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Osteoporosis
Simultaneous detection of major osteoporosis
risk factors Collagen Type 1 a 1 S/s and
Vitamin D Receptor B/b
RDB2055
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CLINICAL RELEVANCE
Osteoporosis
Osteoporosis is a generalized bone disease, characterized by a reduction
in bone density and a disturbed skeletal tissue structure. It causes,
particularly in elderly patients and postmenopausal women, an increased
risk of fracture. Osteoporosis has a complex aetiology and is influenced
by a series of environmental factors such as nutritional habits -
calcium deficiency, alcohol, caffeine - the general lifestyle - lack
of physical exercise, infrequent direct sunshine, smoking - and by
hormones (1).
In addition to this, there is also a clear genetic component. Tests
carried out with twins have shown that genetic factors are responsible
for 80% of the variability in bone density within a population (2).
In recent years the intensive search for genetic markers has led to
the identification of several forms of genetic polymorphism, which
are associated with the decrease of bone tissue and therefore a higher
risk of osteoporosis.
Polymorphism in the vitamin D receptor gene
In 1994 Morrison et al. (3) described a polymorphism in the 3´-region
of the vitamin D receptor gene, which is connected with a disposition
for osteoporosis. According to Morrision et al. 75% of the genetic
effect of variability in bone density can be traced back to this polymorphism.
The polymorphism described by Morrison et al. is placed in a naturally
occurring restriction site of the restriction enzyme BsmI in
the intron between exon 8 and 9. If the restriction site exists, allele
b is present, and if the site is absent, allele B is found. 36% of
all Caucasians have the genotype bb (i.e. are homozygous for the allele
b), 46% have the genotype Bb (heterozygous b and B) and 18% BB (homozygous
B, 4).
Furthermore, in the 3´-region of the gene, two more polymorphous
positions are characterized by the presence or absence of the restriction
sites for the restriction enzymes TaqI (t/T) and ApaI
(a/A) (3). As the BsmI polymorphism occurs in extreme imbalance
in relation to the other polymorphism (3,5), the detection of the
BsmI polymorphism, which was first described and best characterized,
seems sufficient.
The b-allele is associated with a higher bone density (3). This discovery
has been confirmed in several studies carried out on different populations
(4-8). According to Ferrari et al. (4) and Feskanich et al. (8) the
genotype BB is in particular associated with a significantly increased
risk of fractures in elderly people. Gough et al. (5) discovered that
the t-allele, which is coupled with the B-allele, is associated with
an accelerated loss of bone density in female patients suffering from
an early form of rheumatoid arthritis. Patients with the genotype
tt (equivalent to BB) lost on average 4.9% bone density in the lumbar
spinal column over a period of 36 months, whereas patients with the
genotype TT (equivalent to bb) lost only 0.1% (5).
It is unknown by what molecular mechanism the various VDR alleles
influence bone density. One theory is that the different alleles affect
the amount of messenger RNA produced (3).
Poymorphism in the collagen type 1 a 1 gene
Collagen type 1 produces the main protein of the bone matrix and is
encoded by the genes collagen type I a 1 and -a 2 (COLIA1 and COLIA2).
Mutations in the encoding region of these genes lead to severe forms
of Osteogenesis imperfecta.
Grant et al. (9) described a widespreaded polymorphism in the first
intron of the COLIA1 gene, associated with reduced bone density. The
polymorphism is placed in a regulatory region of the gene, a binding
site of the transcription factor Sp1. At nucleotide +2046 there is
a base exchange from G (guanine - allele S) to T (thymidine - allele
s). 61.1% of all Caucasians have the genotype SS (are homozygous for
the allele), 36.2% have the genotype Ss (are heterozygous S and s)
and 2.7% the genotype ss (homozygous s, 10). The allele s is associated
with a lower bone density and a raised risk of fracture (9-12).
Uitterlinden et al. (11) examined 1778 postmenopausal women in the
Rotterdam study. In comparison to women with the genotype SS, women
with the genotype Ss had on average a 2% lower bone density in the
femoral neck and lumbar spinal column. Women with the genotype ss
had a 4% lower density in the femoral neck and 6% in the lumbar spinal
column. Sainz et al. (12) also discovered this connection in prepuberal
girls.
According to these studies and others, the genotypes Ss and ss cause
a predisposition in women for osteoporotic fractures.
The examination of the risk alleles VDR-B and COLIA1-s helps to determine
at an early stage a hereditary disposition for osteoporosis. This
genotyping enables those concerned to take precautions against the
raised risk of osteoporotic fractures in later life. The genotyping
also gives useful additional information on osteodensitometry.
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Literature
(1)
Schettler G und Greten H (1998)
Innere Medizin
Thieme Verlag Stuttgart, 9. Auflage: 623ff
(2)
Pocock NA, Eisman JA, Hopper JL ... (1987)
Genetic determinants of bone mass in adults: a twin study
J Clin Invest 80: 706-710
(3)
Morrison NA, Qi JC, Tokita A ... (1994)
Prediction of bone density from vitamin D receptor alleles
Nature 367: 284-287
(4)
Ferrari S, Rizzoli R und Bonjour J-P (1999)
Genetic aspects of osteoporosis
Curr Opin Rheumatol 11: 294-300
(5)
Gough A, Sambrook P, Devlin J ... (1998)
Effect of Vitamin D Receptor Gene Alleles on Bone Loss in Early Rheumatoid
Arthritis
J Rheumatol 25: 864-868
(6)
Sigurdsson G, Magnusdottir DN, Kristinsson JÖ ... (1997)
Association of BsmI vitamin-D receptor gene polymorphism with combined
bone mass in spine and proximal femur in Icelandic women
J Intern Med 241: 501-50
(7)
Kikuchi R, Uemura T, Gorai I ... (1999)
Early and late postmenopausal bone loss is associated with BsmI vitamin
D receptor gene polymorphism in Japanese women
Calcif Tissue Int 64: 102-106
(8)
Feskanich D, Hunter DJ, Willett WC ... (1998)
Vitamin D receptor genotype and the risk of bone fractures in women
Epidemiology 9: 535-539
(9)
Grant SFA, Reid DM, Blake G ... (1996)
Reduced bone density and osteoporosis associated with a polymorphic
Sp1 binding site in the collagen type I a 1 gene
Nature genetics 14: 203-205
(10)
Keen RW, Woodford-Richens KL, Grant SFA ... (1999)
Association of Polymorphism at the Type I Collagen (COLIA1) Locus
with Reduced Bone Mineral Density, Increased Fracture Risk, and Increased
Collagen Turnover
Arthritis Rheum 42: 285-290
(11)
Uitterlinden AG, Burger H, Huang Q ... (1998)
Relation of Alleles of the Collagen Type Ia 1 Gene to Bone Density
and the Risk of Osteoporotic Fractures in Postmenopausal Women
N Eng J Med 338: 1016-1021
(12)
Sainz J, Van Tornout JM, Sayre J ... (1999)
Association of Collagen Type 1 a 1 Gene Polymorphism with Bone Density
in Early Childhood
J Clin Endocrinol Metab 84: 853-855
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