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Nature Reviews. Endocrinology Dec 2015In the past, the growth hormone (GH)-insulin-like growth factor 1 (IGF-1) axis was often considered to be the main system that regulated childhood growth and, therefore,... (Review)
Review
In the past, the growth hormone (GH)-insulin-like growth factor 1 (IGF-1) axis was often considered to be the main system that regulated childhood growth and, therefore, determined short stature and tall stature. However, findings have now revealed that the GH-IGF-1 axis is just one of many regulatory systems that control chondrogenesis in the growth plate, which is the biological process that drives height gain. Consequently, normal growth in children depends not only on GH and IGF-1 but also on multiple hormones, paracrine factors, extracellular matrix molecules and intracellular proteins that regulate the activity of growth plate chondrocytes. Mutations in the genes that encode many of these local proteins cause short stature or tall stature. Similarly, genome-wide association studies have revealed that the normal variation in height seems to be largely due to genes outside the GH-IGF-1 axis that affect growth at the growth plate through a wide variety of mechanisms. These findings point to a new conceptual framework for understanding short and tall stature that is centred not on two particular hormones but rather on the growth plate, which is the structure responsible for height gain.
Topics: Animals; Body Height; Gene Dosage; Growth Disorders; Growth Plate; Human Growth Hormone; Humans; Insulin-Like Growth Factor I
PubMed: 26437621
DOI: 10.1038/nrendo.2015.165 -
Frontiers in Endocrinology 2020Humans show marked variation in body size around the world, both within and among populations. At present, the tallest people in the world are from the Netherlands and... (Review)
Review
Humans show marked variation in body size around the world, both within and among populations. At present, the tallest people in the world are from the Netherlands and the Balkan countries, while the shortest populations are central African Pygmies. There are genetic, genetic plasticity, developmental, and environmental bases for size variation in from the recent past and the present. Early populations of species also have shown considerable size variation. Populations from the present and the past are also marked by sexual dimorphism, which, itself, shows group variation. There is abundant evidence for the effects of limited food and disease on human growth and resultant adult body size. This environmental influence has been reflected in "secular trends" (over a span of years) in growth and adult size from socioeconomic prosperity or poverty (availability of resources). Selective and evolutionary advantages of small or large body size also have been documented. Heritability for human height is relatively great with current genome-wide association studies (GWAS) identifying hundreds of genes leading to causes of growth and adult size variation. There are also endocrinological pathways limiting growth. An example is the reduced tissue sensitivity to human growth hormone (HGH) and insulin-like growth factor (IGF-1) in Philippine and African hunter-gatherer populations. In several short-statured hunter-gatherer populations (Asian, African, and South American), it has been hypothesized that short life expectancy has selected for early maturity and truncated growth to enhance fertility. Some island populations of humans and other mammals are thought to have been selected for small size because of limited resources, especially protein. The high-protein content of milk as a staple food may contribute to tall stature in East African pastoral peoples. These and other evolutionary questions linked to life history, male competition, reproduction, and mobility are explored in this paper.
Topics: Adult; Animals; Biological Evolution; Body Height; Body Size; Ethnicity; Genetic Variation; Genome-Wide Association Study; Growth Disorders; Growth and Development; Humans; Mammals; Phenotype
PubMed: 32210916
DOI: 10.3389/fendo.2020.00107 -
The Journal of Clinical Endocrinology... Sep 2018In the last decade, genome-wide association studies (GWASs) have catalyzed our understanding of the genetics of height and have identified hundreds of regions of the... (Review)
Review
CONTEXT
In the last decade, genome-wide association studies (GWASs) have catalyzed our understanding of the genetics of height and have identified hundreds of regions of the genome associated with adult height and other height-related body measurements.
EVIDENCE ACQUISITION
GWASs related to height were identified via PubMed search and a review of the GWAS catalog.
EVIDENCE SYNTHESIS
The GWAS results demonstrate that height is highly polygenic: that is, many thousands of genetic variants distributed across the genome each contribute to an individual's height. These height-associated regions of the genome are enriched for genes in known biological pathways involved in growth, such as fibroblast growth factor signaling, as well as for genes expressed in relevant tissues, such as the growth plate. GWASs can also uncover previously unappreciated biological pathways, such as the STC2/PAPPA/IGFBP4 pathway. The genes implicated by GWASs are often the same genes that are the genetic causes of Mendelian growth disorders or skeletal dysplasias, and GWAS results can provide complementary information about these disorders.
CONCLUSIONS
Here, we review the rationale behind GWASs and what we have learned from GWASs for height, including how it has enhanced our understanding of the underlying biology of human growth. We also highlight the implications of GWASs in terms of prediction of adult height and our understanding of Mendelian growth disorders.
