Genetics, epigenetics and the scoliogeny of adolescent idiopathic scoliosis: how much is genetics and how much is it epigenetics as a new paradigm?

Bone & Joint 

Clinical lead, Dr Theodoros Grivas and guest authors
Genetics, epigenetics and the scoliogeny of adolescent idiopathic scoliosis: how much is genetics and how much is it epigenetics as a new paradigm?
Article authors: TB Grivas, RG Burwell, PH Dangerfield, A Moulton
Scoliogeny is suggested to include the processes of aetiology, pathogenesis and pathomechanism of scoliosis.1 It is widely recognized that genetics play a role in the scoliogeny of idiopathic scoliosis, a complex disease which in some subjects may involve poorly understood environmental factors.1-3 Some recently-acquired knowledge on genetics and non-genetic factors for adolescent idiopathic scoliosis (AIS) scoliogeny is summarised in a recent paper by Burwell et al.1 In connection with the genetic variant hypothesis of disease and non-genomic factors. Butcher and Beckwrite:
“A spate of high-powered genome-wide association studies (GWAS) have recently identified numerous single-nucleotide polymorphisms (SNPs) robustly linked with complex disease. Despite interrogating the majority of common human variation, these SNPs only account for a small proportion of the phenotypic variance, which suggests genetic factors are acting in concert with non-genetic factors. Although environmental measures are logical covariants for genotype-phenotype investigations, another non-genetic intermediary exists, epigenetics.
The word epigenetics was coined by Waddington to link the two fields of developmental biology and genetics, hitherto considered as separate disciplines; there are several definitions of epigenetics with different meanings for different scientists.5 Elsewhere we outline a novel molecular perspective encompassing epigenetic modifications and interactions at vertebral growth plates for normal postnatal spinal growth and the aetiopathogenesis of AIS.5Epigenetics is now generally defined as information heritable during cell division but not contained within the DNA sequence itself, termed epigenetic modification.5-9 There are three major ways organisms modify their DNAs inherited messages without changing DNA sequence:
·         enzymes methylate DNA to modulate transcription;
·         histone modifications and nucleosome positioning to induce or repress target sequences; and
·         non-coding small RNAs to modify the expression of specific genes where there is therapeutic potential.
DNA methylation is an epigenetic mechanism operating at the interface between genome and environment to regulate phenotypic plasticity with a complex regulation across the genome during the first decade of life; it depends on dietary methionine and folate, both of which are affected by the nutritional state of the individual. Epigenetic modifications provides multicellular organisms with a system of normal gene regulation that silences portions of the genome and keeps them silent as tissues differentiate as epigenotypes: errors in this complex system from environmental and stochastic events termed epimutations can give rise to abnormal gene silencing, which may result in phenotypic variation and common disease.5-9 Epigenetic mechanisms such as DNA methylation are considered to be important in the development of different diseases.10,11 In recent studies physical exercise has been shown to influence genome-wide DNA methylation pattern in human skeletal muscle12and adipose tissue.11
Research into the role of environmental factors and epigenetics has exploded in the last decade but only a small number of publications relate environmental factors to the scoliogeny of AIS. In a review we identified several domains containing potential environmental risk factors for AIS scoliogeny:5
·         food and growth connection, nutrition,
·         relative osteopenia and life-style factors,
·         physical activities of patients with AIS,
·         geographic latitude and the prevalence of   AIS,
·         maternal age and socio-economic status,
·         heated indoor swimming pools infants and delayed epigenetic effects,
·         hypothesis of developmental instability for scoliosis,
·         monozygotic twins and spinal radiology in AIS (Fig. 1).
In monozygotic twins, exactly-similar scoliotic curves are not always found. Do epigenetic mechanisms make monozygotic twins develop different curves?
Non-surgical treatments for AIS involving physical exercises and brace treatments can be considered as exerting environmental effects on the spine.Asymmetric internal pressure of the intervertebral disc and vertebral growth plate in scoliosis suggests an abnormal stress environment generates a positive feedback of cellular changes, resulting in curve progression due to a combination of factors.13,14
