Exploring the role of CYP19A1 single nucleotide polymorphisms in the pathogenesis of female pattern hair loss

Background: It has been suggested that the single nucleotide polymorphism (SNP) of the CYP19A1 gene encoding aromatase may affect the development of female pattern hair loss (FPHL). Objective: Our aim was to investigate the association of CYP19A1 gene SNPs with FPHL in a Chinese population. Methods: Two hundred Chinese Han patients with FPHL and 200 controls were enrolled into our study. SNaPshot technology was used to detect CYP19A1 gene candidate SNPs. Results: The allele frequencies and distributions of rs6493497 and rs7176005 were significantly different between FPHL and control subjects (p < 0.001 and p < 0.001 vs. p < 0.001 and p = 0.003). Conclusion: The rs6493497 and rs7176005 SNPs of the CYP19A1 gene may be genetic markers that influence the risk of FPHL in this Chinese population.

Objectives: The objectives of this study are as follows: (1) To study the levels of testosterone and dehydroepiandrosterone sulfate (DHEAS) in females with acne and/or female pattern hair loss (FPHL) and (2) to study the correlation of the severity of acne and/or FPHL with serum levels of testosterone and DHEAS. Materials and Methods: A cross-sectional study was carried out in the department of dermatology and venereology, of a tertiary care institution over a period of 1 year among patients who presented with acne and/or FPHL. Acne was graded using Leeds revised acne grading system and FPHL with Ludwig scale. Competitive immunoenzymatic colorimetric method for quantitative determination of testosterone and DHEAS concentrations in serum (“DiaMetra” kits) was performed. Correlation between quantitative variables was assessed by Pearson correlation and Spearman rank correlation. Results: A total of 84 patients with acne and/FPHL were studied over a period of 1 year. Fifty-one (60.7%) patients had acne, 21 (25%) had FPHL, and 12 (14.3%) patients had both. The mean levels of testosterone in acne, FPHL, and in patients with both were 1.14 ± 4.65 ng/ml, 0.51 ± 0.17 ng/ml, and 0.53 ± 0.24 ng/ml, respectively. The mean DHEAS in patients with acne, FPHL, and with both was 4.64 ± 4.96 μg/ml, 4.96 ± 5.34 μg/ml, and 6.34 ± 5.37 μg/ml, respectively. The Spearman rank correlation between the level of testosterone and the grades of inflammatory acne in face and FPHL was 0.193 and -0.16, respectively. The Spearman rank correlation of DHEAS with the grades of inflammatory acne in face and FPHL was 0.092 and 0.01, respectively. Limitations: The study carried out in a tertiary referral center, not reflecting the status of the condition in general population was the major limitation. Conclusion: This study in a localized population could not elicit a significant statistical correlation between serum levels of total testosterone and DHEAS with severity of acne or FPHL. However, a majority of patients with acne, FPHL, or both had low levels of total testosterone which were discordant with most of the previous studies. Half of the study population with coexisting acne and FPHL had high levels of DHEAS which suggests the need to study the role of DHES in patients with coexistence of acne and FPHL.

Androgenetic alopecia (AGA) is a prevalent, multifactorial form of hair loss involving complex aetiological factors, such as altered androgen regulation and energy metabolism. Existing treatments offer limited success, thus highlighting the need for advanced, personalised therapeutic strategies. This study focuses on correlating the genetic mechanisms of AGA with molecular targets involved in the response to current treatment modalities. An anonymised database including 26,607 patients was subjected to analysis. The dataset included information on patients' genotypes in 26 single nucleotide polymorphisms (SNPs), specifically, and diagnosed AGA grades, representing a broad range of ethnic backgrounds. In our sample, 64.6% of males and 35.4% of females were diagnosed with female pattern hair loss. This distribution aligns well with prior studies, thus validating the representativeness of our dataset. AGA grading was classified using the Hamilton-Norwood and Ludwig scales, although no association was found to the grade of the disease. SNP association analysis revealed eight SNPs, namely rs13283456 (PTGES2), rs523349 (SRD5A2), rs1800012 (COL1A1), rs4343 (ACE), rs10782665 (PTGFR), rs533116 (PTGDR2), rs12724719 (CRABP2) and rs545659 (PTGDR2), to be statistically significant with a p-value below 0.05. The study establishes a preliminary association between eight specific SNPs and AGA. These genetic markers offer insights into the variability of therapeutic responses, thus underlining the importance of personalised treatment approaches. Our findings show the potential for more targeted research to understand these SNPs' and further roles in AGA pathophysiology and in modulating treatment response.

