Functional connectivity response to acute pain assessed by fNIRS is associated with BDNF genotype in fibromyalgia: an exploratory study.

Fibromyalgia is a heterogenous primary pain syndrome whose severity has been associated with descending pain modulatory system (DPMS) function and functional connectivity (FC) between pain processing areas. The brain-derived neurotrophic factor (BDNF) Val66Met single nucleotide polymorphism has been linked to vulnerability to chronic pain. In this cross-sectional imaging genetics study, we investigated fibromyalgia, the relationship between BDNF Val66Met heterozygous genotypes (Val/Met), and the functional connectivity (FC) response pattern to acute pain stimulus in the motor (MC) and prefrontal (PFC) cortex assessed by near-infrared spectroscopy (fNIRS) before and after a cold pressor test utilizing water (0-1 °C). Also, we assessed the relationship between this genotype with the DPMS function and quality of life. We included 42 women (Val/Val = 30; Val/Met = 12) with fibromyalgia, ages 18-65. The MANCOVA comparing Val/Met to Val/Val genotypes showed higher ΔFC between left(l)-PFC-l-MC (ß = 0.357, p = 0.048), l-PFC-right(r)-PFC (ß = 0.249, p = 0.012), l-PFC-r-MC (ß = 0.226, p = 0.022), and l-MC-r-PFC (ß = 0.260, p = 0.016). Val/Met genotypes showed higher efficiency of the DPMS and lower disability due to pain. Here we show that fibromyalgia patients carrying the Val/Met BDNF genotype presented an increased ΔFC across MC and PFC in response to acute pain associated with differences in acute pain perception and fibromyalgia symptoms.

Fibromyalgia: A Review of Related Polymorphisms and Clinical Relevance.

Fibromyalgia (FM) is a chronic pain syndrome that affects the central nervous system and generates disability, which is characterized by generalized pain, fatigue, and functional decline. In this review, we aimed to identify the polymorphisms related to the pathophysiology of FM and the clinical characteristics generated by genetic influence. Only original studies with genes related to FM were considered, totaling 27 articles. The genes found were: MTHFR, RGS4, MYT1L, TACR1, SCN9A, DRD3, ADRB2, IL-4, HLA-DRB1, EDN1, CNR1, TAAR1, OPRM1, ADRA1A, ADRB3, BDNF, GRIA4, HTR3A, HTR3B, HTR2A, SERPINA 1 or A1AT, NRXN3, GCH1, MEFV, TRPV3, SLC6A4, ACE I/D, TSPO, COMT, and MAOA. Several genes related to different pain syndromes and altered pain thresholds have been identified and some polymorphisms were related to susceptibility to FM. It was observed that 73.33% of the genes related to FM were also associated with some psychological disorders, such as anxiety, depression, schizophrenia, and obsessive and compulsive disorder, and 40.00% with pain sensitivity and/or migraine, besides other disorders associated (drug addiction, autoimmune disorders, circulatory problems, and metabolic alterations). This review demonstrated an association of FM and genetic polymorphisms that can expand our knowledge about the pathophysiology of this disease.

Pain catastrophizing is associated with the Val66Met polymorphism of the brain-derived neurotrophic factor in fibromyalgia.

BACKGROUND: Fibromyalgia (FM) is a musculoskeletal chronic pain syndrome that impacts negatively patient's daily lives. Its pathogenesis is characterized by a complex relationship between biological and psychosocial factors not fully understood yet. Pain catastrophizing is associated with FM and is an important predictor of outcomes. This study aimed to answer two questions: (i) whether the allele and genotype frequencies of BDNF Val66Met (rs6265) polymorphism differs between FM patients and healthy controls (HC); and (ii) if the BDNF Val66Met polymorphism is a factor that predicts pain catastrophizing in FM. METHODS: In a cross-sectional design, 108 FM patients and 108 HC were included. FM patients responded to the Brazilian Portuguese version of the Pain Catastrophizing Scale (BP-PCS) to assess pain catastrophizing, as well as other validated tools for anxiety (The State-Trait Anxiety Inventory - STAI), depression (Beck Depression Inventory II - BDI-II) and functional aspects (Fibromyalgia Impact Questionnaire - FIQ; Central Sensitization Inventory validated and adapted for Brazilian population - CSI-BP; Pittsburgh Sleep Quality Index - PSQI; and Resilience Scale). All subjects were genotyped for the BDNF Val66Met polymorphism. RESULTS: Val allele was significantly more frequent in FM patients compared to the control group (p < 0.05). Also, FM patients with Val/Val genotype showed more pain catastrophizing thoughts, and this genotype was significantly associated with magnification and rumination dimensions of BP-PCS (p < 0.05). Furthermore, there were significant differences in levels of anxiety and symptoms of depression, years of education, and the functional situation between the FM and control groups. CONCLUSIONS: The findings show an association of BDNF Val66Met polymorphism with pain catastrophizing in FM, which opens new avenues to comprehend the interplay between molecular genetic characteristics and neuroplasticity mechanisms underpinning FM.

