Candidate genes in polycystic ovary syndrome.
Franks S,Gharani N,McCarthy M
Human reproduction update
The candidate gene approach has already paid some dividends in trying to understand the complex genetics of polycystic ovary syndrome (PCOS). In terms of steroidogenic abnormalities, CYP11a-encoding P450 side chain cleavage-appears to be a major susceptibility locus. In relation to the well-described metabolic disturbances in PCOS, the insulin gene variable number tandem repeat (VNTR) appears to be a promising candidate, at least in populations studied in the UK. Finally, genes implicated in ovarian follicular development may have a role in the aetiology of PCOS, as demonstrated by recent identification of the follistatin gene as a potential disease locus. It seems unlikely that PCOS can be explained on the basis of a single gene disorder although, in a given family, one gene may have a predominant effect. An oligogenic model seems the most appropriate basis on which to understand the genetic origins of this very common disorder. The candidate gene approach has been useful to date, but it may prove important in the near future to perform an anonymous genome-wide scan to identify hitherto unheralded susceptibility loci.
Functional genetic polymorphisms and female reproductive disorders: Part I: Polycystic ovary syndrome and ovarian response.
Simoni M,Tempfer C B,Destenaves B,Fauser B C J M
Human reproduction update
BACKGROUND:The identification of polymorphisms associated with a disease can help to elucidate its pathogenesis, and this knowledge can be used to improve prognosis for women with a particular disorder, such as polycystic ovary syndrome (PCOS). Since an altered response to ovarian stimulation is also a characteristic of the disease, further knowledge about its aetiology could help in defining the parameters that determine the response of an individual to ovarian stimulation. METHODS:PubMed and EMBASE databases were systematically searched for gene association studies published until the end of August 2007, using search criteria relevant to PCOS and ovarian response to stimulation. Data from additional papers identified through hand searches were also included; 139 publications were reviewed. RESULTS:Several genes involved in ovarian function and metabolism are associated with increased susceptibility to PCOS, but none is strong enough to correlate alone with susceptibility to the disease, or response to therapy. A single-nucleotide polymorphism in exon 10 of the FSH receptor (FSHR) gene, FSHR p.N680S, was consistently identified as having a significant association with ovarian response to FSH. CONCLUSIONS:No consistent association between gene polymorphism and PCOS could be identified. The FSHR gene may play a significant role in the success of ovarian stimulation, and can be used as a marker to predict differences in FSHR function and ovarian response to FSH. Genotyping the FSHR p.N680S polymorphism may provide a means of identifying a population of poor responders before in vitro fertilization procedures are initiated.
The fibroblast growth factor family: neuromodulation of affective behavior.
Turner Cortney A,Watson Stanley J,Akil Huda
In this review, we propose a broader view of the role of the fibroblast growth factor (FGF) family in modulating brain function. We suggest that some of the FGF ligands together with the FGF receptors are altered in individuals with affective disorder and modulate emotionality in animal models. Thus, we propose that members of the FGF family may be genetic predisposing factors for anxiety, depression, or substance abuse; that they play a key organizing role during early development but continue to play a central role in neuroplasticity in adulthood; and that they work not only over extended time frames, but also via rapid signaling mechanisms, allowing them to exert an "on-line" influence on behavior. Therefore, the FGF family appears to be a prototype of "switch genes" that are endowed with organizational and modulatory properties across the lifespan, and that may represent molecular candidates as biomarkers and treatment targets for affective and addictive disorders.
Serotonin receptors and their function in sleep, anxiety disorders and depression.
