Vitamin-D-receptor-gene polymorphisms and change in lumbar-spine bone mineral density

This chapter describes basic principles of receptor action including definitions of agonists, antagonists, inverse agonists, including basic pharmacology of receptor binding, activation and inhibition. All classes of receptors relevant to endocrinology are described, organized by receptor class, and sometimes subclass. Each class/subclass has a general description of receptor structure, expression, subcellular localization, binding, activation, downstream signaling, and deactivation. For a given class of receptors, nonendocrine receptors and ligands of the same class may be described where relevant. For example, in the description of G protein–coupled receptors the variety of ligands is described, both endocrine and nonendocrine including light, odorants and pheromones, small molecules, and proteins. Germline mutations of each receptor (whether activating or inactivating) are described along with the resulting endocrine disorder and its phenotype. In some cases germline mutations causing syndromes that do not have an endocrine phenotype are listed but not fully described. Genotype phenotype correlations are discussed where relevant. Treatment of each disorder may be briefly described but is not the focus of this chapter.

Vitamin D receptor (VDR) gene has an important role as a candidate gene for the regulation of bone mass in osteoporosis. However, its association with bone mineral density (BMD) is controversial and has not been established in different ethnic populations. To enhance the understanding of VDR gene polymorphism in the context of BMD, we investigated the plausible genetic association of TaqI and ApaI polymorphism with BMD in North Indian postmenopausal women with osteoporosis.254 osteoporotic women (Age 55.82 ± 6.91) and 254 postmenopausal non osteoporotic women (Age 54.76 ± 6.26) were included in the study. VDR TaqI and ApaI polymorphism were determined by PCR (polymerase chain reaction) and RFLP (restriction fragment length polymorphism). BMD was assessed by dual energy X-ray absorptiometry (DXA) at the lumbar spine (L₁-L₄), hip, forearm and femoral neck. The average BMD with TT genotype was significantly lower at lumbar spine, hip and forearm. The Frequency of TT genotype and t allele was significantly high in osteoporotic women when compared with controls. The average BMD with Aa genotype was higher in ApaI. Furthermore, comparison of frequency distribution of genotype and allele for VDR ApaI between osteoporotic patients and controls did not show any significant difference. Our findings revealed that TaqI gene TT genotype was associated with low BMD in North Indian osteoporotic women. Moreover, TT genotype and t allele associated significantly with osteoporosis in postmenopausal women. Therefore, VDR TaqI gene is an important determinant of risk factor for osteoporosis.

Osteoporosis and its consequence of fragility fracture are complex traits resulting from interactions of multiple genetic and environmental factors. Moreover, the response to antiosteoporotic therapies is highly variable among individuals, and this variability may also be partly determined by genetic factors. In the past decade, there has been substantial progress in the genetics and genomics of osteoporosis, but few advances in pharmacogenetics and pharmacogenomics of osteoporosis. Several genetic variants associated with bone mineral density and fracture risk have been identified by genome-wide association studies (GWAS). However, no genetic variants have been conclusively shown to be associated with response to antiosteoporotic therapies. Although the possibility of gene-based individualized assessment of fracture risk and personalized therapy in osteoporosis care is not yet realized, progress that has been made is reviewed.

Mineralization of bones is an important function of calcium; calcium homeostasis is regulated by parathyroid hormone (PTH), vitamin D, and calcitonin. Genetic defects in PTH (e.g., DiGeorge syndrome) and defects in calcium-sensing receptor (CaSR), multiple endocrine neoplasia type 1, cell division cycle, G-protein alpha S, and GATA binding protein-3 genes result in defects in secretion/action of PTH. Defects in vitamin D receptor; vitamin D binding protein; and cytochrome P450, family 24, subfamily A, polypeptide-1 (CYP24A1) genes affect vitamin D. Other genes (e.g., low-density lipoprotein receptor-related protein-5, interleukin-6, and lactase) impact calcium homeostasis. Genome-wide association studies have identified several loci, including diacylglycerol kinase, glucokinase regulatory protein (GCKR), CaSR, and CYP24A1 that are associated with bone density. Genotype associations with calcium homeostasis and bone mineralization are modified by calcium intake; thus gene-related health conditions may be modified to some degree by varying dietary calcium intake.

To study the role of VDR polymorphisms as risk factor for RA and osteoporosis, and whether osteoporosis complicating RA is due to RA or VDR polymorphisms.

VDR gene polymorphisms ApaI, TaqI, BsmI and FokI were typed by RFLP for 128 RA patients, 30 postmenopausal osteoporotic females and 150 healthy controls.

Significant differences were found between patients and healthy controls in the frequency of BsmI and TaqI (Pc < 0.05) but no significant associations were found for FokI and ApaI polymorphisms except for aa genotype (Pc < 0.001). Titers of RF were higher with aa and bb genotypes. Anti-CCP and CRP levels were higher with aa genotype and more bone loss was associated with Bb genotype. Ff genotype frequency was higher in RA patients with osteoporosis than those without osteoporosis.

The ApaI, BsmI and TaqI polymorphisms may be a susceptibility risk factors for RA and the Ff genotype may be responsible for development of osteoporosis in RA Egyptian patients. However, the present study needs to be replicated in a large number of patients from allover the Egypt and also in multi-ethnic populations.