerted Action Project--European Congenital Anomalies and Twins (Eurocat).

The European Economic Community (EEC) is promoting a network of locally funded centers in the nine EEC countries, surveying a total of approximately 140,800 births per year for selected congenital malformations and multiple births. The objectives and aims of the study are explained and some of the methods to set guidelines detailed.

Inheritance of static and dynamic arm strength and some of its determinants.

Maximal static, eccentric and concentric torques and arm components estimated by anthropometry and measured by computed tomography were evaluated in 25 male monozygotic twins and 16 dizygotic twins (22.4 +/- 3.7 years). The importance of genetic and environmental factors in the observed variation in these measurements was estimated by genetic model-fitting techniques. In this sample of young adult male twins, genetic factors were significant in most of the strength measurements, arm muscle components and muscle activation variables. The contribution of genetic factors in strength measures depended on the angle, contraction type and to some extent on contraction velocity. For isometric strength, angle-specificity in genetic and environmental variation could be attributed to the degree of variability in muscle activation and performance discomfort at each specific angle, with the highest unique environmental impact at extreme angles. The high genetic contribution at 170 degrees, but not at 50 degrees, possibly expressed different contributions of genetic factors in the muscle-length factor and moment arm in torques at both angles. The importance of genetic factors in eccentric arm flexor strength (62-82%) was larger than for concentric flexion (29-65%), as the pattern of genetic determination followed the torque-velocity curve. Genetic variations in contractile and elastic components, contributing differently to eccentric and concentric torques, together with velocity-dependent actin-myosin binding factors, could account for the observed differences. The broad heritability was very high for all anthropometric and arm cross-sectional area measurements (> 85%) and common environmental factors were only significant for anthropometrically estimated mid-arm muscle tissue are (48%). Heritability estimates of different arm muscularity measurements were comparable.

Predictive power of individual genetic and environmental factor scores.

This study explores the use of an individual's genetic (IGFS) and environmental factor score (IEFS), constructed using genetic model fitting of a multivariate strength phenotype. Maximal isometric and dynamic strength measures, one maximal repetition load (1RM) and muscle cross-sectional area (MCSA) were measured in 25 monozygotic and 16 dizygotic twin pairs. The use of IGFS and IEFS in predicting the sensitivity to environmental stress was evaluated by the association of the scores with strength training gains after a 10-week high resistance strength training programme. Results show a high contribution of genetic factors to the covariation between maximal strength and muscle cross-sectional area (84-97%) at pre-training evaluation. Individual factor scores explained the largest part of the variation in IRM and other strength measures at pre-training and post-training evaluation respectively. Genes that are switched on due to training stress (gene-environment interaction) could explain the decrease in explained variation over time. A negative correlation was found between IGFS and strength training gains (-0.24 to -0.51, P < 0.05); individuals with a high IGFS tend to gain less strength than individuals with low IGFS. Individual environmental factor scores have lower differential power. The predictive value of the IGFS has potential utility in identifying an individual's susceptibility to environmental stress in a variety of multifactorial characteristics, eg diseases and impairments, and for selection of sib pairs for QTL analyses.