scholarly journals Androgen Receptor Gene CAG Repeat Polymorphism and X-Chromosome Inactivation in Children with Premature Adrenarche

2008 ◽  
Vol 93 (4) ◽  
pp. 1304-1309 ◽  
Author(s):  
Saila Lappalainen ◽  
Pauliina Utriainen ◽  
Tiina Kuulasmaa ◽  
Raimo Voutilainen ◽  
Jarmo Jääskeläinen
Keyword(s):  
Androgen Receptor ◽  
X Chromosome ◽  
Receptor Gene ◽  
X Chromosome Inactivation ◽  
Cag Repeat ◽  
Chromosome Inactivation ◽  
University Hospital ◽  
Healthy Children ◽  
Adrenal Androgen ◽  
Premature Adrenarche

Abstract Context: There is variation in the adrenal androgen levels and clinical findings of children with premature adrenarche (PA). Objectives: We hypothesized that androgen sensitivity, indicated by the length of CAG repeat in the X-chromosomal androgen receptor (AR) gene has a role in the polygenic pathogenesis of PA. Design and Patients: We performed a cross-sectional association study among 73 Finnish Caucasian children with PA (10 boys and 63 girls) and 97 age- and gender-matched healthy controls (18 boys and 79 girls). Main Outcome Measures: AR gene methylation-weighted CAGn(mwCAGn) via CAGn length and X-chromosome inactivation analysis and clinical phenotype were determined. Setting: The study took place at a university hospital. Results: PA subjects had significantly shorter mwCAGn than controls [mean difference (95% confidence interval); 0.76 (0.14–1.38); P = 0.017]. AR gene mwCAGn did not correlate with androgen or SHBG levels in either group. In children with PA, mwCAGn correlated positively with body mass index (BMI) (τ = 0.19; P = 0.02). The mean of mwCAGn was significantly shorter in PA children with lower BMI compared with PA children with higher BMI [BMI sd score < 0.79, n = 35, vs. BMI sd score > 0.79, n = 36; 1.13 (0.38–1.87), P = 0.004] and in PA children with lower BMI compared with healthy children with same BMI (P = 0.004). Conclusions: The AR gene CAGn polymorphism may have a significant role in the pathogenesis of PA, especially in lean children.

scholarly journals X-Chromosome Inactivation Patterns and Androgen Receptor Functionality Influence Phenotype and Social Characteristics as Well as Pharmacogenetics of Testosterone Therapy in Klinefelter Patients

2004 ◽  
Vol 89 (12) ◽  
pp. 6208-6217 ◽  
Author(s):  
Michael Zitzmann ◽  
Marion Depenbusch ◽  
Jörg Gromoll ◽  
Eberhard Nieschlag
Keyword(s):  
Androgen Receptor ◽  
X Chromosome ◽  
Body Height ◽  
X Chromosome Inactivation ◽  
Cag Repeat ◽  
Chromosome Inactivation ◽  
Social Characteristics ◽  
Social Traits ◽  
Arm Span ◽  
Androgen Effects

Abstract Klinefelter syndrome is characterized by a vast range of phenotypes related to androgen effects. Testosterone (T) acts via the X-linked androgen receptor gene carrying the CAG repeat (CAGn) polymorphism, the length of which is inversely associated with androgen action and might account for the marked variation in phenotypes. In 77 newly diagnosed and untreated Klinefelter patients with a 47,XXY karyotype we assessed phenotype and social traits in relation to X-weighted biallelic CAGn length using X-chromosome inactivation analysis after digestion of leukocyte DNA with methylation-sensitive HpaII. Forty-eight men were hypogonadal and received T substitution therapy; in these, pharmacogenetic effects were investigated. The shorter CAGn allele was preferentially inactive. CAGn length was positively associated with body height. Bone density and the relation of arm span to body height were inversely related to CAGn length. The presence of long CAGn was predictive for gynecomastia and smaller testes, whereas short CAGn were associated with a stable partnership and professions requiring higher standards of education also when corrected for family background. There was a trend for men with longer CAGn to be diagnosed earlier in life. Under T substitution, men with shorter CAGn exhibited a more profound suppression of LH levels, augmented prostate growth, and higher hemoglobin concentrations. A significant genotype-phenotype association exists in Klinefelter patients: androgen effects on appearance and social characteristics are modulated by the androgen receptor CAGn polymorphism. The effects of T substitution are pharmacogenetically modified. This finding is magnified by preferential inactivation of the more functional short CAGn allele.

