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

Abstract

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.

Background

The widespread chronic pain is a recognized cardinal symptom of fibromyalgia [1, 2]. Nevertheless, manifestations of central sensitization syndrome (CSS), such as fatigue, body stiffness, sleep disturbances, depression, anxiety, cognitive problems, and pain catastrophizing co-occur [1, 2]. The CSS refers to an amplification of pain by central nervous system mechanisms, and it is considered a main mechanism generator of pain hypersensitivity in conditions such as FM [3].

Positive and negative emotions and attention state can amplify the pain perception [4]. Pain catastrophizing is an exaggerated negative mental set brought to bear during an actual or an anticipated painful experience [5]. It comprises three dimensions: helplessness, magnification, and rumination [5]. More severe pain, as well as higher levels of pain behavior and disability, is detected in individuals who score higher on measures of pain catastrophizing [6]. Pain catastrophizing is a psychological factor that markedly predicts variability in the perception of pain as well as in the development of chronic pain conditions [6]. It has been associated with increased activity in pain-related areas of the brain [7, 8], and a decrease in the functioning of opioid-mediated endogenous analgesic systems [9]. Notably, the brain-derived neurotrophic factor (BDNF) is involved in central sensitization phenomena [10].

The BDNF is a neurotrophin from the nerve growth factor family implicated in several molecular processes in the central nervous system (CNS) [11, 12] modulating the formation, maturation, and plasticity of neuronal synapses [13]. The BDNF strengthens excitatory (glutamatergic) synapses and weakens inhibitory (GABAergic) synapses. Although preliminary, studies have indicated that the BDNF polymorphisms can be proneness factors to the severity of psychological symptoms associated with chronic pain (e.g., anxiety, depression, etc.) [14, 15]. The most common single nucleotide polymorphism in the BDNF gene (c.196G > A, dbSNP: rs6265) causes an amino acid substitution of valine to methionine at amino acid residue 66 (Val66Met; rs6265). This polymorphism alters intracellular trafficking and packaging of pro-BDNF and, consequently, the regulated secretion of the mature peptide [16]. Individuals with one or two copies of the BDNF Met allele seem to have decreased brain plasticity [17]. According to recent genome-wide study, the Val allele is related to a higher risk of chronic postsurgical pain [18]. And, it has been associated with the severity of depression [19, 20]). Thus, Val66Met polymorphism is a candidate for individual differences observed in neuroplasticity and, therefore, in behavioral pain conditions. Despite the well-known clinical relevance of pain catastrophizing, the neurobiological underpinnings of the phenomenon have just begun to be specified [21]. Furthermore, there is a persistent gap in the literature to investigate whether inter-subject genetic variation on BDNF Val66Met polymorphism might be a predictive factor of pain catastrophizing.

Thus, this study aimed to answer two questions: (i) whether the allele and genotype frequencies of BDNF Val66Met polymorphism differs between FM patients and HC; (ii) if the BDNF Val66Met polymorphism is a factor that markedly predicts pain catastrophizing in FM. Our hypothesis is that catastrophizing may be influenced by genetic factors and pain catastrophizing can predispose patients to more severe symptoms.

Methods

Design, settings and subjects

We conducted an exploratory cross-sectional study. This study was reported following the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) guidelines [22]. The Ethics Committee Board of the Hospital de Clínicas de Porto Alegre (HCPA) and Universidade Luterana do Brazil (ULBRA) approved the protocol of this study. All participants consent overtly before their participation.

Recruitment, inclusion and exclusion criteria

We recruited women older than 18. Patients were recruited from outpatient palliative medicine and pain clinics at a private-public hospital, physiotherapy clinics from the metropolitan region of Porto Alegre, Brazil, and by website and social network disclosure. Healthy volunteers were recruited from a blood donation service at the same hospital. Inclusion criteria for patients were: previous diagnosis of FM according to the American College of Rheumatology criteria [23]. Patients who presented illicit drug abuse or comorbidity with oncological disease were excluded. HC included in the study denied any condition of chronic pain, fibromyalgia, systemic lupus erythematosus, arthrosis, or rheumatoid arthritis or use of antidepressant drugs. Both groups were recruited from June 2016 to March 2018. FM patients were matched with controls according to age and gender.

Dependent and independent variables of main interest

The dependent variable was the Brazilian Portuguese version of the Pain Catastrophizing Scale (BP-PCS) (total score) and its domains: helplessness, magnification, and rumination (subscales’ scores) [24]. The main interest factors were the genotypes of Val66Met BDNF (rs6265) polymorphism.

