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1.
Artigo em Inglês | MEDLINE | ID: mdl-33166066

RESUMO

BACKGROUND: Rheumatoid arthritis (RA) is chronic, painful, disabling condition resulting in significant impairments in physical, emotional, and social health. We used different methods and perspectives to evaluate the responsiveness of PROMIS® short forms (SFs) and identify minimal and meaningful score changes. METHODS: Adults with RA enrolled in a multi-site prospective observational cohort completed PROMIS Physical Function, Pain Interference, Fatigue, Participation in Social Roles/Activities SFs, PROMIS-29, and pain, patient global, and rated change in specific symptoms and RA (a little vs. lot better or worse) at the second visit. Physicians recorded joint counts, MD Global Assessment, and change in RA at visit 2. We compared mean score differences for minimal and meaningful improvement/worsening using patient and MD change ratings and distribution-based methods, and visually inspected empirical cumulative distribution function curves by change categories. RESULTS: The 348 adults were mostly (81%) female with longstanding RA. Using patient ratings, generally 1-3 point differences were observed for minimal change and 3-7 points for meaningful change. Larger differences were observed with patient vs. physician ratings and for symptom-specific vs. RA change. Mean differences were similar among SF versions. Prespecified hypotheses about change in PROMIS Physical Function, Pain Interference, Fatigue and Participation and legacy scales were supported. CONCLUSIONS: PROMIS SFs and the PROMIS-29 Profile are responsive to change and generally distinguish between minimal and meaningful improvement and worsening in key RA domains. These data add to a growing body of evidence demonstrating robust psychometric properties of PROMIS and supporting use in RA care, research, and decision-making.

2.
Am J Hum Genet ; 107(4): 622-635, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32946763

RESUMO

Quantifying the functional effects of complex disease risk variants can provide insights into mechanisms underlying disease biology. Genome-wide association studies have identified 39 regions associated with risk of epithelial ovarian cancer (EOC). The vast majority of these variants lie in the non-coding genome, where they likely function through interaction with gene regulatory elements. In this study we first estimated the heritability explained by known common low penetrance risk alleles for EOC. The narrow sense heritability (hg2) of EOC overall and high-grade serous ovarian cancer (HGSOCs) were estimated to be 5%-6%. Partitioned SNP heritability across broad functional categories indicated a significant contribution of regulatory elements to EOC heritability. We collated epigenomic profiling data for 77 cell and tissue types from Roadmap Epigenomics and ENCODE, and from H3K27Ac ChIP-seq data generated in 26 ovarian cancer and precursor-related cell and tissue types. We identified significant enrichment of risk single-nucleotide polymorphisms (SNPs) in active regulatory elements marked by H3K27Ac in HGSOCs. To further investigate how risk SNPs in active regulatory elements influence predisposition to ovarian cancer, we used motifbreakR to predict the disruption of transcription factor binding sites. We identified 469 candidate causal risk variants in H3K27Ac peaks that are predicted to significantly break transcription factor (TF) motifs. The most frequently broken motif was REST (p value = 0.0028), which has been reported as both a tumor suppressor and an oncogene. Overall, these systematic functional annotations with epigenomic data improve interpretation of EOC risk variants and shed light on likely cells of origin.


Assuntos
Carcinoma Epitelial do Ovário/genética , Proteínas Correpressoras/genética , Cistadenocarcinoma Seroso/genética , Elementos Facilitadores Genéticos , Histonas/genética , Proteínas do Tecido Nervoso/genética , Neoplasias Ovarianas/genética , Alelos , Sítios de Ligação , Carcinoma Epitelial do Ovário/diagnóstico , Carcinoma Epitelial do Ovário/patologia , Mapeamento Cromossômico , Proteínas Correpressoras/metabolismo , Cistadenocarcinoma Seroso/diagnóstico , Cistadenocarcinoma Seroso/patologia , Feminino , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Histonas/metabolismo , Humanos , Padrões de Herança , Proteínas do Tecido Nervoso/metabolismo , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/patologia , Penetrância , Polimorfismo de Nucleotídeo Único , Risco
3.
Rheumatology (Oxford) ; 59(7): 1662-1670, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31665477

