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

Omar Al Bagha, Paul N. Tasker, Fiona E A McGuigan, David M. Reid, Stuart H. Ralston

Research output: Contribution to journalArticle

40 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)2289-2295
Number of pages7
JournalHuman Molecular Genetics
Volume11
Issue number19
Publication statusPublished - 15 Sep 2002
Externally publishedYes

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Receptors, Tumor Necrosis Factor, Type II
Linkage Disequilibrium
Bone Density
Bone and Bones
Haplotypes
Pelvic Bones
Genes
Single Nucleotide Polymorphism
Femur Neck
Exons
Population
Osteoporosis
human TNF protein
Hip
Spine
Cohort Studies
Chromosomes
Alleles
Body Weight
Regression Analysis

ASJC Scopus subject areas

  • Genetics

Cite this

Linkage disequilibrium between polymorphisms in the human TNFRSF1B gene and their association with bone mass in perimenopausal women. / Al Bagha, Omar; Tasker, Paul N.; McGuigan, Fiona E A; Reid, David M.; Ralston, Stuart H.

In: Human Molecular Genetics, Vol. 11, No. 19, 15.09.2002, p. 2289-2295.

Research output: Contribution to journalArticle

Al Bagha, Omar ; Tasker, Paul N. ; McGuigan, Fiona E A ; Reid, David M. ; Ralston, Stuart H. / Linkage disequilibrium between polymorphisms in the human TNFRSF1B gene and their association with bone mass in perimenopausal women. In: Human Molecular Genetics. 2002 ; Vol. 11, No. 19. pp. 2289-2295.
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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 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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