The genetic and epigenetic contributions to the development of nutritional rickets

Abstract

Nutritional rickets is an important disease in global health. Although nutritional rickets commonly manifests as bony deformities, there is an increased risk of life-threatening seizures secondary to hypocalcaemia. Dietary vitamin D deficiency is associated with the development of nutritional rickets among children and infants. This is especially true in populations of darker skinned individuals in high-latitude environments due to decreased ultraviolet light exposure, and in populations in tropical and subtropical climates due to cultural practices. A growing body of evidence has demonstrated that genetic factors might influence the likelihood of developing nutritional rickets by influencing an individual's susceptibility to develop deficiencies in vitamin D and/or calcium. This evidence has been drawn from a variety of different techniques ranging from traditional twin studies to next generation sequencing techniques. Additionally, the role of the epigenome in the development of rickets, although poorly understood, may be related to the effects of DNA methylation and non-coding RNAs on genes involved in bone metabolism. This review aims to provide an overview of the current evidence that investigates the genetic and epigenetic determinants of nutritional rickets.

Keywords: bone metabolism; epigenetic; genetics; nutrition – clinical; rickets.

Figure 1

Vitamin D₂ is synthesised from ergosterol found in yeast and fungi (17). Ultraviolet B (UVB) rays act on 7-dehydrocholesterol to form previtamin-D₃ in the skin which subsequently undergoes a temperature-dependant isomerisation to vitamin D₃. Vitamin D binding protein (VDBP) transports vitamins D₂ and D₃ to the liver where they undergo 25-hydroxylation to calcidiol (also known as 25(OH)D). This is mediated by 25 hydroxylases such as CYP2R1 (21). 25(OH)D is bound to VDBP and transported to the kidney, where it is filtered through the glomerulus and subsequently reabsorbed into the renal proximal tubular epithelium. This reabsorption occurs through endocytosis and is mediated by the cell surface receptors megalin and cubulin (22). 25(OH)D undergoes 1α-hydroxylation in the kidney and is converted to calcitriol (also known as 1,25-(OH)2D), the active metabolite of 25(OH)D (22, 23). This is mediated by alpha hydroxylases, (such as CYP27B1). 25(OH)D and 1,25(OH)₂D are inactivated by CYP24A1 in the kidneys (24).