The important question is: how much genetics and how much epigenetics are involved in the scoliogeny of AIS? The answer to this question may provide insight into the aetiology of “idiopathic” scoliosis and potentially direct therapeutic management to less invasive treatment strategies. This aspiration is in accordance with the statement of Bird whose laboratory was the first to map patterns of DNA methylation in the vertebrate genome,7 “....over the next decade new approaches will be applied to a wide range of diseases, allowing us to realise the promise of epigenetics.9  This new paradigm may include not only AIS for which one case was reported,15 but also other musculoskeletal growth disorders, such as infantile idiopathic scoliosis,5,16 juvenile idiopathic scoliosis,5 Perthes’ disease17 and club foot.18
Figure 1 depicts two pairs of monozygotic scoliotic twins. On the left, the spinal radiographs of two monozygotic twins, 20 years old. They have the same type of curves, but of different Cobb angle. On the right, the spinal radiographs of two monozygotic twins 13 years old treated with a brace. The one has a Lenke 3C (double major) and the second a Lenke 2B (double thoracic). (Courtesy Dr Jean Claude De Mauroy).
1. Burwell RG, Dangerfield PH, Moulton A, Grivas TB, Cheng JCY. Whither the etiopathogenesis (and scoliogeny) of adolescent idiopathic scoliosis?Incorporating presentations on scoliogeny at the 2012 IRSSD and SRS meetings.Scoliosis 2013;8:4.
2. Wise CA, Gao X, Shoemaker S, Gordon D, Herring JA. Understanding genetic factors in idiopathic scoliosis, a complex disease of childhood. Curr Genomics 2008;9:51-9.
3. Wang WJ, Yeung HY, Chu WC, et al. Top theories for the etiopathogenesis of adolescent idiopathic scoliosis. J Pediatr Orthop 2011;31:S14-S27.
4. Butcher LM, Beck S. Future impact of integrated high-throughput methylome analyses on human health and disease. J Genet Genomics2008;35:391–401.
5. Burwell RG, Dangerfield PD, Moulton A, Grivas  TB. Adolescent idiopathic scoliosis (AIS), environment, exposome and epigenetics: a molecular perspective of postnatal normal spinal growth and the etiopathogenesis of AIS with consideration of a network approach and possible implications for medical therapy. Scoliosis 2011;6:26.
6. Bjornsson HT, Fallin MD, Feinberg AP. An integrated epigenetic and genetic approach to common human disease. Trends Genet 2004;20:350–8.
7. Suzuki MM, Bird A. DNA methylation landscapes: provocative insights from epigenomics. Nat Rev Genet 2008;9:465-76.8. Nelissen EC, van Montfoort AP, Dumoulin JC, Evers JL. Epigenetics and the placenta. Hum Reprod Update2011;17:397–417.
9. Bird A. Epigenetics: Instant Expert 29. New Scientist 2013;217:i-viii.
10. Gluckman PD, Hanson MA, Beedle AS, Buklijas T, Low FM. Epigenetics of human diseaseIn Epigenetics linking genotype and phenotype in development and evolution. Chapter 22. Hallgrimsson B, Hall BK (eds). Berkeley: University of California Press; 2011:398-423.
11. Rönn T, Volkov P, Davegårdh C, et al. A six months exercise intervention influences the genome-wide DNA methylation pattern in human adipose tissue.PLoS Genet 2013;9:e1003572.
12. Nitert MD, Dayeh T, Volkov P, et al. Impact of an exercise intervention on DNA methylation in skeletal muscle from first-degree relatives of patients with type 2 diabetes. Diabetes 2012;61:3322-32.
13. Bibby SR, Meir A, Fairbank JC, Urban JP.  Cell viability and the physical environment in the scoliotic intervertebral disc. Stud Health Technol Inform2002;91:41 9-21.
14. Meir A, McNally DS, Fairbank JC, Jones D, Urban JP. The internal pressure and stress environment of the scoliotic intervertebral disc: a review. Proc Inst Mech Eng H 2008;222:209-19.
15. Wise C. State of the art review of the genetic basis of idiopathic scoliosis. In 50th Anniversary International Phillip Zorab Symposium, Royal College of Surgeons of England, London, UK, June 20-21 2013.
16. Wynne-Davies R, Littlejohn A, Gormley J. Aetiology and interrelationship of some common skeletal deformities. (Talipes equinovarus and calcaneovalgus, metatarsus varus, congenital dislocation of the hip, and infantile idiopathic scoliosis). J Med Genet 1982;19:321-8.
17. Perry DC, Bruce CE, Pope D, et al. Legg-Calvé-Perthes disease in the UK: geographic and temporal trends in incidence reflecting differences in degree of deprivation in childhood. Arthritis Rheum 2012; 64:1673-9.
18. Engesaeter LB. Increasing incidence of club foot: changes in the genes or the environment? Acta Orthop 2006;77:837-838.
Author details:
Theodoros B Grivas , Department of Trauma and Orthopedics, “Tzanio” General Hospital, Tzani and Afendouli 1 st, Piraeus 18536, Greece
R Geoffrey Burwell, Centre for Spinal Studies and Surgery, Nottingham University Hospitals Trust, Queen’s Medical Centre Campus, Nottingham, UK
Peter H Dangerfield,University of Liverpool, Staffordshire University and Royal Liverpool Children’s Hospital, Liverpool, UK
Alan Moulton, Department of Orthopaedic Surgery, King’s Mill Hospital, Mansfield, UK
February 2014

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