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1.
J Periodontal Res ; 55(1): 32-40, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31292966

RESUMO

OBJECTIVE: The purpose of this study was to investigate involvement of the P2X7 receptor in the rare condition, localized aggressive periodontitis. MATERIAL AND METHODS: Peripheral blood from 220 African Americans (103 with localized aggressive periodontitis and 117 healthy unrelated controls) was stimulated with lipopolysaccharide from E coli and Porphyromonas gingivalis. P2RX7 single nucleotide polymorphisms rs208294 (H155Y), rs1718119 (T348A), rs2230911 (T357S) and rs3751143 (E496A) were genotyped in 103 localized aggressive periodontitis patients and 117 healthy unrelated subjects. We examined genetic association between four P2RX7 single nucleotide polymorphisms and localized aggressive periodontitis, and tested for correlations between the single nucleotide polymorphisms and inflammatory response to lipopolysaccharide in blood samples from these patients. RESULTS: A significant association with localized aggressive periodontitis was observed with rs1718119 A (Thr) allele (P = 0.0063, odds ratio = 1.904) and with a haplotype containing this allele (P = 0.0075). Additionally, significant correlations with these data were found: the rs1718119 G allele correlated with greater production of IL-6, IL-2 and GM-CSF; the C (His) allele of rs208294 correlated with lower levels of IL-12p40; and the C (Thr) allele of rs2230911 correlated with greater levels of G-CSF. CONCLUSION: The data from these analyses support a possible biological relationship between P2RX7 genetic variants and inflammatory response in localized aggressive periodontitis patients.

2.
Acta Neuropathol ; 139(1): 157-174, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31664505

RESUMO

In Neurofibromatosis type 1, NF1 gene mutations in Schwann cells (SC) drive benign plexiform neurofibroma (PNF), and no additional SC changes explain patient-to-patient variability in tumor number. Evidence from twin studies suggests that variable expressivity might be caused by unidentified modifier genes. Whole exome sequencing of SC and fibroblast DNA from the same resected PNFs confirmed biallelic SC NF1 mutations; non-NF1 somatic SC variants were variable and present at low read number. We identified frequent germline variants as possible neurofibroma modifier genes. Genes harboring variants were validated in two additional cohorts of NF1 patients and by variant burden test. Genes including CUBN, CELSR2, COL14A1, ATR and ATM also showed decreased gene expression in some neurofibromas. ATM-relevant DNA repair defects were also present in a subset of neurofibromas with ATM variants, and in some neurofibroma SC. Heterozygous ATM G2023R or homozygous S707P variants reduced ATM protein expression in heterologous cells. In mice, genetic Atm heterozygosity promoted Schwann cell precursor self-renewal and increased tumor formation in vivo, suggesting that ATM variants contribute to neurofibroma initiation. We identify germline variants, rare in the general population, overrepresented in NF1 patients with neurofibromas. ATM and other identified genes are candidate modifiers of PNF pathogenesis.

3.
Pharmacogenomics J ; 2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31806881

RESUMO

Genetic polymorphisms have been shown to affect opioid requirement for pain relief. However, true genetic effect is often difficult to assess due to underlying pain conditions and placebo effects. The goal of this study was to understand how common polymorphisms affect opioid effects while controlling for these factors. A randomized, double-blind, placebo-controlled study was implemented to assess how opioid effects are modulated by COMT (rs6269, rs4633, rs4848, rs4680), OPRM1 (A118G), and OPRK1 (rs1051660, rs702764, rs16918875). One hundred and eight healthy subjects underwent experimental pain testing before and after morphine, butorphanol, and placebo (saline). Association analysis was performed between polymorphisms/haplotypes and opioid response, while correcting for race, gender, placebo effects, and multiple comparisons. Pressure pain was significantly associated with rs6269 and rs4633 following butorphanol. The AA genotype of rs4680 or A_T_C_A/ A_T_C_A (rs6269_rs4633_ rs4818_rs4680) diplotype of COMT, combined with the AG genotype of OPRM1 A118G, showed significantly increased pressure pain threshold from butorphanol. Opioid effects on pressure, ischemic, heat pain, and side effects were nominally associated with several SNPs and haplotypes. Effects were often present in one opioid but not the other. This indicates that these polymorphisms affect pain relief from opioids, and that their effects are opioid and pain modality specific.