Instruments and assessments

All tools, adapted and validated for the Brazilian population, were responded by the clinical group, except the Beck Depression Inventory II (BDI-II) and State-Trait Anxiety Inventory (STAI), which were answered by both clinical and control groups.

  1. a)

    Brazilian Portuguese version of the Pain Catastrophizing Scale (BP-PCS [24];) was applied to assess pain catastrophizing. It consists of 13 items (rated on a 5-point Likert-type scale) to assess patient’s thoughts and feelings when they are in pain. The scale is divided into three domains: helplessness (6 items), magnification (3 items), and rumination (4 items). The BP-PCS total score ranges from 0 to 52 points. A cutoff score of 30 represents clinically relevant level of catastrophizing [25].

  2. b)

    Resilience Scale adapted for the Brazilian population [26] was used to evaluate emotional resilience, defined as levels of positive psychosocial adaptation in the face of important life events. It comprises 25 items rated on a 7-point Likert-type scale and total score ranges from 25 to 175 points. Higher scores indicate higher resilience.

  3. c)

    Central Sensitization Inventory validated and adapted for Brazilian population (CSI-BP [27]) was applied to assess the severity of central sensitization. The inventory consists of 25 statements rated on 5-point Likert-type scale regarding current health symptoms (part A). Information about Central Sensitization Syndromes and related conditions are collected in part B of the inventory. The cutoff point suggested by CSI-BP is 35. The total score ranges from zero to 100.

  4. d)

    The Brazilian validated version of the Fibromyalgia Impact Questionnaire (FIQ [28];) was used to assess the impact of FM in quality of life of patients. The questionnaire consists of 10 items, and the higher the score obtained, the greater the impact of fibromyalgia on quality of life (maximum total score is 100).

  5. e)

    Pittsburgh Sleep Quality Index (PSQI) validated for Brazilian Portuguese [29] was used to evaluate the sleep quality and disturbances over a 1-month period. The index consists of multiple-choice questions that investigate: frequency of sleep disturbances; subjective sleep quality; typical bedtime; time of awakening; sleep latency; and, sleep duration. A global score ranges from zero to 21 whereas scores > 5 suggests poor sleep quality.

  6. f)

    Brazilian Portuguese version of the Beck Depression Inventory II (BDI-II [30];) was used to evaluate depressive symptoms in patients and controls. The BDI-II consists of 21 sets of statements about depression symptoms regarding the last 15 days, is rated from a zero to 3 ordinal scale (total score ranges from zero to 63 points). Patients can be classified according to severity of symptoms: 0–13, minimal/no depression; 14–19, mild depression; 20–28, moderate depression; and 29–63, severe depression.

  7. g)

    The State-Trait Anxiety Inventory (STAI) – short version, adapted to Brazilian Portuguese with a shorter version [31] was applied to evaluate anxiety. The scale is Likert-type and divided in two parts for the assessment of two types of anxiety: state-anxiety - a fact-driven transient anxiety; and, trait-anxiety - stable personality disposition, showing general level of fearfulness. The score ranges from 13 to 52 for the state-anxiety scale, and from 12 to 36 for the trait-anxiety scale. Higher scores denote higher levels of anxiety.

  8. h)

    Standardized Questionnaire was used to assess socio-demographic and health data (with extended medical information questions for FM patients).

Genetic analyses

Blood samples were collected by venipuncture in 4 ml tubes containing Ethylenediamine tetraacetic acid (EDTA), and centrifuged for plasma and cell separation. Total DNA was purified using the method described by Lahiri and Nurnberger [32]. The genotyping of Val66Met BDNF (rs6265) polymorphism was performed on a StepOnePlus™ Real-Time PCR System (Applied Biosystems Inc., Foster City, USA) using a predesigned TaqMan™ SNP genotyping assay (Thermo Fisher Scientific; catalog 4,351,379, assay ID: C__11592758_10).

Statistical analyses

Descriptive data are presented as mean (M), standard deviation (SD), standard error of mean (S.E.M.), frequency and percentages (%). For the inferential analyses, variables were compared between groups using Student’s t test or the nonparametric Mann-Whitney test for continuous variables and the chi-square test for categorical variables. Allele frequencies were determined by direct counting of the alleles and departures from Hardy-Weinberg equilibrium were evaluated by the chi-square test. Correlations between variables were tested by Pearson’s r coefficient. All tests were two-tailed and performed in SPSS software, version 18.0 (SPSS Inc., USA). P < 0.05 was considered statistically significant.