RESUMO

OBJECTIVE: To evaluate the impact of integrating patient-reported outcomes (PROs) into routine clinics, from the perspective of patients with RA, clinicians and other staff. METHODS: We conducted a prospective cohort study using a mixed methods sequential explanatory design at an academic arthritis clinic. RA patients completed selected Patient-Reported Outcomes Measurement Information System measures on tablets in the waiting room. Results were immediately available to discuss during the visit. Post-visit surveys with patients and physicians evaluated topics discussed and their impact on decision making; patients rated confidence in treatment. Focus groups or interviews with patients, treating rheumatologists and clinic staff were conducted to understand perspectives and experiences. RESULTS: Some 196 patients and 20 rheumatologists completed post-visit surveys at 816 and 806 visits, respectively. Focus groups were conducted with 24 patients, 10 rheumatologists and 4 research/clinic staff. PROs influenced medical decision-making and RA treatment changes (38 and 18% of visits, respectively). Patients reported very high satisfaction and treatment confidence. Impact on clinical workflow was minimal after a period of initial adjustment. PROs were valued by patients and physicians, and provided new insight into how patients felt and functioned over time. Reviewing results together improved communication, and facilitated patient-centred care, shared decision making, and the identification of new symptoms and contributing psychosocial/behavioural factors. CONCLUSION: PRO use at RA visits was feasible, increased understanding of how disease affects how patients feel and function, facilitated shared decision-making, and was associated with high patient satisfaction and treatment confidence.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Comunicação , Tomada de Decisões , Participação do Paciente , Satisfação do Paciente , Relações Médico-Paciente , Adulto , Idoso , Artrite Reumatoide/psicologia , Atitude do Pessoal de Saúde , Tomada de Decisão Clínica , Feminino , Pesquisas sobre Serviços de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Assistência Centrada no Paciente/métodos , Estudos Prospectivos , Pesquisa Qualitativa
5.
BMC Genomics ; 20(1): 745, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619158

RESUMO

BACKGROUND: The development of next generation sequencing (NGS) methods led to a rapid rise in the generation of large genomic datasets, but the development of user-friendly tools to analyze and visualize these datasets has not developed at the same pace. This presents a two-fold challenge to biologists; the expertise to select an appropriate data analysis pipeline, and the need for bioinformatics or programming skills to apply this pipeline. The development of graphical user interface (GUI) applications hosted on web-based servers such as Shiny can make complex workflows accessible across operating systems and internet browsers to those without programming knowledge. RESULTS: We have developed GENAVi (Gene Expression Normalization Analysis and Visualization) to provide a user-friendly interface for normalization and differential expression analysis (DEA) of human or mouse feature count level RNA-Seq data. GENAVi is a GUI based tool that combines Bioconductor packages in a format for scientists without bioinformatics expertise. We provide a panel of 20 cell lines commonly used for the study of breast and ovarian cancer within GENAVi as a foundation for users to bring their own data to the application. Users can visualize expression across samples, cluster samples based on gene expression or correlation, calculate and plot the results of principal components analysis, perform DEA and gene set enrichment and produce plots for each of these analyses. To allow scalability for large datasets we have provided local install via three methods. We improve on available tools by offering a range of normalization methods and a simple to use interface that provides clear and complete session reporting and for reproducible analysis. CONCLUSION: The development of tools using a GUI makes them practical and accessible to scientists without bioinformatics expertise, or access to a data analyst with relevant skills. While several GUI based tools are currently available for RNA-Seq analysis we improve on these existing tools. This user-friendly application provides a convenient platform for the normalization, analysis and visualization of gene expression data for scientists without bioinformatics expertise.


Assuntos
Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , Análise de Sequência de RNA/métodos , Software , Interpretação Estatística de Dados , Visualização de Dados , Internet , Reprodutibilidade dos Testes , Interface Usuário-Computador
6.
PLoS Genet ; 14(12): e1007813, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30566500

RESUMO

Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed based on the two criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a fixed-effect, inverse-weighted-variance meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (near PLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Only one locus differed significantly in its association by diagnostic criteria; otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or non-NIH Rotterdam criteria across common variants at 13 loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Linkage disequilibrium score regression analysis revealed genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease, indicating shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. The data thus demonstrate 3 novel loci associated with PCOS and similar genetic architecture for all diagnostic criteria. The data also provide the first genetic evidence for a male phenotype for PCOS and a causal link to depression, a previously hypothesized comorbid disease. Thus, the genetics provide a comprehensive view of PCOS that encompasses multiple diagnostic criteria, gender, reproductive potential and mental health.