Topics: Body Height; Genome-Wide Association Study; Growth; Growth Disorders; Humans; Multifactorial Inheritance; Signal Transduction
PubMed: 29982553
DOI: 10.1210/jc.2018-01126 -
Journal of Physiological Anthropology Dec 2015Height and skeletal morphology strongly relate to life style. Parallel to the decrease in physical activity and locomotion, modern people are slimmer in skeletal... (Review)
Review
Height and skeletal morphology strongly relate to life style. Parallel to the decrease in physical activity and locomotion, modern people are slimmer in skeletal proportions. In German children and adolescents, elbow breadth and particularly relative pelvic breadth (50th centile of bicristal distance divided by body height) have significantly decreased in recent years. Even more evident than the changes in pelvic morphology are the rapid changes in body height in most modern countries since the end-19th and particularly since the mid-20th century. Modern Japanese mature earlier; the age at take-off (ATO, the age at which the adolescent growth spurt starts) decreases, and they are taller at all ages. Preece-Baines modelling of six national samples of Japanese children and adolescents, surveyed between 1955 and 2000, shows that this gain in height is largely an adolescent trend, whereas height at take-off (HTO) increased by less than 3 cm since 1955; adolescent growth (height gain between ATO and adult age) increased by 6 cm. The effect of globalization on the modern post-war Japanese society ("community effect in height") on adolescent growth is discussed.
Topics: Adolescent; Adult; Body Height; Child; Female; Humans; Japan; Life Style; Male; Reference Values; Young Adult
PubMed: 26642759
DOI: 10.1186/s40101-015-0080-4 -
Current Osteoporosis Reports Oct 2019The goal of the review is to provide a comprehensive overview of the current understanding of the mechanisms underlying variation in human stature. (Review)
Review
PURPOSE OF REVIEW
The goal of the review is to provide a comprehensive overview of the current understanding of the mechanisms underlying variation in human stature.
RECENT FINDINGS
Human height is an anthropometric trait that varies considerably within human populations as well as across the globe. Historically, much research focus was placed on understanding the biology of growth plate chondrocytes and how modifications to core chondrocyte proliferation and differentiation pathways potentially shaped height attainment in normal as well as pathological contexts. Recently, much progress has been made to improve our understanding regarding the mechanisms underlying the normal and pathological range of height variation within as well as between human populations, and today, it is understood to reflect complex interactions among a myriad of genetic, environmental, and evolutionary factors. Indeed, recent improvements in genetics (e.g., GWAS) and breakthroughs in functional genomics (e.g., whole exome sequencing, DNA methylation analysis, ATAC-sequencing, and CRISPR) have shed light on previously unknown pathways/mechanisms governing pathological and common height variation. Additionally, the use of an evolutionary perspective has also revealed important mechanisms that have shaped height variation across the planet. This review provides an overview of the current knowledge of the biological mechanisms underlying height variation by highlighting new research findings on skeletal growth control with an emphasis on previously unknown pathways/mechanisms influencing pathological and common height variation. In this context, this review also discusses how evolutionary forces likely shaped the genomic architecture of height across the globe.
Topics: Anthropometry; Biological Evolution; Body Height; Genome-Wide Association Study; Humans; Phenotype
PubMed: 31441021
DOI: 10.1007/s11914-019-00527-9 -
Endocrinology and Metabolism Clinics of... Jun 2017Short stature is a common and heterogeneous condition that is often genetic in etiology. For most children with genetic short stature, the specific molecular causes... (Review)
Review
Short stature is a common and heterogeneous condition that is often genetic in etiology. For most children with genetic short stature, the specific molecular causes remain unknown; but with advances in exome/genome sequencing and bioinformatics approaches, new genetic causes of growth disorders have been identified, contributing to the understanding of the underlying molecular mechanisms of longitudinal bone growth and growth failure. Identifying new genetic causes of growth disorders has the potential to improve diagnosis, prognostic accuracy, and individualized management, and help avoid unnecessary testing for endocrine and other disorders.
Topics: Body Height; Bone Development; Growth Disorders; Humans
PubMed: 28476223
DOI: 10.1016/j.ecl.2017.01.001 -
Current Opinion in Pediatrics Aug 2015Recent basic studies have yielded important new insights into the molecular mechanisms that regulate growth locally. Simultaneously, clinical studies have identified new... (Review)
Review
PURPOSE OF REVIEW
Recent basic studies have yielded important new insights into the molecular mechanisms that regulate growth locally. Simultaneously, clinical studies have identified new molecular defects that cause growth failure and overgrowth, and genome-wide association studies have elucidated the genetic basis for normal human height variation.
RECENT FINDINGS
The Hippo pathway has emerged as one of the major mechanisms controlling organ size. In addition, an extensive genetic program has been described that allows rapid body growth in the fetus and infant but then causes growth to slow with age in multiple tissues. In human genome-wide association studies, hundreds of loci associated with adult stature have been identified; many appear to involve genes that function locally in the growth plate. Clinical genetic studies have identified a new genetic abnormality, microduplication of Xq26.3, that is responsible for growth hormone excess, and a gene, DNMT3A, in which mutations cause an overgrowth syndrome through epigenetic mechanisms.
SUMMARY
These recent advances in our understanding of somatic growth not only provide insight into childhood growth disorders but also have broader medical applications because disruption of these regulatory systems contributes to oncogenesis.
