Multiple Genetic Loci for Bone Mineral Density and Fractures
This study implicates five genetic loci in bone mineral density. Two of these loci are new; three implicate genes known to be involved in bone remodeling, such as the receptor activator of nuclear factor-κB ligand gene ( RANKL ). Analyses showed that three of the loci are associated with osteoporoti...
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| Published in | The New England journal of medicine Vol. 358; no. 22; pp. 2355 - 2365 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Boston, MA
Massachusetts Medical Society
29.05.2008
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0028-4793 1533-4406 1533-4406 |
| DOI | 10.1056/NEJMoa0801197 |
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| Abstract | This study implicates five genetic loci in bone mineral density. Two of these loci are new; three implicate genes known to be involved in bone remodeling, such as the receptor activator of nuclear factor-κB ligand gene (
RANKL
). Analyses showed that three of the loci are associated with osteoporotic fracture.
This study implicates five genetic loci in bone mineral density. Two of these loci are new; three implicate genes known to be involved in bone remodeling.
Osteoporosis confers substantive morbidity and mortality and associated costs and predisposes people to fragility fractures at the hip, spine, forearm, or other skeletal sites.
1
It is a common disease affecting both sexes in populations of various ancestries, although elderly women of European descent are at the highest risk.
2
Bone density is the single best predictor of osteoporotic fractures and is a valuable tool in evaluation of the risk of fractures.
3
,
4
There is abundant evidence for a genetic contribution to variation in bone mineral density, with heritability estimates between 0.6 and 0.8.
5
Bone mineral density is also influenced by environmental . . . |
|---|---|
| AbstractList | This study implicates five genetic loci in bone mineral density. Two of these loci are new; three implicate genes known to be involved in bone remodeling, such as the receptor activator of nuclear factor-κB ligand gene (
RANKL
). Analyses showed that three of the loci are associated with osteoporotic fracture.
This study implicates five genetic loci in bone mineral density. Two of these loci are new; three implicate genes known to be involved in bone remodeling.
Osteoporosis confers substantive morbidity and mortality and associated costs and predisposes people to fragility fractures at the hip, spine, forearm, or other skeletal sites.
1
It is a common disease affecting both sexes in populations of various ancestries, although elderly women of European descent are at the highest risk.
2
Bone density is the single best predictor of osteoporotic fractures and is a valuable tool in evaluation of the risk of fractures.
3
,
4
There is abundant evidence for a genetic contribution to variation in bone mineral density, with heritability estimates between 0.6 and 0.8.
5
Bone mineral density is also influenced by environmental . . . Bone mineral density influences the risk of osteoporosis later in life and is useful in the evaluation of the risk of fracture. We aimed to identify sequence variants associated with bone mineral density and fracture.BACKGROUNDBone mineral density influences the risk of osteoporosis later in life and is useful in the evaluation of the risk of fracture. We aimed to identify sequence variants associated with bone mineral density and fracture.We performed a quantitative trait analysis of data from 5861 Icelandic subjects (the discovery set), testing for an association between 301,019 single-nucleotide polymorphisms (SNPs) and bone mineral density of the hip and lumbar spine. We then tested for an association between 74 SNPs (most of which were implicated in the discovery set) at 32 loci in replication sets of Icelandic, Danish, and Australian subjects (4165, 2269, and 1491 subjects, respectively).METHODSWe performed a quantitative trait analysis of data from 5861 Icelandic subjects (the discovery set), testing for an association between 301,019 single-nucleotide polymorphisms (SNPs) and bone mineral density of the hip and lumbar spine. We then tested for an association between 74 SNPs (most of which were implicated in the discovery set) at 32 loci in replication sets of Icelandic, Danish, and Australian subjects (4165, 2269, and 1491 subjects, respectively).Sequence variants in five genomic regions were significantly associated with bone mineral density in the discovery set and were confirmed in the replication sets (combined P values, 1.2x10(-7) to 2.0x10(-21)). Three regions are close to or within genes previously shown to be important to the