Lack of Association Between Androgen Receptor Polymorphisms and Bone Mineral Density or Physical Function in Older Men

Kenny, Anne M.; McGee, Dan; Joseph, Cherian; Covault, Jonathan; Abreu, Christine; Raisz, Lawrence G.

doi:10.1080/07435800500406221

Cited by 20 publications

(11 citation statements)

References 22 publications

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“…However, other studies reported no association of CAG repeat length with body composition (Lapauw et al 2007) or with physical performance in old men (Kenny et al 2005).…”

Section: Cross-sectional Genetic Association Studiesmentioning

confidence: 91%

Genes and the ageing muscle: a review on genetic association studies

Garatachea

Lucía

2011

AGE

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Western populations are living longer. Ageing decline in muscle mass and strength (i.e. sarcopenia) is becoming a growing public health problem, as it contributes to the decreased capacity for independent living. It is thus important to determine those genetic factors that interact with ageing and thus modulate functional capacity and skeletal muscle phenotypes in older people. It would be also clinically relevant to identify 'unfavourable' genotypes associated with accelerated sarcopenia. In this review, we summarized published information on the potential associations between some genetic polymorphisms and muscle phenotypes in older people. A special emphasis was placed on those candidate polymorphisms that have been more extensively studied, i.e. angiotensinconverting enzyme (ACE) gene I/D, α-actinin-3 (ACTN3) R577X, and myostatin (MSTN) K153R, among others. Although previous heritability studies have indicated that there is an important genetic contribution to individual variability in muscle phenotypes among old people, published data on specific gene variants are controversial. The ACTN3 R577X polymorphism could influence muscle function in old women, yet there is controversy with regards to which allele (R or X) might play a 'favourable' role. Though more research is needed, up-to-date MSTN genotype is possibly the strongest candidate to explain variance among muscle phenotypes in the elderly. Future studies should take into account the association between muscle phenotypes in this population and complex gene-gene and gene-environment interactions.

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“…However, other studies reported no association of CAG repeat length with body composition (Lapauw et al 2007) or with physical performance in old men (Kenny et al 2005).…”

Section: Cross-sectional Genetic Association Studiesmentioning

confidence: 91%

Genes and the ageing muscle: a review on genetic association studies

Garatachea

Lucía

2011

AGE

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“…Shorter alleles of the CAG repeat polymorphism in exon 1 of the androgen receptor gene ( AR ) reportedly increase its transcriptional activity.

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Co‐activators and androgens tend to bind more strongly to the androgen receptor when the CAG repeat is shorter, resulting in stronger androgen effects. Longer CAG repeat length has previously been shown to associate with slower age‐related decline in testosterone levels in men

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and increased bone loss in some but not all studies.

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The estrogen receptors α (ERα) and β (ERβ) are transcription factors activated by 17β‐estradiol that bind estrogen response elements to activate gene expression. They can be co‐expressed, form heterodimers, and bind the same elements because of their similarity; however, ERα is thought to be the major receptor for mediating estrogen action in bone.…”

Section: Introductionmentioning

confidence: 99%

Genetic Variation in Sex Hormone Genes Influences Heel Ultrasound Parameters in Middle-Aged and Elderly Men: Results From the European Male Aging Study (EMAS)

Limer

Pye

Thomson

et al. 2009

Journal of Bone and Mineral Research

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Genes involved in sex hormone pathways are candidates for influencing bone strength. Polymorphisms in these genes were tested for association with heel quantitative ultrasound (QUS) parameters in middle-aged and elderly European men. Men 40-79 yr of age were recruited from population registers in eight European centers for the European Male Aging Study (EMAS). Polymorphisms were genotyped in AR, ESR1, ESR2, CYP19A1, CYP17A1, SHBG, SRD5A2, LHB, and LHCGR. QUS parameters broadband ultrasound attenuation (BUA) and speed of sound (SOS) were measured in the heel and used to derive BMD. The relationships between QUS parameters and polymorphisms were assessed using linear regression adjusting for age and center. A total of 2693 men, with a mean age of 60.1 ± 11.1 (SD) yr were included in the analysis. Their mean BUA was 80.0 ± 18.9 dB/Mhz, SOS was 1550.2 ± 34.1 m/s, and BMD was 0.542 ± 0.141 g/cm 2 . Significant associations were observed between multiple SNPs in a linkage disequilibrium (LD) block within CYP19A1, peaking at the TCT indel with the deletion allele associating with reduced ultrasound BMD in heterozygotes (b =20.016, p = 20.005) and homozygotes (b = 20.029, p = 0.001). The results for BUA and SOS were similar. Significant associations with QUS parameters were also observed for the CAG repeat in AR and SNPs in CYP17A1, LHCGR, and ESR1. Our data confirm evidence of association between bone QUS parameters and polymorphisms in CYP19A1, as well as modest associations with polymorphisms in CYP17A1, ESR1, LHCGR, and AR in a population sample of European men; this supports a role for genetically determined sex hormone actions in influencing male bone health.