Lower limb muscle strength and serotonin receptor gene polymorphism as factors associated in women with fibromyalgia.

BACKGROUND: Fibromyalgia (FM) is a chronic pain syndrome characterized by generalized skeletal muscle chronic pain. Its etiology is not well defined, because there are several factors that may trigger it such as physical and/or emotional stresses, or a genetic susceptibility, involving serotonergic, dopaminergic and catecholaminergic paths. The objective of this study was to investigate the association between the strength of the lower limb, genetic polymorphism of the serotonin receptor gene HTR2A in women with fibromyalgia. METHODS: In this observational study of case-control type 48 women were evaluated who belonged to the group with FM (52 ± 12 years) and 100 women in the control group (58 ± 11 years). Socio demographic and anthropometric data were collected and peripheral blood samples for DNA extraction; genotypic analyzes were performed by means of PCR in real time by TaqMan® system. The lower limb muscle strength was assessed through the test of sitting down and standing up for 30 s. The chi-square test or Fischer Exact was used for possible associations among the variables; the t-test for independent samples was used to compare the averages among the groups; the value of significance adopted was 5%. RESULTS: There was an association between the polymorphism of the HTR2A gene with FM, demonstrating that carriers of the genotype GG have 24.39 times more likely to develop the syndrome (IC95% 5.15-115.47; p = 0.01). It was observed an association between FM and the test to sit and stand up demonstrating that women with fibromyalgia have lower limb muscle strength (p = 0.01). The study showed that the white race has 3.84 times more likely to develop FM (p = 0.01). CONCLUSION: The results of this study suggest that women of Caucasian ethnicity with GG genotype or G allele presented greater risk of developing fibromyalgia and that these patients have lower limb muscle strength compared to the control group.

Epigenetics insights into chronic pain: DNA hypomethylation in fibromyalgia-a controlled pilot-study.

To evaluate changes in DNA methylation profiles in patients with fibromyalgia (FM) compared to matched healthy controls (HCs). All individuals underwent full clinical and neurophysiological assessment by cortical excitability (CE) parameters measured by transcranial magnetic stimulation. DNA from the peripheral blood of patients with FM (n = 24) and HC (n = 24) were assessed using the Illumina-HumanMethylation450 BeadChips. We identified 1610 differentially methylated positions (DMPs) in patients with FM displaying a nonrandom distribution in regions of the genome. Sixty-nine percent of DMP in FM were hypomethylated compared to HC. Differentially methylated positions were enriched in 5 genomic regions (1p34; 6p21; 10q26; 17q25; 19q13). The functional characterization of 960 genes related to DMPs revealed an enrichment for MAPK signaling pathway (n = 18 genes), regulation of actin cytoskeleton (n = 15 genes), and focal adhesion (n = 13 genes). A gene-gene interaction network enrichment analysis revealed the participation of DNA repair pathways, mitochondria-related processes, and synaptic signaling. Even though DNA was extracted from peripheral blood, this set of genes was enriched for disorders such as schizophrenia, mood disorders, bulimia, hyperphagia, and obesity. Remarkably, the hierarchical clusterization based on the methylation levels of the 1610 DMPs showed an association with neurophysiological measurements of CE in FM and HC. Fibromyalgia has a hypomethylation DNA pattern, which is enriched in genes implicated in stress response and DNA repair/free radical clearance. These changes occurred parallel to changes in CE parameters. New epigenetic insights into the pathophysiology of FM may provide the basis for the development of biomarkers of this disorder.

Cyclodextrin-complexed Ocimum basilicum leaves essential oil increases Fos protein expression in the central nervous system and produce an antihyperalgesic effect in animal models for fibromyalgia.

