Common Genetic Variation of the Low‐Density Lipoprotein Receptor‐Related Protein 5 and 6 Genes Determines Fracture Risk in Elderly White Men
Both LRP5 and LRP6 genes have been implicated to play a role in bone metabolism. In a large population‐based study, we related common variation in both genes to bone parameters and fractures. LRP5 variation was associated to both BMD and frame size, whereas both LRP5 and 6 variations were associated...
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| Published in | Journal of bone and mineral research Vol. 21; no. 1; pp. 141 - 150 |
|---|---|
| Main Authors | , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Washington, DC
John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)
01.01.2006
American Society for Bone and Mineral Research |
| Subjects | |
| Online Access | Get full text |
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| Abstract | Both LRP5 and LRP6 genes have been implicated to play a role in bone metabolism. In a large population‐based study, we related common variation in both genes to bone parameters and fractures. LRP5 variation was associated to both BMD and frame size, whereas both LRP5 and 6 variations were associated with an increased fracture risk in males.
Introduction: The low‐density lipoprotein receptor‐related protein 5 (LRP5) gene has a clear role in rare BMD traits and also in normal variation in peak BMD. We examined whether common variation in LRP5 and its close homolog, LRP6, plays a role in BMD in old age and fractures, the main clinical endpoint of osteoporosis.
Materials and Methods: We analyzed four variants of LRP5 and one amino acid variant of the LRP6 gene in a large prospective population‐based cohort study of elderly subjects.
Results and Conclusions: In men, the LRP5 1330‐valine variant was associated with decreased BMD at the lumbar spine and the femoral neck with evidence for an allele‐dose effect (p = 0.001 and 0.01, respectively). The Val allele was also associated with decreased vertebral body size and femoral neck width. Haplotype analysis of studied polymorphisms did not improve the association found and suggested that the 1330 variant was driving the association. We observed a borderline significant association of the LRP6 Ile1062Val polymorphism with height and vertebral body size in males. Male carriers of the LRP5 1330‐valine variant had a 60% increased risk for fragility fractures, and the LRP6 1062‐valine allele also conferred a 60% higher risk. Carriers of both the risk alleles of LRP5 and 6 had a 140% (p = 0.004) higher risk compared with noncarriers of both risk alleles and accounted for 10% of the fractures in males. The fracture risks were independent of age, height, weight, and BMD. In women, all of these associations were weaker and less consistent compared with men. The polymorphisms that were found associated were both situated in potentially important domains of the receptor and show considerable evolutionary conservation, which is evidence for functional importance of these residues. |
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| AbstractList | Both LRP5 and LRP6 genes have been implicated to play a role in bone metabolism. In a large population-based study, we related common variation in both genes to bone parameters and fractures. LRP5 variation was associated to both BMD and frame size, whereas both LRP5 and 6 variations were associated with an increased fracture risk in males. The low-density lipoprotein receptor-related protein 5 (LRP5) gene has a clear role in rare BMD traits and also in normal variation in peak BMD. We examined whether common variation in LRP5 and its close homolog, LRP6, plays a role in BMD in old age and fractures, the main clinical endpoint of osteoporosis. We analyzed four variants of LRP5 and one amino acid variant of the LRP6 gene in a large prospective population-based cohort study of elderly subjects. In men, the LRP5 1330-valine variant was associated with decreased BMD at the lumbar spine and the femoral neck with evidence for an allele-dose effect (p = 0.001 and 0.01, respectively). The Val allele was also associated with decreased vertebral body size and femoral neck width. Haplotype analysis of studied polymorphisms did not improve the association found and suggested that the 1330 variant was driving the association. We observed a borderline significant association of the LRP6 Ile1062Val polymorphism with height and vertebral body size in males. Male carriers of the LRP5 1330-valine variant had a 60% increased risk for fragility fractures, and the LRP6 1062-valine allele also conferred a 60% higher risk. Carriers of both the risk alleles of LRP5 and 6 had a 140% (p = 0.004) higher risk compared with noncarriers of both risk alleles and accounted for 10% of the fractures in males. The fracture risks were independent of age, height, weight, and BMD. In women, all of these associations were weaker and less consistent compared with men. The polymorphisms that were found associated were both situated in potentially important domains of the receptor and show considerable evolutionary conservation, which is evidence for functional importance of these residues. Both LRP5 and LRP6 genes have been implicated to play a role in bone metabolism. In a large population-based study, we related common variation in both genes to bone parameters and fractures. LRP5 variation was associated to both BMD and frame size, whereas both LRP5 and 6 variations were associated with an increased fracture risk in males.UNLABELLEDBoth LRP5 and LRP6 genes have been implicated to play a role in bone metabolism. In a large population-based study, we related common variation in both genes to bone parameters and fractures. LRP5 variation was associated to both BMD and frame size, whereas both LRP5 and 6 variations were associated with an increased fracture risk in males.The low-density