biologic characteristics of bone: the receptor activator of nuclear factor-kappaB ligand gene (RANKL) (chromosomal location, 13q14), the osteoprotegerin gene (OPG) (8q24), and the estrogen receptor 1 gene (ESR1) (6q25). The two other regions are close to the zinc finger and BTB domain containing 40 gene (ZBTB40) (1p36) and the major histocompatibility complex region (6p21). The 1p36, 8q24, and 6p21 loci were also associated with osteoporotic fractures, as were loci at 18q21, close to the receptor activator of the nuclear factor-kappaB gene (RANK), and loci at 2p16 and 11p11.RESULTSSequence variants in five genomic regions were significantly associated with bone mineral density in the discovery set and were confirmed in the replication sets (combined P values, 1.2x10(-7) to 2.0x10(-21)). Three regions are close to or within genes previously shown to be important to the biologic characteristics of bone: the receptor activator of nuclear factor-kappaB ligand gene (RANKL) (chromosomal location, 13q14), the osteoprotegerin gene (OPG) (8q24), and the estrogen receptor 1 gene (ESR1) (6q25). The two other regions are close to the zinc finger and BTB domain containing 40 gene (ZBTB40) (1p36) and the major histocompatibility complex region (6p21). The 1p36, 8q24, and 6p21 loci were also associated with osteoporotic fractures, as were loci at 18q21, close to the receptor activator of the nuclear factor-kappaB gene (RANK), and loci at 2p16 and 11p11.We have discovered common sequence variants that are consistently associated with bone mineral density and with low-trauma fractures in three populations of European descent. Although these variants alone are not clinically useful in the prediction of risk to the individual person, they provide insight into the biochemical pathways underlying osteoporosis.CONCLUSIONSWe have discovered common sequence variants that are consistently associated with bone mineral density and with low-trauma fractures in three populations of European descent. Although these variants alone are not clinically useful in the prediction of risk to the individual person, they provide insight into the biochemical pathways underlying osteoporosis. Background Bone mineral density influences the risk of osteoporosis later in life and is useful in the evaluation of the risk of fracture. We aimed to identify sequence variants associated with bone mineral density and fracture. Methods We performed a quantitative trait analysis of data from 5861 Icelandic subjects (the discovery set), testing for an association between 301,019 single-nucleotide polymorphisms (SNPs) and bone mineral density of the hip and lumbar spine. We then tested for an association between 74 SNPs (most of which were implicated in the discovery set) at 32 loci in replication sets of Icelandic, Danish, and Australian subjects (4165, 2269, and 1491 subjects, respectively). Results Sequence variants in five genomic regions were significantly associated with bone mineral density in the discovery set and were confirmed in the replication sets (combined P values, 1.2×10-7 to 2.0×10-21 ). Three regions are close to or within genes previously shown to be important to the biologic characteristics of bone: the receptor activator of nuclear factor-κB ligand gene (RANKL ) (chromosomal location, 13q14), the osteoprotegerin gene (OPG ) (8q24), and the estrogen receptor 1 gene (ESR1 ) (6q25). The two other regions are close to the zinc finger and BTB domain containing 40 gene (ZBTB40 ) (1p36) and the major histocompatibility complex region (6p21). The 1p36, 8q24, and 6p21 loci were also associated with osteoporotic fractures, as were loci at 18q21, close to the receptor activator of the nuclear factor-κB gene (RANK ), and loci at 2p16 and 11p11. Conclusions We have discovered common sequence variants that are consistently associated with bone mineral density and with low-trauma fractures in three populations of European descent. Although these variants alone are not clinically useful in the prediction of risk to the individual person, they provide insight into the biochemical pathways underlying osteoporosis. Bone mineral density influences the risk of osteoporosis later in life and is useful in the evaluation of the risk of fracture. We aimed to identify sequence variants associated with bone mineral density and fracture. We performed a quantitative trait analysis of data from 5861 Icelandic subjects (the discovery set), testing for an association between 301,019 single-nucleotide polymorphisms (SNPs) and bone mineral density of the hip and lumbar spine. We then tested for an association between 74 SNPs (most of which were implicated in the discovery set) at 32 loci in replication sets of Icelandic, Danish, and Australian subjects (4165, 