Aromatase enzyme coded by the CYP19A1 gene catalyzes the final step of estrogen biosynthesis and is of major significance in endocrine regulation of breast cancer (BCa). Human CYP19A1 gene expression is regulated through the utilization of various non-translated tissue selective first exons, each controlled by unique sets of e.g. hormones and cytokines. Extragonadal expression pattern and regulation of human CYP19A1 gene is significantly different from that of rodents, which has been a major obstacle in studies focusing on regulation of aromatase gene expression in vivo. To study the tissue-selective regulation of human CYP19A1 gene in vivo, we have generated a transgenic reporter mouse model, hARO-Luc mouse, with a construct composing of a 100-kbp-long 5’-regulatory region of the human CYP19A1 gene attached to a luciferase (Luc) reporter gene. The aim of this study was to investigate human CYP19A1 gene expression in human BCa xenografts, to determine how the BCa cells regulate CYP19A1 gene expression in tumor associated stroma in vivo. In vitro, BCa cells have been shown to induce CYP19A1 gene expression in human breast derived fibroblasts. Furthermore, in order to study the regulation of the human CYP19A1 gene expression in hARO-Luc derived undifferentiated fibroblasts, mesenchymal stromal cells were isolated from bone marrow of female reporter mice. In these cells, human CYP19A1 gene expression was induced by dexamethasone ± TNFα, and PGE2 that are among factors known to drive aromatase gene expression in human mammary fibroblasts through promoters I.4 and I.3/PII. In order to investigate human CYP19A1 expression in BCa xenografts and tumor surrounding mammary gland, the hARO-Luc reporter mice were cross-bred with athymic nude mice. Estrogen-responsive MCF-7 or T47D cells or non-estrogen-responsive MDA-MB-231 cells were injected into inguino-abdominal mammary fat pads of athymic female hARO-Luc mice, and mice that received MCF-7 or T47D cells were also implanted s.c. with estradiol releasing pellet to induce the estrogen-dependent tumor growth. The reporter gene activity was measured from tissue homogenates. MCF-7 and T47D tumors had 5-10 -fold higher Luc activity as compared with the intact mammary gland, indicating a strong up-regulation of the reporter gene in host derived tumor stroma. In contrast, in MDA-MB-231 tumor bearing mice the reporter activity in tumors was only slightly higher as compared with the intact mammary gland. Furthermore, reporter gene activity in mammary gland surrounding MDA-MB-231 tumors was 2-fold higher than in the tumor itself. In conclusion, the data indicate that human BCa cells up-regulate expression of human aromatase gene in the tumor associated stroma in vivo. Citation Format: Päivi Järvensivu, Leena Strauss, Sari Mäkelä, Matti Poutanen, Niina Saarinen. A reporter mouse model reveals that human CYP19A1 (aromatase) gene expression is induced in breast cancer xenograft stroma and surrounding mammary gland by the cancer cells in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1402. doi:10.1158/1538-7445.AM2013-1402

Background: The objective of this study was to investigate the possibility of standardizing the Bolton ratio analysis as a diagnostic measure for both Iraqi and Egyptian orthodontic populations within three Angle' classification groups. Materials and methods: Two hundred forty pretreatment study casts (one hundred twenty of each population) were included in this study and divided into three Angle' classification groups. The mesiodistal crown diameters of all teeth were measured for computing the anterior and total Bolton ratios. Analysis of variance was performed to compare the mean ratios of Bolton analysis as a function of the Angle classification.HSD test was used to specify the classes of malocclusion that have significant differences. Results: No statistically significant differences were determined in the mean values of the anterior ratio among the angle classification groups in both Iraqi and Egyptian populations. No statistically significant differences were determined in the mean values of the overall ratio among the angle classification groups in Iraqi population. While there were statistically significant differences in the mean values of overall ratio among the angle classification groups in Egyptian population. This difference is specified with in class II malocclusion of Egyptian population. Conclusion: Anterior Bolton ratio can be standardized for both Iraqi and Egyptian orthodontic populations. While the overall ratio can be standardized only in class I and III malocclusions of both populations.