4.
Pain ; 160(11): 2473-2486, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31246731

RESUMO

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder resulting from germline mutations in the NF1 gene, which encodes neurofibromin. Patients experience a variety of symptoms, but pain in the context of NF1 remains largely underrecognized. Here, we characterize nociceptive signaling and pain behaviors in a miniswine harboring a disruptive NF1 mutation (exon 42 deletion). We present the first characterization of pain-related behaviors in a pig model of NF1, identifying unchanged agitation scores, lower tactile thresholds (allodynia), and decreased response latencies to thermal laser stimulation (hyperalgesia) in NF1 (females only) pigs. Male NF1 pigs with tumors showed reduced sleep quality and increased resting, 2 health-related quality-of-life symptoms found to be comorbid in people with NF1 pain. We explore these phenotypes in relationship to suppression of the increased activity of the N-type voltage-gated calcium (CaV2.2) channel by pharmacological antagonism of phosphorylation of a regulatory protein-the collapsin response mediator protein 2 (CRMP2), a known interactor of neurofibromin, and by targeting the interface between the α subunit of CaV2.2 and the accessory ß-subunits with small molecules. Our data support the use of NF1 pigs as a large animal model for studying NF1-associated pain and for understanding the pathophysiology of NF1. Our findings demonstrate the translational potential of 2 small molecules in reversing ion channel remodeling seen in NF1. Interfering with CaV2.2, a clinically validated target for pain management, might also be a promising therapeutic strategy for NF1-related pain management.

5.
Proc Natl Acad Sci U S A ; 116(13): 6075-6080, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30867289

RESUMO

Genetic mutations affecting chromatin modifiers are widespread in cancers. In malignant peripheral nerve sheath tumors (MPNSTs), Polycomb repressive complex 2 (PRC2), which plays a crucial role in gene silencing, is inactivated through recurrent mutations in core subunits embryonic ectoderm development (EED) and suppressor of zeste 12 homolog (SUZ12), but mutations in PRC2's main catalytic subunit enhancer of zeste homolog 2 (EZH2) have never been found. This is in contrast to myeloid and lymphoid malignancies, which harbor frequent loss-of-function mutations in EZH2. Here, we investigated whether the absence of EZH2 mutations in MPNST is due to a PRC2-independent (i.e., noncanonical) function of the enzyme or to redundancy with EZH1. We show that, in the absence of SUZ12, EZH2 remains bound to EED but loses its interaction with all other core and accessory PRC2 subunits. Through genetic and pharmacological analyses, we unambiguously establish that EZH2 is functionally inert in this context, thereby excluding a PRC2-independent function. Instead, we show that EZH1 and EZH2 are functionally redundant in the slowly proliferating MPNST precursors. We provide evidence that the compensatory function of EZH1 is alleviated upon higher proliferation. This work reveals how context-dependent redundancies can shape tumor-type specific mutation patterns in chromatin regulators.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Neoplasias/metabolismo , Complexo Repressor Polycomb 2/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Cromatina/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação/genética , Neoplasias/genética , Neurofibroma/genética , Neurofibroma/metabolismo , Complexo Repressor Polycomb 2/genética
6.
Neuro Oncol ; 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30722027

RESUMO

Background: Neurofibromatosis type 1 (NF1) is a tumor-predisposition disorder caused by germline mutations in NF1. NF1 patients have an 8-16% lifetime risk of developing a malignant peripheral nerve sheath tumor (MPNST), a highly-aggressive soft-tissue sarcoma, often arising from pre-existing benign plexiform neurofibromas (PN) and atypical neurofibromas (ANF). ANF are distinct from both PN and MPNST, representing an intermediate step in malignant transformation. Methods: In the first comprehensive genomic analysis of ANF originating from multiple patients, we performed tumor/normal whole-exome sequencing (WES) of 16 ANFs. In addition, we conducted WES of three MPNSTs, copy-number meta-analysis of 26 ANFs and 28 MPNSTs, and whole transcriptome sequencing analysis of five ANFs and five MPNSTs. Results: We identified a low number of mutations (median 1, range 0-5) in the exomes of ANFs (only NF1 somatic mutations were recurrent), and frequent deletions of CDKN2A/B (69%) and SMARCA2 (42%). We determined that polycomb repressor complex 2 (PRC2) genes EED or SUZ12 were frequently mutated, deleted or downregulated in MPNSTs but not in ANFs. Our pilot gene expression study revealed upregulated NRAS, MDM2, CCND1/2/3 and CDK4/6 in ANFs and MPNSTs, and overexpression of EZH2 in MPNSTs only. Conclusions: The PN-ANF transition is primarily driven by the deletion of CDKN2A/B. Further progression from ANF to MPNST likely involves broad chromosomal rearrangements and frequent inactivation of the PRC2 genes, loss of the DNA repair genes, and copy-number increase of signal transduction, cell cycle and pluripotency self-renewal genes.