2269, and 1491 subjects, respectively). Sequence variants in five genomic regions were significantly associated with bone mineral density in the discovery set and were confirmed in the replication sets (combined P values, 1.2x10(-7) to 2.0x10(-21)). Three regions are close to or within genes previously shown to be important to the biologic characteristics of bone: the receptor activator of nuclear factor-kappaB ligand gene (RANKL) (chromosomal location, 13q14), the osteoprotegerin gene (OPG) (8q24), and the estrogen receptor 1 gene (ESR1) (6q25). The two other regions are close to the zinc finger and BTB domain containing 40 gene (ZBTB40) (1p36) and the major histocompatibility complex region (6p21). The 1p36, 8q24, and 6p21 loci were also associated with osteoporotic fractures, as were loci at 18q21, close to the receptor activator of the nuclear factor-kappaB gene (RANK), and loci at 2p16 and 11p11. We have discovered common sequence variants that are consistently associated with bone mineral density and with low-trauma fractures in three populations of European descent. Although these variants alone are not clinically useful in the prediction of risk to the individual person, they provide insight into the biochemical pathways underlying osteoporosis. |
| Author | Halldorsson, Bjarni V Ingvarsson, Thorvaldur Gulcher, Jeffrey R Stefansson, Kari Walters, G. Bragi Jonsdottir, Thorbjorg Thorsteinsdottir, Unnur Saemundsdottir, Jona Bagger, Yu Styrkarsdottir, Unnur Eisman, John A Nguyen, Tuan V Gretarsdottir, Solveig Gudbjartsson, Daniel F Christiansen, Claus Center, Jacqueline R Sigurdsson, Gunnar Kong, Augustine |
| Author_xml | – sequence: 1 givenname: Unnur surname: Styrkarsdottir fullname: Styrkarsdottir, Unnur – sequence: 2 givenname: Bjarni V surname: Halldorsson fullname: Halldorsson, Bjarni V – sequence: 3 givenname: Solveig surname: Gretarsdottir fullname: Gretarsdottir, Solveig – sequence: 4 givenname: Daniel F surname: Gudbjartsson fullname: Gudbjartsson, Daniel F – sequence: 5 givenname: G. Bragi surname: Walters fullname: Walters, G. Bragi – sequence: 6 givenname: Thorvaldur surname: Ingvarsson fullname: Ingvarsson, Thorvaldur – sequence: 7 givenname: Thorbjorg surname: Jonsdottir fullname: Jonsdottir, Thorbjorg – sequence: 8 givenname: Jona surname: Saemundsdottir fullname: Saemundsdottir, Jona – sequence: 9 givenname: Jacqueline R surname: Center fullname: Center, Jacqueline R – sequence: 10 givenname: Tuan V surname: Nguyen fullname: Nguyen, Tuan V – sequence: 11 givenname: Yu surname: Bagger fullname: Bagger, Yu – sequence: 12 givenname: Jeffrey R surname: Gulcher fullname: Gulcher, Jeffrey R – sequence: 13 givenname: John A surname: Eisman fullname: Eisman, John A – sequence: 14 givenname: Claus surname: Christiansen fullname: Christiansen, Claus – sequence: 15 givenname: Gunnar surname: Sigurdsson fullname: Sigurdsson, Gunnar – sequence: 16 givenname: Augustine surname: Kong fullname: Kong, Augustine – sequence: 17 givenname: Unnur surname: Thorsteinsdottir fullname: Thorsteinsdottir, Unnur – sequence: 18 givenname: Kari surname: Stefansson fullname: Stefansson, Kari |
| BackLink | http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20384459$$DView record in Pascal Francis https://www.ncbi.nlm.nih.gov/pubmed/18445777$$D View this record in MEDLINE/PubMed |
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| CODEN | NEJMAG |
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| Snippet | This study implicates five genetic loci in bone mineral density. Two of these loci are new; three implicate genes known to be involved in bone remodeling, such... Bone mineral density influences the risk of osteoporosis later in life and is useful in the evaluation of the risk of fracture. We aimed to identify sequence... Background Bone mineral density influences the risk of osteoporosis later in life and is useful in the evaluation of the risk of fracture. We aimed to identify... |
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| SubjectTerms | Adolescent Adult Aged Aged, 80 and over Australia Biological and medical sciences Bone density Bone Density - genetics Denmark Estrogen Receptor alpha - genetics Female Fractures Fractures, Bone - genetics General aspects Genotype Humans Iceland Investigative techniques, diagnostic techniques (general aspects) Linear Models Male Medical sciences Methods Middle Aged Mortality Older people Osteoarticular system. Muscles Osteoporosis Osteoporosis - genetics Osteoprotegerin - genetics Polymorphism, Single Nucleotide Quantitative Trait Loci Radiodiagnosis. Nmr imagery. Nmr spectrometry RANK Ligand - genetics |
| Title | Multiple Genetic Loci for Bone Mineral Density and Fractures |
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