Epistasis between CYP19A1 and ESR1 polymorphisms is associated with premature ovarian failure

Serum dehydroepiandrosterone sulfate and the use of clomiphene citrate in anovulatory women

Female pattern hair loss (FPHL) is a common hair loss disorder in women and has a complex mode of inheritance. The etiopathogenesis of FPHL is largely unknown; however, it is hypothesized that FPHL and male pattern baldness [androgenetic alopecia (AGA)] share common genetic susceptibility alleles. Our recent findings indicate that the major AGA locus, an X-chromosome region containing the androgen receptor and the ectodysplasin A2 receptor (EDA2R) genes, may represent a common genetic factor underlying both early-onset FPHL and AGA. This gives further support for the widespread assumption of shared susceptibility loci for FPHL and AGA. However, we could not demonstrate association of further AGA risk loci, including 20p11, 1p36.22, 2q37.3, 7p21.1, 7q11.22, 17q21.31, and 18q21.1, with FPHL. Interestingly, a recent study identified four novel AGA risk loci in chromosomal regions 2q35, 3q25.1, 5q33.3, and 12p12.1. In particular, the 2q35 locus and its gene WNT10A point to an as-yet unknown involvement of the WNT signaling pathway in AGA. We hypothesized that the novel loci and thus also the WNT signaling may have a role in the etiopathogenesis of FPHL and therefore examined the role of these novel AGA risk loci in our FPHL samples comprising 440 German and 145 UK affected patients, 500 German unselected controls (blood donors), and 179 UK supercontrols. Patients and controls were genotyped for the top two single nucleotide polymorphisms at each of the four AGA loci. However, none of the genotyped variants displayed any significant association. In conclusion, the results of this study provide no support for the hypothesis that the novel AGA loci influence susceptibility to FPHL.

Hair diversity, its style, colour, shape and growth pattern is one of our most defining characteristics. The natural versus temporary style is influenced by what happens to our hair during our lifetime, such as genetic hair loss, sudden hair shedding, greying and pathological hair loss in the various forms of alopecia because of genetics, illness or medication. Despite the size and global value of the hair care market, our knowledge of what controls the innate and within-lifetime characteristics of hair diversity remains poorly understood. In the last decade, drivers of knowledge have moved into the arena of genetics where hair traits are obvious and measurable and genetic polymorphisms are being found that raise valuable questions about the biology of hair growth. The recent discovery that the gene for trichohyalin contributes to hair shape comes as no surprise to the hair biologists who have believed for 100years that hair shape is linked to the structure and function of the inner root sheath. Further conundrums awaiting elucidation include the polymorphisms in the androgen receptor (AR) described in male pattern alopecia whose location on the X chromosome places this genetic contributor into the female line. The genetics of female hair loss is less clear with polymorphisms in the AR not associated with female pattern hair loss. Lifestyle choices are also implicated in hair diversity. Greying, which also has a strong genetic component, is often suggested to have a lifestyle (stress) influence and hair follicle melanocytes show declining antioxidant protection with age and lowered resistance to stress. It is likely that hair research will undergo a renaissance on the back of the rising information from genetic studies as well as the latest contributions from the field of epigenetics.

