Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1995-03-02
1997-01-14
Jones, W. Gary
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
435 912, 536 243, 536 2431, 536 2432, 536 2433, C12Q 168, C12P 1934, C07H 2102, C07H 2104
Patent
active
055938337
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a method of identifying allelic differences in trans-acting factors as a means of identifying individuals at risk to suffer from an adverse pathophysiological condition. The method of the present invention is particularly useful in assessing allelic variations in the vitamin D receptor gene and thereby predicting predisposition to low or high bone density. Moreover these variants could be used to predict long-term risk of osteoporosis as well as predicting response to different modalities of therapy. This effect is also a model of determination of predisposition to or resistance to other pathological or physiological variations due to other transcription factor gene variants and thus determining risk of disease and of response to therapy. Such transcriptional regulators could be, but are not limited to, ligand-activated gene regulators. such as the steroid/retinoid/thyroid hormone receptor gene family.
BACKGROUND TO THE INVENTION
Vitamin D functions as a potent regulator of bone and calcium homeostasis as well as of cellular differentiation and replication in many target tissues. It acts as its dihydroxylated metabolite (1,25-dihydroxyvitamin D, or calcitriol) through the highly specific vitamin D receptor (1). This trans-acting transcriptional activator protein mediates calcitriol action in the regulation of the expression of target genes. Cloning the vitamin D receptor gene (2,3) showed it to be a member of the ligand-activated receptor superfamily that includes the receptors for steroid hormones (glucocorticoids, progesterone, estrogen, androgen, and mineralocorticoids) as well as thyroid hormones and vitamin A derivatives (4,5), natural regulators of a large number of physiological and developmental processes. The mechanisms by which these receptor proteins mediate the regulation of gene expression has been a subject of intense research. Rare overt mutations have been identified that compromise the function of receptors and that cause major functional disorders in humans and animals. For example, mutations in the vitamin D receptor gene, resulting in vitamin D-resistant rickets (6), and in the androgen receptor, resulting in androgen insensitivity (7), have been reported, and in the estrogen receptor gene an infrequent natural polymorphism has been correlated with a high rate of spontaneous abortion (8). However, despite a wealth of molecular information, little is known of the potential contribution of natural allelic variation in receptor genes to diversity of response to steroidal hormones in normal physiology and in disease states.
Osteoporosis is a major public health problem among the elderly in most Western countries involving both enormous health care costs and debilitating long-term effects (Riggs NEJM). Since therapy of established osteoporosis remains far from satisfactory, prevention is the best choice. Preventative strategies for osteoporosis must focus upon development of peak bone density in early adulthood and minimisation of age-related and postmenopausal bone loss. Evidence from twin and family studies have shown strong genetic effects on peak bone density that is modifiable by hormonal factors, nutrition and life style (Kelly et al, OI). Twin studies have demonstrated that monozygotic twin pairs have a much greater concordance for axial and appendicular bone density than do dizygotic pairs. Analysis of these data indicated that these genetic factors account for approximately 75% of the total variation on bone density. This effect has been confirmed in mother-daughter pair studies. The present inventors analysed the potential mechanisms of this genetic effect in the twin model. The present inventors found that the genetic effect was apparent in certain biochemical indices of bone turnover, such as osteocalcin, a marker of bone formation. Moreover amongst dizygotic twins the higher osteocalcin level was associated with the lower bone density. The present inventors have also found that the genetic effect can be shown with equal
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Eisman John A.
Kelly Paul J.
Morrison Nigel A.
Fredman Jeffrey
Garvan Institute of Medical Research
Jones W. Gary
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