In addition to vitamin-D–related genes, other genes have also been found to be associated with calcium intake and bone mineralization. Some years ago the low-density lipoprotein receptor-related protein-5 (LRP5) gene was reported to be involved in rare bone disorders, and the role of the Wnt/β-catenin pathway was described in the regulation of bone homeo- stasis. Reports suggest that variants in these genes (i.e., LRP5 and Wnt/β-catenin) also contribute to variations in bone traits (Lara-Castillo and Johnson, 2015). In a study on 9- to 18-year-old Iranian children, the effect of LRP5 polymorphisms on bone density and biochemical markers were studied. These authors found that one LRP5 polymorphism (rs556442) did not have a significant influence on serum calcium; however, lean body mass was greater in the GG genotype and total body bone area, spine bone density, and femoral bone mineral content (BMC) were lower in the AG heterozygous genotype.
Thus it was concluded that this LRP5 polymorphism was positively associated with bone density in this group of children (Ashouri et al., 2014).
Four common polymorphisms of LRP5 (rs1784235, rs491347, rs4988321, and rs4988330) were also assessed for their association with BMD and calcium intake in Greek postmenopausal women. Although none of the polymorphisms were
associated with the presence of osteoporosis, all polymorphisms were associated with spine BMD. These authors also found an interaction of the rs4988321 SNP with dietary intake of calcium. The carriers of the A allele had significantly lower spine BMD in comparison with the GG homozygotes in the lowest calcium intake group (<680 mg/day); however, in the highest calcium intake group no differences were found in the genotypes. It was concluded that a higher calcium intake attenuated the negative effect of these polymorphisms on bone density (Stathopoulou et al., 2010).
Associations have also been described between interleukin (IL)-6 promoter polymorphisms and bone mass. In a cross-sectional study in premenarchal Chinese girls, the authors examined the association among IL-6 promoter alleles (-174G/C and -634C/G), bone mass, and calcium intake. However, these authors did not detect polymorphisms in the IL-6 -174G/C locus; all were GG homozygotes. The IL-6 -634C/G polymorphism was significantly associated with bone mass. Girls with the CC genotype had higher levels of bone mass than those with G allele carriers. Calcium had a greater impact on total body BMC in G allele carriers than in CC carriers, and the G-allele–associated lower total body BMC was found only in subjects with low dietary calcium intake. Thus it was concluded that the IL-6 -634C/G polymorphism was significantly associated with BMD and that the association was modified by calcium intake in these young Chinese girls (Li et al., 2008).
Associations between dietary factors and IL-6 polymorphisms with bone mass have also been investigated in the Fram- ingham Offspring Cohort. From the study cohort, 1574 unrelated men and women were genotyped for IL-6 -572 and -174 alleles, and interaction analyses with lifestyle factors and BMD measurements at the hip were performed. In models in which the main effects of IL-6 polymorphisms and association with BMD were studied, no associations were found in either gender. However, interactions between IL-6 -174 genotypes and years since menopause, estrogen status, dietary calcium, and vitamin D intake were observed in women, and BMD was significantly lower with the -174 GG genotype compared with CC, and intermediate with GC, in women with calcium intake less than 940 mg/day. In estrogen-deficient women with poor calcium intake, there were significant differences in the BMD between genotypes CC and GG. Thus these authors concluded that IL-6 genetic variations were prominently associated with hip BMD in late postmenopausal women, especially in those with inadequate calcium intake. However, IL-6 polymorphisms were not significant determinants of bone mass in women or men in another study. However, these associations were not seen in men (Ferrari et al., 2004).
Thus several studies have examined the association between IL-6 polymorphisms and BMD. A meta-analysis suggested that there are modest effects of the -634C/G and -174G/C polymorphisms on bone density. Even so, there were insufficient data on the interactions with diet; hence these authors suggested that large-scale and well-designed studies are required to further investigate gene–gene and gene–environment interactions related to IL-6 polymorphisms and bone density in vari- ous populations (Zhao et al., 2013; Wang et al., 2013).
