Genetic control of susceptibility to osteoporosis

S Ralston

    Research output: Contribution to journalArticle

    213 Citations (Scopus)

    Abstract

    Osteoporosis is a common disease with a strong genetic component. Twin studies have shown that genetic factors play an important role in regulating bone mineral density (BMD), ultrasound properties of bone, skeletal geometry, and bone turnover as well as contributing to the pathogenesis of osteoporotic fracture itself. These phenotypes are determined by the combined effects of several genes and environmental influences, but occasionally, osteoporosis or unusually high bone mass can occur as the result of mutations in a single gene. Examples are the osteoporosis-pseudoglioma syndrome, caused by inactivating mutations in the lipoprotein receptor-related protein 5 gene and the high bone mass syndrome, caused by activating mutations of the same gene. Genome-wide linkage studies in man have identified loci on chromosomes 1p36, 1q21, 2p21, 5q33-35, 6p11-12, and 11q12-13 that show definite or probable linkage to BMD, but so far, the causative genes remain to be identified. Linkage studies in mice have similarly identified several loci that regulate BMD, and a future challenge will be to investigate the syntenic loci in humans. A great deal of research has been done on candidate genes; among the best studied are the vitamin D receptor and the collagen type I a 1 gene. Polymorphisms of vitamin D receptor have been associated with bone mass in several studies, and there is evidence to suggest that this association may be modified by dietary calcium and vitamin D intake. A functional polymorphism. affecting an Sp1 binding site has been identified in the collagen type I a 1 gene that predicts osteoporotic fractures independently of bone mass by influencing collagen gene regulation and bone quality.

    An important problem with most candidate gene studies is small sample size, and this has led to conflicting results in different populations. Some researchers are exploring the use of meta-analysis to try and address this issue and gain an accurate estimate of effect size for different polymorphisms in relation to relevant clinical endpoints, such as BMD and fracture. From a clinical standpoint, advances in knowledge about the genetic basis of osteoporosis are important, because they offer the prospect of developing genetic markers for the assessment of fracture risk and the opportunity to identify molecules that will be used as targets for the design of new drugs for the prevention and treatment of bone disease.

    Original languageEnglish
    Pages (from-to)2460-2466
    Number of pages6
    JournalJournal of Clinical Endocrinology and Metabolism
    Volume87
    Issue number6
    DOIs
    Publication statusPublished - 2002

    Keywords

    • BONE-MINERAL DENSITY
    • D-RECEPTOR GENE
    • QUANTITATIVE TRAIT LOCI
    • TRANSFORMING GROWTH-FACTOR-BETA-1 GENE
    • SP1 BINDING-SITE
    • VITAMIN-D
    • JAPANESE WOMEN
    • GENOME SCREEN
    • HIP-FRACTURE
    • LINKAGE DISEQUILIBRIUM

    Cite this

    Genetic control of susceptibility to osteoporosis. / Ralston, S.

    In: Journal of Clinical Endocrinology and Metabolism, Vol. 87, No. 6, 2002, p. 2460-2466.

    Research output: Contribution to journalArticle

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    AB - Osteoporosis is a common disease with a strong genetic component. Twin studies have shown that genetic factors play an important role in regulating bone mineral density (BMD), ultrasound properties of bone, skeletal geometry, and bone turnover as well as contributing to the pathogenesis of osteoporotic fracture itself. These phenotypes are determined by the combined effects of several genes and environmental influences, but occasionally, osteoporosis or unusually high bone mass can occur as the result of mutations in a single gene. Examples are the osteoporosis-pseudoglioma syndrome, caused by inactivating mutations in the lipoprotein receptor-related protein 5 gene and the high bone mass syndrome, caused by activating mutations of the same gene. Genome-wide linkage studies in man have identified loci on chromosomes 1p36, 1q21, 2p21, 5q33-35, 6p11-12, and 11q12-13 that show definite or probable linkage to BMD, but so far, the causative genes remain to be identified. Linkage studies in mice have similarly identified several loci that regulate BMD, and a future challenge will be to investigate the syntenic loci in humans. A great deal of research has been done on candidate genes; among the best studied are the vitamin D receptor and the collagen type I a 1 gene. Polymorphisms of vitamin D receptor have been associated with bone mass in several studies, and there is evidence to suggest that this association may be modified by dietary calcium and vitamin D intake. A functional polymorphism. affecting an Sp1 binding site has been identified in the collagen type I a 1 gene that predicts osteoporotic fractures independently of bone mass by influencing collagen gene regulation and bone quality.An important problem with most candidate gene studies is small sample size, and this has led to conflicting results in different populations. Some researchers are exploring the use of meta-analysis to try and address this issue and gain an accurate estimate of effect size for different polymorphisms in relation to relevant clinical endpoints, such as BMD and fracture. From a clinical standpoint, advances in knowledge about the genetic basis of osteoporosis are important, because they offer the prospect of developing genetic markers for the assessment of fracture risk and the opportunity to identify molecules that will be used as targets for the design of new drugs for the prevention and treatment of bone disease.

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    KW - SP1 BINDING-SITE

    KW - VITAMIN-D

    KW - JAPANESE WOMEN

    KW - GENOME SCREEN

    KW - HIP-FRACTURE

    KW - LINKAGE DISEQUILIBRIUM

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