Leonard B E
Psychotherapy and psychosomatics
Thirty-three years ago, Gaddum and Picarelli classified the serotonin receptors in the guinea pig ileum into D and M types based on the activity of dibenzyline (D) and morphine (M) to block contractions of intestinal smooth muscle caused by serotonin. The subsequent location of specific ligand binding sites for serotonin in the brain has led to the identification of 14 serotonin receptor sub-types in rat brain. The cloning of these receptor sub-types has been of importance in enabling them to be classified as specific-protein molecules encoded by specific genes. The problem now arises with regard to the linking of the changes in the cellular activity of the various receptor sub-types with the plethora of behavioural changes that arise as a consequence of the actions of serotonin in the brain. The present review summarizes the evidence implicating the role of specific serotonin receptor sub-types in sleep, anxiety states, schizophrenia and depression. A summary of the relationship between these receptor sub-types and their possible involvement in the aetiology of schizophrenia, depression, anxiety and sleep disorders.
Transduction of psychosocial stress into the neurobiology of recurrent affective disorder.
Post R M
The American journal of psychiatry
Early clinical observations and recent systematic studies overwhelmingly document a greater role for psychosocial stressors in association with the first episode of major affective disorder than with subsequent episodes. The author postulates that both sensitization to stressors and episode sensitization occur and become encoded at the level of gene expression. In particular, stressors and the biochemical concomitants of the episodes themselves can induce the protooncogene c-fos and related transcription factors, which then affect the expression of transmitters, receptors, and neuropeptides that alter responsivity in a long-lasting fashion. Thus, both stressors and episodes may leave residual traces and vulnerabilities to further occurrences of affective illness. These data and concepts suggest that the biochemical and anatomical substrates underlying the affective disorders evolve over time as a function of recurrences, as does pharmacological responsivity. This formulation highlights the critical importance of early intervention in the illness in order to prevent malignant transformation to rapid cycling, spontaneous episodes, and refractoriness to drug treatment.
The genetics of mood disorders.
Lau Jennifer Y F,Eley Thalia C
Annual review of clinical psychology
Studying the genetics of mood disorders has never been more exciting. We have moved rapidly from establishing the genetic basis of depression to asking questions about how genes are expressed. This has been made possible by the capacity to collect and sequence DNA for large samples cheaply. But "multidisciplinary" approaches investigating interrelationships between risk factors have also been increasingly adopted, encouraging collaborations between those studying genes and those studying the brain, cognition, and/or the social environment. In this review, we first describe findings from quantitative and molecular studies investigating the genetic basis of depression. Second, we present overviews of three hot topics of genetic research: gene-environment interplay, which considers how genetic factors shape exposure and responses toward the social environment; endophenotypic research, which identifies neurophysiological and psychological mediators of genetic risk; and epigenetics, which explain how early environments can foster changes in gene expression, altering subsequent emotional development.
Diagnostic Value of Serum hsa_circ_0141720 in Patients with Acute Ischemic Stroke.
Chen Yun,Wang Bo,Liu Wenming,Xu Peng,Song Li
BACKGROUND:The current study aims to observe the expression of hsa_circ_0141720 in the serum of patients with acute cerebral infarction (ACI) and to explore its clinical value in the diagnosis of ACI. METHODS:Eighty patients with ACI within the previous 48 hours were selected, and 30 healthy persons in the same period were selected as the control. Microarray analysis was performed to evaluate the changes of circRNA profiles, and RT-PCR was used to validate the findings. Pearson's correlation assay was performed to analyze the correlation between the level of hsa_circ_0141720 and other clinical indicators. RESULTS:Microarray analysis identified eight differentially expressed cirRNAs in the serum of ACI patients. RT-PCR validated that the expression of hsa_circ_0141720 in serum of ACI patients was increased the most. Hence, we mainly focused on hsa_circ_0141720 in the following study. ROC curve analysis showed that when the cutoff value for serum hsa_circ_0141720 was 2.03, the sensitivity and specificity were 89.7% and 95.6%, respectively. Further study showed that enhanced hsa_circ_0141720 expression was positively correlated with the National Institutes of Health Stroke Scale (NIHSS) scores and infarct volume of ACI patients. Moreover, upregulation of hsa_circ_0141720 was also positively correlated with increased expression of serum interleukin 6 (IL-6) and plasma high-sensitivity C relative protein (hs-CRP) in patients with ACI. CONCLUSIONS:In summary, enhanced expression of hsa_circ_0141720 in the serum of patients with ACI was related to the severity of the disease and it may be used as a new serological index for the diagnosis of ACI.