Results

The study recruited 112 subjects with FM, nevertheless 3 subjects were excluded because did not meet the inclusion criteria and one participant was excluded by problems during blood collection. The sample comprises 216 subjects (108 FM and 108 HC). Patients had the same geographic origin and are mainly of European ancestry. The clinical and demographic characteristics of the FM sample and controls groups are shown in Table 1. In the FM sample 81.5% of the patients used pain relief medications, most (51.9%) performed physical exercise, mostly aerobic. And, 58.3% of the patients searched for complementary methods for pain management.

Table 1 – Socio-demographic and clinical characteristics of FM patients and controls (n = 216)

Among FM patients, 30.6% spontaneously reported traumatic life events. Childhood traumatic experiences reported through CSI-BP (item 24) were detected in most patients (51.9%). When we compared socio-demographic characteristics among FM and HC, there were significant differences in years of education and functional situation between groups. Indeed, as expected, there were also significant differences in anxiety and depressive symptoms, between FM and control groups (Table 1).

Allele and genotype frequencies of the Val66Met BDNF polymorphism are shown in Table 2. Allele frequencies were significantly different between FM and control groups (p < 0.05). The genotype frequencies are in Hardy-Weinberg equilibrium in both groups.

Table 2 − Allele and genotype frequencies of the Val66Met variant (n = 216)

The score on the BP-PCS was compared between Val/Val and Val/Met genotypes in the FM patients (Fig. 1). Val/Val genotype was significantly associated to magnification and rumination domains (p < 0.05). FM patients carrying the Val/Val genotype displayed higher scores in pain catastrophizing scale (total score) and in the helplessness domain compared to the Val/Met genotype. However, these differences were non-significant. Analysis of endophenotypes involved in FM and their association with Val66Met BDNF polymorphism are shown in Supplementary Table 1.

Fig. 1
figure1

Pain catastrophizing scale (total and sub-scales’ scores) in the FM sample according to Val66Met genotypes. Notes. Data are shown as mean and error standard of mean (S.E.M.)

Total BP-PCS scores and subscores and total FIQ and BP-SCI scores were correlated according to Val66Met genotypes (Table 3). Impact of FM in quality of life of patients showed positive relation with central sensitization symptoms regardless of genotypes. Also, catastrophizing showed positive relation with central sensitization symptoms and impact of FM in quality of life in both groups. However, strong and moderate positive correlations were mostly found in the Val/Met group.

Table 3 - Correlation between pain catastrophizing, central sensitization and impact of fibromyalgia according to genotype (n = 108)

Discussion

In the present study the main findings are that Val allele is more frequent in FM, while the Met allele is most frequent in the control subjects, and that in FM the BDNF Val/Val homozygotes are a potential genetic risk factor associated with higher scores in the Pain Catastrophizing Scale domains: magnification and rumination. From a conceptual perspective, this emerging finding helps to explain the neurobiology processes underpinning pain catastrophizing. Its potential clinical relevance is aligned with the view that pain catastrophizing has been a predictive factor of treatment response [5, 33]. Thus, it may help to integrate the interplay between Val66Met polymorphism and clinical symptoms in the bedside clinical assessment.

In this framework, the higher magnification and rumination levels in the homozygotes Val/Val gives support for this hypothesis that this genotype do not provide sufficient compensatory mechanisms to improve the resilience of the neurobiological system involved in the physiopathology of chronic pain, whereas the severity of these symptoms can be a dysfunctional response related to somatosensory processes. This could an evidence of a distinct subjective pain experience in those with higher levels catastrophizing, somatization, depression, anxiety, and anger [34,35,36]. As have been noted, these behaviors can indicate the patients have difficulties in recruiting healthy coping strategies and exacerbate psychological and clinical symptoms [37,38,39].

Accordingly, a previous study showed that individuals Val/Val exposed to stressful events early in life presented increased anxiety and higher volumes of brain structures, such as the amygdala and medial prefrontal gray matter [40]. Furthermore, in another study evaluating anxiety, Val homozygotes had higher levels of trait-anxiety compared to Met allele carriers [14]. Also, an over-representation of the Val allele and lower frequency of the Met allele was detected in patients with bipolar disorders [41]. Likewise, an earlier study with a similar perspective, showed that pain catastrophizing was associated with the rs1176744 polymorphism of the serotonin receptor 3B (5-HT3B) gene in healthy individuals [42].