Assuntos
Síndrome do Ovário Policístico/diagnóstico , Síndrome do Ovário Policístico/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Fenótipo
7.
Gynecol Oncol ; 147(3): 705-713, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29054568

RESUMO

Epithelial ovarian cancer (EOC) is a heterogeneous disease with a major heritable component. The different histotypes of invasive disease - high grade serous, clear cell, endometrioid and mucinous - are associated with different underlying genetic susceptibility and epidemiological and lifestyle risk factors, all of which contribute to the different biology and clinical characteristics of each histotype. A combination of familial and population based sequencing studies, and genome wide association studies (GWAS) have identified a range of genetic susceptibility alleles for EOC comprising rare but highly penetrant genes (e.g. BRCA1, BRCA2) that are responsible for familial clustering of ovarian cancer cases; more moderate penetrance susceptibility genes (e.g. BRIP1, RAD51C/D, MSH6); and multiple common but low penetrance susceptibility alleles identified by GWAS. Identifying genetic risk alleles for ovarian cancer has had a significant impact on disease prevention strategies; for example it is now routine clinical practice for individuals with germline BRCA1 and BRCA2 mutations to undergo risk reducing salpingo-oophorectomy. Because ovarian cancers are commonly diagnosed at a late clinical stage when the prognosis is poor, the continued development of genetic risk prediction and prevention strategies will represent an important approach to reduce mortality due to ovarian cancer. Advances in genomics technologies that enable more high-throughput genetic testing, combined with research studies that identify additional EOC risk alleles will likely provide further opportunities to establish polygenic risk prediction approaches, based on combinations of rare high/moderate penetrance susceptibility genes and common, low penetrance susceptibility alleles. This article reviews the current literature describing the genetic and epidemiological components of ovarian cancer risk, and discusses both the opportunities and challenges in using this information for clinical risk prediction and prevention.


Assuntos
Neoplasias Epiteliais e Glandulares/epidemiologia , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Carcinoma Epitelial do Ovário , Feminino , Predisposição Genética para Doença , Humanos
8.
Fertil Steril ; 106(1): 25-32, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27179787

RESUMO

The field of the genetics of polycystic ovary syndrome (PCOS) has relatively recently moved into the era of genome-wide association studies. This has led to the discovery of 16 robust loci for PCOS. Some loci contain genes with clear roles in reproductive (LHCGR, FSHR, and FSHB) and metabolic (INSR and HMGA2) dysfunction in the syndrome. The next challenge facing the field is the identification of causal variants and genes and the role they play in PCOS pathophysiology. The potential for gene discovery to improve diagnosis and treatment of PCOS is promising, though there is much to be done in the field before the current findings can be translated to the clinic.


Assuntos
Variação Genética , Síndrome do Ovário Policístico/genética , Reprodução/genética , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hereditariedade , Humanos , Fenótipo , Síndrome do Ovário Policístico/diagnóstico , Síndrome do Ovário Policístico/epidemiologia , Síndrome do Ovário Policístico/fisiopatologia , Saúde Reprodutiva , Fatores de Risco
9.
Fertil Steril ; 105(2): 467-73.e4, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26493122

RESUMO

OBJECTIVE: To evaluate genes involved in androgen receptor (AR) signaling as candidate genes for polycystic ovary syndrome (PCOS). DESIGN: Two groups of women with PCOS and control women (discovery and replication cohorts), were genotyped for single-nucleotide polymorphisms (SNPs) in eight genes for AR chaperones and co-chaperones: HSPA1A, HSPA8, ST13, STIP1, PTGES3, FKBP4, BAG1, and STUB1. Single-nucleotide polymorphisms were tested for association with PCOS status and with androgenic and metabolic parameters. SETTING: Tertiary referral center. PATIENT(S): Discovery cohort: 354 women with PCOS and 161 control women. Replication cohort: 397 women with PCOS and 306 control women. INTERVENTION(S): Phenotypic and genotypic assessment. MAIN OUTCOME MEASURE(S): Single-nucleotide polymorphism genotypes, association with PCOS status, and androgenic and metabolic parameters. RESULT(S): In the discovery cohort, FKBP4 SNPs rs2968909 and rs4409904 were associated with lower odds of PCOS. This finding was not confirmed in the replication cohort analysis; however, when combining the two cohorts, rs4409904 was associated with lower odds of PCOS. In subjects with PCOS in the replication cohort as well as in the combined cohort, rs2968909 was associated with lower body mass index. CONCLUSION(S): Single-nucleotide polymorphisms in FKBP4, which codes for the AR co-chaperone FKBP52, may be associated with PCOS and body mass index in patients with PCOS. The remaining genes studied do not seem to be major contributors to the development of PCOS. These findings warrant confirmation in future studies, and genes encoding other androgen pathway components remain to be studied.