Serum hsa_circ_101178 as a Potential Biomarker for Early Prediction of Osteoarthritis.
BACKGROUND:Early detection and treatment are of great importance in the management of osteoarthritis (OA). The current study aims to evaluate the relationship between serum circRNA hsa_circ_101178 and the severity of OA. METHODS:Western Ontario McMaster University Osteoarthritis Index (WOMAC) pain scores and Kellgren-Lawrence (KL) grading system were used to evaluate the symptomatic and radiological severity of OA patients. RT-PCR was carried out to explore the level of hsa_circ_101178 in serum and synovial fluid (SF) of OA patients. Spearman's correlation assay was used to analyze the correlation between serum hsa_circ_101178 and WOMAC score or KL grading. The diagnostic value of serum hsa_circ_101178 was evaluated using receiver operating characteristic (ROC) curves. RESULTS:Serum and SF hsa_circ_101178 levels were significantly higher in OA patients than those in controls. Further study showed a positive correlation between serum and SF hsa_circ_101178 levels. Moreover, serum hsa_circ_101178 were positively correlated with the severity of OA according to KL grading. Meanwhile, serum hsa_circ_101178 was also positively correlated with WOMAC-pain scores. ROC analysis showed the AUC of serum hsa_circ_101178 was 0.835 in screening OA patients from controls. CONCLUSIONS:Upregulation of serum hsa_circ_101178 may play a crucial role in the pathogenesis of OA and can be a useful biomarker for early diagnosis of OA.
Three CircRNAs Function as Potential Biomarkers for Colorectal Cancer.
Zhang Jinling,Cai Ang,Zhao Yu
BACKGROUND:Colorectal cancer (CRC) is one of the most frequently diagnosed cancers worldwide. Based on clinical data, CRC could be cured by surgery with favorable outcomes if diagnosed at an early stage. The present study aimed to determine whether circ-FMN2, circ-LMNB1, and circ-ZNF609 may serve as potential biomarkers for CRC. METHODS:Expression levels of circ-FMN2, circ-LMNB1, and circ-ZNF609 were detected in serum samples from 88 CRC patients and 68 healthy volunteers by real-time quantitative PCR (RT-qPCR). The correlation between circRNA expressions and clinicopathological parameters was analyzed subsequently. The ROC curve analysis and survival curves were calculated and compared in order to explore the diagnostic and prognostic values of circ-RNAs in CRC. RESULTS:The results verified that circ-FMN2, circ-LMNB1, and circ-ZNF609 were significantly elevated in serum samples of CRC patients compared with healthy controls (p < 0.01). Increased circ-FMN2, circ-LMNB1, and circ-ZNF609 expressions were markedly positively correlated with histological grade (p < 0.0001, p = 0.0014, p = 0.0303), lymph nodes metastasis (p < 0.0001, p < 0.0001, p = 0.0093), and TNM stage (p = 0.0055, p = 0.0110, p < 0.000). Meanwhile, the ROC curve analysis verified the diagnostic accuracy of circ-FMN2, circ-LMNB1, and circ-ZNF609 with AUC of 0.9153 (95% CI = 0.8707 ~ 0.9599), 0.9627 (95% CI = 0.9351 ~ 0.9903), and 0.8711 (95% CI = 0.8151 ~ 0.9270), respectively. Furthermore, the CRC patients with high circ-FMN2, circ-LMNB1, and circ-ZNF609 had significantly worse outcomes than those with low expression (p = 0.0267, p = 0.0145, p = 0.0194). CONCLUSIONS:The present study elucidated that circ-FMN2, circ-LMNB1, and circ-ZNF609 may function as potential diagnostic and prognostic indicators for CRC detection.