X Chromosome Inactivation Pattern is not Associated With Interindividual Variations in Thyroid Volume: A Study of Euthyroid Danish Female Twins

2009 ◽  
Vol 12 (5) ◽  
pp. 502-506 ◽  
Author(s):  
Thomas Heiberg Brix ◽  
Pia Skov Hansen ◽  
Finn Noe Bennedbæk ◽  
Steen Joop Bonnema ◽  
Kirsten Ohm Kyvik ◽  
...  
Keyword(s):  
X Chromosome ◽  
Twin Pair ◽  
Receptor Gene ◽  
Thyroid Volume ◽  
X Chromosome Inactivation ◽  
Cag Repeat ◽  
Chromosome Inactivation ◽  
Pcr Analysis ◽  
Autoimmune Thyroid ◽  
The Impact

AbstractAhigher frequency of skewed X chromosome inactivation (XCI) is found in patients with autoimmune thyroid disease (AITD) than in controls. Although goitre is often present in AITD, a recent study failed to show an association between XCI and clinically overt nontoxic goitre. However, the etiology of overt goitre is complex, and the mechanisms influencing thyroid volume may involve fewer factors than the mechanisms underlying overt goitre. In order to examine the impact of XCI on thyroid volume in euthyroid females, we studied whether within cohort (n= 138) and within twin pair (n= 69) differences in XCI are correlated with differences in thyroid volume. XCI was determined by PCR analysis of a polymorphic CAG repeat in the first exon of the androgen receptor gene. Thyroid volume was determined by ultrasound. Neither in the within cohort nor in the within twin pair analysis could we demonstrate a statistically significant association between XCI and thyroid volume: Regression coefficient (β) = 0.023 (95% confidence interval, –0.062–0.108),p= 0.592 and β = 0.038 (–0.080–0.156),p= 0.521, respectively. Controlling for potential confounders such as zygosity, age, TSH, smoking habits and use of oral contraceptives did not change the findings. In conclusion, in a sample of euthyroid Danish female twins, we found no evidence of a relationship between XCI pattern and thyroid volume.

scholarly journals Predictive values of X-chromosome inactivation patterns and clinicohematologic parameters for vascular complications in female patients with essential thrombocythemia

Blood ◽  
2002 ◽  
Vol 100 (5) ◽  
pp. 1596-1601 ◽  
Author(s):  
Lee-Yung Shih ◽  
Tung-Liang Lin ◽  
Chang-Liang Lai ◽  
Po Dunn ◽  
Jin-Hou Wu ◽  
...  
Keyword(s):  
X Chromosome ◽  
Essential Thrombocythemia ◽  
Receptor Gene ◽  
Vascular Complications ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Predictive Values ◽  
Female Patients ◽  
Increased Risk ◽  
Risk For Thrombosis

Essential thrombocythemia (ET) is a heterogeneous disorder in which the clonality of hematopoiesis varies. The clinical significance of clonality status in ET remains to be determined. We used the human androgen receptor gene (HUMARA)–polymerase chain reaction assay to investigate X-chromosome inactivation patterns (XCIPs) and their value in predicting vascular complications in 89 female patients with ET. Fifty-four (68.4%) patients had a clonal pattern of XCIP, and 15 (19.0%) had a polyclonal pattern. The remaining 20 patients had either an ambiguous or a homozygous pattern of XCIP and were therefore excluded from further analysis. Patients with clonal XCIPs were older (P = .029) and were at greater risk for thrombosis (P = .007) than were those with polyclonal XCIPs. We did not find a correlation between the occurrence of hemorrhage and XCIP (P = .492). Advanced age was predictive of thrombosis and hemorrhage. Platelet count did not influence the risk for vascular complications. Hypertension was significantly correlated with thrombotic events (P = .002), whereas diabetes mellitus and hypercholesterolemia were of no predictive value. In a multivariate analysis, age was the significant predictor of thrombosis (P = .030); however, XCIPs (P = .083) and hypertension (P = .073) tended to predict thrombosis. Our results suggest that older patients who have clonal XCIPs or hypertension are at increased risk for thrombosis and should be monitored closely for this complication.

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