O. basilicum leaves produce essential oils (LEO) rich in monoterpenes. The short half-life and water insolubility are limitations for LEO medical uses. ß-Cyclodextrin (ß-CD) has been employed to improve the pharmacological properties of LEO. We assessed the antihyperalgesic profile of LEO, isolated or complexed in ß-CD (LEO/ß-CD), on an animal model for fibromyalgia. Behavioral tests: mice were treated every day with either LEO/ß-CD (25, 50 or 100 mg/kg, p.o.), LEO (25 mg/kg, p.o.), tramadol (TRM 4 mg/kg, i.p.) or vehicle (saline), and 60 min after treatment behavioral parameters were assessed. Therefore, mice were evaluated for mechanical hyperalgesia (von Frey), motor coordination (Rota-rod) and muscle strength (Grip Strength Metter) in a mice fibromyalgia model. After 27 days, we evaluated the central nervous system (CNS) pathways involved in the effect induced by experimental drugs through immunofluorescence protocol to Fos protein. The differential scanning analysis (DSC), thermogravimetry/derivate thermogravimetry (TG/DTG) and infrared absorption spectroscopy (FTIR) curves indicated that the products prepared were able to incorporate the LEO efficiently. Oral treatment with LEO or LEO-ßCD, at all doses tested, produced a significant reduction of mechanical hyperalgesia and we were able to significantly increase Fos protein expression. Together, our results provide evidence that LEO, isolated or complexed with ß-CD, produces analgesic effects on chronic non-inflammatory pain as fibromyalgia.

A SCN9A gene-encoded dorsal root ganglia sodium channel polymorphism associated with severe fibromyalgia.

BACKGROUND: A consistent line of investigation suggests that autonomic nervous system dysfunction may explain the multi-system features of fibromyalgia (FM); and that FM is a sympathetically maintained neuropathic pain syndrome. Dorsal root ganglia (DRG) are key sympathetic-nociceptive short-circuit sites. Sodium channels located in DRG (particularly Nav1.7) act as molecular gatekeepers for pain detection. Nav1.7 is encoded in gene SCN9A of chromosome 2q24.3 and is predominantly expressed in the DRG pain-sensing neurons and sympathetic ganglia neurons. Several SCN9A sodium channelopathies have been recognized as the cause of rare painful dysautonomic syndromes such as paroxysmal extreme pain disorder and primary erythromelalgia. The aim of this study was to search for an association between fibromyalgia and several SCN9A sodium channels gene polymorphisms. METHODS: We studied 73 Mexican women suffering from FM and 48 age-matched women who considered themselves healthy. All participants filled out the Fibromyalgia Impact Questionnaire (FIQ). Genomic DNA from whole blood containing EDTA was extracted by standard techniques. The following SCN9A single-nucleotide polymorphisms (SNP) were determined by 5' exonuclease TaqMan assays: rs4371369; rs4387806; rs4453709; rs4597545; rs6746030; rs6754031; rs7607967; rs12620053; rs12994338; and rs13017637. RESULTS: The frequency of the rs6754031 polymorphism was significantly different in both groups (P = 0.036) mostly due to an absence of the GG genotype in controls. Interestingly; patients with this rs6754031 GG genotype had higher FIQ scores (median = 80; percentile 25/75 = 69/88) than patients with the GT genotype (median = 63; percentile 25/75 = 58/73; P = 0.002) and the TT genotype (median = 71; percentile 25/75 = 64/77; P = 0.001). CONCLUSION: In this ethnic group; a disabling form of FM is associated to a particular SCN9A sodium channel gene variant. These preliminary results raise the possibility that some patients with severe FM may have a dorsal root ganglia sodium channelopathy.

Influence of catechol-O-methyltransferase (COMT) gene polymorphisms in pain sensibility of Brazilian fibromialgia patients.

Fibromyalgia syndrome (FS) is a rheumatic syndrome affecting to 2-3% of individuals of productive age, mainly women. Neuroendocrine and genetic factors may play a significant role in development of the disease which is characterized by diffuse chronic pain and presence of tender points. Several studies have suggested an association between FS, especially pain sensitivity, and polymorphism of the catechol-O-methyltransferase (COMT) gene. The aim of the present study was to characterize the SNPs rs4680 and rs4818 of the COMT gene and assess its influence in pain sensitivity of patients with fibromyalgia screened by the Fibromyalgia Impact Questionnaire (FIQ). DNA was extracted from peripheral blood of 112 patients with fibromyalgia and 110 healthy individuals and was used as template in PCR for amplification of a 185-bp fragment of the COMT gene. The amplified fragment was sequenced for analyses of the SNPs rs4680 and rs4818. The frequency of mutant genotype AA of SNP rs6860 was 77.67% in patients with FS and 28.18% for the control group. For the SNP rs4818, the frequency of mutant genotype CC was 73.21 and 39.09% for patients with FS and controls, respectively. Moreover, the FIQ score was higher in patients with the homozygous mutant genotype for SNPs rs4680 (87.92 points) and rs4818 (86.14 points). These results suggest that SNPs rs4680 and rs4818 of the COMT gene may be associated with fibromyalgia and pain sensitivity in FS Brazilian patients.