Although the design of this study prevents establishing a cause-consequence relationship between the Val66Met polymorphism and the rumination and magnification in the FM, these findings may hold clinical implications. One of them is the idea that some genetic characteristics related to neuroplasticity processes may predispose individuals with FM to more severe clinical symptoms. Besides, they reinforce the assumption that the severity of rumination and magnification is a challenge in the management of pain symptoms because they adversely compromise the prognosis of FM. From the point of view of a coping style, pain catastrophizing may become a maladaptive response, leading to a substantial negative impact in the quality of life of FM patients [43]. Furthermore, it is one of the strongest predictors of the outcomes of therapeutic approaches in chronic pain [5, 33].

The BDNF Val66Met polymorphism has been investigated in several pathological conditions in humans [44,45,46]. The Met allele was reported as a protective factor against anxiety disorders due to its putative impairment of amygdala-dependent aversive memory acquisition/consolidation [47]. However, there is controversy regarding which allele of Val66Met polymorphism is associated with risk or protection (harmful or beneficial) in relation to pathological conditions [41, 45,46,47,48]. It is possible that the Met allele has pleiotropic effects. The downregulation of synaptic plasticity by Met, particularly in excitatory glutamatergic circuits is discussed as protective against psychiatric disorders [49], despite Met allele being associated with reduced cognitive performance, which suggests decreased brain plasticity [16, 17, 50, 51]. According to an earlier study in a paradigm of use-dependent plasticity, authors found reduced changes in motor cortical excitability in Met carriers [52]. Although we are aware that our results open a way to advance in the comprehension of the complex pathophysiology of FM, which is mediated by multiple systems (i.e., GABAergic, glutamatergic, noradrenergic, serotonergic, etc.), this findings need to be interpreted cautiously.

Aligned with this perspective of the relationship between the BDNF polymorphism and clinical symptoms, it is plausible that Met allele determine some mechanisms associated with the improvement of dysfunctional circuits involved in the imbalance of excitatory and inhibitory systems underlying pain catastrophizing. This hypothesis finds some support in a previous study that found a positive correlation between pain catastrophizing and cortical disinhibition [2]. Another study gives support for this assumption as well, due to the authors found an association between increased cortical disinhibition and higher serum levels of BDNF in chronic pain [53]. From a theoretical perspective, this association may indicate a deteriorated function of cortical inhibition.

BDNF Val66Met frequencies vary widely among different populations [48]. We detected significant differences in allele frequencies of the BDNF Val66Met polymorphism between FM patients and controls. The frequency of the minor allele (Met) (16.2%) observed in our control group was consistent with those previously reported in control groups of studies performed in the Brazilian population [54, 55].

Certain limitations must be considered in the interpretation of our findings. First, despite our sample size was large in comparison to previous reports in the literature concerning genetic variants of FM [56,57,58,60,61], its statistical power is limited. Second, this is a cross-sectional study, which may limit causality identification of the demographic and clinical variables investigated. Finally, it is not simple to understand how to apply this knowledge about pain catastrophizing and BDNF Val66Met polymorphism in the clinical practice.

Conclusion

In conclusion, the present study showed an association between Val66Met BDNF polymorphism with the FM, providing new insights into the genetically specified processing of pain catastrophizing. However, further studies are needed to elucidate if the role of Val66Met BDNF polymorphism could help to plan personalized therapeutic approaches in FM.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

BDI-II:

Beck Depression Inventory II

BDNF:

Brain-derived neurotrophic factor

BP PCS:

Brazilian Portuguese - Pain Catastrophizing Scale

CNS:

Central nervous system

CSI-BP:

Central Sensitization Inventory validated and adapted for Brazilian population

CSS:

Central sensitization syndrome

EDTA:

Ethylenediamine tetraacetic acid

FIQ:

Fibromyalgia Impact Questionnaire

FM:

Fibromyalgia

HC:

Healthy controls

HCPA:

Hospital de Clínicas de Porto Alegre

PCR:

Polymerase chain reaction

PSQI:

Pittsburgh Sleep Quality Index

S.E.M:

Standard error of mean

SD:

Standard deviation

STAI:

State-Trait Anxiety Inventory

STROBE:

Strengthening the Reporting of Observational studies in Epidemiology

ULBRA:

Universidade Luterana do Brasil

References

  1. 1.

    Clauw DJ. Fibromyalgia: a clinical review. JAMA. 2014;311(15):1547–55.

    PubMed  Google Scholar 

  2. 2.

    Volz MS, Suarez-Contreras V, Portilla AL, Fregni F. Mental imagery-induced attention modulates pain perception and cortical excitability. BMC Neurosci. 2015;16:15.