Assuntos
Androgênios/metabolismo , Síndrome do Ovário Policístico/genética , Polimorfismo de Nucleotídeo Único , Transdução de Sinais/genética , Proteínas de Ligação a Tacrolimo/genética , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Síndrome do Ovário Policístico/diagnóstico , Síndrome do Ovário Policístico/metabolismo , Fatores de Proteção , Fatores de Risco , Centros de Atenção Terciária , Adulto Jovem
10.
PLoS Genet ; 11(8): e1005455, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26305227

RESUMO

Genome wide association studies (GWAS) have revealed 11 independent risk loci for polycystic ovary syndrome (PCOS), a common disorder in young women characterized by androgen excess and oligomenorrhea. To put these risk loci and the single nucleotide polymorphisms (SNPs) therein into functional context, we measured DNA methylation and gene expression in subcutaneous adipose tissue biopsies to identify PCOS-specific alterations. Two genes from the LHCGR region, STON1-GTF2A1L and LHCGR, were overexpressed in PCOS. In analysis stratified by obesity, LHCGR was overexpressed only in non-obese PCOS women. Although not differentially expressed in the entire PCOS group, INSR was underexpressed in obese PCOS subjects only. Alterations in gene expression in the LHCGR, RAB5B and INSR regions suggest that SNPs in these loci may be functional and could affect gene expression directly or indirectly via epigenetic alterations. We identified reduced methylation in the LHCGR locus and increased methylation in the INSR locus, changes that are concordant with the altered gene expression profiles. Complex patterns of meQTL and eQTL were identified in these loci, suggesting that local genetic variation plays an important role in gene regulation. We propose that non-obese PCOS women possess significant alterations in LH receptor expression, which drives excess androgen secretion from the ovary. Alternatively, obese women with PCOS possess alterations in insulin receptor expression, with underexpression in metabolic tissues and overexpression in the ovary, resulting in peripheral insulin resistance and excess ovarian androgen production. These studies provide a genetic and molecular basis for the reported clinical heterogeneity of PCOS.


Assuntos
Metilação de DNA , Síndrome do Ovário Policístico/genética , Adulto , Estudos de Casos e Controles , Ilhas de CpG , Epigênese Genética , Feminino , Heterogeneidade Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Síndrome do Ovário Policístico/metabolismo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Gordura Subcutânea , Biologia de Sistemas , Transcriptoma
11.
J Clin Transl Endocrinol ; 2(3): 99-104, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26236647

RESUMO

OBJECTIVE: Insulin resistance is a common feature of polycystic ovary syndrome (PCOS). The insulin signaling pathway consists of two major pathways, the metabolic and the mitogenic cascades. The many components of these pathways have not been comprehensively analyzed for differential expression in insulin-responsive tissues in PCOS. The goal of this study was to determine whether the core elements of the insulin signal transduction cascade were differentially expressed in subcutaneous adipose tissue (SAT) between PCOS and controls. MATERIALS/METHODS: Quantitative real-time PCR for 36 insulin signaling pathway genes was performed subcutaneous adipose tissue from 22 white PCOS and 13 healthy controls. RESULTS: Genes in the insulin signaling pathway were not differentially expressed in subcutaneous adipose tissue between PCOS and controls (P>0.05 for all). Components mainly of the mitogenic pathway were correlated with both androgens and metabolic phenotypes. Expression levels of five genes (MKNK1, HRAS, NRAS, KRAS, and GSK3A) were positively correlated with total testosterone level (ρ>0, P<0.05). Inverse correlation was found between expression of six genes (HRAS, MAP2K2, NRAS, MAPK3, GRB2, and SHC1) and metabolic traits (body mass index, fasting glucose, fasting insulin, and HOMA-IR) (ρ<0, P<0.05). CONCLUSIONS: Differential expression of core insulin signaling pathway components in subcutaneous adipose tissue is not a major contributor to the pathogenesis of PCOS. Correlation between clinical phenotypes and expression of several genes in the mitogenic limb of the insulin signaling pathway suggests mitogenic signaling by insulin may regulate steroidogenesis and glucose homeostasis.

