Androgen Receptor Locus Research Articles

Androgen Receptor Copy Number Variation and Androgenetic Alopecia: A Case-Control Study

BackgroundThe functional polymorphism that explains the established association of the androgen receptor (AR) with androgenetic alopecia (AGA) remains unidentified, but Copy Number Variation (CNV) might be relevant. CNV involves changes in copy number of large segments of DNA, leading to the altered dosage of gene regulators or genes themselves. Two recent reports indicate regions of CNV in and around AR, and these have not been studied in relation to AGA. The aim of this preliminary case-control study was to determine if AR CNV is associated with AGA, with the hypothesis that CNV is the functional AR variant contributing to this condition.Methodology/Principal FindingsMultiplex Ligation-dependent Probe Amplification was used to screen for CNV in five AR exons and a conserved, non-coding region upstream of AR in 85 men carefully selected as cases and controls for maximal phenotypic contrast. There was no evidence of CNV in AR in any of the cases or controls, and thus no evidence of significant association between AGA and AR CNV.Conclusions/SignificanceThe results suggest this form of genomic variation at the AR locus is unlikely to predispose to AGA.

Fluorescence In situ Hybridization Analysis of Circulating Tumor Cells in Metastatic Prostate Cancer

To assess the feasibility of characterizing gene copy number alteration by fluorescence in situ hybridization (FISH) of circulating tumor cells (CTC) isolated using the CellSearch system in patients with progressive castration-resistant metastatic prostate cancer. We used probe combinations that included the androgen receptor (AR) and MYC genes for FISH analysis of CTC samples collected from 77 men with castration-resistant metastatic prostate cancer. High-level chromosomal amplification of AR was detected in 38% and relative gain of MYC in 56% of samples analyzed. No such abnormalities were detected in samples with CTC counts of <10, reflecting ascertainment difficulty in these lower count samples. The CTC isolated from our patient cohort present a very similar molecular cytogenetic profile to that reported for late-stage tumors and show that FISH analysis of CTC can be a valuable, noninvasive surrogate for routine tumor profiling. That as many as 50% of these patients have substantial amplification of the AR locus indicates that androgen signaling continues to play an important role in late-stage prostate cancer.

X-Linked Clonality Analysis of Human Embryonic Stem Cells ( hESC ) Before and after induction of Hematopoietic Differentiation

Human ES cell lines represent an invaluable tool of research for the study of normal and pathological development. In this study we asked whether the human ES cell lines currently used for research purposes are derived from single outgrowths using X-linked clonality analysis. Amongst the cell lines tested, the female H9 cell line was informative at the Humara (human androgen receptor) locus by the presence of two CAG repeats allowing distinction of paternal (Xp) and maternal (Xm) X chromosomes. Clonal analysis was performed upon Hpa II digestion of DNA purified from total H9 cells (passages 27–61), single H9 cell clones generated from single cell cloning, single embryoid bodies (EB) (day 4, day 14) as well as from single hematopoietic progenitors. The same analysis was performed after induction of hematopoietic differentiation in liquid cultures in the presence of hematopoietic permissive conditions (co-culture in the presence of OP-9 cell line). Clonality was evaluated by calculating the Relative Corrected Index (RCI) which is the ratio of the intensity of peaks generated by Hpa II-digested and undigested DNA. In several experiments, all passages of H9 cell lines examined ( p27, p28, p31, p61) were found to exhibit a monoclonal pattern with disappearance of the same allele A upon Hpa II digestion (RCI > 10). 13 clonal cultures of H9 obtained by single cell cloning exhibited also the same clonal pattern with digestion of the same allele and RCI values between 6–14. Similarly, DNA purified from EB's at different stages was found to be clonal. In DNA obtained from 75 individual hematopoietic progenitors (CFU-GM, CFU-G), clonal analysis revealed the same clonal pattern in each, with disappearance of the same allele A. However, clonal analysis performed in 10 hematopoietic colonies, revealed unexpectedly, an equal digestion of Humara alleles with RCI < 2 (polyclonal pattern). Finally, in two experiments, hematopoietic cells recovered from liquid cultures exhibited an absolute clonal pattern (Total disappearance of the same allele A). Interestingly, quantification of X-Inactivation Specific Transcript (XIST) RNA in H9 and day14 EB's by RT-PCR did not show any evidence of XIST expression both before and after differentiation. Altogether, our data suggest that XCI has already been initiated in undifferentiated H9 cells and this inactivation is maintained, at least in the Humara locus in the absence of XIST. The monoclonal pattern of the cell line can be due to the fact that H9 ES cell line might have arisen from a limited number of stem cells having undergone XCI at a very early stage, with maintenance of the methylation status at this locus during mesodermal and hematopoietic commitment. Conversely, hematopoietic differentiation might occur from several mesodermal progenitors having inactivated the same X chromosome in H9 at the Humara locus. Despite the fact that hematopoietic progenitors and differentiated hematopoietic cells originating from H9 exhibited also a clonal pattern, a partial reactivation of the inactive X chromosome during hematopoietic differentiation could occur, and may explain the “polyclonal” pattern obtained in 10 CFU-GM analyzed. Overall, X-linked clonality testing could be an important issue before considering the potential clinical applications, in all female hES cell lines.