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Harte SE, Harris RE, Clauw DJ. The neurobiology of central sensitization. J Appl Behav Res. 2018;23(2):e12137.

    Google Scholar 

  4. 4.

    Crofford LJ. Psychological aspects of chronic musculoskeletal pain. Best Pract Res Clin Rheumatol. 2015;29(1):147–55.

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Sullivan MJL, Thorn B, Keefe FJ, Martin M, Bradley LA, Lefebvre JC. Theoretical perspectives on the relation between catastrophizing and pain. Clin J Pain. 2001;17(1):52–64.

    CAS  PubMed  Google Scholar 

  6. 6.

    Sullivan MJL, Adams A, Rhodenizer T, Stanish WD. A psychosocial risk factor targeted intervention for the prevention of chronic pain and disability following whiplash injury. Phys Ther. 2006;86(1):8–18.

    PubMed  Google Scholar 

  7. 7.

    Gracely RH, Geisser ME, Giesecke T, Grant MA, Petzke F, Williams DA, et al. Pain catastrophizing and neural responses to pain among persons with fibromyalgia. Brain. 2004;127(Pt4):835–43.

    CAS  PubMed  Google Scholar 

  8. 8.

    Seminowicz DA, Davis KD. Cortical responses to pain in healthy individuals depends on pain catastrophizing. Pain. 2006;120(3):297–306.

    PubMed  Google Scholar 

  9. 9.

    Edwards RR, Kronfli T, Haythornthwaite JA, Smith MT, McGuire L, Page GG. Association of catastrophizing with interleukin-6 responses to acute pain. Pain. 2008;140(1):135–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Nijs J, Meeus M, Versijpt J, Moens M, Bos I, Knaepen K, et al. Brain-derived neurotrophic factor as a driving force behind neuroplasticity in neuropathic and central sensitization pain: a new therapeutic target? Expert Opin Ther Targets. 2015;19(4):565–76.

    CAS  PubMed  Google Scholar 

  11. 11.

    Teixeira AL, Barbosa IG, Diniz BS, Kummer A. Circulating levels of brain-derived neurotrophic factor: correlation with mood, cognition and motor function. Biomark Med. 2010;4(6):871–87.

    CAS  PubMed  Google Scholar 

  12. 12.

    Park H, Poo M. Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci. 2013;14(1):7–23.

    CAS  PubMed  Google Scholar 

  13. 13.

    Miró E, Lupiáñez J, Hita E, Martínez MP, Sánchez AL, Buela-Casal G. Attentional deficits in fibromyalgia and its relationships with pain, emotional distress and sleep dysfunction complaints. Psychol Health. 2011;26(6):765–80.

    PubMed  Google Scholar 

  14. 14.

    Lang UE, Hellweg R, Kalus P, Bajbouj M, Lenzen KP, Sander T, et al. Association of a functional BDNF polymorphism and anxiety-related personality traits. Psychopharmacology. 2005;180(1):95–9.

    CAS  PubMed  Google Scholar 

  15. 15.

    Zhao M, Chen L, Yang J, Han D, Fang D, Qiu X, et al. BDNF Val66Met polymorphism, life stress and depression: a meta-analysis of gene-environment interaction. J Affect Disord. 2018;227:226–35.

    CAS  PubMed  Google Scholar 

  16. 16.

    Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, et al. The BDNF val66met polymorphism affects activity-depend secretion of BDNF and human memory and hippocampal function. Cell. 2003;112(2):257–69.

    CAS  PubMed  Google Scholar 

  17. 17.

    Dincheva I, Glatt CE, Lee FS. Impact of the BDNF Val66Met polymorphism on cognition: implications for behavioral genetics. Neuroscientist. 2012;18(5):439–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Tian Y, Liu X, Jia M, Yu H, Lichtner P, Shi Y, et al. Targeted genotyping identifies susceptibility locus in brain-derived Neurotrophic factor for chronic postsurgical pain. Anesthesiology. 2018;128(5):587–97.

    CAS  PubMed  Google Scholar 

  19. 19.

    Verhagen M, van der Meij A, van Deurzen PA, Janzing JG, Arias-Vásquez A, Buitelaar JK, et al. Meta-analysis of the BDNF Val66Met polymorphism in major depressive disorder: effects of gender and ethnicity. Mol Psychiatry. 2010;15(3):260–71.

    CAS  PubMed  Google Scholar 

  20. 20.