12.
J Clin Endocrinol Metab ; 100(1): E182-6, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25303487

RESUMO

CONTEXT: Two genome-wide association studies (GWAS) of polycystic ovary syndrome (PCOS) have identified 11 susceptibility loci in Chinese individuals. Some of the risk loci identified in Chinese cohorts, mostly from the first GWAS, have been replicated in Europeans. Replication of the loci from the second GWAS in European cohorts is necessary to determine whether the same variants confer risk for PCOS in multiple ethnicities. OBJECTIVE: The objective of the study was to determine the effects of the Chinese GWAS loci in European-origin individuals. DESIGN: This was a genetic association study. SETTING: The study was conducted at a tertiary care academic center. PATIENTS: Eight hundred forty-five European subjects with PCOS and 845 controls participated in the study. INTERVENTIONS: INTERVENTIONS included blood sampling and genotyping. MAIN OUTCOME MEASURE: The association between PCOS and 12 independent single-nucleotide polymorphisms mapping to seven of the Chinese GWAS loci in a European cohort was measured. RESULTS: Variants in DENND1A (P = .0002), THADA (P = .035), FSHR (P = .007), and INSR (P = .046) were associated with PCOS in Europeans. The genetic risk score, generated for each subject based on the total number of risk alleles, was associated with the diagnosis of PCOS (P < .0001) and remained associated (P = .02), even after exclusion of the four variants individually associated with PCOS. CONCLUSIONS: At least four of the PCOS susceptibility loci identified in the Chinese GWAS are associated with PCOS in Europeans. The overall genetic burden for PCOS, as demonstrated by the risk score, is also associated with the diagnosis of PCOS in Europeans. The PCOS susceptibility loci identified in the Chinese GWAS are thus likely to play an important role in the etiology of PCOS across ethnicities.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Síndrome do Ovário Policístico/genética , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Antígenos CD/genética , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/genética , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Proteínas de Neoplasias/genética , Receptor de Insulina/genética , Receptores do FSH/genética
13.
J Clin Endocrinol Metab ; 97(9): E1750-7, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22723319

RESUMO

CONTEXT: Polycystic ovary syndrome (PCOS) is a heterogeneous common genetic disorder characterized by hyperandrogenemia and insulin resistance. Alterations in gene expression profiles of the ovary and adipose tissue identified the candidate gene FBJ murine osteosarcoma viral oncogene homolog (FOS) for further investigation of expression changes in metabolic tissues and genetic studies. OBJECTIVE: The objective of the study was to confirm the underexpression of the FOS gene in sc adipose and determine whether variants in this gene are risk factors for PCOS. DESIGN: RT-PCR was performed in sc fat from women with and without PCOS. Genotyping of single-nucleotide polymorphisms in the FOS locus was performed to test for association with PCOS. SETTING: The study was conducted at a tertiary care academic institution. PARTICIPANTS: Twenty-two PCOS and 13 control subjects were recruited for gene expression studies. We assembled a discovery genotyping cohort of 354 cases and 161 controls and a replication cohort of 476 cases and 315 controls, all of whom were Caucasian. MAIN MEASUREMENTS: Gene expression by quantitative real-time RT-PCR, FOS genotype, and PCOS status were measured. RESULTS: FOS expression was confirmed to be reduced in PCOS adipose tissue. Three single-nucleotide polymorphisms were significantly associated with PCOS in the discovery cohort (rs8006998, P = 0.0031; rs8013918, P = 0.0006; rs8013942, P = 0.0087). rs8006998 was also associated with PCOS in the replication cohort (P = 0.013). CONCLUSIONS: Differential gene expression in sc fat and genetic association at the FOS locus in PCOS subjects implicates a role for this transcription factor in PCOS. FOS dysfunction may be a common factor between hyperandrogenism and insulin resistance.


