History

Genes & Polymorphisms

Listed below are the genes and polymorphisms analyzed and being processed:

Analyzed:

Undergoing Processing:

Analyzed:

Estrogen Receptor Alpha - ESR1

Gene Location:  6q25.1
Expression: The estrogen recpetor is a nuclear hormone receptor. Estrogen receptor isoforms are expressed in osteoblasts, osteoclasts, and bone marrow stromal cells.
Polymorphisms studied in GENOMOS:
Structure: The ESR1 gene spans 450 kilobases and is composed by eight coding exons (in red) and nine non-coding 5'UTR exons (A, B, C, D, E1, E2, F, T1, and T2, in blue). The estrogen receptor protein is 597 amino acids in size, several splice variants exist, which form dimers with the 'wild-type' and effects the function of the receptor.

Key references:

L. Becherini, et al., Evidence of a linkage disequilibrium between polymorphisms in the human estrogen receptor alpha gene and their relationship to bone mass variation in postmenopausal Italian women.
Hum Mol Genet. 2000 Aug 12;9(13):2043-50

J.B.J. van Meurs, et al., Association of 5' estrogen receptor alpha gene polymorphisms with bone mineral density, vertebral bone area and fracture risk.
Hum Mol Genet. 2003 Jul 15;12(14):1745-54.

J.P. Ioannidis et al., Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes.
JAMA. 2004 Nov 3;292(17):2105-14

Collagen type I alpha 1 - COL1A1

Gene Location: 17q21.31-q22
Expression:
Polymorphisms studied in GENOMOS:
 The Sp1 polymorphism is in the fourth Sp1 binding site in intron 1.
Structure: The COL1A1 gene is 18 kb in size and is composed of 52 exons. Exons 6 to 49 encode the alpha helical domain. Most of these exons are 45 bp, 54 bp or multiple of 45 bp or 54 bp.
COL1A Gene Structure
Key references:

S.F. Grant et al., Reduced bone density and osteoporosis associated with a polymorphic Sp1 binding site in the collagen type I alpha 1 gene.
Nat Genet. 1996 Oct;14(2):203-5

A.G. Uitterlinden et al., Relation of alleles of the collagen type Ialpha1 gene to bone density and the risk of osteoporotic fractures in postmenopausal women.
N Engl J Med.1998 Apr 9;338(15):1016-21

Vitamin D Receptor - VDR

Gene Location:  12q12-q14
Expression: The vitamin D3 receptor plays an essential role in calcium and phosphate homeostasis and skeletal metabolism and is expressed in osteoblasts.
Polymorphisms studied in GENOMOS:
 The Cdx2 polymorphism is located in the promoter region of the VDR gene, with the A-allele giving higher transcriptional activity of the gene.
The FokI RFLP is located in the coding region of the VDR gene and has an effect on the activity of the receptor
The BsmI, ApaI and TaqI RFLPs are located in the 3' end of the gene.
Structure: 14 exons spanning approximately 75 kb. The noncoding 5' end includes exons 1A through 1F, while its translated product is encoded by 8 additional exons.
The DNA sequence upstream to exon 1A is GC-rich and does not contain an apparent TATA box. Several potential binding sites for the transcription factor SP1 and other activators exist. Three unique mRNA isoforms are produced as a result of the differential splicing of exons 1B and 1C.
VDR Gene Structure
Key references:

S. Nejentsev, et al., Comparative high-resolution analysis of linkage disequilibrium and tag single nucleotide polymorphisms between populations in the vitamin D receptor gene.
Hum Mol Genet. 2004 Aug 1;13(15):1633-9

Y. Fang, et al., Promoter and 3'-untranslated-region haplotypes in the Vitamin D Receptor gene predispose to osteoporotic fracture: the Rotterdam Study.
Am J Hum Genet. 2005 Nov;77(5):807-23

Transforming GrowthFactor beta 1 - TGFB1

Gene Location:  19q13.1.
Expression: TGFB1 is present in the bone matrix and refulates osteoblast proliferation and differentiation and directly affects bone formation in vivo.
Polymorphisms studied in GENOMOS:
Structure:  The TGFB1 gene has 7 exons spanning approximately 23kb
TGFB Structure
Key references:

B. Langdahl et al., Polymorphisms in the transforming growth factor beta 1 gene and osteoporosis. 
Bone 2003 Mar; 32(3):297-310

Undergoing Processing:

Low Density Lipoprotein Receptor-Related Protein 5 - LRP5

Gene Location:  11q13.4
Expression: LRP5 is expressed in osteoblasts and affects bone mass accrual during growth.
Polymorphisms studied in GENOMOS:
Structure: The LRP5 gene spans over 100 kb and is composed of 23 exons.
LDP5 Gene Structure
Key references:

S. Ferrari et al., Polymorphisms in the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with variation in vertebral bone mass, vertebral bone size, and stature in whites.
Am J Hum Genet. 2004 May; 74(5):866-75

J.B.J. van Meurs et al., Common genetic variation of the low-density lipoprotein receptor-related protein 5 and 6 determines fracture risk in elderly white men.
J Bone Miner Res. 2006 Jan; 21(1):141-50

Low Density Lipoprotein Receptor-Related Protein 6 - LRP6

Gene Location:  12p13.3-p11.2
Expression: LRP6 is expressed in bone.
Polymorphisms studied in GENOMOS:
 The I1062V polymorphism in LRP6 lies within the fourth YWTD beta-propeller domain, which is located in the dickkopf-binding region.
Structure: The LRP6 gene is about 150 kb in size and is composed of 23 exons
LDP6 Gene Structure
Key references:

J.B.J. van Meurs et al., Common genetic variation of the low-density lipoprotein receptor-related protein 5 and 6 determines fracture risk in elderly white men.
J Bone Miner Res. 2006 Jan; 21(1):141-50