    Lavebratt C, Åberg E, Sjöholm LK, Forsell Y. Variations in FKBP5 and BDNF genes are suggestively associated with depression in a Swedish population-based cohort. J Affect Disord. 2010;125(1–3):249–55.

    CAS  PubMed  Google Scholar 

  21. 21.

    Campbell CM, Edwards RR. Mind-body interactions in pain: the neurophysiology of anxious and catastrophic pain-related thoughts. Transl Res. 2009;153(3):97–101.

    PubMed  PubMed Central  Google Scholar 

  22. 22.

    von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP. The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. Ann Intern Med. 2007;147(8):573–7.

    Google Scholar 

  23. 23.

    Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Häuser W, Katz RL, Mease PJ, Russell AS, Russell IJ, Walitt B. 2016 revisions to the 2010/2011 fibromyalgia diagnostic criteria. Semin Arthritis Rheum. 2016;46(3):319–29.

    PubMed  Google Scholar 

  24. 24.

    Sehn F, Chachamovich E, Vidor LP, Dall-Agnol L, de Souza IC, Torres IL, et al. Cross-cultural adaptation and validation of the Brazilian Portuguese version of the pain catastrophizing scale. Pain Med. 2012;13(11):1425–35.

    PubMed  Google Scholar 

  25. 25.

    Sullivan MJL. The Pain Catastrophizing Scale: user manual. 5th edition. Montreal, Quebec, McGill University, School of Physical and Occupational Therapy; 2009. p. 1–36.

    Google Scholar 

  26. 26.

    Pesce RP, Assis SG, Avanci JQ, Santos NC, Malaquias JV, Carvalhaes R. Cross-cultural adaptation, reliability and validity of the resilience scale. Cad Saude Publica. 2005;21(2):436–48.

    PubMed  Google Scholar 

  27. 27.

    Caumo W, Antunes LC, Elkfury JL, Herbstrith EG, Busanello Sipmann R, Souza A, et al. The central sensitization inventory validated and adapted for a Brazilian population: psychometric properties and its relationship with brain-derived neurotrophic factor. J Pain Res. 2017;10:2109–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Marques AP, Santos AMB, Ana Assumpção A, Matsutani LK, Lage LV, Pereira CAB. Validation of the brazilian version of the fibromyalgia impact questionnaire (FIQ). Rev Bras Reumatol. 2006;46(1):24–31.

    Google Scholar 

  29. 29.

    Bertolazi AN, Fagondes SC, Hoff LS, Dartora EG, Miozzo IC, de Barba ME, et al. Validation of the Brazilian Portuguese version of the Pittsburgh sleep quality index. Sleep Med. 2011;12(1):70–5.

    PubMed  Google Scholar 

  30. 30.

    Gorenstein C, Pang WY, Argimon IL, Werlang BSG. Inventário Beck de Depressão-II. Manual. Casa do Psicólogo: São Paulo; 2011.

    Google Scholar 

  31. 31.

    Kaipper MB, Chachamovich E, Hidalgo MP, Torres IL, Caumo W. Evaluation of the structure of Brazilian state-trait anxiety inventory using a Rasch psychometric approach. J Psychosom Res. 2010;68(3):223–33.

    PubMed  Google Scholar 

  32. 32.

    Lahiri DK, Nurnberger JI Jr. A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res. 1991;19(19):5444.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Craner JR, Gilliam WP, Sperry JA. Rumination, magnification, and helplessness: how do different aspects of pain catastrophizing relate to pain severity and functioning? Clin J Pain. 2016;32(12):1028–35.

    PubMed  Google Scholar 

  34. 34.

    Ochsner KN, Ludlow DH, Knierim K, Hanelin J, Ramachandran T, Glover GC, et al. Neural correlates of individual differences in pain-related fear and anxiety. Pain. 2006;120(1–2):69–77.

    PubMed  Google Scholar 

  35. 35.

    Pelletier R, Higgins J, Bourbonnais D. Addressing Neuroplastic changes in distributed areas of the nervous system associated with chronic musculoskeletal disorders. Phys Ther. 2015;95(11):1582–91.

    PubMed  Google Scholar 

  36. 36.

    Zhuo M. Neural mechanisms underlying anxiety-chronic pain interactions. Trends Neurosci. 2016;39(3):136–45.

    CAS  PubMed  Google Scholar 

  37. 37.

    Benyon K, Muller S, Hill S, Mallen C. Coping strategies as predictors of pain and disability in older people in primary care: a longitudinal study. BMC Fam Pract. 2013;14:67.