Susceptibility variants for male-pattern baldness on chromosome 20p11

We carried out a genome-wide association study in 296 individuals with male-pattern baldness (androgenetic alopecia) and 347 controls. We then investigated the 30 best SNPs in an independent replication sample and found highly significant association for five SNPs on chromosome 20p11 (rs2180439 combined P = 2.7 x 10(-15)). No interaction was detected with the X-chromosomal androgen receptor locus, suggesting that the 20p11 locus has a role in a yet-to-be-identified androgen-independent pathway.

Clonal status of fibrous dysplasia

The purpose of this study was to elucidate the clonality of fibrous dysplasia based on X-chromosome inactivation mosaicism and polymorphism in female somatic cells at the phosphoglycerate kinase (PGK) and androgen receptor (AR) loci using microdissection technology. Nine patients with fibrous dysplasia were examined using clonality assays based on X-chromosome inactivation mosaicism. Lesions and surrounding soft tissues were microdissected from paraffin sections, and genomic DNA was extracted, pretreated with Hpa II or Hha I, and the PGK and AR genes were amplified by nested PCR. The single nucleotide polymorphism (SNP) at the PGK locus was identified by incubation with Bst XI and agarose gel electrophoresis. The CAG repeat length polymorphism at the AR locus was revealed on denaturing polyacrylamide gels and visualised by silver staining. Microscopically, typical histological characteristics were seen in each sample. Lesions consisted of varying proportions of fibrous tissue and immature trabecular bone. Tissue consisted of collagenous fibres and fish-hook or comma-shaped trabecular bone without rows of cuboidal appositional osteoblasts on the surface. Restriction fragment length polymorphism (RFLP) of AR was found in seven of nine cases. The results of clonality assays demonstrated that seven cases of fibrous dysplasia were monoclonal, suggesting that they are neoplastic lesions. We conclude that fibrous dysplasia may not be a hyperplastic lesion, but a neoplastic lesion. Additional studies with larger sample sizes will be needed to conclusively prove our hypothesis.

Shorter CAG repeats in androgen receptor and non-GG genotypes in prostate-specific antigen loci are associated with decreased risk of benign prostatic hyperplasia and prostate cancer

The age-adjusted risk of prostate cancer (PC) has increased in Singapore since 1968 . We investigated the relationship between polymorphisms in four genes, androgen receptor (AR), prostate-specific antigen (PSA), 5α-reductase type II (SRD5A2) and cytochrome P450c17α (CYP17) and PC and benign prostatic hyperplasia (BPH). Men with shorter CAG repeats in AR and above 69 years at diagnosis showed a trend of decreased PC risk (OR = 0.28, 95% CI = 0.08–1.03; p = 0.05). Shorter CAG repeats and non-GG genotypes in the AR and PSA loci, respectively, showed a trend of decreased PC risk (OR = 0.25, 95% CI = 0.06–1.03; p = 0.06) and a significantly decreased BPH risk (OR = 0.38, 95% CI = 0.15–0.94; p = 0.04). The results indicate that allelic variation in PSA promoter activity may be androgen dependent and interaction of genes in androgen pathway may influence the risk of BPH and PC in Singapore males.