Topics: Body Height; Child; Child Nutritional Physiological Phenomena; Child, Preschool; Gene Expression Profiling; Genome-Wide Association Study; Growth Disorders; Growth Plate; Hippocampus; Humans; Infant; Infant, Newborn; Mutation; Phenotype; Quantitative Trait Loci; Signal Transduction
PubMed: 26087427
DOI: 10.1097/MOP.0000000000000235 -
Indian Heart Journal 2021Atrial fibrillation (AF) is characterized by abnormal heart rhythm. Among other well-known associations, recent studies suggest an association of AF with height. Height... (Review)
Review
Atrial fibrillation (AF) is characterized by abnormal heart rhythm. Among other well-known associations, recent studies suggest an association of AF with height. Height is related to 50 diseases spanning different body systems, AF is one of them. Since AF, a heterogeneous disease process, is influenced by structural, neural, electrical, and hemodynamic factors, height alters this process through its contribution to increasing atrial and ventricular size, leading to altered conduction patterns, autonomic dysregulation, and development of AF. Multiple underlying mechanisms associate height with AF. Apart from these indirect mechanisms, genome-wide association studies suggest the involvement of the same genes in AF and growth pathways. Tall stature is independently associated with a higher risk of AF development in healthy individuals. Since adult height is achieved much earlier than the onset of AF, protective measures can be taken in individuals with increased height to monitor, manage, and prevent the progression of AF.
Topics: Atrial Fibrillation; Body Height; Heart Rate; Humans; Risk Factors
PubMed: 33714405
DOI: 10.1016/j.ihj.2020.11.008 -
Advances in Nutrition (Bethesda, Md.) Mar 2012Ponderal and linear growth of children has been widely studied; however, epidemiologic evidence of a relationship between the two is inconsistent. Child undernutrition... (Review)
Review
Ponderal and linear growth of children has been widely studied; however, epidemiologic evidence of a relationship between the two is inconsistent. Child undernutrition in the form of low height for age and low weight for height continues to burden the developing world. A downward shift in the distribution of height for age in the first 2 y of life is commonly observed in many developing countries and is usually summarized as the percentage stunted (height for age Z-score <-2). Similar shifts are seen in weight for height; however, weight-for-height shifts are often less extreme, perhaps because weight for height is more tightly biologically controlled. Low height for age and low weight for height in childhood share some common factors, including food insecurity, infectious diseases, and inappropriate feeding practices. Reductions in weight for height, generally seen as a short-term response to inadequate dietary intake or utilization, are thought to precede decreases in height for age; however, given an adequate diet and no further insults, catch-up linear growth can occur. Serial instances of decreased weight for height, however, are thought to limit the degree of catch-up growth attained, contributing to linear growth retardation. Additional research is needed to identify the factors associated with recovery of linear growth after a child experiences decreased weight for height. Although the direct relationship between weight for height and height for age is likely limited, each of these measurements indicates important information about the general health of children and their risk of the development of illness or dying; therefore, eliminating the downward shift of height for age and weight for height in developing countries should be prioritized as a public policy.
Topics: Body Height; Body Weight; Child, Preschool; Developing Countries; Health Status; Humans; Infant; Infant, Newborn; Risk Factors
PubMed: 22516736
DOI: 10.3945/an.111.001099 -
Cancer Causes & Control : CCC Apr 2016We previously showed that childhood height is positively associated with prostate cancer risk. It is, however, unknown whether childhood height exerts its effects...
PURPOSE
We previously showed that childhood height is positively associated with prostate cancer risk. It is, however, unknown whether childhood height exerts its effects independently of or through adult height. We investigated whether and to what extent childhood height has a direct effect on the risk of prostate cancer apart from adult height.
METHODS
We included 5,871 men with height measured at ages 7 and 13 years in the Copenhagen School Health Records Register who also had adult (50-65 years) height measured in the Danish Diet, Cancer and Health study. Prostate cancer status was obtained through linkage to the Danish Cancer Registry. Direct and total effects of childhood height on prostate cancer risk were estimated from Cox regressions.
RESULTS
From 1996 to 2012, 429 prostate cancers occurred. Child and adult heights were positively and significantly associated with prostate cancer risk. When adjusted for adult height, height at age 7 years was no longer significantly associated with the risk of prostate cancer. Height at 13 years was significantly and positively associated with prostate cancer risk even when adult height was adjusted for; per height z-score the hazard ratio was 1.15 [95% confidence interval (CI) 1.01-1.32].
CONCLUSIONS
The effect of height at 13 years on the risk of prostate cancer was not entirely mediated through adult height, suggesting that child height and adult height may be associated with prostate cancer through different pathways.
Topics: Adolescent; Aged; Body Height; Child; Cohort Studies; Humans; Male; Middle Aged; Proportional Hazards Models; Prostatic Neoplasms; Risk Factors
PubMed: 26951518
DOI: 10.1007/s10552-016-0731-8