Male pattern baldness (MPB), also known as androgenetic alopecia, represents the most prevalent form of progressive hair loss in humans. It is characterized by a distinctive pattern of hair loss progression from the scalp; however, its underlying mechanism remains elusive and is influenced by hereditary, immune, and environmental factors. Genome-wide association studies (GWASs) have uncovered numerous risk genes/loci among European individuals with MPB. However, the validation of these susceptibility genes/loci within Han Chinese men remains largely unexplored. The aim of this study was to investigate whether the 71 susceptibility loci identified in a recent GWAS among European men also confer risk for MPB in Chinese men. Forty-seven single nucleotide polymorphisms (SNPs) previously reported in GWASs of MPB were selected and genotyped in independent individuals comprising 499 Han Chinese cases and 1,489 controls using the Sequenom MassArray system. After stringent quality control measures, 25 SNPs were subjected to statistical analyses. Cochran-Armitage trend test was used to evaluate the association between SNPs and disease susceptibility. To address multiple tests, Bonferroni correction was conducted, setting the threshold for statistical significance at a p-value <2 × 10-3 (0.05/25). The rs13405699 SNP located at 2q31.1 exhibited a significant association with MPB in Han Chinese men (p = 4.84 × 10-5, OR = 1.37, 95% CI: 1.18-1.59). Moreover, the difference in rs13405699 genotype distribution between MPB cases and controls was statistically significant (p = 7.00 × 10-5). Genotype-based association analysis suggested that the recessive model provided the best fit for the rs13405699 polymorphism. This study represents the first confirmation of the association between the rs13405699 SNP at 2q31.1 and MPB within the Han Chinese population, thereby enhancing our understanding of the genetic underpinnings of MPB.

The Egyptian cattle populations, especially the Egyptian Menufi and Saidi populations with a wider distribution across the Nile valley and delta, is possessing high genetic variability. Information about comparison between the groups of Egyptian cattle population in Egypt based their genetic distance values provide some benefits for the Egyptian government to design future conservation and breeding programs as well as enrich the Egyptian cattle genetic resources. The study is indicating that the analyzed three Egyptian and BalTar crossbred have been genetically differentiated in line with their geographical separations. In all likelihood there has been just minimal hereditary trade among the Egyptian populations. The microsatellite markers utilized as a part of this work was for the most part appropriate in surveying genetic diversity in the Egyptian cattle populations analyzed, uncovering elevated amounts of genetic variability, assessed by both the number of alleles and heterozygosity.

Background: The exact association between clinical and biochemical hyperandrogenism (HA) is heterogeneous and cannot be ascertained, especially in normoandrogenic women. Aim: Evaluate any association between clinical HA phenotypes and biochemical parameters in premenopausal women with female pattern hair loss (FPHL). Methods: A cross-sectional observational study on 362 women with different degrees of FPHL, who were assessed for general characteristics, the degree of FPHL by Sinclair’s score, hirsutism by modified Ferriman-Gallwey (mFG) score. Evaluation for biochemical HA included total testosterone (TT), sex-hormone-binding globulin (SHBG), calculated free testosterone (FT), calculated bioavailable testosterone (BT), and dehydroepiandrosterone sulfate (DHEA-S). The variables of clinical HA which were used in this study are FPHL, hirsutism, and acne. We used the Free and Bioavailable Testosterone Calculator to calculate the FT and BT. Results: The enrolled young premenopausal women’s age range was (14-47 years). Around 78% of them were overweight or obese. Eighty-percent of women had a mild FPHL, with a median duration of three years where 2/3 of women had a duration < 3 years, and had no significant relationship to FPHL degree. About 73% of women had either a mild to moderate hirsutism, and around 16% had acne. The biochemical HA was confirmed in around 52% of women (n=188), who show high levels of calculated FT. The calculated BT is high in 78.5% of the enrolled women (n=284). The means of biochemical indicators for HA were in their reference ranges or slightly above, with no specific change pattern with the corresponding FPHL severity. None of these parameters had a significant relationship to the severity of FPHL. The duration of FPHL was not affected by any presumed variable of clinical or biochemical HA. Conclusions: FPHL severity is associated with other clinical HA signs like hirsutism and acne, but not to HA’s biochemical parameter. Other parameters, like SHBG, HOMA-IR, and BMI, had no significant relation to the severity of FPHL. Clinical implications: FPHL severity does not correlate with the magnitude of hyperandrogenism. The assessment of women with FPHL is primarily clinical. The biochemical picture assists the diagnostic process.