lipoprotein receptor-related protein 5 (LRP5) gene has a clear role in rare BMD traits and also in normal variation in peak BMD. We examined whether common variation in LRP5 and its close homolog, LRP6, plays a role in BMD in old age and fractures, the main clinical endpoint of osteoporosis.INTRODUCTIONThe low-density lipoprotein receptor-related protein 5 (LRP5) gene has a clear role in rare BMD traits and also in normal variation in peak BMD. We examined whether common variation in LRP5 and its close homolog, LRP6, plays a role in BMD in old age and fractures, the main clinical endpoint of osteoporosis.We analyzed four variants of LRP5 and one amino acid variant of the LRP6 gene in a large prospective population-based cohort study of elderly subjects.MATERIALS AND METHODSWe analyzed four variants of LRP5 and one amino acid variant of the LRP6 gene in a large prospective population-based cohort study of elderly subjects.In men, the LRP5 1330-valine variant was associated with decreased BMD at the lumbar spine and the femoral neck with evidence for an allele-dose effect (p = 0.001 and 0.01, respectively). The Val allele was also associated with decreased vertebral body size and femoral neck width. Haplotype analysis of studied polymorphisms did not improve the association found and suggested that the 1330 variant was driving the association. We observed a borderline significant association of the LRP6 Ile1062Val polymorphism with height and vertebral body size in males. Male carriers of the LRP5 1330-valine variant had a 60% increased risk for fragility fractures, and the LRP6 1062-valine allele also conferred a 60% higher risk. Carriers of both the risk alleles of LRP5 and 6 had a 140% (p = 0.004) higher risk compared with noncarriers of both risk alleles and accounted for 10% of the fractures in males. The fracture risks were independent of age, height, weight, and BMD. In women, all of these associations were weaker and less consistent compared with men. The polymorphisms that were found associated were both situated in potentially important domains of the receptor and show considerable evolutionary conservation, which is evidence for functional importance of these residues.RESULTS AND CONCLUSIONSIn men, the LRP5 1330-valine variant was associated with decreased BMD at the lumbar spine and the femoral neck with evidence for an allele-dose effect (p = 0.001 and 0.01, respectively). The Val allele was also associated with decreased vertebral body size and femoral neck width. Haplotype analysis of studied polymorphisms did not improve the association found and suggested that the 1330 variant was driving the association. We observed a borderline significant association of the LRP6 Ile1062Val polymorphism with height and vertebral body size in males. Male carriers of the LRP5 1330-valine variant had a 60% increased risk for fragility fractures, and the LRP6 1062-valine allele also conferred a 60% higher risk. Carriers of both the risk alleles of LRP5 and 6 had a 140% (p = 0.004) higher risk compared with noncarriers of both risk alleles and accounted for 10% of the fractures in males. The fracture risks were independent of age, height, weight, and BMD. In women, all of these associations were weaker and less consistent compared with men. The polymorphisms that were found associated were both situated in potentially important domains of the receptor and show considerable evolutionary conservation, which is evidence for functional importance of these residues. Both LRP5 and LRP6 genes have been implicated to play a role in bone metabolism. In a large population-based study, we related common variation in both genes to bone parameters and fractures. LRP5 variation was associated to both BMD and frame size, whereas both LRP5 and 6 variations were associated with an increased fracture risk in males. The low-density lipoprotein receptor-related protein 5 (LRP5) gene has a clear role in rare BMD traits and also in normal variation in peak BMD. We examined whether common variation in LRP5 and its close homolog, LRP6, plays a role in BMD in old age and fractures, the main clinical endpoint of osteoporosis. We analyzed four variants of LRP5 and one amino acid variant of the LRP6 gene in a large prospective population-based cohort study of elderly subjects. In men, the LRP5 1330-valine variant was associated with decreased BMD at the lumbar spine and the femoral neck with evidence for an allele-dose effect (p = 0.001 and 0.01, respectively). The Val allele was also associated with decreased vertebral body size and femoral neck width. Haplotype analysis of studied polymorphisms did not improve the association found and suggested that the 1330 variant was driving the association. We observed a borderline significant association of the LRP6 Ile1062Val polymorphism with height and vertebral body size in males. Male carriers of the LRP5 1330-valine variant had a 60% increased risk for fragility fractures, and the LRP6 1062-valine allele also conferred a 60% higher risk. Carriers of both the risk alleles of LRP5 and 6 had a 140% (p = 0.004) higher risk compared with noncarriers of both risk alleles and accounted for 10% of the fractures in males. The fracture risks were independent of age, height, weight, and BMD. In women, all of these associations were weaker and less consistent compared with men. The polymorphisms that were found associated were both situated in potentially important domains of the receptor and show considerable evolutionary conservation, which is evidence for functional importance of these residues. Both LRP5 and LRP6 genes have been implicated to play a role in bone metabolism. In a large population-based study, we related common variation in both genes to bone parameters and fractures. LRP5 variation was associated to both BMD and frame size, whereas both LRP5 and 6 variations were associated with an increased