The CAG Repeat Polymorphism in the AR Gene Affects High Density Lipoprotein Cholesterol and Arterial Vasoreactivity

Zitzmann, Michael; Brune, Maik; Kornmann, Britta; Gromoll, Jörg; Eckardstein, Sigrid von; Eckardstein, Arnold von; Nieschlag, Eberhard

doi:10.1210/jcem.86.10.7889

Cited by 100 publications

(97 citation statements)

References 70 publications

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“…Since the amount of blood drawn was restricted to 60 ml, multiple determinants were assessed and serum was scarce, complete parameters including leptin, insulin and c-peptide concentrations were assesssed in 106 volunteers. Other results of this study have been published previously [38,39].…”

Section: Methodssupporting

confidence: 62%

“…By its attenuating influence on androgenicity, a high number of CAGr exerts adverse effects on fat mass and insulin sensitivity and thereby also on cardiovascular risk. Simultaneously, however, testosterone and a low number of CAGr in the AR gene decrease HDL-cholesterol via direct effects on pivotal genes of HDL metabolism as well as on endothelium-dependent and independent vasoreactivity [39]. Therefore, similar to testosterone, the CAGr polymorphism in the AR gene seems to play an ambiguous role in the determination of atheroclerotic risk.…”

Section: Discussionmentioning

confidence: 99%

“…A variable number of CAG repeats (CAGr) in exon 1 of the AR gene on the X-chromosome, which normally ranges between 9 and 35 [27,28] encodes for a variable number of glutamine residues in the aminoterminal domain of the receptor and is inversely associated with the transcriptional activity of testosterone target genes [29,30]. As clinical consequences, the number of CAGr was shown to be inversely associated with the risk of prostate cancer [27,28,31,32,33], benign prostatic hyperplasia [34,35], sperm production [36,37], bone density [38], endothelial function and HDL-cholesterol concentrations [39] as well as depression [40]. Furthermore, abnormal expansion of the CAGr length leads to Kennedy's disease, which is accompanied by morphological hypoandrogenic traits [41,42].…”

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confidence: 99%

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The CAG repeat polymorphism in the androgen receptor gene modulates body fat mass and serum concentrations of leptin and insulin in men

Zitzmann¹,

Gromoll²,

et al. 2003

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Aims/hypothesis. The relationship of androgens to the metabolic syndrome has not been resolved. The polymorphic number of CAG repeats within the androgen receptor gene is inversely associated with the transcriptional activity of target genes.This polymorphism might thus influence testosterone effects on body fat content and serum concentrations of leptin and insulin. The direct and indirect role of androgens within the metabolic syndrome should become clearer if this genetically determined effector is taken into account. Methods. The hypothesis was investigated in a crosssectional study involving 106 healthy 20-50 year old males. Results. Multiple regression models showed a positive independent correlation of the CAG repeat number with body fat content, leptin and insulin (partial r=0.39, 0.36 and 0.28, p<0.001, p<0.001 and p=0.006, respectively). Factor analysis yielded a five-dimensional model: two dimensions were influenced by the androgen receptor polymorphism, namely "body composition" which consisted of leptin, body fat mass, insulin, the number of CAG repeats (positive loadings) and physical activity (negative loading), and "lipid profile" which comprised low density lipoprotein cholesterol, cigarette smoking, triglycerides (positive loadings) as well as high density lipoprotein cholesterol and number of CAG repeats (negative loadings). Conclusions/interpretation. A low number of CAG repeats were independently associated with protective parameters (low body fat mass and plasma insulin) as well as with adverse parameters (low high density lipoprotein cholesterol concentrations). This suggests that the pivotal role of this polymorphism in modulating androgen effects on cardiovascular risk factors is of a complex nature and implies that its clinical impact, similar to that of androgens, is dependent on exogenous cofactors. [Diabetologia (2003) 46:31-39] Keywords Testosterone, body fat, leptin, insulin, androgen receptor, CAG repeat polymorphism. Corresponding author: E. Nieschlag, Institute of Reproductive Medicine of the University, Domagkstr. 11, 48129 Münster, Germany, E-mail: nieschl@uni-muenster.de Abbreviations: Ar, Adrogen Receptor; BFM, body fat mass; CAG, cytosin-adenin-guanin; CAGr, CAG repeats; FFM, fat free mass; HDL, high density lipoprotein; SHBG, sex hormone binding globuline; TBW, total body water; WHR, waist-to-hip ratio. Diabetologia (2003) 46:31-39 DOI 10.1007 The CAG repeat polymorphism in the androgen receptor gene modulates body fat mass and serum concentrations of leptin and insulin in men The term "metabolic syndrome" describes a pre-diabetic and pro-atherogenic state which is characterized by overweight, impaired glucose tolerance, hyperinsulinaemia, arterial hypertension, low concentrations of high density lipoprotein (HDL) cholesterol, hypertriglyceridaemia and disturbed haemostasis [1,2,3,4,5,6]. Several cross-sectional population studies found correlations between serum concentrations of testosterone and these cardiovascular risk factors, which, however, were opposi...