Assuntos
Genes fos/genética , Predisposição Genética para Doença/genética , Síndrome do Ovário Policístico/genética , Tecido Adiposo/metabolismo , Adulto , Western Blotting , Índice de Massa Corporal , Estudos de Coortes , DNA/biossíntese , DNA/genética , Replicação do DNA , Feminino , Expressão Gênica/genética , Expressão Gênica/fisiologia , Estudos de Associação Genética , Genótipo , Humanos , Resistência à Insulina/genética , Desequilíbrio de Ligação , Síndrome do Ovário Policístico/epidemiologia , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Gordura Subcutânea/metabolismo
14.
PLoS Genet ; 8(3): e1002559, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22412388

RESUMO

Crohn's disease (CD) is a complex disorder resulting from the interaction of intestinal microbiota with the host immune system in genetically susceptible individuals. The largest meta-analysis of genome-wide association to date identified 71 CD-susceptibility loci in individuals of European ancestry. An important epidemiological feature of CD is that it is 2-4 times more prevalent among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Europeans (NJ). To explore genetic variation associated with CD in AJs, we conducted a genome-wide association study (GWAS) by combining raw genotype data across 10 AJ cohorts consisting of 907 cases and 2,345 controls in the discovery stage, followed up by a replication study in 971 cases and 2,124 controls. We confirmed genome-wide significant associations of 9 known CD loci in AJs and replicated 3 additional loci with strong signal (p<5×10⁻6). Novel signals detected among AJs were mapped to chromosomes 5q21.1 (rs7705924, combined p = 2×10⁻8; combined odds ratio OR = 1.48), 2p15 (rs6545946, p = 7×10⁻9; OR = 1.16), 8q21.11 (rs12677663, p = 2×10⁻8; OR = 1.15), 10q26.3 (rs10734105, p = 3×10⁻8; OR = 1.27), and 11q12.1 (rs11229030, p = 8×10⁻9; OR = 1.15), implicating biologically plausible candidate genes, including RPL7, CPAMD8, PRG2, and PRG3. In all, the 16 replicated and newly discovered loci, in addition to the three coding NOD2 variants, accounted for 11.2% of the total genetic variance for CD risk in the AJ population. This study demonstrates the complementary value of genetic studies in the Ashkenazim.


Assuntos
Doença de Crohn/genética , Estudo de Associação Genômica Ampla , Judeus/genética , Cromossomos Humanos Par 5/genética , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação
15.
J Med Genet ; 49(2): 90-5, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22180642

RESUMO

BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with a strong familial component. PCOS is characterised by hyperandrogenaemia and irregular menses. A recent genome-wide association study (GWAS) of PCOS in a Chinese cohort identified three reproducible PCOS susceptibility loci mapping to 2p16.3 (luteinising hormone/choriogonadotropin receptor; LHCGR), 2p21 (thyroid associated protein; THADA), and 9q33.3 (DENN/MADD domain containing 1A; DENNDIA). The impact of these loci in non-Chinese PCOS cohorts remains to be determined. METHODS AND RESULTS: The study tested association with PCOS of seven single nucleotide polymorphisms mapping to the three Chinese PCOS loci in two European derived PCOS cohorts (cohort A = 939 cases and 957 controls; cohort B = 535 cases and 845 controls). Cases fulfilled the National Institute of Child Health & Human Development criteria for PCOS. Variation in DENND1A was strongly associated with PCOS in the study cohort (p(combined cohorts)=10(-8)); multiple variants in THADA were also associated with PCOS, while there was no significant evidence for association of LHCGR variation with PCOS. The present study had >80% power to detect an effect of similar size as was observed by Chen et al for DENND1A and THADA, but reduced power (at <40%) for LHCGR at p=0.0001. The study had sufficient power (57-88%) for LHCGR at p=0.01. CONCLUSIONS: At least two of the PCOS susceptibility loci identified in the Chinese PCOS GWAS (DENND1A and THADA) are also associated with PCOS in European derived populations, and are therefore likely to be important in the aetiology of PCOS regardless of ethnicity. The analysis of the LHCGR gene was not sufficiently powered to detect modest effects.