Promoter methylation correlates with reduced Smad4 expression in advanced prostate cancer

Transforming growth factor-beta (TGF-beta) is a potent growth inhibitor in a wide range of cell types. A transducer of TGF-beta signaling known as Mothers against decapentaplegic homologue 4 (Smad4) is a known tumor suppressor found on chromosome 18q21.1 and is typically inactivated by deletion or mutation in pancreatic and colorectal cancers. The purpose of the article is to investigate Smad4 expression, gene copy number and methylation status in advanced cases of prostate cancer. We have employed Methylation Specific PCR (MSP) to identify methylation sites within the Smad4 promoter and combined this with quantitative real-time PCR to look for correlates between methylation status and Smad4 expression and to examine androgen receptor (AR) expression. Bacterial artificial chromosome-comparative genomic hybridization (BAC-CGH) has been used to look for genomic amplifications and deletions which may also contribute to expression changes. We fail to find evidence of genomic deletions or amplifications affecting the Smad4 locus on chromosome 18 but show a correlation between promoter methylation and the loss of Smad4 expression in the same material. We confirm that the AR locus on the X chromosome is amplified in 30% of the advanced clinical samples and that this correlates with increased transcript levels as previously reported by other groups. This indicates that epigenetic changes affect the expression of the Smad4 protein in prostate cancer and points to methylation of the promoter as a novel marker of and contributor to the disease warranting further study.

X chromosome inactivation patterns in patients with idiopathic premature ovarian failure

X chromosome aberrations have been reported as the cause of extremely skewed X chromosome inactivation (XCI). The purpose of this study was to investigate whether skewed XCI is associated with idiopathic premature ovarian failure (POF). The XCI status was evaluated in Korean women by the methylation assay of androgen receptor locus in 126 idiopathic POF patients (35.3 +/- 13.9 years old, mean +/- SD) and 126 age-matched controls (35.2 +/- 13.9 years). The incidence of skewed XCI in POF group was compared with that of control. The correlation between age and skewed XCI was also evaluated within both groups. The incidence of extremely skewed XCI (>or=90%) was 3.9 versus 2.7% (P = 0.710) in POF and control group, respectively. No significant differences were found in the incidence of skewed XCI on all three levels (>or=90, >or=80 and >or=70%) compared between these two groups. The calculation of correlation coefficients showed that, in both POF and control group, there were no significant correlations between age and XCI ratio. Neither was there increasing tendency of skewed XCI according to the increase of age in both groups. Furthermore, there were no significant differences when the XCI ratios were analysed according to the age of onset of ovarian failure. The incidence of skewed XCI in Korean POF population was not significantly different from control, implying that skewed XCI may not be associated with idiopathic POF. There were also no significant correlations between age and skewed X-inactivation patterns in both groups.