Influência da interação entre qualidade ambiental e o SNP T102C do gene HTR2A sobre a suscetibilidade à fibromialgia / Influence of the interaction between environmental quality and T102C SNP in the HTR2A gene on fibromyalgia susceptibility

OBJETIVO: Investigar a influência genética da variante T102C do gene do receptor 2A de serotonina (HTR2A) e sua interação com aspectos do meio ambiente, como exposição a ruídos, trânsito, clima, oportunidades de adquirir novas informações, segurança física e proteção, dentre outras, como possíveis fatores de risco para o desenvolvimento da síndrome da fibromialgia (SFM). MÉTODOS: Foram avaliados 41 pacientes com SFM e 49 indivíduos-controle. Os fatores ambientais foram avaliados pela aplicação do domínio V do questionário WHOQOL-100 (OMS). Solicitou-se aos pacientes que as respostas representassem os momentos antes do surgimento dos sintomas. A variante T102C do gene do receptor 2A de serotonina (HTR2A) foi determinada por PCR-RFLP. RESULTADOS: Na amostra de pacientes, o número de portadores do alelo 102C foi maior do que o encontrado na amostra controle (76,5% vs. 50%; P = 0,028). Os escores do domínio V foram menores em pacientes quando comparados aos controles (P < 0,001). O fator "falta de oportunidades de adquirir novas informações e habilidades" elevou em quase 14 vezes a chance de desenvolvimento da síndrome (P = 0,009). "Baixa qualidade de cuidados sociais e de saúde", somada à presença do alelo 102C, elevou em mais de 90 vezes (P = 0,005). Contudo, indivíduos portadores desse mesmo alelo que possuem alta qualidade de cuidados sociais e de saúde não se encontram sob risco de desenvolver a SFM. CONCLUSÕES: Esses dados sugerem que tais fatores podem predispor à SFM, especialmente em portadores do alelo 102C. Entretanto, são necessárias investigações com amostras maiores.

OBJECTIVES: This study aimed to investigate the genetic influence of the T102C polymorphism of the 2A serotonin receptor gene (HTR2A) and its interaction with environmental aspects, such as exposure to noise, traffic, climate, and opportunities to acquire new information, physical protection, and security, among others, as possible risk factors for developing fibromyalgia syndrome (FMS). METHODS: Forty-one FMS patients and 49 controls were evaluated. Environmental factors were evaluated by application of the V domain of the WHOQOL-100 questionnaire. Patients were asked that their answers represented only the periods preceding the onset of symptoms. The T102C variant of the HTR2A gene was determined through PCR/RFLP. RESULTS: Among patients, the frequency of carriers of the 102C allele was higher than in controls (76.5% vs. 50%; P = 0.028). The scores of the V domain were lower in patients than in controls, indicating a worst perception of the environmental quality by patients (P < 0.001). The factor "lack of opportunities for acquiring new information and skills" increased the chance of developing FMS by almost 14-fold (P = 0.009). The factor "low quality of social care and health" together with the presence of the 102C allele also increased this chance by more than 90-fold (P = 0.005). However, carriers of the same allele who have high quality social care and health are not at a higher risk to develop FMS. CONCLUSION: These data suggest that these factors may predispose to FMS, especially in carriers of the 102C allele. However, studies with larger samples are required to confirm this hypothesis.

Influence of the interaction between environmental quality and T102C SNP in the HTR2A gene on fibromyalgia susceptibility.

OBJECTIVES: This study aimed to investigate the genetic influence of the T102C polymorphism of the 2A serotonin receptor gene (HTR2A) and its interaction with environmental aspects, such as exposure to noise, traffic, climate, and opportunities to acquire new information, physical protection, and security, among others, as possible risk factors for developing fibromyalgia syndrome (FMS). METHODS: Forty-one FMS patients and 49 controls were evaluated. Environmental factors were evaluated by application of the V domain of the WHOQOL-100 questionnaire. Patients were asked that their answers represented only the periods preceding the onset of symptoms. The T102C variant of the HTR2A gene was determined through PCR/RFLP. RESULTS: Among patients, the frequency of carriers of the 102C allele was higher than in controls (76.5% vs. 50%; P = 0.028). The scores of the V domain were lower in patients than in controls, indicating a worst perception of the environmental quality by patients (P < 0.001). The factor "lack of opportunities for acquiring new information and skills" increased the chance of developing FMS by almost 14-fold (P = 0.009). The factor "low quality of social care and health" together with the presence of the 102C allele also increased this chance by more than 90-fold (P = 0.005). However, carriers of the same allele who have high quality social care and health are not at a higher risk to develop FMS. CONCLUSION: These data suggest that these factors may predispose to FMS, especially in carriers of the 102C allele. However, studies with larger samples are required to confirm this hypothesis.

Serotonin receptor (5-HT 2A) and catechol-O-methyltransferase (COMT) gene polymorphisms: triggers of fibromyalgia?

