Tumour necrosis factor superfamily member 11 gene promoter polymorphisms modulate promoter activity and influence bone mineral density in postmenopausal women with osteoporosis

Simona Mencej, Omar Al Bagha, Janez Preželj, Tomaž Kocjan, Janja Marc

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Tumour necrosis factor superfamily member 11 (TNFSF11) gene, that codes for receptor activator of nuclear factor-κB ligand, is one of the candidate genes for the genetic susceptibility to osteoporosis. As variations in the TNFSF11 gene promoter could alter its expression, the aim of the study was to evaluate the functional influence of three polymorphisms in the promoter and to investigate their association with bone mineral density (BMD) and biochemical markers in postmenopausal women. A total of 404 postmenopausal women were genotyped for the presence of TNFSF11 gene promoter polymorphisms -290C> T, -643C> T and -693G> C. Two common haplotypes, CCG and TTC, which occur in 44.3 and 49.3% of subjects respectively, were subjected to functional analysis. Amplified fragments were cloned into pGL3-basic reporter plasmid, which was co-transfected with pRL-TK plasmid into HEK293 cells. Dual luciferase reporter assay was performed. BMD and biochemical markers were measured. Reporter gene analysis showed significantly higher luciferase activity in CCG than in TTC haplotype (P=0.018). Both showed association with lumbar spine BMD (BMD-Is; P=0.005 and 0.007 for TTC and CCG respectively), whereas in femoral neck there was no association with BMD. In postmenopausal osteoporosis, association with BMD-Is was established in -290C> T, -643C> T and -693G> C (P values: 0.001, 0.041 and 0.013 respectively). Association with femoral neck BMD was shown in -693G> G (P=0.049). No association was found with biochemical markers in any of the groups. Our results suggest that in postmenopausal osteoporosis, TNFSF11 gene promoter polymorphisms -290C> T, -643C> T and -693G> C play a functional role in the genetic regulation of BMD.

Original languageEnglish
Pages (from-to)273-279
Number of pages7
JournalJournal of Molecular Endocrinology
Volume40
Issue number5-6
DOIs
Publication statusPublished - May 2008
Externally publishedYes

Fingerprint

Bone Density
Osteoporosis
Tumor Necrosis Factor-alpha
Genes
Postmenopausal Osteoporosis
Biomarkers
Femur Neck
Luciferases
Haplotypes
Plasmids
HEK293 Cells
Genetic Predisposition to Disease
Cytoplasmic and Nuclear Receptors
Reporter Genes
Spine
Ligands

ASJC Scopus subject areas

  • Medicine(all)
  • Molecular Biology
  • Endocrinology

Cite this

Tumour necrosis factor superfamily member 11 gene promoter polymorphisms modulate promoter activity and influence bone mineral density in postmenopausal women with osteoporosis. / Mencej, Simona; Al Bagha, Omar; Preželj, Janez; Kocjan, Tomaž; Marc, Janja.

In: Journal of Molecular Endocrinology, Vol. 40, No. 5-6, 05.2008, p. 273-279.

Research output: Contribution to journalArticle

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abstract = "Tumour necrosis factor superfamily member 11 (TNFSF11) gene, that codes for receptor activator of nuclear factor-κB ligand, is one of the candidate genes for the genetic susceptibility to osteoporosis. As variations in the TNFSF11 gene promoter could alter its expression, the aim of the study was to evaluate the functional influence of three polymorphisms in the promoter and to investigate their association with bone mineral density (BMD) and biochemical markers in postmenopausal women. A total of 404 postmenopausal women were genotyped for the presence of TNFSF11 gene promoter polymorphisms -290C> T, -643C> T and -693G> C. Two common haplotypes, CCG and TTC, which occur in 44.3 and 49.3{\%} of subjects respectively, were subjected to functional analysis. Amplified fragments were cloned into pGL3-basic reporter plasmid, which was co-transfected with pRL-TK plasmid into HEK293 cells. Dual luciferase reporter assay was performed. BMD and biochemical markers were measured. Reporter gene analysis showed significantly higher luciferase activity in CCG than in TTC haplotype (P=0.018). Both showed association with lumbar spine BMD (BMD-Is; P=0.005 and 0.007 for TTC and CCG respectively), whereas in femoral neck there was no association with BMD. In postmenopausal osteoporosis, association with BMD-Is was established in -290C> T, -643C> T and -693G> C (P values: 0.001, 0.041 and 0.013 respectively). Association with femoral neck BMD was shown in -693G> G (P=0.049). No association was found with biochemical markers in any of the groups. Our results suggest that in postmenopausal osteoporosis, TNFSF11 gene promoter polymorphisms -290C> T, -643C> T and -693G> C play a functional role in the genetic regulation of BMD.",
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