Influence of LRP5 Polymorphisms on Normal Variation in BMD

Abstract

Genetic studies based on cohorts with rare and extreme bone phenotypes have shown that the LRP5 gene is an important genetic modulator of BMD. Using family-based and case-control approaches, this study examines the role of the LRP5 gene in determining normal population variation of BMD and describes significant association and suggestive linkage between LRP5 gene polymorphisms and BMD in >900 individuals with a broad range of BMD.Introduction: Osteoporosis is a common, highly heritable condition determined by complex interactions of genetic and environmental etiologies. Genetic factors alone can account for 50 -80% of the interindividual variation in BMD. Mutations in the LRP5 gene on chromosome 11q12-13 have been associated with rare syndromes characterized by extremely low or high BMD, but little is known about the contribution of this gene to the development of osteoporosis and determination of BMD in a normal population. Materials and Methods:To examine the entire spectrum of low to high BMD, 152 osteoporotic probands, their families (597 individuals), and 160 women with elevated BMD (T score Ͼ 2.5) were recruited. BMD at the lumbar spine, femoral neck, and hip were measured in each subject using DXA. Results: PAGE sequencing of the LRP5 gene revealed 10 single nucleotide polymorphisms (SNPs), 8 of which had allele frequencies of Ͼ5%, in exons 8, 9, 10, 15, and 18 and in introns 6, 7, and 21. Within families, a strong association was observed between an SNP at nucleotide C171346A in intron 21 and total hip BMD (p Ͻ 1 ϫ 10

Genetic variation at the low-density lipoprotein receptor-related protein 5 (LRP5) locus modulates Wnt signaling and the relationship of physical activity with bone mineral density in men

“…28 A third study confirmed both linkage and association of LRP5 alleles with BMD in 152 osteoporotic probands, their families and 160 women with BMD greater than 2.5 standard deviations above young normals, all recruited from a single region in England. 29 In keeping with our own findings that LRP5 SNPs #5 and #6 in exons 9 and 10 were associated with BMD in men, but not women, the latter study reported within-family association between an intronic SNP near exon 21 and BMD of the hip, which was stronger in males. Moreover, linkage analysis revealed linkage between SNP #9 and total hip and femoral neck BMD, and comparing osteoporotic probands to unrelated postmenopausal women with high BMD revealed three other SNPs in exons 8 (rs545382), 9 (rs2277268), and 21 (IVS21 +52c<a) to be associated with BMD.…”

“…It is possible therefore that differences in muscle strength or physical activity between men and women could modulate the influence of LRP5 polymorphisms on bone mass that in some previous studies have demonstrated gender-specific effects. [28][29][30] There were several potential limitations to our study. First there were some inconsistencies between the significant main effects of a SNP #6 mostly on the hip in men ≤60 years and the interaction of this SNP with physical activity in all men on spine BMD.…”

Increased Bone Turnover in Patients with Hypercholesterolemia

“…Some found an association of hypercholesterolemia with lower BMD [5][6][7][8][9][10], and others with higher BMD [11], while yet others found no association at all [12,13]. On the other hand, both in vitro and in vivo animal model studies have demonstrated some detrimental effects of hypercholesterolemia or dyslipidemia on bone metabolism [14][15][16][17][18][19][20][21][22][23]. In in vitro studies, osteoblastic differentiation has been shown to be inhibited by atherogenic lipids [14,15].…”

“…The mevalonate pathway has recently been proposed as essential for not only the synthesis of cholesterol but also the regulation of bone cell proliferation or apoptosis [16,17,24]. In addition, LDL receptor-related protein 5 (LRP5) has recently been identified as a critical regulator of osteoblastic proliferation [18], and a mutation in LRP5 as causing significant reduction in BMD in both humans and mice [19,20]. More recently, a mutation in LRP6, a closely related homolog of LRP5, has been shown to lead to reduced bone mass in mice [21], and to be genetically linked with early coronary disease, metabolic risk factors, and osteoporosis in humans [22].…”

“…Clarifying bone metabolism in hypercholesterolemia will be helpful for ascertaining whether the above-mentioned potentially detrimental effects detected in in vitro or animal models [14][15][16][17][18][19][20][21][23][24][25] also exist in humans. In addition, such clarification should aid the search for an answer for the controversial findings of previous clinical studies [5][6][7][8][9][10][11][12][13] of the relationship between hypercholesterolemia and osteoporosis, and will promote our understanding of the underlying pathomechanisms, if any, for these two diseases.…”