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).

Polymorphism 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.