7.
J Pain Res ; 11: 2497-2508, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30425562

RESUMO

Background: We investigated interactions between genetic and psychological factors in predicting shoulder impairment phenotypes. We hypothesized that pro-inflammatory genes would display stronger relationships compared with pain-related genes when combined with psychological factors for predicting phenotypic changes. Subjects and methods: Altogether, 190 participants completed a 5-day experimental protocol. An experimental shoulder injury model was used to induce physical impairment, and a priori selected genetic (pain-related, pro-inflammatory) and psychological (anxiety, depressive symptoms, pain catastrophizing, fear of pain, kinesiophobia) factors were included as predictors of interest. Impairment phenotypes were injury-induced deficits in range of motion (ROM) and strength. After controlling for age, sex, and race, genetic and psychological predictors were entered separately as main effects and interaction terms in regression models for each phenotype. Results: Strong statistical evidence was provided for interactions between: 1) IL-1ß (rs1143634) and fear of pain for predicting loss of shoulder flexion and abduction, 2) IL-1ß (rs1143634) and anxiety for predicting loss of flexion, and 3) IL-1ß (rs1143634) and depressive symptoms for predicting loss of internal rotation. In addition, the interaction between OPRM1 (rs1799971) and fear of pain as well as COMT (rs4818) and pain catastrophizing provided strong statistical evidence for predicting strength loss. Conclusion: Pro-inflammatory gene variants contributed more to physical impairment with two single nucleotide polymorphisms (SNPs; IL-1ß [rs1143634] and TNF/LTA [rs2229094]) interacting with psychological factors to predict six shoulder impairment phenotypes. In comparison, two pain-related gene SNPs (OPRM1 [rs1799971] and COMT [rs4818]) interacted with psychological factors to predict four shoulder impairment phenotypes (abduction: 5-day average loss; strength loss: 5-day average, peak, and relative loss).

8.
Sci Data ; 5: 180106, 2018 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-29893754

RESUMO

Neurofibromatosis type I (NF1) is an autosomal dominant genetic condition characterized by peripheral nervous system tumors (PNSTs), including plexiform neurofibromas (pNFs) that cause nerve dysfunction, deformity, pain damage to adjacent structures, and can undergo malignant transformation. There are no effective therapies to prevent or treat pNFs. Drug discovery efforts are slowed by the 'benign' nature of the Schwann cells that are the progenitor cells of pNF. In this work we characterize a set of pNF-derived cell lines at the genomic level (via SNP Arrays, RNAseq, and Whole Exome- Sequencing), and carry out dose response-based quantitative high-throughput screening (qHTS) with a collection of 1,912 oncology-focused compounds in a 1536-well microplate cell proliferation assays. Through the characterization and screening of NF1-/-, NF1+/+ and NF1+/- Schwann cell lines, this resource introduces novel therapeutic avenues for the development for NF1 associated pNF as well as all solid tumors with NF1 somatic mutations. The integrated data sets are openly available for further analysis at http://www.synapse.org/pnfCellCulture.


Assuntos
Perfilação da Expressão Gênica , Neurofibromatose 1 , Células de Schwann , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Humanos , Neurofibroma Plexiforme/genética , Neurofibroma Plexiforme/patologia , Neurofibroma Plexiforme/terapia , Neurofibromatose 1/genética , Neurofibromatose 1/patologia , Neurofibromatose 1/terapia
9.
Oncotarget ; 9(32): 22571-22585, 2018 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-29854299

RESUMO

Malignant peripheral nerve sheath tumor (MPNST) is a type of soft-tissue sarcoma strongly associated with dysfunction in neurofibromin; an inhibitor of the RAS pathway. We performed high-throughput screening of an array of FDA approved and promising agents in clinical development both alone and in combination at physiologically achievable concentrations against a panel of established MPNST cell line models. We found that drugs targeting a variety of factors in the RAS pathway can effectively lead to cell death in vitro with considerable drug combination synergy in regimens that target MEK or mTOR. We observed that the degree of relative sensitivity to chemotherapeutic agents was associated with the status of neurofibromin in these cell line models. Using a combination of agents that target MEK and mTORC1/2, we effectively silenced RAS/PI3K/MEK/mTOR signaling in vitro. Moreover, we employed RNAi against NF1 to establish that MPNST drug sensitivity is directly proportional to relative level of intracellular neurofibromin. Thus, two-drug combinations that target MEK and mTORC1/2 are most effective in halting the RAS signaling cascade, and the relative success of this and related small molecule interventions in MPNSTs may be predicated upon the molecular status of neurofibromin.

