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

Lappalainen, Saila; Utriainen, Pauliina; Kuulasmaa, Tiina; Voutilainen, Raimo; Jääskeläinen, Jarmo

doi:10.1210/jc.2007-2707

Cited by 42 publications

(35 citation statements)

References 38 publications

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“…In addition, an ACTH receptor polymorphism has been found to be associated with the severity of PA also indicating a modulatory effect of the hypothalamic-pituitary-adrenal (HPA) axis in this condition (37). In the same cohort, Lappalainen et al (38) could also show that mean CAG repeat length of the androgen receptor (AR) gene is shorter in PA girls and that a polymorphic allele of the transcription factor TCF7L2, involved in the Wnt signalling pathway, was more frequent in PA subjects (39). However, genomewide association studies in appropriately powered cohorts of children with early androgen excess are currently lacking.…”

Section: Adrenarche Pubarche and Pubertymentioning

confidence: 86%

Premature adrenarche: novel lessons from early onset androgen excess

Idkowiak

Lavery

Dhir

et al. 2011

European Journal of Endocrinology

110

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Adrenarche reflects the maturation of the adrenal zona reticularis resulting in increased secretion of the adrenal androgen precursor DHEA and its sulphate ester DHEAS. Premature adrenarche (PA) is defined by increased levels of DHEA and DHEAS before the age of 8 years in girls and 9 years in boys and the concurrent presence of signs of androgen action including adult-type body odour, oily skin and hair and pubic hair growth. PA is distinct from precocious puberty, which manifests with the development of secondary sexual characteristics including testicular growth and breast development. Idiopathic PA (IPA) has long been considered an extreme of normal variation, but emerging evidence links IPA to an increased risk of developing the metabolic syndrome (MS) and thus ultimately cardiovascular morbidity. Areas of controversy include the question whether IPA in girls is associated with a higher rate of progression to the polycystic ovary syndrome (PCOS) and whether low birth weight increases the risk of developing IPA. The recent discoveries of two novel monogenic causes of early onset androgen excess, apparent cortisone reductase deficiency and apparent DHEA sulphotransferase deficiency, support the notion that PA may represent a forerunner condition for PCOS. Future research including carefully designed longitudinal studies is required to address the apparent link between early onset androgen excess and the development of insulin resistance and the MS.

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Section: Adrenarche Pubarche and Pubertymentioning

confidence: 86%

Premature adrenarche: novel lessons from early onset androgen excess

Idkowiak

Lavery

Dhir

et al. 2011

European Journal of Endocrinology

110

View full text Add to dashboard Cite

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“…Postdigestion PCR products therefore represent methylated (inactive X chromosome) DNA sequence. PCR products were sized using 5% denaturing polyacrylamide gel electrophoresis in an ABI Prism 3730 DNA automated sequencer, and analyzed by using Genescan Analysis 3.1 software (Applied Biosystems) as described previously (28).…”

Section: Methodsmentioning

confidence: 99%

Sex-specific association of X-linked Toll-like receptor 7 (TLR7) with male systemic lupus erythematosus

Shen

Deng

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

262

200

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Systemic lupus erythematosus (SLE) is a multisystem, autoimmune disease that predominantly affects women. Previous findings that duplicated Toll-like receptor 7 (Tlr7) promotes lupus-like disease in male BXSB mice prompted us to evaluate TLR7 in human SLE. By using a candidate gene approach, we identified and replicated association of a TLR7 3′UTR SNP, rs3853839 (G/C), with SLE in 9,274 Eastern Asians (P combined = 6.5 × 10 −10 ), with a stronger effect in male than female subjects [odds ratio, male vs. female = 2.33 (95% CI = 1.64-3.30) vs. 1.24 (95% CI = 1.14-1.34); P = 4.1 × 10]. G-allele carriers had increased TLR7 transcripts and more pronounced IFN signature than C-allele carriers; heterozygotes had 2.7-fold higher transcripts of G-allele than C-allele. These data established a functional polymorphism in type I IFN pathway gene TLR7 predisposing to SLE, especially in Chinese and Japanese male subjects. functional polymorphism | disease susceptibility | autoimmunity | type I interferon S ystemic lupus erythematosus [SLE; Online Mendelian Inheritance in Man (OMIM) no. 152700] is a multisystem, autoimmune disease with strong genetic and environmental components (1). SLE predominantly affects women, with a female-to-male ratio of approximately 9:1. Male patients with SLE, although rare, tend to have more severe disease and poorer outcome (2), suggesting potential sex dimorphism in the disease development. Although the sex effect has often been attributed to sex hormones, the fact that XXY male subjects have approximately a 14-fold higher risk of developing SLE than 46 XY men indicates that X-linked genes may be risk factors for human SLE (3).Located at Xp22.2, Toll-like receptor 7 (TLR7; OMIM no. 300365) and its functionally related gene TLR8 (OMIM no. 300366) encode proteins that play critical roles in pathogen recognition and activation of innate immunity (4). They recognize endogenous RNA-containing autoantigens and induce the expression of type I IFN, a pivotal cytokine in the pathogenesis of SLE (5). In lupus-prone BXSB mice, the translocation of a segmental duplication of X chromosome to Y chromosome creates the Y-linked autoimmune accelerator (Yaa) locus, which was associated with autoreactive B cell responses to RNA-related antigens and exacerbation of glomerulonephritis in male mice (6). Although translocated X chromosome segment in Yaa may contain as many as 16 genes, the major gene for causation of the autoimmune phenotypes was identified to be TLR7 (7), making it a potential susceptibility gene for SLE. By using a candidate gene approach, we report herein that a functional polymorphism in 3′UTR of TLR7 is associated with SLE in Chinese and Japanese populations, with a stronger effect in male than female subjects. ResultsDiscovery and Replication of the Association of a TLR7 3′UTR SNP with SLE in Eastern Asian Population. We genotyped 27 SNPs from the TLR7-TLR8 region (12 in TLR7 and 15 in TLR8) in 1,434 SLE cases and 1,591 control subjects of Eastern Asian ancestry using the Beadstation Infinium II...