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“…21,22 In men, the results are more variable. Three studies found no association between CAG repeat length and BMD, 14,18,19 Langdahl et al 15 found a positive association, and negative association was found in 2 studies. 16,17 Whether these studies did not find similar results due to small sample size or the cross-sectional design of most studies is not yet clear.…”

Section: Discussionmentioning

confidence: 96%

CAG Repeat Polymorphism in Relation to Bone Mass, Metabolism, and Fractures

Joseph¹,

Kenny²

2005

The Endocrinologist

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The number of polyglutamine repeats at the amino terminal determine the androgen receptor polymorphism. The number of polyglutamine repeats is influenced by the number of CAG repeats in the androgen receptor gene. Studies have evaluated the association between CAG repeat polymorphism and bone mineral density, bone turnover markers, and fractures. Both men and women were studied. While differences in CAG repeat polymorphism appear to affect androgen receptor function, the current data do not indicate any consistent effect of androgen receptor gene polymorphism on bone. This could be secondary to a small effect of polymorphism in a complex polygenic disease such as osteoporosis and may require much more extensive study. (The Endocrinologist 2005;15: 23-26) Learning Objectives • Recall what available studies have shown about how polymorphism of CAG repeat length in the androgen receptor gene may relate to bone mass and bone metabolism in men and women. • Describe what is known about how differences in CAG repeat length may influence androgen receptor function. • Give examples of abnormalities in bone and other tissues that may be associated with CAG repeat length.A ndrogen deficiency results in bone loss and androgen treatment can increase bone mass. This can occur both by direct genomic effects mediated by the androgen receptor 1 and by conversion of androgens to estrogens. Recent studies have suggested that a polymorphism of the androgen receptor ͓gene located in long arm of X chromosome (Xq11-12)͔ consisting of variable numbers of polyglutamine repeats (determined by AR gene CAG repeat length) in the N-terminal domain may affect bone metabolism. 2,3 This polymorphism was originally identified in men with the syndrome of spinal and bulbar muscular atrophy (Kennedy syndrome) in which a large (usually between 40 and 62) number of CAG repeats is found. 4,5 There may also be effects on androgen responsiveness within the usual range of CAG repeat from 9 to 40. Shorter repeat lengths are associated with increased transactivation activity of the androgen receptor. 6 Moreover, shorter CAG repeat are associated with more rapid declines in testosterone levels with aging 7-9 and with an increased prevalence of prostate cancer in black men. 10 -12 In this review, we will examine the available data on the association between CAG repeat length and bone metabolism, including our own unpublished study. These studies vary in their conclusions concerning the role of androgen receptor polymorphisms. Thus, at this point, there can be no definite answer as to the role of this genetic variation. The fact that women carry 2 X chromosomes (one of the X chromosomes undergoes random inactivation) and men carry a single X chromosome makes it difficult to interpret study findings. The selection of either the maternal or paternal X chromosome for inactivation occurs by a process involving random choice between the 2 Xs. 13 This random inactivation of X chromosomes in women results in 2 alleles with different CAG repeat lengths of equal distr...

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Lack of Association Between Androgen Receptor Polymorphisms and Bone Mineral Density or Physical Function in Older Men

Cited by 20 publications

References 22 publications

Genes and the ageing muscle: a review on genetic association studies

Genes and the ageing muscle: a review on genetic association studies

Genetic Variation in Sex Hormone Genes Influences Heel Ultrasound Parameters in Middle-Aged and Elderly Men: Results From the European Male Aging Study (EMAS)

CAG Repeat Polymorphism in Relation to Bone Mass, Metabolism, and Fractures

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