10.
JCI Insight ; 3(12)2018 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-29925695

RESUMO

Loss of the NF1 tumor suppressor gene causes the autosomal dominant condition, neurofibromatosis type 1 (NF1). Children and adults with NF1 suffer from pathologies including benign and malignant tumors to cognitive deficits, seizures, growth abnormalities, and peripheral neuropathies. NF1 encodes neurofibromin, a Ras-GTPase activating protein, and NF1 mutations result in hyperactivated Ras signaling in patients. Existing NF1 mutant mice mimic individual aspects of NF1, but none comprehensively models the disease. We describe a potentially novel Yucatan miniswine model bearing a heterozygotic mutation in NF1 (exon 42 deletion) orthologous to a mutation found in NF1 patients. NF1+/ex42del miniswine phenocopy the wide range of manifestations seen in NF1 patients, including café au lait spots, neurofibromas, axillary freckling, and neurological defects in learning and memory. Molecular analyses verified reduced neurofibromin expression in swine NF1+/ex42del fibroblasts, as well as hyperactivation of Ras, as measured by increased expression of its downstream effectors, phosphorylated ERK1/2, SIAH, and the checkpoint regulators p53 and p21. Consistent with altered pain signaling in NF1, dysregulation of calcium and sodium channels was observed in dorsal root ganglia expressing mutant NF1. Thus, these NF1+/ex42del miniswine recapitulate the disease and provide a unique, much-needed tool to advance the study and treatment of NF1.


Assuntos
Modelos Animais de Doenças , Neurofibromatose 1 , Neurofibromina 1/metabolismo , Suínos , Animais , Manchas Café com Leite , Éxons/genética , Fibroblastos/metabolismo , Proteínas Ativadoras de GTPase/genética , Gânglios Espinais/metabolismo , Deleção de Genes , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Canais Iônicos , Aprendizagem , Masculino , Memória , Mutação , Neurofibroma , Neurofibromatose 1/genética , Neurofibromatose 1/patologia , Neurofibromina 1/genética , Neurofibromina 1/fisiologia , Transdução de Sinais
11.
Exp Neurol ; 299(Pt B): 289-298, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29055717

RESUMO

Plexiform neurofibromas (PNs), which may be present at birth in up to half of children with type 1 neurofibromatosis (NF1), can cause serious loss of function, such as quadriparesis, and can undergo malignant transformation. Surgery is the first line treatment although the invasive nature of these tumors often prevents complete resection. Recent clinical trials have shown promising success for some drugs, notably selumetinib, an inhibitor of MAP kinase kinase (MEK). We have developed three-dimensional (3D) cell culture models of immortalized cells from NF1 PNs and of control Schwann cells (SCs) that we believe mimic more closely the in vivo condition than conventional two-dimensional (2D) cell culture. Our goal is to facilitate pre-clinical identification of potential targeted therapeutics for these tumors. Three drugs, selumetinib (a MEK inhibitor), picropodophyllin (an IGF-1R inhibitor) and LDN-193189 (a BMP2 inhibitor) were tested with dose-response design in both 2D and 3D cultures for their abilities to block net cell growth. Cell lines grown in 3D conditions showed varying degrees of resistance to the inhibitory actions of all three drugs. For example, control SCs became resistant to growth inhibition by selumetinib in 3D culture. LDN-193189 was the most effective drug in 3D cultures, with only slightly reduced potency compared to the 2D cultures. Characterization of these models also demonstrated increased proteolysis of collagen IV in the matrix by the PN driver cells as compared to wild-type SCs. The proteolytic capacity of the PN cells in the model may be a clinically significant property that can be used for testing the ability of drugs to inhibit their invasive phenotype.


Assuntos
Antineoplásicos/farmacologia , Técnicas de Cultura de Células , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Neurofibroma Plexiforme/patologia , Benzimidazóis/farmacologia , Proteína Morfogenética Óssea 2/antagonistas & inibidores , Células Cultivadas , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Genes da Neurofibromatose 1 , Genes Reporter , Humanos , Proteínas Luminescentes/análise , Proteínas Luminescentes/genética , MAP Quinase Quinase 1/antagonistas & inibidores , Terapia de Alvo Molecular , Neurofibroma Plexiforme/tratamento farmacológico , Neurofibroma Plexiforme/genética , Neurofibromatose 1/patologia , Fenótipo , Podofilotoxina/análogos & derivados , Podofilotoxina/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Células de Schwann/citologia , Transdução Genética , Células Tumorais Cultivadas
12.
Mol Pain ; 13: 1744806917724259, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28741447