INTRODUCTION: Fibromyalgia is a rheumatic syndrome characterized by diffuse and chronic pain associated with fatigue, sleep disorders, anxiety, depression, memory loss, and dizziness. Although the physiological mechanisms that control fibromyalgia have not been precisely established, neuroendocrine, genetic or molecular factors may be involved in fibromyalgia. OBJECTIVE: The aim of the present study was to characterize serotonin receptor (5-HT2A) and catechol-O-methyltransferase (COMT) gene polymorphisms in Brazilian patients with fibromyalgia and to evaluate the participation of these polymorphisms in the etiology of the disease. MATERIAL AND METHODS: Genomic DNA extracted from 102 blood samples (51 patients, 51 controls) was used for molecular characterization of the 5-HT2A and COMT gene polymorphisms by PCR-RFLP. RESULTS: Analysis of the 5-HT2A polymorphism revealed a frequency of 25.49% C/C, 49.02% T/C and 25.49% T/T in patients, and of 17.65% C/C, 62.74% T/C and 19.61% T/T in the control group, with no differences between the two groups.Analysis of the COMT polymorphism in patients showed a frequency of 17.65% and 45.10% for genotypes H/H and L/H, respectively. In the control group the frequency was 29.42% for H/H and 60.78% for L/H, also with no differences between the two groups. However, there was a significant difference in the frequency of the L/L genotype between patients (37.25%) and controls (9.8%), which permitted differentiation between the two groups. CONCLUSION: The L/L genotype was more frequent among fibromyalgia patients. Though considering a polygenic situation and environmental factors, the molecular study of the rs4680 SNP of the COMT gene may be helpful to the identification of susceptible individuals.

Interação entre qualidade do meio ambiente, estresse e a variação do gene APOE na determinação da suscetibilidade à fibromialgia / Association between environmental quality, stress and APOE gene variation in fibromyalgia susceptibility determination

INTRODUÇÃO: A fibromialgia se trata de uma desordem multifatorial, cuja etiologia reside na interação entre a susceptibilidade genética e o ambiente. No entanto, poucos trabalhos procuram detectar quais seriam os fatores considerados de risco. OBJETIVO: Investigar a influência genética e sua interação com qualidade ambiental e com estresse como possíveis fatores de risco para o desenvolvimento da fibromialgia. PACIENTES E MÉTODOS: Neste estudo transversal, foram investigados dois grupos de mulheres, sendo 47 com diagnóstico clínico de fibromialgia, e 41 mulheres do grupo controle, todas da comunidade de Novo Hamburgo, RS. O polimorfismo do gene da apolipoproteína E (APOE) foi analisado, a partir do DNA extraído do sangue total de ambas as amostras. Os fatores ambientais foram avaliados através do inventário de sintomas para adultos de Lipp (ISSL), para a averiguação do estresse comportamental, e da aplicação do domínio V do WHOQOL-100. RESULTADOS: Dentre as pacientes, foram encontradas mais mulheres com níveis altos de estresse, quando comparado à amostra controle (P < 0,001); além disto, os escores médios do domínio V do WHOQOL-100, que avalia qualidade do meio ambiente, foram inferiores neste grupo (P < 0,001). As frequências genotípicas e alélicas do gene APOE foram similares entre os dois grupos. A análise multivariada demonstrou que baixos escores do WHOQOL-100, aumentaram a chance de desenvolvimento da doença em 57,7 vezes (P < 0,001), e que altos níveis de estresse foram significativamente relacionados com a doença (OR = 197,2; P < 0,001). Essa abordagem apontou para uma interação entre estresse e a presença do alelo E*2 (P = 0,028). A doença foi muito mais frequente em pacientes com altos níveis de estresse que não eram portadoras do alelo E*2 (OR estimado = 265,1), quando comparada a pacientes com o mesmo nível de estresse e portadoras do alelo E*2 (OR estimado = 1,06). CONCLUSÃO: A presença do alelo E*2 pode indicar possível ...