fracture risk in males. Introduction: The low-density lipoprotein receptor-related protein 5 (LRP5) gene has a clear role in rare BMD traits and also in normal variation in peak BMD. We examined whether common variation in LRP5 and its close homolog, LRP6, plays a role in BMD in old age and fractures, the main clinical endpoint of osteoporosis. Materials and Methods: We analyzed four variants of LRP5 and one amino acid variant of the LRP6 gene in a large prospective population-based cohort study of elderly subjects. Results and Conclusions: In men, the LRP5 1330-valine variant was associated with decreased BMD at the lumbar spine and the femoral neck with evidence for an allele-dose effect (p = 0.001 and 0.01, respectively). The Val allele was also associated with decreased vertebral body size and femoral neck width. Haplotype analysis of studied polymorphisms did not improve the association found and suggested that the 1330 variant was driving the association. We observed a borderline significant association of the LRP6Ile1062Val polymorphism with height and vertebral body size in males. Male carriers of the LRP5 1330-valine variant had a 60% increased risk for fragility fractures, and the LRP61062-valine allele also conferred a 60% higher risk. Carriers of both the risk alleles of LRP5 and 6 had a 140% (p = 0.004) higher risk compared with noncarriers of both risk alleles and accounted for 10% of the fractures in males. The fracture risks were independent of age, height, weight, and BMD. In women, all of these associations were weaker and less consistent compared with men. The polymorphisms that were found associated were both situated in potentially important domains of the receptor and show considerable evolutionary conservation, which is evidence for functional importance of these residues. Both LRP5 and LRP6 genes have been implicated to play a role in bone metabolism. In a large population‐based study, we related common variation in both genes to bone parameters and fractures. LRP5 variation was associated to both BMD and frame size, whereas both LRP5 and 6 variations were associated with an increased fracture risk in males. Introduction: The low‐density lipoprotein receptor‐related protein 5 (LRP5) gene has a clear role in rare BMD traits and also in normal variation in peak BMD. We examined whether common variation in LRP5 and its close homolog, LRP6, plays a role in BMD in old age and fractures, the main clinical endpoint of osteoporosis. Materials and Methods: We analyzed four variants of LRP5 and one amino acid variant of the LRP6 gene in a large prospective population‐based cohort study of elderly subjects. Results and Conclusions: In men, the LRP5 1330‐valine variant was associated with decreased BMD at the lumbar spine and the femoral neck with evidence for an allele‐dose effect (p = 0.001 and 0.01, respectively). The Val allele was also associated with decreased vertebral body size and femoral neck width. Haplotype analysis of studied polymorphisms did not improve the association found and suggested that the 1330 variant was driving the association. We observed a borderline significant association of the LRP6 Ile1062Val polymorphism with height and vertebral body size in males. Male carriers of the LRP5 1330‐valine variant had a 60% increased risk for fragility fractures, and the LRP6 1062‐valine allele also conferred a 60% higher risk. Carriers of both the risk alleles of LRP5 and 6 had a 140% (p = 0.004) higher risk compared with noncarriers of both risk alleles and accounted for 10% of the fractures in males. The fracture risks were independent of age, height, weight, and BMD. In women, all of these associations were weaker and less consistent compared with men. The polymorphisms that were found associated were both situated in potentially important domains of the receptor and show considerable evolutionary conservation, which is evidence for functional importance of these residues. |
| Author | van Meurs, Joyce BJ Jhamai, Mila Uitterlinden, André G Hofman, Albert van Leeuwen, Johannes PTM Rivadeneira, Fernando Hugens, Wendy Pols, Huibert AP |
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| Keywords | Human Diseases of the osteoarticular system genetic association Fracture Trauma Protein Lipoprotein LDL Osteoarticular system Osteoporosis Vertebrata Mammalia Gene low-density lipoprotein receptor-related protein 6 low-density lipoprotein receptor-related protein 5 Genetics Elderly Polymorphism Biological receptor |
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| PublicationTitle | Journal of bone and mineral research |
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| Snippet | Both LRP5 and LRP6 genes have been implicated to play a role in bone metabolism. In a large population‐based study, we related common variation in both genes... Both LRP5 and LRP6 genes have been implicated to play a role in bone metabolism. In a large population-based study, we related common variation in both genes... |
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| SubjectTerms | Aged Aged, 80 and over Amino Acid Substitution Biological and medical sciences Bone Density - genetics Cohort Studies European Continental Ancestry Group Female Fractures, Bone - genetics Fundamental and applied biological sciences. Psychology genetic association Humans LDL-Receptor Related Proteins - genetics Linkage Disequilibrium Low Density Lipoprotein Receptor-Related Protein-5 Low Density Lipoprotein Receptor-Related Protein-6 Male Middle Aged osteoporosis Osteoporosis - genetics polymorphism Polymorphism, Genetic Risk Factors Sex Factors Skeleton and joints Vertebrates: osteoarticular system, musculoskeletal system |
| Title | Common Genetic Variation of the Low‐Density Lipoprotein Receptor‐Related Protein 5 and 6 Genes Determines Fracture Risk in Elderly White Men |
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