RESUMO

Abstract: Pain is one of the most prominent symptoms of osteoarthritis. However, there is often discordance between the pain experienced by individuals with osteoarthritis and the degree of articular pathology. This suggests that individual differences, including genetic variability in the central processing of nociceptive stimuli, may impact the presentation of osteoarthritis. Here, we show that the single nucleotide polymorphism rs16868943 in the collagen gene COL11A2 is significantly associated with lowered heat pain tolerance on the arm in participants with knee osteoarthritis (P = 1.21 × 10−6, P = 0.0053 after Bonferroni correction, beta = −3.42). A total of 161 knee osteoarthritis participants were included and evaluated for heat, punctate and pressure pain sensitivity of the affected knee and the ipsilateral arm. Each participant was genotyped for 4392 single nucleotide polymorphisms in genes implicated in pain perception, inflammation and mood and tested for association with pain sensitivity. The minor A allele of single nucleotide polymorphism rs16868943 was significantly associated with lower arm heat pain tolerance after correction for age, gender, race, and study site. This single nucleotide polymorphism was also nominally associated with other measures of heat pain sensitivity, including lowered knee heat pain tolerance (P = 1.14 × 10−5, P = 0.05 after Bonferroni correction), lowered arm heat pain threshold (P = 0.0039, uncorrected) and lowered knee heat pain threshold (P = 0.003, uncorrected). Addition of genotypes from 91 participants without knee pain produced a significant interaction between knee osteoarthritis status and the rs16868943 single nucleotide polymorphism in heat pain tolerance (P = 1.71 × 10−5), such that rs16868943 was not associated with heat pain tolerance in participants without knee pain (P = 0.12, beta = 1.3). This is the first study to show genetic association with heat pain tolerance in individuals with osteoarthritis. The association is specific to participants who have already developed knee osteoarthritis, suggesting that the COL11A2 gene, which has previously been associated with familial osteoarthritis, may play a role in pain sensitization after the development of osteoarthritis.


Assuntos
Colágeno Tipo XI/genética , Osteoartrite do Joelho/genética , Percepção da Dor/efeitos dos fármacos , Dor/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Feminino , Genótipo , Temperatura Alta , Humanos , Articulação do Joelho/metabolismo , Articulação do Joelho/fisiopatologia , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/diagnóstico , Medição da Dor/métodos
13.
Contemp Clin Trials ; 56: 9-17, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28315479

RESUMO

BACKGROUND: Chronic musculoskeletal pain conditions are a prevalent and disabling problem. Preventing chronic musculoskeletal pain requires multifactorial treatment approaches that address its complex etiology. Prior cohort studies identified a high risk subgroup comprised of variation in COMT genotype and pain catastrophizing. This subgroup had increased chance of heightened pain responses (in a pre-clinical model) and higher 12month post-operatives pain intensity ratings (in a clinical model). This pre-clinical trial will test mechanisms and efficacy of personalized pain interventions matched to the genetic and psychological characteristics of the high-risk subgroup. METHODS: Potential participants will be screened for high risk subgroup membership, appropriateness for exercise-induced muscle injury protocol, and appropriateness for propranolol administration. Eligible participants that consent to the study will then be randomized into one of four treatment groups; 1) personalized pharmaceutical and psychological education; 2) personalized pharmaceutical and general education; 3) placebo pharmaceutical and psychological education; 4) placebo pharmaceutical and psychological education. Over the 5-day study period participants will complete an exercise-induced muscle injury protocol and receive study interventions. Pain and disability assessments will be completed daily, with primary outcomes being duration of shoulder pain (number of days until recovery), peak shoulder pain intensity, and peak shoulder disability. Secondary outcomes include inflammatory markers, psychological mediators, and measures of pain sensitivity regulation. CONCLUSION: This pre-clinical trial builds on prior cohort studies and its completion will provide foundational data supporting efficacy and mechanisms of personalized interventions for individuals that may be at increased risk for developing chronic shoulder pain. TRIAL REGISTRATION: ClinicalTrials.gov registry, NCT02620579 (Registered on November 13, 2015).