INTRODUCTION: Fibromyalgia is a multifactorial disease, of which etiology is based on interaction between genetic susceptibility and environment. However, few studies attempted to identify the risk factors. OBJECTIVE: To investigate the genetic influence and its interaction with environmental quality and stress, as possible risk factors for fibromyalgia development. PATIENTS AND METHODS: This cross-sectional study investigated two groups of women, of which 47 had a clinical diagnosis of fibromyalgia, and 41 women comprising thre control group, all from the town of Novo Hamburgo, RS. The apolipoprotein E (APOE) gene polymorphism was analyzed in DNA extracted from total blood, in both samples. Environmental factors were studied through Lipp's Inventory of Stress Symptoms for Adults and by applying the WHOQOL-100 domain V. RESULTS: Among the patients, more women had high stress levels when compared to the control sample (P < 0.001); moreover, the average scores of the WHOQOL-100 domain V, which analyze environment quality, were lower in this group (P < 0.001). APOE genotypic and allelic frequencies were similar between the two groups. Multivariate analysis showed that low WHOQOL-100 scores increase the chance of disease development by 57.7 times (P < 0.001), and that high stress levels were related with the disease (OR = 197.2; P < 0.001). This approach pointed out an interaction between stress and presence of E*2 allele (P = 0.028). Fibromyalgia was much more frequent in patients with high stress levels that were E*2 non-carriers (estimated OR = 265.1), when compared to patients with the same stress level, but E*2 carriers (estimated OR = 1.06). CONCLUSION: E*2 allele presence could have a protective action regarding the association between fibromyalgia and stress.

Polimorfismos dos genes do receptor de serotonina (5-HT2A) e da catecol-O-metiltransferase (COMT): fatores desencadeantes da fibromialgia? / Serotonin receptor (5-HT 2A) and catechol-O-methyltransferase (COMT) gene polymorphisms: Triggers of fibromyalgia?

INTRODUÇÃO: A fibromialgia é uma síndrome reumática caracterizada por dor difusa e crônica associada a fadiga, insônia, ansiedade, depressão, perda de memória e tontura. Embora os mecanismos fisiológicos que controlam a fibromialgia não tenham sido estabelecidos, fatores neuroendócrinos, genéticos ou moleculares podem estar envolvidos. OBJETIVO: O objetivo do presente estudo foi caracterizar os polimorfismos dos genes do receptor de serotonina (5-HT2A) e da catecolO-metiltransferase (COMT) em pacientes brasileiros com fibromialgia, a fim de avaliar sua participação na etiologia da doença. MATERIAL E MÉTODOS: O DNA genômico extraído de 102 amostras de sangue (51 pacientes, 51 controles) foi usado para a caracterização molecular dos polimorfismos dos genes 5-HT2A e COMT, por meio de PCR-RFLP. RESULTADOS: A análise molecular dos polimorfismos do gene 5-HT2A demonstrou frequências de 25,49 por cento C/C, 49,02 por cento T/C e 25,49 por cento T/T, nos pacientes com fibromialgia, e 17,65 por cento C/C, 62,74 por cento T/C e 19,61 por cento T/T, no grupo controle, não apresentando diferença significativa entre o grupo de pacientes e o grupo controle. Os polimorfismos do gene da COMT em pacientes com fibromialgia apresentaram uma frequência de 17,65 por cento e 45,10 por cento para os genótipos H/H e L/H, respectivamente. No grupo controle, as frequências foram de 29,42 por cento, para H/H, e 60,78 por cento, para L/H, sem diferença significativa entre ambos os grupos. Entretanto, houve diferença significativa na frequência do genótipo L/L em pacientes (37,25 por cento) e controles (9,8 por cento), o que permitiu a diferenciação entre os dois grupos. CONCLUSÃO: A frequência do genótipo L/L foi maior nos pacientes com fibromialgia. Apesar de a fibromialgia envolver uma situação poligênica e fatores ambientais, o estudo molecular do SNP rs4680 do gene da COMT pode auxiliar a identificação de indivíduos suscetíveis.

INTRODUCTION: Fibromyalgia is a rheumatic syndrome characterized by diffuse and chronic pain associated with fatigue, sleep disorders, anxiety, depression, memory loss, and dizziness. Although the physiological mechanisms that control fibromyalgia have not been precisely established, neuroendocrine, genetic or molecular factors may be involved in fibromyalgia. OBJECTIVE: The aim of the present study was to characterize serotonin receptor (5-HT2A) and catecholO-methyltransferase (COMT) gene polymorphisms in Brazilian patients with fibromyalgia and to evaluate the participation of these polymorphisms in the etiology of the disease. MATERIAL AND METHODS: Genomic DNA extracted from 102 blood samples (51 patients, 51 controls) was used for molecular characterization of the 5-HT2A and COMT gene polymorphisms by PCR-RFLP. RESULTS: Analysis of the 5-HT2A polymorphism revealed a frequency of 25.49 percent C/C, 49.02 percent T/C and 25.49 percent T/T in patients, and of 17.65 percent C/C, 62.74 percent T/C and 19.61 percent T/T in the control group, with no differences between the two groups.Analysis of the COMT polymorphism in patients showed a frequency of 17.65 percent and 45.10 percent for genotypes H/H and L/H, respectively. In the control group the frequency was 29.42 percent for H/H and 60.78 percent for L/H, also with no differences between the two groups. However, there was a significant difference in the frequency of the L/L genotype between patients (37.25 percent) and controls (9.8 percent), which permitted differentiation between the two groups. CONCLUSION: The L/L genotype was more frequent among fibromyalgia patients. Though considering a polygenic situation and environmental factors, the molecular study of the rs4680 SNP of the COMT gene may be helpful to the identification of susceptible individuals.