Genetic disorders of lactose intolerance have also been associated with reduced calcium intake, bone density, and fractures in postmenopausal women. Lactase deficiency, an autosomal-recessive condition due to A -13910 T/C dimor- phism (LCT) near the lactase phlorizin hydrolase gene, is reported to have an effect on calcium supply and osteoporotic fractures in the elderly. Reports suggested that the LCT (T/C-13910) polymorphism is associated with milk intolerance and thus reduced milk calcium intake and reduced BMD (Obermayer-Pietsch et al., 2004). In a further report by the same group, the authors evaluated whether lactose also decreases intestinal calcium absorption in subjects with lactase deficiency and whether lactose-reduced diet and lactose-free calcium supplementation could maintain BMD. They concluded that decreased calcium intake as well as lactose-associated impaired calcium absorption may predispose subjects with reduced lactase to osteoporosis and that calcium supplementation may help to maintain BMD (Obermayer-Pietsch et al., 2007).
Given the number of genes that are associated with regulation of blood calcium concentrations and bone mineralization, genome-wide association studies (GWAS) have explored loci influencing calcium concentrations and hence bone health.
Studying the relationship between calcium intake and genetic makeup may lead to a better understanding of the scientific basis of the interaction of calcium-related genes and the biological response triggered by calcium intake. Thus in a recent study genetic polymorphisms influencing serum calcium levels in east Asians were investigated. These authors found the strongest relationship between an SNP in CaSR and calcium levels. Furthermore, the cystatin A (CSTA), diacylglycerol kinase (DGKD), and glucokinase regulatory protein (GCKR) loci were also found to be significantly associated with cal- cium levels in Europeans and Indians (Vinayagamoorthy et al., 2015). Little is known about the relationship of DGKD with calcium-associated disorders; members of this large family of enzymes bind to and regulate proteins activated by either dia- cylglycerol or phosphatidic acid (Luo et al., 2004). DGKD has been shown to have calcium-binding activity and it is more active in the presence of calcium (Yamada et al., 1997). In one of the first reports on the association of DGKD with bone, the DGKD axis was described to be a critical regulator of bone homeostasis via its actions on osteoclast differentiation and transcription factor c-Fos expression (Zamani et al., 2015). GCKR has also been reported to be associated with calcium levels in African-American and European-American children (Chang et al., 2015). In another GWAS study, the authors identified and replicated one known and six new loci influencing serum calcium near genes linked to bone metabolism.
Molecular Aspects of Calcium and Bone Mineralization Chapter | 6 63
Of these, DGKD, GCKR, CaSR, and CYP24A1 polymorphisms were associated with BMD in the general population.
In their supporting mouse studies, these authors demonstrated a relationship between these loci and gene expression in response to dietary calcium intake (O’Seaghdha et al., 2013).
CONCLUSIONS
Calcium is the most abundant mineral in the human body, and 99% of the body’s calcium is found in bones and teeth. Serum calcium concentrations are kept stable, with variations that do not exceed 2–3%, by PTH, vitamin D, and calcitonin. Various genetic mutations/polymorphisms affecting the action of PTH, vitamin D, or their receptors may affect the absorption of calcium and mineralization of bones. The varying associations of genes with calcium and bone metabolism are possibly due to the differing levels of calcium intake in the populations studied as well as the age of participants and the genetic makeup.
Studying the relationship between calcium intake and genetic makeup may lead to a better understanding of the scientific basis of the interaction between calcium-related genes and the biological response triggered by calcium intake. GWAS studies have identified six to seven loci, including DGKD, GCKR, CaSR, and CYP24A1, which are associated with bone density in the general population. Associations of genes with calcium homeostasis and bone mineralization may be modi- fied by calcium intake; thus gene-related health conditions may be modified to some degree by modifying dietary calcium intake. Therefore knowledge of genes related to calcium intake may help in modifying lifestyle for improving bone health.
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