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Alschuler KN, Molton IR, Jensen MP, Riddle DL. Prognostic value of coping strategies in a community-based sample of persons with chronic symptomatic knee osteoarthritis. Pain. 2013;154(12):2775–81.

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    Sullivan MJL, Lynch ME, Clark AJ. Dimensions of catastrophic thinking associated with pain experience and disability in patients with neuropathic pain conditions. Pain. 2005;113(3):310–5.

    PubMed  Google Scholar 

  40. 40.

    Gatt JM, Nemeroff CB, Dobson-Stone C, Paul RH, Bryant RA, Schofield PR, Gordon E, Kemp AH, Williams LM. Interactions between BDNF Val66met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety. Mol Psychiatry. 2009;14(7):681–95.

    CAS  PubMed  Google Scholar 

  41. 41.

    Sklar P, Gabriel SB, McInnis MG, Bennett P, Lim YM, Tsan G, et al. Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Mol Psychiatry. 2002;7(6):579–93.

    CAS  PubMed  Google Scholar 

  42. 42.

    Horjales-Araujo E, Demontis D, Lund EK, Finnerup NB, Børglum AD, Jensen TS, et al. Polymorphism in serotonin receptor 3B is associated with pain catastrophizing. PLoS One. 2013;8(11):e78889.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Borsbo B, Peolsson M, Gerdle B. Catastrophizing, depression, and pain: correlation with and influence on quality of life and health – a study of chronic whiplash-associated disorders. J Rehabil Med. 2008;40(7):562–9.

    PubMed  Google Scholar 

  44. 44.

    Schumacher J, Jamra RA, Becker T, Ohlraun S, Klopp N, Binder EB, et al. Evidence for a relationship between genetic variants at the brain-derived neurotrophic factor (BDNF) locus and major depression. Biol Psychiatry. 2005;58(4):307–14.

    CAS  PubMed  Google Scholar 

  45. 45.

    Quian L, Zhao J, Shi Y, Zhao X, Feng G, Xu F, et al. Brain-derived neurotrophic factor and risk of schizophrenia: an association study and meta-analysis. Biochem Biophys Res Commun. 2007;353(3):738–43.

    Google Scholar 

  46. 46.

    Kaess M, Preis SR, Lieb W, Beiser AS, Yang Q, Chen TC, et al. Circulating brain-derived neurotrophic factor concentrations and the risk of cardiovascular disease in the community. J Am Heart Assoc. 2015;4(3):e001544.

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    Lonsdorf TB, Weike AI, Golkar A, Schalling M, Hamm AO, Öhman A. Amygdala-dependent fear conditioning in humans is modulated by the BDNFval66met polymorphism. Behav Neurosci. 2010;124(1):9–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Petryshen TL, Sabeti PC, Aldinger KA, Fry B, Fan JB, Schaffner SF, et al. Population genetic study of the brain-derived neurotrophic factor (BDNF) gene. Mol Psychiatry. 2010;15(8):810–5.

    CAS  PubMed  Google Scholar 

  49. 49.

    Lipsky RH, Marini AM. Brain-derived neurotrophic factor in neuronal survival and behavior-related plasticity. Ann N Y Acad Sci. 2007;1122:130–43.

  50. 50.

    Hariri AR, Goldberg TE, Mattay VS, Kolachana BS, Callicott JH, Egan MF, et al. Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci. 2003;23(17):6690–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Rybakowski JK, Borkowska A, Czerski PM, Skibinska M, Hauser J. Polymorphism of the brain-derived neurotrophic factor gene and performance on a cognitive prefrontal test in bipolar patients. Bipolar Disord. 2003;5(72):468–72.

    CAS  PubMed  Google Scholar 

  52. 52.

    Kleim JA, Chan S, Pringle E, Schallert K, Procaccio V, Jimenez R, et al. BDNF val66met polymorphism is associated with modified experience-dependent plasticity in human motor cortex. Nat Neurosci. 2006;9(6):735–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Caumo W, Deitos A, Carvalho S, Leite J, Carvalho F, Dussan-Sarria JA, et al. Motor cortex excitability and BDNF levels in chronic musculoskeletal pain according to structural pathology. Front Hum Neurosci. 2016;10:357.

    PubMed  PubMed Central  Google Scholar 

  54. 54.

    Rocha FF, Malloy-Diniz L, Lage NV. Positive association between MET allele (BDNF Val66Met polymorphism) and obsessive-compulsive disorder. Rev Bras Psiquiatr. 2010;32(3):323–4.