Association between environmental quality, stress and APOE gene variation in fibromyalgia susceptibility determination.

INTRODUCTION: Fibromyalgia is a multifactorial disease, of which etiology is based on interaction between genetic susceptibility and environment. However, few studies attempted to identify the risk factors. OBJECTIVE: To investigate the genetic influence and its interaction with environmental quality and stress, as possible risk factors for fibromyalgia development. PATIENTS AND METHODS: This cross-sectional study investigated two groups of women, of which 47 had a clinical diagnosis of fibromyalgia, and 41 women comprising thre control group, all from the town of Novo Hamburgo, RS. The apolipoprotein E (APOE) gene polymorphism was analyzed in DNA extracted from total blood, in both samples. Environmental factors were studied through Lipp's Inventory of Stress Symptoms for Adults and by applying the WHOQOL-100 domain V. RESULTS: Among the patients, more women had high stress levels when compared to the control sample (P < 0.001); moreover, the average scores of the WHOQOL-100 domain V, which analyze environment quality, were lower in this group (P < 0.001). APOE genotypic and allelic frequencies were similar between the two groups. Multivariate analysis showed that low WHOQOL-100 scores increase the chance of disease development by 57.7 times (P < 0.001), and that high stress levels were related with the disease (OR = 197.2; P < 0.001). This approach pointed out an interaction between stress and presence of E*2 allele (P = 0.028). Fibromyalgia was much more frequent in patients with high stress levels that were E*2 non-carriers (estimated OR = 265.1), when compared to patients with the same stress level, but E*2 carriers (estimated OR = 1.06). CONCLUSION: E*2 allele presence could have a protective action regarding the association between fibromyalgia and stress.

Association of adrenergic receptor gene polymorphisms with different fibromyalgia syndrome domains.

OBJECTIVE: Fibromyalgia (FM) patients have signs of relentless sympathetic hyperactivity associated with hyporeactivity to stress. Adrenergic receptors (ARs) are parts of the sympathetic nervous system that are fundamental for maintenance of homeostasis. We undertook this study to correlate alpha-AR and beta-AR gene polymorphisms with the presence of FM and with different domains of the FM syndrome as measured by the Fibromyalgia Impact Questionnaire (FIQ). METHODS: We studied 78 Mexican FM patients and 48 age-matched controls as well as 78 Spanish FM patients and 71 controls. All subjects studied were women. Single-nucleotide polymorphisms (SNPs) of alpha(1A)-AR (rs574584, rs1383914, rs1048101, and rs573542), beta(2)-AR (rs1042713 and rs1042714), and beta(3)-AR (rs4994) were analyzed by 5' exonuclease TaqMan polymerase chain reaction. Polymorphic haplotypes were constructed after linkage disequilibrium analysis. RESULTS: The beta(2)-AR AC haplotype was a risk factor for the presence of FM. This haplotype had an increased frequency in Mexican patients compared with Mexican controls (42.1% versus 30.5%; P = 0.04). Similarly, 50.4% of Spanish patients had this haplotype compared with 40.0% of Spanish controls (P = 0.05). In Spanish patients, the alpha(1A)-AR SNP rs1383914 was associated with the presence of FM (P = 0.01), and the alpha(1A)-AR SNP rs1048101 was linked with FIQ disability (P = 0.02). Mexican patients with the rs574584 GG genotype presented the highest FIQ score compared with Mexican patients with other genotypes (P = 0.01), and in Mexicans SNP rs574584 was associated with FIQ morning stiffness (P = 0.04) and with FIQ tiredness upon awakening (P = 0.02). CONCLUSION: AR gene polymorphisms are related to the risk of developing FM and are also linked to different domains of the FM syndrome.

Dorsal root ganglia, sodium channels, and fibromyalgia sympathetic pain.