Assuntos
Catastrofização/genética , Catastrofização/psicologia , Catecol O-Metiltransferase/genética , Dor de Ombro/psicologia , Dor de Ombro/terapia , Adolescente , Antagonistas Adrenérgicos beta/uso terapêutico , Adulto , Idoso , Dor Crônica/psicologia , Dor Crônica/terapia , Exercício Físico/fisiologia , Feminino , Genótipo , Humanos , Mediadores da Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Medição da Dor , Educação de Pacientes como Assunto/organização & administração , Propranolol/uso terapêutico , Psicoterapia/métodos , Projetos de Pesquisa , Fatores Sexuais , Lesões do Ombro/complicações , Dor de Ombro/etiologia , Adulto Jovem
14.
Nat Genet ; 48(11): 1418-1424, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27723757

RESUMO

Vitiligo is an autoimmune disease in which depigmented skin results from the destruction of melanocytes, with epidemiological association with other autoimmune diseases. In previous linkage and genome-wide association studies (GWAS1 and GWAS2), we identified 27 vitiligo susceptibility loci in patients of European ancestry. We carried out a third GWAS (GWAS3) in European-ancestry subjects, with augmented GWAS1 and GWAS2 controls, genome-wide imputation, and meta-analysis of all three GWAS, followed by an independent replication. The combined analyses, with 4,680 cases and 39,586 controls, identified 23 new significantly associated loci and 7 suggestive loci. Most encode immune and apoptotic regulators, with some also associated with other autoimmune diseases, as well as several melanocyte regulators. Bioinformatic analyses indicate a predominance of causal regulatory variation, some of which corresponds to expression quantitative trait loci (eQTLs) at these loci. Together, the identified genes provide a framework for the genetic architecture and pathobiology of vitiligo, highlight relationships with other autoimmune diseases and melanoma, and offer potential targets for treatment.


Assuntos
Doenças Autoimunes/genética , Predisposição Genética para Doença , Vitiligo/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Melanoma/genética , Locos de Características Quantitativas , Medição de Risco
15.
Lab Invest ; 96(10): 1105-15, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27617404

RESUMO

Neurofibromas, which are benign Schwann cell tumors, are the hallmark feature in the autosomal dominant condition neurofibromatosis 1 (NF1) and are associated with biallelic loss of NF1 gene function. There is a need for effective therapies for neurofibromas, particularly the larger, plexiform neurofibromas. Tissue culture is an important tool for research. However, it is difficult to derive enriched human Schwann cell cultures, and most enter replicative senescence after 6-10 passages, impeding cell-based research in NF1. Through exogenous expression of human telomerase reverse transcriptase and murine cyclin-dependent kinase (mCdk4), normal (NF1 wild-type), neurofibroma-derived Schwann cells heterozygous for NF1 mutation, and neurofibroma-derived Schwann cells homozygous for NF1 mutation were immortalized, including some matched samples from the same NF1 patient. Initial experiments employed retroviral vectors, while subsequent work utilized lentiviral vectors carrying these genes because of improved efficiency. Expression of both transgenes was required for immortalization. Molecular and immunohistochemical analysis indicated that these cell lines are of Schwann cell lineage and have a range of phenotypes, many of which are consistent with their primary cultures. This is the first report of immortalization and detailed characterization of multiple human NF1 normal nerve and neurofibroma-derived Schwann cell lines, which will be highly useful research tools to study NF1 and other Schwann tumor biology and conditions.


Assuntos
Técnicas de Cultura de Células , Neurofibromatose 1 , Células de Schwann , Animais , Linhagem Celular Tumoral , Quinase 4 Dependente de Ciclina/genética , Humanos , Camundongos , Transplante de Neoplasias , Telomerase/genética
16.
Arthritis Care Res (Hoboken) ; 68(11): 1671-1680, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-26945673

RESUMO

OBJECTIVE: To identify novel combinations of genetic and psychological factors that predicted 12-month postoperative pain and disability outcomes following arthroscopic shoulder surgery. METHODS: A prospective presurgical cohort (n = 150) was recruited to complete validated psychological questionnaires and have their DNA collected from saliva. DNA was genotyped for a priori selected genes involved with pain modulation (ADRB2, OPRM1, AVPR1A, GCH1, and KCNS1) and inflammation (IL1B, TNF/LTA, and IL6). The outcome measures of interest were the Brief Pain Inventory and Disabilities of the Arm, Shoulder, and Hand questionnaire. Followup for the cohort was at 3, 6, and 12 months postoperatively. After controlling for age, sex, race, and preoperative status, genetic and psychological factors were entered as main effects and interaction terms in separate general linear models for predicting postoperative pain and disability outcomes. RESULTS: Seven interactions involving pain-modulatory genes were identified. Three provided strong statistical evidence for different outcomes, including KCNS1 and kinesiophobia for preoperative pain intensity, ADRB2 and depressive symptoms for postoperative course, and GCH1 and anxiety symptoms for 12-month pain-intensity outcome. Ten interactions involving inflammatory genes were identified. Three provided strong statistical evidence for the 12-month postoperative course outcome, including 2 different IL6 single-nucleotide polymorphism and pain catastrophizing, and IL6 and depressive symptoms. CONCLUSION: The current study identified novel genetic and psychological interactions that can be used in future studies to further understand the development of persistent postoperative pain and investigate the effectiveness of tailored treatment.