Assuntos
Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/genética , Proteínas de Neoplasias/genética , Síndrome do Ovário Policístico/genética , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Fatores de Troca do Nucleotídeo Guanina , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
16.
Steroids ; 77(4): 317-22, 2012 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-22178785

RESUMO

The role of metabolic disturbance in polycystic ovary syndrome (PCOS) has been well established, with insulin resistance and the resulting compensatory hyperinsulinemia thought to promote hyperandrogenemia. Genome-wide association studies (GWAS) have established a large number of loci for metabolic conditions such as type 2 diabetes and obesity. A subset of these loci has been investigated for a role in PCOS; these studies generally have not revealed a confirmed role for these loci in PCOS risk. However, a large scale investigation of genes related to these pathways has not previously been performed. We conducted a two stage case control association study of 121,715 single nucleotide polymorphisms (SNPs) selected to represent susceptibility loci associated with traits such as type 2 diabetes, obesity measures, lipid levels and cardiovascular function using the Cardio-Metabochip in 847 PCOS cases and 845 controls. Several hypothesis-generating associations with PCOS were observed (top SNP rs2129107, P=3.8×10(-6)). We did not find any loci definitively associated with PCOS after strict correction for multiple testing, suggesting that cardio-metabolic loci are not major risk factors underlying the susceptibility to PCOS.


Assuntos
Sistema Cardiovascular/metabolismo , Estudo de Associação Genômica Ampla , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/metabolismo , Adulto , Estatura/genética , Sistema Cardiovascular/fisiopatologia , Estudos de Coortes , Complicações do Diabetes/sangue , Complicações do Diabetes/genética , Complicações do Diabetes/metabolismo , Complicações do Diabetes/fisiopatologia , Feminino , Loci Gênicos/genética , Humanos , Contagem de Leucócitos , Metabolismo dos Lipídeos/genética , Pessoa de Meia-Idade , Contagem de Plaquetas , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/fisiopatologia , Polimorfismo de Nucleotídeo Único/genética
17.
PLoS One ; 6(5): e20120, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21611153

RESUMO

Novel pathways in polycystic ovary syndrome (PCOS) are being identified in gene expression studies in PCOS tissues; such pathways may contain key genes in disease etiology. Previous expression studies identified both dickkopf homolog 1 (DKK1) and DnaJ (Hsp40) homolog, subfamily B, member 1 (DNAJB1) as differentially expressed in PCOS tissue, implicating them as candidates for PCOS susceptibility. To test this, we genotyped a discovery cohort of 335 PCOS cases and 198 healthy controls for three DKK1 single nucleotide polymorphisms (SNPs) and four DNAJB1 SNPs and a replication cohort of 396 PCOS cases and 306 healthy controls for 1 DKK1 SNP and 1 DNAJB1 SNP. SNPs and haplotypes were determined and tested for association with PCOS and component phenotypes. We found that no single nucleotide polymorphisms were associated with PCOS risk; however, the major allele of rs1569198 from DKK1 was associated with increased total testosterone (discovery cohort P = 0.0035) and dehydroepiandrosterone sulfate (replication cohort P = 0.05). Minor allele carriers at rs3962158 from DNAJB1 had increased fasting insulin (discovery cohort P = 0.003), increased HOMA-IR (discovery cohort P = 0.006; replication cohort P = 0.036), and increased HOMA-%B (discovery cohort P = 0.004). Carriers of haplotype 2 at DNAJB1 also had increased fasting insulin, HOMA-IR, and HOMA-%B. These findings suggest that genetic variation in DKK1 and DNAJB1 may have a role in the hyperandrogenic and metabolic dysfunction of PCOS, respectively. Our results also demonstrate the utility of gene expression data as a source of novel candidate genes in PCOS, a complex and still incompletely defined disease, for which alternative methods of gene identification are needed.


Assuntos
Bases de Dados Genéticas , Regulação da Expressão Gênica , Estudos de Associação Genética/métodos , Síndrome do Ovário Policístico/genética , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Proteínas de Choque Térmico HSP40/genética , Haplótipos/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Desequilíbrio de Ligação/genética , Polimorfismo de Nucleotídeo Único/genética , Reprodutibilidade dos Testes
18.
Fertil Steril ; 95(8): 2538-41.e1-6, 2011 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-21444075

RESUMO

Two cohorts of women with polycystic ovary syndrome (PCOS), comprising 400 probands and affected sisters in 365 families and a case-control group including 395 women with PCOS and 171 healthy women with regular menstrual cycles, were studied to determine whether single-nucleotide polymorphisms (SNPs) identified as susceptibility loci in genomewide association studies of type 2 diabetes are also associated with PCOS. None of the 18 allelic variants in 10 genes previously shown to be associated with type 2 diabetes were found to be associated with PCOS, but some were associated with indices of beta cell function.