Fibromyalgia (FM) is the most frequent cause of generalized pain in the community. Trauma and infection are frequent FM triggering events. A consistent line of investigation suggests that autonomic dysfunction may explain the multi-system features of FM, and that FM is a sympathetically maintained neuropathic pain syndrome. Dorsal root ganglia (DRG) are potential sympathetic-nociceptive short-circuit sites. Sodium channels located in DRG (particularly Nav1.7) act as molecular gatekeepers of pain detection at peripheral nociceptors. Different infecting agents may lie dormant in DGR. Trauma or infection can induce neuroplasticity with an over-expression of sympathetic fibers and sodium channels in DRG. Nerve growth factor (NGF) mediates these phenotypic changes, which enable catecholamines and/or sympathetic impulses to activate nociceptors. Several DRG sodium "channelopathies" have been recently associated to rare painful-dysautonomic syndromes, such as primary erythermalgia and paroxysmal extreme pain disorder (formerly familial rectal pain syndrome). We propose that enhanced DRG excitability may play a key role in FM pain. Individuals at risk would be those with genetically determined sympathetic hyperactivity, or those with inherent sodium channelopathies. Today's stressful environment may contribute to permanent sympathetic hyperactivity. Trauma or infection would induce sodium channels up-regulation and sympathetic sprouting in DRG through NGF over-expression. High levels of NGF have been reported in the cerebro-spinal fluid of FM patients. These post-traumatic (or post-infective) phenotypic changes would induce a sympathetically maintained neuropathic pain syndrome resulting in widespread pain, allodynia and paresthesias - precisely, the key clinical features of FM. If this hypothesis proves to be true, then sodium channel blockers could become therapeutic options for FM pain.

May genetic factors in fibromyalgia help to identify patients with differentially altered frequencies of immune cells?

There is common agreement that fibromyalgia (FM) is an extremely heterogeneous entity. Patients differ in their clinical symptoms, endocrine and immune parameters. In this study we evaluated endocrine and immunological features of distinct subsets of FM patients. In contrast to previous attempts to identify subsets of FM patients, based solely on their psychological and cognitive features, herein we propose to separate FM patients by genetic features. Allelic expression of the polymorphic promoter region of the serotonin transporter (5-HTTLPR) was analysed as a relevant genetic factor for FM. Seventy-five patients meeting the American College of Rheumatology criteria and 27 healthy age-matched controls participated in this study. All controls and FM patients were submitted to genotyping of 5-HTTLPR. Twenty-seven FM patients, who were able to discontinue hypnotic, sedative or psychotropic prescription medications for at least 2 weeks, were then subdivided into L (homozygote LL) or S groups (genotypes LS and SS). They were evaluated for salivary cortisol levels, absolute number of leucocyte subpopulations, including natural killer (NK) cells and activated T and B lymphocytes. Both groups presented decreased cortisol levels, more intense in the L group, increased all B lymphocytes subsets and reduced CD4+CD25high T lymphocytes. The L group had increased CD4+CD25low activated T lymphocytes, while the S group displayed elevated CD4+ human leucocyte antigen D-related (HLA-DR)+ activated T lymphocytes and decreased NK cells. We demonstrate that genetic factors may help to identify FM individuals with differentially altered frequencies of immune cells.

Catechol-O-methyltransferase gene haplotypes in Mexican and Spanish patients with fibromyalgia.

Autonomic dysfunction is frequent in patients with fibromyalgia (FM). Heart rate variability analyses have demonstrated signs of ongoing sympathetic hyperactivity. Catecholamines are sympathetic neurotransmitters. Catechol-O-methyltransferase (COMT), an enzyme, is the major catecholamine-clearing pathway. There are several single-nucleotide polymorphisms (SNPs) in the COMT gene associated with the different catecholamine-clearing abilities of the COMT enzyme. These SNPs are in linkage disequilibrium and segregate as 'haplotypes'. Healthy females with a particular COMT gene haplotype (ACCG) producing a defective enzyme are more sensitive to painful stimuli. The objective of our study was to define whether women with FM, from two different countries (Mexico and Spain), have the COMT gene haplotypes that have been previously associated with greater sensitivity to pain. All the individuals in the study were female. Fifty-seven Mexican patients and 78 Spanish patients were compared with their respective healthy control groups. All participants filled out the Fibromyalgia Impact Questionnaire (FIQ). Six COMT SNPs (rs2097903, rs6269, rs4633, rs4818, rs4680, and rs165599) were genotyped from peripheral blood DNA. In Spanish patients, there was a significant association between three SNPs (rs6269, rs4818, and rs4680) and the presence of FM when compared with healthy controls. Moreover, in Spanish patients with the 'high pain sensitivity' haplotype (ACCG), the disease, as assessed by the FIQ, was more severe. By contrast, Mexican patients displayed only a weak association between rs6269 and rs165599, and some FIQ subscales. In our group of Spanish patients, there was an association between FM and the COMT haplotype previously associated with high pain sensitivity. This association was not observed in Mexican patients. Studies with a larger sample size are needed in order to verify or amend these preliminary results.

Hereditary inflammatory vasculitis with persistent nodules. A genetically-determined new entity probably related to lupus erythematosus

A family of 3 generations is reported, in which several members had recurrent nodules over the limbs since early....