Assuntos
Artroscopia/efeitos adversos , Dor Pós-Operatória/genética , Dor Pós-Operatória/psicologia , Dor de Ombro/genética , Dor de Ombro/psicologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ansiedade/genética , Ansiedade/psicologia , Catastrofização/genética , Catastrofização/psicologia , Depressão/genética , Depressão/psicologia , Avaliação da Deficiência , Feminino , Seguimentos , GTP Cicloidrolase/análise , Humanos , Interleucina-6/análise , Masculino , Pessoa de Meia-Idade , Medição da Dor , Dor Pós-Operatória/fisiopatologia , Polimorfismo de Nucleotídeo Único , Canais de Potássio de Abertura Dependente da Tensão da Membrana/análise , Estudos Prospectivos , Receptores Adrenérgicos beta 2/análise , Ombro/cirurgia , Dor de Ombro/fisiopatologia , Inquéritos e Questionários , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
17.
Pain ; 156(1): 148-56, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25599310

RESUMO

Tailored treatment based on individual risk factors is an area with promise to improve options for pain relief. Musculoskeletal pain has a biopsychosocial nature, and multiple factors should be considered when determining risk for chronic pain. This study investigated whether subgroups comprised genetic and psychological factors predicted outcomes in preclinical and clinical models of shoulder pain. Classification and regression tree analysis was performed for an exercise-induced shoulder injury cohort (n = 190) to identify high-risk subgroups, and a surgical pain cohort (n = 150) was used for risk validation. Questionnaires for fear of pain and pain catastrophizing were administered before injury and preoperatively. DNA collected from saliva was genotyped for a priori selected genes involved with pain modulation (COMT and AVPR1A) and inflammation (IL1B and TNF/LTA). Recovery was operationalized as a brief pain inventory rating of 0/10 for current pain intensity and <2/10 for worst pain intensity. Follow-up for the preclinical cohort was in daily increments, whereas follow-up for the clinical cohort was at 3, 6, and 12 months postoperatively. Risk subgroups comprised the COMT high pain sensitivity variant and either pain catastrophizing or fear of pain were predictive of heightened shoulder pain responses in the preclinical model. Further analysis in the clinical model identified the COMT high pain sensitivity variant and pain catastrophizing subgroup as the better predictor. Future studies will determine whether these findings can be replicated in other anatomical regions and whether personalized medicine strategies can be developed for this risk subgroup.


Assuntos
Catastrofização/diagnóstico , Catastrofização/psicologia , Medição da Dor/psicologia , Dor de Ombro/diagnóstico , Dor de Ombro/psicologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Medo/psicologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor/métodos , Estudos Prospectivos , Fatores de Risco , Adulto Jovem
18.
Med Sci Sports Exerc ; 46(10): 1871-81, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24598699

RESUMO

PURPOSE: The pain experience has multiple influences, but little is known about how specific biological and psychological factors interact to influence pain responses. The current study investigated the combined influences of genetic (pro-inflammatory) and psychological factors on several preclinical shoulder pain phenotypes. METHODS: An exercise-induced shoulder injury model was used, and a priori selected genetic (IL1B, TNF/LTA region, and IL6 single nucleotide polymorphisms (SNP)) and psychological (anxiety, depression symptoms, pain catastrophizing, fear of pain, and kinesiophobia) factors were included as the predictors of interest. The phenotypes were pain intensity (5-d average and peak reported on numerical rating scale), upper extremity disability (5-d average and peak reported on the Quick Disabilities of the Arm, Shoulder and Hand instrument), and duration of shoulder pain (d). RESULTS: After controlling for age, sex, and race, the genetic and psychological predictors were entered separately as main effects and interaction terms in regression models for each pain phenotype. Results from the recruited cohort (n = 190) indicated strong statistical evidence for the interactions between 1) TNF/LTA SNP rs2229094 and depression symptoms for average pain intensity and duration and 2) IL1B two SNP diplotype and kinesiophobia for average shoulder pain intensity. Moderate statistical evidence for prediction of additional shoulder pain phenotypes included interactions of kinesiophobia, fear of pain, or depressive symptoms with TNF/LTA rs2229094 and IL1B. CONCLUSIONS: These findings support the combined predictive ability of specific genetic and psychological factors for shoulder pain phenotypes by revealing novel combinations that may merit further investigation in clinical cohorts to determine their involvement in the transition from acute to chronic pain conditions.