Skewed X-Chromosome Inactivation in Scleroderma

Scleroderma is a female-prevalent autoimmune disease of unclear etiology. Two fundamental gender differences, skewed X-chromosome inactivation (XCI) and pregnancy-related microchimerism, have been implicated in scleroderma. We investigated the XCI patterns of female scleroderma patients and the parental origin of the inactive X chromosome in those patients having skewed XCI patterns (>80%). In addition, we investigated whether a correlation exists between XCI patterns and microchimerism in a well-characterized cohort. About 195 female scleroderma patients and 160 female controls were analyzed for the androgen receptor locus to assess XCI patterns in the DNA extracted from peripheral blood cells. Skewed XCI was observed in 67 (44.9%) of 149 informative patients and in 10 of 124 healthy controls (8.0%) [odds ratio (OR) = 9.3 (95% confidence interval (CI) 4.3-20.6, P < 0.0001)]. Extremely skewed XCI (>90%) was present in 44 of 149 patients (29.5%) but only in 3 of 124 controls (2.4%; OR = 16.9; 95% CI 4.8-70.4, P < 0.0001). Parental origin of the inactive X chromosome was investigated for ten patients for whom maternal DNA was informative, and the inactive X chromosome was of maternal origin in eight patients and of paternal origin in two patients. Skewed XCI mosaicism could be considered as an important risk factor in scleroderma.

X-chromosomal inactivation analysis of uterine leiomyomas reveals a common clonal origin of different tumor nodules in some multiple leiomyomas

Uterine leiomyomas were shown to be clonal lesions, but the relationship among different tumor nodules in multiple uterine leiomyomas remains unresolved. In this study, X-chromosomal inactivation patterns of these tumor nodules were shown by allelic polymorphism analysis through polymerase-chain reaction at the phosphoglycerate kinase and androgen receptor loci following pretreatment with the methylation-sensitive restriction enzyme HpaII or HhaI. A total number of 113 cases of uterine leiomyomas were examined. Monoclonality was demonstrated in all of the 315 nodules from 76 informative cases. The inter-nodular relationship was evaluated in 55 multiple cases with 294 tumor nodules. Different inactivation patterns were observed in 20 cases, demonstrating a multicentric origin, while an identical inactivated allele was found in all or most of the nodules in the rest of the cases, indicating a common clonal origin. The occurrence of the unicentric cases appeared to be associated with an elevated mitotic activity. Seven nodules from a multinodular case with a morphology indicative of mitotically active leiomyoma were shown to carry the identical inactivated allele, which demonstrates their unicellular origin and malignant nature. In addition, the same androgen receptor gene alteration was identified in two discrete leiomyoma nodules from a uterus. These results approve the monoclonality of uterine leiomyomas and demonstrate the presence of unicentric multiple leiomyomas.

Fibrous dysplasia: molecular clonality analysis of 21 cases

To investigate the neoplastic nature of fibrous dysplasia by molecular clonality approaches. Twenty-one cases of fibrous dysplasia were examined by clonality assays based on X-chromosomal inactivation mosiacism. Lesional and non-lesional tissues were microdissected from paraffin sections followed by DNA extraction. The DNA was predigested by HpaII or HhaI, and then amplified by nested PCR targeting phosphoglycerate kinase (PGK) and androgen receptor (AR) genes. Single nucleotide polymorphism (SNP) at the PGK locus was identified by incubation of the PCR products with Bst XI and agarose gel electrophoresis, and CAG repeat length polymorphism at AR locus was determined by denaturing polyacrylamide gel electrophoresis and visualized by silver staining. Microscopically, all 21 cases showed characteristic features of fibrous dysplasia, including spindle fibrous cell proliferation and immature bone trabeculae at various proportions. DNA polymorphisms at AR locus and SNP of PGK gene were found in 15 of 21, and 4 of 21 cases, respectively. All 19 cases were monoclonal in nature. Two cases showed no polymorphism at either AR or PGK gene locus. Fibrous dysplasia is likely a clonal, neoplastic process. Additional studies of larger number of cases are needed for a definitive conclusion.