Female pattern hair loss (FPHL) is a common trait in which androgens and oestrogens may have a pathogenic role. The aromatase enzyme converts androgens to oestrogens in scalp hair follicles and is differentially expressed in balding and nonbalding scalps of women. Sequence variation in the gene encoding aromatase, CYP19A1, might influence the risk of developing FPHL. To examine the role of CYP19A1 genetic variation in the heritability of FPHL. We investigated associations between FPHL and 61 tag single nucleotide polymorphisms (SNPs) representing variation in and around CYP19A1 in 484 caucasian women with grades 3-5 FPHL on the Sinclair scale, and 471 caucasian women with no evidence of hair loss. For the tag SNP rs4646 (overall genotype frequencies: CC, 53.6%; AC, 39.3%; AA, 7.1%), the genotype CC was more frequent in women with FPHL (58.1%) than controls (48.9%) (P = 0.006). Although this result did not achieve experiment-wide significance (P < 0.001 by permutation testing), subanalyses according to sources of recruitment and ages at presentation revealed consistent patterns of association. In particular, young cases (< 40 years) had the highest frequency of the CC genotype (68.2%) among all subgroups. These findings suggest that the common rs4646 C allele, which has been associated previously with higher circulating oestrogen levels, might be associated with predisposition to FPHL.

The global demand for products that effectively prevent the development of male-pattern baldness (MPB) has drastically increased. However, there is currently no established genetic model for the estimation of MPB risk. We conducted a prediction analysis using single-nucleotide polymorphisms (SNPs) identified from previous GWASs of MPB in a total of 2725 German and Dutch males. A logistic regression model considering the genotypes of 25 SNPs from 12 genomic loci demonstrates that early-onset MPB risk is predictable at an accuracy level of 0.74 when 14 SNPs were included in the model, and measured using the area under the receiver-operating characteristic curves (AUC). Considering age as an additional predictor, the model can predict normal MPB status in middle-aged and elderly individuals at a slightly lower accuracy (AUC 0.69-0.71) when 6-11 SNPs were used. A variance partitioning analysis suggests that 55.8% of early-onset MPB genetic liability can be explained by common autosomal SNPs and 23.3% by X-chromosome SNPs. For normal MPB status in elderly individuals, the proportion of explainable variance is lower (42.4% for autosomal and 9.8% for X-chromosome SNPs). The gap between GWAS findings and the variance partitioning results could be explained by a large body of common DNA variants with small effects that will likely be identified in GWAS of increased sample sizes. Although the accuracy obtained here has not reached a clinically desired level, our model was highly informative for up to 19% of Europeans, thus may assist decision making on early MPB intervention actions and in forensic investigations.

Objective: Hair diseases are associated with mental illness. However, the relationship between schizophrenia with AGA is missing. In this study, we explored the causal relationship between androgenetic alopecia (AGA) and schizophrenia. Methods: A bidirectional Mendelian randomization (MR) analysis was conducted to determine the causal relationship between AGA and schizophrenia using data from the IEU OpenGWAS database (https://gwas.mrcieu.ac.uk/). The methods used for forward and reverse MR analyses included the inverse variance weighted (IVW) method, MR-Egger method, weighted median, weighted mode, and simple mode approaches. Heterogeneity was assessed with the MR-Egger and IVW methods, and Cochran’s Q test was used to evaluate heterogeneity. MR-Egger regression was used to assess pleiotropy, and a leave-one-out method was applied to evaluate the dependence of MR results on specific single-nucleotide polymorphisms (SNPs). Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed for genes influencing the causal relationship between exposure and outcome at SNP sites. Results: Forward MR analysis revealed a significant causal relationship between AGA and schizophrenia (OR [95% CI], 0.996 [0.992–0.999]; P = 0.025), while reverse MR analysis showed no causal association between schizophrenia and AGA (OR [95% CI], 1.061[0.965–1.165]; P = 0.220). No heterogeneity or pleiotropy was observed. GO enrichment and KEGG pathway analyses indicated that affected genes at SNP sites in forward MR analysis were associated with pyrimidine metabolism, nucleotide metabolism, galactose metabolism, ion activity, the mTOR signaling pathway, and RNA degradation. Conclusion: A causal relationship between AGA and schizophrenia was identified in forward MR analysis, while schizophrenia showed no causal association with AGA in reverse MR analysis.