Silencing hsa_circRNA_0008035 exerted repressive function on osteosarcoma cell growth and migration by upregulating microRNA-375.
Gong Gu,Han Zhifeng,Wang Wenjun,Xu Qinli,Zhang Jingzhe
Cell cycle (Georgetown, Tex.)
Traditionally, circular RAN hsa_circ_0008035 was proven to function as a tumor inhibitor in gastric cancer. Nevertheless, much less was known about hsa_circ_0008035 in osteosarcoma (OSA). This project was undertaken to assess the role of hsa_circ_0008035 in OSA. Hsa_circ_0008035 level in serum of OSA patients, OSA tissues and cell lines were measured by reverse transcription-quantitative PCR. After downregulation or overexpression of hsa_circ_0008035, cell proliferation, apoptosis and migration were tested in MG63, SAOS-2 or hFOB1.19 cells. Meanwhile, the expression level of miR-375 was analyzed. The binding between hsa_circ_0008035 and miR-375 was confirmed using bioinformatics and luciferase assay. Subsequently, the effects of miR-375 inhibition on MG63 cell growth and migratory potential were reevaluated. Eventually, the activating status of Notch pathway was assessed by Western blot. Our results demonstrated that hsa_circ_0008035 was overexpressed in serum of OSA patients, OSA tissues and cells. Silencing hsa_circRNA_0008035 impeded OSA cell growth and migration, while hsa_circ_0008035 facilitated cell behaviors of hFOB1.19 cells. Additionally, hsa_circ_0008035 negatively modulated miR-375 expression. Meanwhile, miR-375 inhibition overturned the suppressive effects of silencing hsa_circRNA_0008035 on OSA cell behaviors. Furthermore, silencing hsa_circ_0008035 perturbed Notch pathway by adjusting miR-375 expression. In conclusion, silencing hsa_circRNA_0008035 exerted repressive function on OSA cell growth and migration and Notch pathway by accelerating miR-375.
Upregulation of circRNA_0000285 serves as a prognostic biomarker for nasopharyngeal carcinoma and is involved in radiosensitivity.
Shuai Mingxia,Hong Jangwei,Huang Donghai,Zhang Xin,Tian Yongquan
Despite significant medical advancement, nasopharyngeal carcinoma (NPC) remains one of the most difficult types of cancer to detect and treat. Circular RNA (circRNA) signatures may be used as prognostic and predictive factors for cancer. Previous studies indicated that the biological role of circular homeodomain interacting protein kinase 3 (HIPK3) has cancer type-specificity. The HIPK3 gene locus formats three circRNA isoforms: circRNA_100783, circRNA_0000285 and circRNA_100782. However, their roles in NPC remain unknown. In the present study, whether these circRNAs could be used as a biomarker for NPC diagnosis and predicting treatment response was investigated. Reverse transcription-quantitative polymerase chain reaction was performed to measure the levels of circRNA_100783, circRNA_0000285 and circRNA_100782 in NPC and adjacent tissues. In addition, the circRNA_0000285 levels were further confirmed in serum samples from patients with NPC and healthy controls. The results demonstrated that circRNA_0000285, but not circRNA_100782 and circRNA_100783, was significantly increased in NPC tissues and serum samples from patients with NPC, compared with adjacent tissues and serum samples from healthy controls, respectively. Furthermore, circRNA_0000285 expression was increased in patients with radioresistant NPC, compared with patients with radiosensitive NPC. Further analysis demonstrated that circRNA_0000285 was significantly associated with tumor size (P<0.001), differentiation (P=0.022), lymph node metastasis (P=0.035), distant metastasis (P=0.022) and Tumor-Node-Metastasis stage (P<0.001). Additionally, univariate and multivariate analyses indicated that circRNA_0000285 may be an independent prognostic factor for the outcome of patients with NPC. The present data indicated that circRNA_0000285 may be a novel biomarker for NPC and is involved in NPC radiosensitivity.