Non‐random maternal X‐chromosome inactivation associated with PHACES

The acronym PHACES is used to describe the association of posterior fossa malformations, hemangiomas, arterial anomalies (cardiovascular or cerebrovascular), coarctation of the aorta and cardiac defects, eye abnormalities, and sternal or ventral defects. We report a female patient with an uncommon variant of this neurocutaneous disorder who manifested a sternal cleft; supraumbilical raphe; hemangiomas of the face, chest, and extremities; micrognathia and cerebrovascular anomalies. A literature review of PHACES patients with both sternal cleft and supraumbilical raphe showed a marked female predilection. Taken together with cases of sternal cleft, supraumbilical raphe and facial hemangiomas tabulated by Gorlin et al. (1994), 91% (40/44) of patients are female. One affected male died shortly after birth. We hypothesized that the gender bias in PHACES results from mutation in an X-linked dominant gene often lethal in males, and performed X-inactivation analysis of the polymorphic androgen receptor locus in this family. We documented consistently skewed X-inactivation (80%/20% in two independent analyses) in the unaffected mother and consistently random X-inactivation (47:53 and 61:39 in independent analyses) in the proband. These findings are consistent with favorably skewed X-inactivation producing a normal maternal phenotype, a phenomenon documented in X-linked dominant Rett syndrome.

Skewed X‐chromosome inactivation is associated with primary but not secondary ovarian failure

Premature ovarian failure (POF) is the occurrence of menopause before the age of 40, and may present with either primary or secondary amenorrhea. Numerous cases of POF in women with X-chromosome deletions or translocations have been reported; thus, it is possible that smaller rearrangements undetectable by conventional cytogenetics may contribute to POF in some patients. In females with an abnormal X chromosome, cells with inactivation of the normal X may be selected against, causing skewed X-chromosome inactivation (XCI). We therefore assessed XCI by methylation sensitive restriction digestion and PCR amplification at the androgen receptor (AR) locus, in 4 primary and 55 secondary POF patients and 109 control women. In samples heterozygous at AR and therefore informative for the skewing assay, the frequency of skewed XCI among the women with secondary amenorrhea was identical to that in control women, with 4 out of 48 (8.3%) secondary ovarian failure patients and 8 out of 97 (8.2%) control women having > or =90% skewing. Notably, all three primary amenorrhea patients that were informative at AR had skewed XCI > or =90% (P = 0.001 vs. control women; Fisher's exact test). To investigate whether X-chromosome copy number alterations were responsible, DNA from selected patients with skewed XCI was examined by high resolution DNA microarray, however no potential regions of DNA addition or deletion were confirmed by FISH or PCR. X-chromosome abnormalities undetectable by array, or reduced follicular pool due to an early trisomic rescue event, may explain the skewed XCI observed in POF patients presenting with primary amenorrhea.

Clonality of the peripheral papilloma and cancerous cells of breast

To study the clonality status of peripheral papilloma (peri-MP), ductal carcinoma in situ (DCIS), and normal tissue of the breast using an assay based on inactivation mosaicism of the length-polymorphic X-chromosomes at the androgen receptor (AR) locus and to explore a reliable way to distinguish the benign and malignant (or pre-malignant) cases judged morphologically. Specimens of breast tissues were obtained from 26 cases of peri-PM, 25 cases of peri-PM with atypical ductal hyperplasia (ADH), and 27 cases pf DCIS, 16 cases of developed canceration, and 20 normal women. DNA was extracted and amplified via nested-PCR with or without previous digestion by the methylation-sensitive restriction endonuclease Hha I. The products were resolved on denaturing polyacrylamide gels and visualized through silver staining. The clonality of these samples was analyzed by showing the lanes. Loss of polymorphism at the AR locus was found in all the cases with DCIS and in 10 cases (10/25, 40.0%) of peri-PM with ADH, indicating the monoclonality of the tumor. Twenty-four cases (92.3%) of the 26 cases with peri-PM and the 20 specimens of normal tissue were shown to be polyclonal. In the 16 cases of developed canceration identical X chromosome inactivation (monoclonal alterations) was observed in the cancer focus, parts of peri-PM with ADH, and the part of DCIS. Normal breast tissue and peri-PM show polyclonality and the peri-PM with ADH shows monoclonality. Clonality analysis may be a useful modality to screen high-risk cases from precancerous lesions or to distinguish between the benign hyperplasia and early carcinoma.