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Section: Methodssupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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The CAG repeat polymorphism in the androgen receptor gene modulates body fat mass and serum concentrations of leptin and insulin in men

Zitzmann¹,

Gromoll²,

et al. 2003

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“…The mechanisms by which hyperandrogenemia might affect endothelial function are complex and controversial. It is possible that testosterone has a direct effect on the vessel wall, as indicated by the localization of androgen receptor (AR) in endothelial and vascular smooth muscle cells [28], influencing vasodilatation by endothelium-dependent and endothelium-independent mechanisms, by genomic and non-genomic effects [29,30]. Zitzmann et al observed that the number of CAG repeats in the AR gene showed a significant positive basic correlation with FMD, GTN-induced vasodilatation.…”

Section: Discussionmentioning

confidence: 99%

“…A control group composed of 32 women (age: 23.06 ±5.37 (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34), BMI: 25.87± 6.89 (16.88-42.86) kg/m 2 ) was selected as to be similar to the group of patients in terms of age and BMI. In the end though, our intention was not fully accomplished because there was still a significant difference in BMI between the groups.…”

Section: Study Protocolmentioning

confidence: 99%

The polycystic ovary syndrome (pcos) status and cardiovascular risk in young women

Ilie¹,

Pepene²,

Marian³

et al. 2010

Open Medicine

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AbstractThe study investigated the presence of early vascular damage and chronic inflammation, and their relationships with hormonal and metabolic parameters in 45 young women with PCOS in comparison with thirty-two healthy age-matched controls. Hormonal and metabolic profiles, high sensitivity C-reactive protein (hsCRP), tumoral necrosis factor-alpha (TNF-α), endothelin-1 (ET-1), brachial flow-mediated vasodilation (FMD) and carotid intima-media thickness (CIMT) were determined in both groups. Compared with the controls, women with PCOS had significantly lower FMD and respectively higher ET-1 levels (p=0.001). No differences were observed between the groups in terms of CIMT or inflammatory markers. In the PCOS group, ET-1 levels were significantly correlated with only testosterone concentrations (r = 0.31, p = 0.037), whereas the hsCRP levels were independently predicted only by body mass index (BMI). Within the total group, the PCOS status was the sole significant predictor of ET-1 levels and the only independent predictor of FMD. In conclusion, there is evidence of endothelial dysfunction associated with increased levels of androgen hormones in young women with PCOS. The combination of endothelial dysfunction and coexistent obesity promoting inflammation contributes to the progression of atherogenesis in PCOS. The PCOS status should be regarded as a predictor marker of cardiovascular risk, along with well-known cardiovascular risk factors.

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Acne

Melnik¹

2011

Harper's Textbook of Pediatric Dermatology

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The CAG Repeat Polymorphism in the AR Gene Affects High Density Lipoprotein Cholesterol and Arterial Vasoreactivity

Cited by 100 publications

References 70 publications

The CAG repeat polymorphism in the androgen receptor gene modulates body fat mass and serum concentrations of leptin and insulin in men

The CAG repeat polymorphism in the androgen receptor gene modulates body fat mass and serum concentrations of leptin and insulin in men

The polycystic ovary syndrome (pcos) status and cardiovascular risk in young women

Acne

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