    PubMed  Google Scholar 

  55. 55.

    Grande I, Magalhaes PVS, Chendo I, Sterz L, Fries GR, Cereser KM, et al. Val66Met polymorphism and serum brain-derived neurotrophic factor in bipolar disorder: an open-label trial. Acta Psychiatr Scand. 2014;129(5):393–400.

    CAS  PubMed  Google Scholar 

  56. 56.

    Potvin S, Larouche A, Normand E, de Souza JB, Gaumond I, Marchand S, et al. No relationship between the ins del polymorphism of the serotonin transporter promoter and pain perception in fibromyalgia patients and healthy controls. Eur J Pain. 2010;14(7):742–6.

    CAS  PubMed  Google Scholar 

  57. 57.

    Matsuda JB, Barbosa FR, Morel LJ, França Sde C, Zingaretti SM, da Silva LM, et al. Serotonin receptor (5-HT 2A) and catechol-O-methyltransferase (COMT) gene polymorphisms: triggers of fibromyalgia? Rev Bras Reumatol. 2010;50(2):141–9.

    PubMed  Google Scholar 

  58. 58.

    Finan PH, Zautra AJ, Davis MC, Lemery-Chalfant K, Covault J, Tennen H. COMT moderates the relation of daily maladaptive coping and pain in fibromyalgia. Pain. 2011;152(2):300–7.

    PubMed  Google Scholar 

  59. 59.

    Xiao Y, He W, Russell IJ. Genetic polymorphisms of the beta2-adrenergic receptor relate to guanosine protein-coupled stimulator receptor dysfunction in fibromyalgia syndrome. J Rheumatol. 2011;38(6):1095–103.

    CAS  PubMed  Google Scholar 

  60. 60.

    Xiao Y, Russell IJ, Liu YG. A brain-derived neurotrophic factor polymorphism Val66Met identifies fibromyalgia syndrome subgroup with higher body mass index and C-reactive protein. Rheumatol Int. 2012;32(8):2479–85.

    CAS  PubMed  Google Scholar 

  61. 61.

    Desmeules J, Chabert J, Rebsamen M, Rapiti E, Piguet V, Besson M, Dayer P, Cedraschi C. Central pain sensitization, COMT Val158Met polymorphism, and emotional factors in fibromyalgia. J Pain. 2014;15(2):129–35.

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank the patients and healthy volunteers.

Funding

This research was supported by grants and material support from the following Brazilian agencies: Coordination for the Improvement of Higher Education Personnel from Brazil (CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior; Finance Code 001), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS, research grant 15/2551–0001012-4), and Postgraduate Research Group at the Hospital de Clínicas de Porto Alegre – FIPE-HCPA. The funding sources had no involvement in the study design, collection, analysis and interpretation of data, writing of the report, and the decision to submit the article for publication.

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Contributions

C.F.S. Alves, W. Caumo and D. Simon designed the study. C.F.S. Alves, J.M. Silvestri, V.S dos Santos, D.F. Cardoso collected the data. C.F.S. Alves, W. Caumo, D. Simon performed the statistical analysis. C.F.S. Alves, W. Caumo, M. Zortea, A. Regner, A.H. de Souza and D. Simon interpreted and discussed the results. C.F.S. Alves, W. Caumo and D. Simon wrote the paper. C.F.S. Alves, W. Caumo, M. Zortea, V.S. dos Santos, A. Regner, A.H. de Souza and D. Simon contributed to the final version of the manuscript. All authors have reviewed and approved the final version of the article, including the authorship list.

Corresponding author

Correspondence to Daniel Simon.

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Ethics approval and consent to participate

This study was approved by the Ethics Committee Board of the Hospital de Clínicas de Porto Alegre (HCPA) and Universidade Luterana do Brazil (ULBRA) - Applications No. 1570266 and 1620891. All subjects signed the informed consent form. The study was conducted in accordance with the principles of the Declaration of Helsinki.

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Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Supplementary information

Additional file 1 Table S1.

Psychological and clinical characteristics in the FM sample according to Val66Met genotypes.

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da Silveira Alves, C.F., Caumo, W., Silvestri, J.M. et al. Pain catastrophizing is associated with the Val66Met polymorphism of the brain-derived neurotrophic factor in fibromyalgia. Adv Rheumatol 60, 39 (2020). https://doi.org/10.1186/s42358-020-00141-9

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Keywords

  • Fibromyalgia
  • Pain catastrophizing
  • BDNF
  • Single nucleotide polymorphism
  • Val66Met