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Linkage disequilibrium between polymorphisms in the human TNFRSF1B gene and their association with bone mass in perimenopausal women

Albagha, Omar M E; Tasker, Paul N; McGuigan, Fiona E A LU ; Reid, David M and Ralston, Stuart H (2002) In Human Molecular Genetics 11(19). p.95-2289
Abstract

Osteoporosis is a multifactorial disease with a strong genetic component characterized by reduced bone density and increased fracture risk. A candidate locus for regulation of hip bone mineral density (BMD) has been identified on chromosome 1p36 by linkage analysis. One of the positional and functional candidate genes located within this region is the tumour necrosis factor receptor superfamily member 1B (TNFRSF1B). In order to investigate whether allelic variation in TNFRSF1B contributes to regulation of bone mass, we studied several polymorphisms of this gene in a population based cohort study of 1240 perimenopausal women from the UK. We studied a T676G change in exon 6 (196: Met-Arg) and three SNPs (G593A, T598G, and T620C) in the... (More)

Osteoporosis is a multifactorial disease with a strong genetic component characterized by reduced bone density and increased fracture risk. A candidate locus for regulation of hip bone mineral density (BMD) has been identified on chromosome 1p36 by linkage analysis. One of the positional and functional candidate genes located within this region is the tumour necrosis factor receptor superfamily member 1B (TNFRSF1B). In order to investigate whether allelic variation in TNFRSF1B contributes to regulation of bone mass, we studied several polymorphisms of this gene in a population based cohort study of 1240 perimenopausal women from the UK. We studied a T676G change in exon 6 (196: Met-Arg) and three SNPs (G593A, T598G, and T620C) in the 3'UTR of the gene. The 3'UTR SNPs were in strong linkage disequilibrium (LD) with each other (P<0.00001), and the exon 6 SNP was in LD with G593A and T598G (P<0.00001). We found no association between T676G alleles and BMD at the spine or hip. However, haplotype analysis showed that subjects homozygous for the A593-T598-C620 haplotype (n=85) had femoral neck BMD values 5.7% lower than those who did not carry the haplotype (n=1155; P<0.00008) and this remained significant after correcting for confounding factors and multiple testing (P<0.0009). Regression analysis showed that the ATC haplotype accounted for 1.2% of the population variance in hip BMD and was the second strongest predictor after body weight. In summary, our work supports the view that allelic variation in the 3'UTR of TNFRSF1B gene contributes to the genetic regulation of bone mass, with effects that are specific for femoral neck BMD.

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Contribution to journal
publication status
published
keywords
3' Untranslated Regions, Bone Density, Female, Femur Neck, Haplotypes, Humans, Linkage Disequilibrium, Middle Aged, Polymorphism, Genetic, Receptors, Tumor Necrosis Factor, Receptors, Tumor Necrosis Factor, Type II, Journal Article, Research Support, Non-U.S. Gov't
in
Human Molecular Genetics
volume
11
issue
19
pages
95 - 2289
publisher
Oxford University Press
external identifiers
  • scopus:0037106438
ISSN
0964-6906
DOI
10.1093/hmg/11.19.2289
language
English
LU publication?
no
id
76a5b8bb-11a5-4961-a8d7-539002681bd6
date added to LUP
2018-01-02 11:03:58
date last changed
2018-08-12 04:41:37
@article{76a5b8bb-11a5-4961-a8d7-539002681bd6,
  abstract     = {<p>Osteoporosis is a multifactorial disease with a strong genetic component characterized by reduced bone density and increased fracture risk. A candidate locus for regulation of hip bone mineral density (BMD) has been identified on chromosome 1p36 by linkage analysis. One of the positional and functional candidate genes located within this region is the tumour necrosis factor receptor superfamily member 1B (TNFRSF1B). In order to investigate whether allelic variation in TNFRSF1B contributes to regulation of bone mass, we studied several polymorphisms of this gene in a population based cohort study of 1240 perimenopausal women from the UK. We studied a T676G change in exon 6 (196: Met-Arg) and three SNPs (G593A, T598G, and T620C) in the 3'UTR of the gene. The 3'UTR SNPs were in strong linkage disequilibrium (LD) with each other (P&lt;0.00001), and the exon 6 SNP was in LD with G593A and T598G (P&lt;0.00001). We found no association between T676G alleles and BMD at the spine or hip. However, haplotype analysis showed that subjects homozygous for the A593-T598-C620 haplotype (n=85) had femoral neck BMD values 5.7% lower than those who did not carry the haplotype (n=1155; P&lt;0.00008) and this remained significant after correcting for confounding factors and multiple testing (P&lt;0.0009). Regression analysis showed that the ATC haplotype accounted for 1.2% of the population variance in hip BMD and was the second strongest predictor after body weight. In summary, our work supports the view that allelic variation in the 3'UTR of TNFRSF1B gene contributes to the genetic regulation of bone mass, with effects that are specific for femoral neck BMD.</p>},
  author       = {Albagha, Omar M E and Tasker, Paul N and McGuigan, Fiona E A and Reid, David M and Ralston, Stuart H},
  issn         = {0964-6906},
  keyword      = {3' Untranslated Regions,Bone Density,Female,Femur Neck,Haplotypes,Humans,Linkage Disequilibrium,Middle Aged,Polymorphism, Genetic,Receptors, Tumor Necrosis Factor,Receptors, Tumor Necrosis Factor, Type II,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  month        = {09},
  number       = {19},
  pages        = {95--2289},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {Linkage disequilibrium between polymorphisms in the human TNFRSF1B gene and their association with bone mass in perimenopausal women},
  url          = {http://dx.doi.org/10.1093/hmg/11.19.2289},
  volume       = {11},
  year         = {2002},
}