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“…None of the 33 individual studies even approached such size, and this indicates the large collaborative efforts needed to confidently demonstrate, or refute, common genetic associations. Recent studies have also reported associations between shorter CAG repeat length and susceptibility to polycystic ovary syndrome in US adults [3] and premature adrenarche in Finnish children [4]. If confirmed, those findings would support the etiological role of increased androgen receptor activity in those conditions and therefore the rationale for androgen receptor blockade therapy.…”

Section: Ken K Ongmentioning

confidence: 80%

Population Genetics and Pharmacogenetics

Ong¹

2008

Yearbook of Pediatric Endocrinology 2008

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Yearbook 2007 [1] trumpeted the arrival of the genome-wide association study, based on the remarkable technology that can accurately genotype hundreds of thousands of single nucleotide polymorphisms (SNPs) in each individual. Into 2008, genome-wide association studies have successfully spearheaded the escalating discoveries of numerous new genetic variants associated with complex traits such as BMI, height, bone mineral density, fasting glucose concentration, and type 1 and type 2 diabetes. Several of these discoveries are described below and also in the accompanying chapters of this Yearbook. These incontrovertible genetic associations point to several new biological mechanisms and hopefully in time will lead to new understandings of disease pathogenesis and treatments. However, to put the success of these approaches into perspective, these new genetic loci still only explain a small fraction of our genetic predisposition to disease, or our inheritance of body size and shape. While 80% of the inter-individual differences in human height is estimated to be due to genetic factors, the recently published staggering combined list of at least 40 new SNPs convincingly associated with height (see Chapter 4: Growth and Growth Factors, pp 43-62) together probably only explain around 5% its variance. Where are the remaining genetic factors? One answer is that the heritability of height, or BMI, is the summative result of several hundreds of SNPs and other common genetic variations, each contributing a tiny individual effect size. Demonstrating these small genetic effects and their interactions with the environment will require enormous sized studies, and this is the focus of several major national 'biobank' initiatives. An intriguing alternative explanation is that heritability is explained by multiple rare variants, which each have a much larger effect on biological function and disease risk than common variants. Different rare variants would contribute the inheritance of height in different pedigrees, i.e. within different families or sub-populations. Emerging evidence for this is described in the final abstract ('The value of rare variants'), while the necessary future sequencing technology is described immediately below ('Mechanism of the year'). Mechanism of the year: your complete genome sequenceeThe complete genome of an individual by massively parallel DNA sequencing 2008;452:872-876 Background: There is much optimism for the impact of 'genomic medicine' on disease and drug response. Complete genome sequencing is needed to realize the full potential of genomics for human health. However, the formidable size of the diploid human genome, approximately 6 gigabases, has prevented the routine use of current sequencing methods to decipher complete individual human genomes. Methods: The authors now report the DNA sequence of a diploid genome of a single individual, James D. Watson, sequenced to 7.4-fold redundancy in 2 months using massively parallel sequencing in picolitersize reaction vessels. Results: The authors...

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

Cited by 42 publications

References 38 publications

Premature adrenarche: novel lessons from early onset androgen excess

Premature adrenarche: novel lessons from early onset androgen excess

Sex-specific association of X-linked Toll-like receptor 7 (TLR7) with male systemic lupus erythematosus

Population Genetics and Pharmacogenetics

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