Molecular studies of identification of genes for osteoporosis: the 2002 update

Abstract

We aim to give a comprehensive review, updated to 2002, of the most important and representative molecular genetic studies, performed mainly within the past decade, that aimed to identify the gene(s) involved in osteoporosis. Early reviews were largely confined to association studies in humans, but we review here, separately, the results of both association and linkage studies in humans, and quantitative trait locus (QTL) mapping in animal models. The main results of all the studies are tabulated for comparison and ease of reference, and to provide a comprehensive retrospective view of molecular genetics studies of osteoporosis. The most striking findings and the most representative studies are singled out for comment regarding the immediacy of their influence on present understanding of the genetics of osteoporosis and on the current status of genetic research in osteoporosis. This is particularly relevant for studies on the association of the vitamin D receptor (VDR) gene, for which there has been a large body of studies and reviews published. The format adopted by this review should be ideal for accommodating future new advances and studies in a fairly young field that is still developing rapidly.

Univariate and bivariate variance component linkage analysis of a whole-genome scan for loci contributing to bone mineral density

“…Marker D2S405 in the same region on 2p23 was reported to be linked to forearm BMD by Niu et al 23 Other regions where we observed interesting lod-scores coincide with regions reported in other studies and/or known to contain candidate genes for bone-related traits. 5,12 A formal meta-analysis will help elucidate whether these findings may in fact indicate the existence of genomic regions containing susceptibility genes for osteoporosis shared across different populations. In particular, chromosome 5q33 yielded lod-scores of more than 1 in both univariate analysis for FN BMD and LS BMD and bivariate analysis for FN/LS BMD and FN/TR BMD in our pedigrees, and coincides with the region reported by Koller et al 24 for FN BMD.…”

Association of single nucleotide polymorphisms in the promoter region of the pro-opiomelanocortin gene (POMC) with low bone mineral density in adult women

“…Like many other common diseases, multiple factors, including genetic variations, determine predisposition for onset or progression of osteoporosis, as has been indicated by genetic-epidemiological studies (Peacock et al 2002;Albagha and Ralston 2003). Numerous studies on genetic risks for osteoporosis have been investigated to date, mainly by association studies and linkage analysis for quantitative trait BMD (Liu et al 2003).…”

Pharmacogenomic approaches to osteoporosis

“…20 In agreement with this theory, many studies showed the association between the Sp1 polymorphism and the risk for osteoporosis or fractures. 5 Although inconsistent association results exist, two meta-analyses 21,22 supported that the presence of the s allele was significantly associated with low BMD and fracture prevalence though such effect on bone metabolism was moderate and could be easily modified by environmental factors. In keeping with this, one pharmacogenetic research demonstrated that the s allele negatively influences BMD response to the etidronate therapy since femoral neck BMD obviously increased in the SS group while decreased in the Ss/ss group.…”

“…23 In the osteoporosis research field, although few haplotype analyses were done in the pharmacogenetic context, some haplotypes of certain candidate genes were already studied and associated with bone phenotypes. 5 Moreover, the underway 'HapMap' project 24 holds promise for the genome-wide association studies that will use haplotype blocks to unravel some mystery of osteoporosis and provide an ideal regimen of treatment for osteoporotic patients according to the complete genetic evaluations. Yet, a large number of SNPs will be required for such whole genome association studies.…”

“…Our recent review systematically tabulated the chromosome regions, showing evidence of linkage with osteoporosis-related phenotypes. 5 Some of them (2p23-24, 1p36, 3q21, 4q31 and 13q34) were replicated to be linked with BMD phenotype, but no region was completely confirmed. However, no genome-wide linkage scan for loci influencing the efficacy of anti-osteoporotic therapies was launched.…”