Adolescent Idiopathic Scoliosis, environment, exposome and epigenetics: a molecular perspective of postnatal normal spine growth and the etiopathogenesis of AIS with consideration of a network approach and possible implicatins for medical therapy.
Authors: R Geoffrey Burwell, Peter H Dangerfield, Alan Moulton and Theodoros B Grivas
Centre for Spinal Studies and Surgery, Nottingham University Hospitals Trust, Queen's Medical Centre Campus, Derby Road, Nottingham, NG7 2UH, UK
University of Liverpool, Ashton Street, L69 3GE, UK
Staffordshire University, Leek Road, Stoke-on-Trent, ST4 2DF, UK
Royal Liverpool Children's Hospital, Eaton Road, Liverpool, L12 2AP, UK
Department of Orthopaedic Surgery, King's Mill Hospital, Sutton Road, Mansfield NG17 4JL, UK
Department of Trauma and Orthopedics, "Tzanio" General Hospital, Tzani and Afendouli 1 st, Piraeus 18536, Greece
AbstractGenetic factors are believed to play an important role in the etiology of adolescent idiopathic scoliosis (AIS). Discordant findings for monozygotic (MZ) twins with AIS show that environmental factors including different intrauterine environments are important in etiology, but what these environmental factors may be is unknown. Recent evidence for common chronic non-communicable diseases suggests epigenetic differences may underlie MZ twin discordance, and be the link between environmental factors and phenotypic differences. DNA methylation is one important 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. The word exposome refers to the totality of environmental exposures from conception onwards, comprising factors in external and internal environments. The word exposome is used here also in relation to physiologic and etiopathogenetic factors that affect normal spinal growth and may induce the deformity of AIS. In normal postnatal spinal growth we propose a new term and concept, physiologic growth-plate exposome for the normal processes particularly of the internal environments that may have epigenetic effects on growth plates of vertebrae.
In AIS, we propose a new term and concept pathophysiologic scoliogenic exposome for the abnormal processes in molecular pathways particularly of the internal environment currently expressed as etiopathogenetic hypotheses; these are suggested to have deforming effects on the growth plates of vertebrae at cell, tissue, structure and/or organ levels that are considered to be epigenetic. New research is required for chromatin modifications including DNA methylation in AIS subjects and vertebral growth plates excised at surgery. In addition, consideration is needed for a possible network approach to etiopathogenesis by constructing AIS diseasomes. These approaches may lead through screening, genetic, epigenetic, biochemical, metabolic phenotypes and pharmacogenomic research to identify susceptible individuals at risk and modulate abnormal molecular pathways of AIS.
The potential of epigenetic-based medical therapy for AIS cannot be assessed at present, and must await new research derived from the evaluation of epigenetic concepts of spinal growth in health and deformity. The tenets outlined here for AIS are applicable to other musculoskeletal growth disorders including infantile and juvenile idiopathic scoliosis.
IntroductionThe principal aim of this paper is to examine the etiopathogenesis of adolescent idiopathic scoliosis (AIS) from the standpoint of epigenetics. To our knowledge this has not previously been addressed. Epigenetics, a relatively recent field now vast and vigorous, evaluates factors concerned with gene expression in relation to environment, disease, normal development and aging, with a complex regulation across the genome during the first decade of life. Butcher and Beck describe epigenetics as follows:
"Although environmental measures are logical covariants for genotype-phenotype investigations, another non-genetic intermediary exists: epigenetics. Epigenetics is the analysis of somatically-acquired and, in some cases, transgenerationally inherited epigenetic modifications that regulate gene expression, and offers to bridge the gap between genetics and environment to understand phenotype. The most widely studied epigenetic mark is DNA methylation. Aberrant methylation at gene promoters is strongly implicated in disease etiology, most notably cancer."
There is controversy relating to the definition of epigenetics which we outline. Taking the broad definition, a view of AIS etiopathogenesis and normal spinal development is presented from an epigenetic standpoint, predicated on a model for other diseases.
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