Assuntos
Diabetes Mellitus Tipo 2/genética , Síndrome do Ovário Policístico/genética , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Células Secretoras de Insulina/metabolismo , Desequilíbrio de Ligação , Fenótipo , Síndrome do Ovário Policístico/metabolismo , Medição de Risco , Fatores de Risco , Estados Unidos
19.
Fertil Steril ; 95(5): 1736-41.e1-11, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21300347

RESUMO

OBJECTIVE: To evaluate association with polycystic ovary syndrome (PCOS) of 295 variants in 39 genes central to metabolic insulin signaling and glycogen synthase kinase 3ß (GSK-3ß) regulation, followed by replication efforts. DESIGN: Case-control association study, with discovery and replication cohorts. SETTING: Subjects were recruited from reproductive endocrinology clinics, and controls were recruited from communities surrounding the University of Alabama at Birmingham and Erasmus Medical Center, Rotterdam. PATIENT(S): A total of 273 cases with PCOS and 173 control subjects in the discovery cohort; and 526 cases and 3,585 control subjects in the replication cohort. All subjects were caucasian. INTERVENTION(S): Phenotypic and genotypic assessment. MAIN OUTCOME MEASURE(S): Detection of 295 single-nucleotide polymorphisms (SNPs), PCOS status. RESULT(S): Several SNPs were associated with PCOS in the discovery cohort. Four insulin receptor (INSR) SNPs and three insulin receptor substrate 2 (IRS2) SNPs associated with PCOS were genotyped in the replication cohort. One INSR SNP (rs2252673) replicated association with PCOS. The minor allele conferred increased odds of PCOS in both cohorts, independent of body mass index. CONCLUSION(S): A pathway-based tagging SNP approach allowed us to identify novel INSR SNPs associated with PCOS, one of which confirmed association in a large replication cohort.


Assuntos
Síndrome do Ovário Policístico/genética , Polimorfismo de Nucleotídeo Único , Receptor de Insulina/genética , Adolescente , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Pessoa de Meia-Idade , Modelos Biológicos , Síndrome do Ovário Policístico/metabolismo , Polimorfismo de Nucleotídeo Único/fisiologia , Receptor de Insulina/metabolismo , Reprodutibilidade dos Testes , Adulto Jovem
20.
PLoS One ; 6(1): e16390, 2011 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-21283731

RESUMO

Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility in women. It is also associated with metabolic disturbances that place women at increased risk for obesity and type 2 diabetes. There is strong evidence for familial clustering of PCOS and a genetic predisposition. However, the gene(s) responsible for the PCOS phenotypes have not been elucidated. This two-phase family-based and case-control genetic study was designed to address the question of whether SNPs identified as susceptibility loci for obesity in genome-wide association studies (GWAS) are also associated with PCOS and elevated BMI. Members of 439 families having at least one offspring with PCOS were genotyped for 15 SNPs previously shown to be associated with obesity. Linkage and association with PCOS was assessed using the transmission/disequilibrium test (TDT). These SNPs were also analyzed in an independent case-control study involving 395 women with PCOS and 176 healthy women with regular menstrual cycles. Only one of these 15 SNPs (rs2815752 in NEGR1) was found to have a nominally significant association with PCOS (χ(2) = 6.11, P = 0.013), but this association failed to replicate in the case-control study. While not associated with PCOS itself, five SNPs in FTO and two in MC4R were associated with BMI as assessed with a quantitative-TDT analysis, several of which replicated association with BMI in the case-control cohort. These findings demonstrate that certain SNPs associated with obesity contribute to elevated BMI in PCOS, but do not appear to play a major role in PCOS per se. These findings support the notion that PCOS phenotypes are a consequence of an oligogenic/polygenic mechanism.


Assuntos
Obesidade/genética , Síndrome do Ovário Policístico/genética , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Receptor Tipo 4 de Melanocortina/genética , Adulto , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Índice de Massa Corporal , Estudos de Casos e Controles , Família , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Adulto Jovem
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