X Inactivation Patterns of Closely, but Not Distantly, Related Cells Are Highly Correlated: Little Evidence for Stem Cell Plasticity in Normal Females

The early, random nature of X inactivation should cause related cells to have similar, but distinctive, active X chromosomes. We assessed the frequency of stem cell plasticity using X inactivation proportions (XIPs), determined at the human androgen receptor locus, in paired tissue samples from healthy individuals. Tissues sampled were stomach (n = 18 informative females), duodenum (n = 18), colon (n = 10) with corresponding peripheral blood samples (n = 33), and varicose veins (n = 28) with corresponding T cells (n = 26) and peripheral blood granulocytes (n = 25). XIPs from samples thought to have common stem cell origins were highly correlated: multiple samples from single vein, r = .80 (n = 24); T cells versus granulocytes, r = .67 (n = 23); duodenum versus stomach, r = .63 (n = 12). Blood cells and vessels are derived from a common hemangioblast, but XIP correlations were moderate or poor: vein versus T cells, r = .42 (n = 26); vein versus granulocytes, r = .11 (n = 25). X inactivation is believed to be a late process in gut, especially hind-gut, with corresponding independence from blood precursors. Correlations with blood cells were low: stomach, r = .23 (18); duodenum, r = .21 (18); colon, r = .034 (10). Any crossover of stem cells between different organs during adult life should increase correlations with age; no such increase was seen. This study confirms that XIPs can be used to track stem cell populations, provides a theoretical basis for the power of such studies, and indicates that hemopoietic stem cell plasticity is, at most, uncommon in normal humans.

Allelic mRNA expression of X-linked monoamine oxidase a (MAOA) in human brain: dissection of epigenetic and genetic factors

A pVNTR repeat polymorphism located in the promoter region of the X-linked MAOA gene has been associated with mental disorders. To explore the effect of polymorphisms and epigenetic factors on mRNA expression, we have measured allelic expression imbalance (AEI) in female human brain tissue, employing two frequent marker single nucleotide polymorphisms (SNPs) in exon 8 (T890G) and exon 14 (C1409T) of MAOA. This approach compares one allele against the other in the same subject. AEI ratios ranged from 0.3 to 4 in prefrontal cortex, demonstrating the presence of strong cis-acting factors in mRNA expression. Analysis of CpG methylation in the MAOA promoter region revealed substantial methylation in females but not in males. MAOA methylation ratios for the three- and four-repeat pVNTR alleles of MAOA did not correlate with X-chromosome inactivation ratios, determined at the X-linked androgen receptor locus, suggesting an alternative process of dosage compensation in females. The extent of allelic MAOA methylation was highly variable and correlated with AEI (R2=0.5 and 0.7 at two CpG loci), indicating that CpG methylation regulates gene expression. Genetic factors appeared also to contribute to the AEI ratios. Genotyping of 13 MAOA polymorphisms in female subjects showed strong association with a haplotype block spanning from the pVNTR to the marker SNP. Therefore, allelic mRNA expression is affected by genetic and epigenetic events, both with the potential to modulate biogenic amine tone in the CNS.

Clonal Nature of Sclerosing Polycystic Adenosis of Salivary Glands Demonstrated by Using the Polymorphism of the Human Androgen Receptor (HUMARA) Locus as a Marker

Sclerosing polycystic adenosis (SPA) is a recently described, rare lesion of the salivary glands that bears a resemblance to epithelial proliferative lesions of the breast. The true nature of the lesion is unknown, but up to now it has been generally believed to represent a pseudoneoplastic sclerosing and inflammatory process. However, local recurrence developed in about one-third of the cases. Superimposed dysplastic changes ranging from low-grade dysplasia to carcinoma in situ were described in SPA. Although no metastases-related and/or disease-related patient deaths were documented, these clinical and histopathologic features raise the possibility that SPA might represent a neoplastic lesion. Polymorphism of the human androgen receptor locus is most frequently used to assess whether the pattern of X-chromosome inactivation is random or nonrandom, the latter strongly indicating clonality. In this study, the assay was applied to tissue from 12 examples of SPA. Three cases (males) were noninformative and 3 cases (females) could not be analyzed owing to poor quality of DNA, but all the remaining 6 lesions satisfied the criteria for monoclonality. We therefore conclude that the findings in the present study are further supporting evidence that SPA is a neoplasm, and not just a reactive process.