Assuntos
Inflamação/genética , Dor de Ombro/genética , Dor de Ombro/psicologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Estudos de Associação Genética , Humanos , Interleucina-1beta/genética , Linfotoxina-alfa/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Ombro/fisiopatologia , Lesões do Ombro , Fator de Necrose Tumoral alfa/genética , Adulto Jovem
19.
J Pain ; 15(1): 68-80, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24373571

RESUMO

UNLABELLED: Chronic pain is influenced by biological, psychological, social, and cultural factors. The current study investigated potential roles for combinations of genetic and psychological factors in the development and/or maintenance of chronic musculoskeletal pain. An exercise-induced shoulder injury model was used, and a priori selected genetic (ADRB2, COMT, OPRM1, AVPR1 A, GCH1, and KCNS1) and psychological (anxiety, depressive symptoms, pain catastrophizing, fear of pain, and kinesiophobia) factors were included as predictors. Pain phenotypes were shoulder pain intensity (5-day average and peak reported on numerical rating scale), upper extremity disability (5-day average and peak reported on the QuickDASH), and shoulder pain duration (in days). After controlling for age, sex, and race, the genetic and psychological predictors were entered as main effects and interaction terms in separate regression models for the different pain phenotypes. Results from the recruited cohort (N = 190) indicated strong statistical evidence for interactions between the COMT diplotype and 1) pain catastrophizing for 5-day average upper extremity disability and 2) depressive symptoms for pain duration. There was moderate statistical evidence for interactions for other shoulder pain phenotypes between additional genes (ADRB2, AVPR1 A, and KCNS1) and depressive symptoms, pain catastrophizing, or kinesiophobia. These findings confirm the importance of the combined predictive ability of COMT with psychological distress and reveal other novel combinations of genetic and psychological factors that may merit additional investigation in other pain cohorts. PERSPECTIVE: Interactions between genetic and psychological factors were investigated as predictors of different exercise-induced shoulder pain phenotypes. The strongest statistical evidence was for interactions between the COMT diplotype and pain catastrophizing (for upper extremity disability) or depressive symptoms (for pain duration). Other novel genetic and psychological combinations were identified that may merit further investigation.


Assuntos
Exercício Físico , Dor de Ombro , Adolescente , Adulto , Traumatismos em Atletas , Catastrofização/complicações , Catecol O-Metiltransferase/genética , Estudos de Coortes , Feminino , Humanos , Canal de Potássio Kv1.1/genética , Masculino , Pessoa de Meia-Idade , Transtornos do Humor/complicações , Medição da Dor , Fenótipo , Valor Preditivo dos Testes , Proteínas de Ligação a RNA/genética , Receptores Adrenérgicos beta 1/genética , Dor de Ombro/etiologia , Dor de Ombro/genética , Dor de Ombro/psicologia , Inquéritos e Questionários , Adulto Jovem
20.
Chem Senses ; 38(8): 719-28, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24000232

RESUMO

The TAS1R genes encode heterodimeric receptors that mediate umami (hTAS1R1 + hTAS1R3) and sweet (hTAS1R2 + hTAS1R3) sensations. The question of interest for this study is if TAS1R1 variation associates with differences in overall taste intensity. We leveraged an existing database of adults (n = 92, primarily European American) to test associations between 2 TAS1R1 single nucleotide polymorphisms (SNPs) (intronic rs17492553, C/T and exonic rs34160967, G/A) and intensity of 4 prototypical tastants (NaCl, sucrose, citric acid, and quinine), applied regionally to fungiform and circumvallate loci, and sampled with the whole mouth. Both SNPs were associated with modest shifts in perceived intensities across all taste qualities. Three genotype groups were represented for the intronic SNP-minor allele homozygotes (TT) averaged 40% lower intensities than did CC homozygotes for all regionally applied tastants, as well as whole-mouth NaCl and citric acid. Similar, but less pronounced, intensity differences were seen for the exonic SNP (GG homozygotes reported greater intensities than did the AA/AG group). Our predominantly European American cohort had a low frequency of AA homozygotes, which may have attenuated the SNP-related differences in perceived intensity. These preliminary findings, if replicated, could add TAS1R1 polymorphisms to the repertoire of genotypic and phenotypic markers of heightened taste sensation.


Assuntos
Polimorfismo de Nucleotídeo Único , Receptores Acoplados a Proteínas-G/genética , Percepção Gustatória , Paladar , Adulto , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
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