Evidence from autoimmune thyroiditis of skewed X-chromosome inactivation in female predisposition to autoimmunity

The etiologic factors in the development of autoimmune thyroid diseases (AITDs) are not fully understood. We investigated the role of skewed X-chromosome inactivation (XCI) mosaicism in female predisposition to AITDs. One hundred and ten female AITDs patients (81 Hashimoto's thyroiditis (HT), 29 Graves' disease (GD)), and 160 female controls were analyzed for the androgen receptor locus by the HpaII/polymerase chain reaction assay to assess XCI patterns in DNA extracted from peripheral blood cells. In addition, thyroid biopsy, buccal mucosa, and hair follicle specimens were obtained from five patients whose blood revealed an extremely skewed pattern of XCI, and the analysis was repeated. Skewed XCI was observed in DNA from peripheral blood cells in 28 of 83 informative patients (34%) as compared with 10 of 124 informative controls (8%, P<0.0001). Extreme skewing was present in 16 patients (19%), but only in three controls (2.4%, P<0.0001). The buccal mucosa, and although less marked, the thyroid specimens also showed skewing. Analysis of two familial cases showed that only the affected individuals demonstrate skewed XCI patterns. Based on these results, skewed XCI mosaicism may play a significant role in the pathogenesis of AITDs.

Systematic Evaluation of Genetic Variation at the Androgen Receptor Locus and Risk of Prostate Cancer in a Multiethnic Cohort Study

No AccessJournal of UrologyUrological Survey: Uro-science1 May 2005Systematic Evaluation of Genetic Variation at the Androgen Receptor Locus and Risk of Prostate Cancer in a Multiethnic Cohort Study Timothy L. RatliffPh.D. Timothy L. RatliffTimothy L. Ratliff More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(05)60735-5AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "Systematic Evaluation of Genetic Variation at the Androgen Receptor Locus and Risk of Prostate Cancer in a Multiethnic Cohort Study." The Journal of Urology, 173(5), p. 1826 © 2005 by American Urological Association, Inc.FiguresReferencesRelatedDetails Volume 173Issue 5May 2005Page: 1826 Advertisement Copyright & Permissions© 2005 by American Urological Association, Inc.MetricsAuthor Information Timothy L. Ratliff More articles by this author Expand All Advertisement PDF downloadLoading ...

Skewed X chromosome inactivation in blood cells of women with scleroderma

Scleroderma (SSc) is an autoimmune disease of unknown etiology. The disease is 3-8 times more frequent in women than in men. The role of X chromosome inactivation (XCI) in the predisposition of women to autoimmunity has been questioned. Until now this has not been illustrated experimentally. This study was undertaken to test the hypothesis that disturbances in XCI mosaicism may be involved in the pathogenesis of the disease in female patients with SSc. Seventy female SSc patients and 160 female controls were analyzed for the androgen receptor locus by the Hpa II/polymerase chain reaction assay to assess XCI patterns in DNA extracted from peripheral blood cells. Furthermore, skin biopsy samples were obtained from 5 patients whose blood revealed an extremely skewed pattern of XCI, and the analysis repeated. Since microchimerism in SSc was reported, Y chromosome sequences were investigated in all samples. Skewed XCI was observed in DNA from peripheral blood cells in 35 of 55 informative patients (64%), as compared with 10 of 124 informative controls (8%) (P < 0.0001). Extreme skewing was present in 27 of the patient group (49%), as compared with only 3 of the controls (2.4%) (P < 0.0001). However, XCI was random in all skin biopsy samples. The potential contribution of microchimerism to the random XCI pattern is highly unlikely based on the medical histories of the patients. Skewed XCI mosaicism may play a significant role in the pathogenesis of SSc.