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

Abstracts

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 ação protetora para a relação entre fibromialgia e estresse

fibromialgia; estresse; qualidade ambiental; interações gene x ambiente; apolipoproteína E

ORIGINAL ARTICLE

^IPhysical Therapist, Master's Degree in Environmental Quality at Universidade Feevale, Adjunct Professor of the Physical Therapy Course at Universidade Feevale

^IIBiomedical Instituto de Ciências da Saúde, Universidade Feevale

^IIIPsychology Undergraduate student, Instituto de Ciências Humanas, Letras e Artes, Universidade Feevale

^IVB.Sc. in Biomedical Sciences, Master's Degree in Environmental Quality at Universidade Feevale

^VPsychologist, Master's Degree and Ph.D. in Psychology; Full Professor of the Psychology Course, and Master's Degree in Accessibility and Social Inclusion at Universidade Feevale

^VIBiologist, Master's Degree and Ph.D. in Genetics and Molecular Biology; Full Professor of the Psychology and Biomedical Sciences Courses, and Master's degree in Environmental Quality at Universidade Feevale

Correspondence to

ABSTRACT

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.

Keywords: fibromyalgia, stress, environmental quality, gene x environment interaction, apolipoprotein E.

INTRODUCTION

Fibromyalgia (FM) is a disease characterized by a clinical history of generalized muscle pain for more than three months and by specific tender points. The diagnosis is basically clinical¹ with no evidence of laboratory or imaging abnormalities. According to Neumann and Buskilla,² the prevalence of fibromyalgia in different countries is estimated at 2% in general population. The syndrome prevalence increases with age (approximately 1% in women aged 18 to 29 years and 7% in women aged 70 to 79 years). To date, no scientific investigation seeking to determine FM prevalence has been published for Brazilian populations.

Studies carried out to date have demonstrated that FM is a multifactorial disease, with a possible genetic susceptibility being necessary, but not enough to trigger it.^2,3 This genetic predisposition, when associated with environmental factors, among which are stressor agents related to psychosocial and emotional aspects, seem to increase the risk for symptom triggering and aggravation. Wood⁴ stated that fibromyalgia has been called a "stress-related disorder" due to the fact that its symptom onset and/or exacerbation occur in the context of stressor events. Van Houdenhove et al.⁵ determined that stress was an etiopathogenic factor for FM, as long as it was associated with genetic predisposition factors.

In spite of this evidence, the genes involved with the disease are yet to be determined, as well as how the gene variability interacts with environmental factors. These investigations are mainly related to serotonergic system genes,^6,7 but no study has attempted to correlate the apolipoprotein E (APOE) gene with fibromyalgia.

The role of APOE on stress response and its association with chronic pain has been recorded by both clinical^8,9 and experimental studies.^10,11 These studies have demonstrated that APOE levels are related with stress response, induced pain in animal models and different types of chronic pain in humans. Still, no study had attempted to associate the variation of apo E protein type, codified by three different alleles called E*2, E*3 and E*4, with fibromyalgia susceptibility.

Therefore, the present study aims at investigating whether the environmental quality and stress levels are fibromyalgia-related factors and also whether any of the APOE gene alleles is associated with the risk of developing fibromyalgia. Additionally, the interaction among these three variables will be tested, in order to determine the association among them as well as their influence on fibromyalgia.

PATIENTS AND METHODS

Patients

The sample consisted of 41 adult female individuals, with a clinical diagnosis of fibromyalgia according to the criteria established by the American College of Rheumatology (ACR),¹ with a mean age of 47.93 ± 11.21 years. The exclusion criteria included the presence of cognitive deficit and motor incapacity. Patients underwent psychological evaluation aimed at determining stress levels through the Lipp Stress Symptom Inventory for Adults (ISSL)¹² and answered a questionnaire on environmental quality (WHOQOL-100 domain V),¹³ which was applied retrospectively, i.e., patients were asked to answer the questions based on the time period before symptom onset.

The control sample consisted of 49 adult female individuals, with a mean age of 41.48 ± 10.78 years. All control individuals were evaluated regarding clinical symptoms and presence of tender points at palpation. The control sample only included individuals that did not meet the criteria for a clinical diagnosis of fibromyalgia, according to the ACR criteria.¹ Moreover, control individuals were submitted to a psychological assessment through the ISLL to determine stress levels and the volunteers also answered the questionnaire on environmental quality (WHOQOL-100 domain V).

All individuals included in the study live in the town of Novo Hamburgo, state of Rio Grande do Sul, Brazil and the FM patients are treated at the Physical Therapy Clinic and/or Extension Project that treats FM patients at Centro Universitário Feevale.

Genotyping methods

DNA from both samples was extracted from total blood, following the technique described by Lahiri and Nurnberger.¹⁴ The APOE exon 4 polymorphism was genotyped through the PCR/RFLP technique, as described by de Andrade et al.,¹⁵ at the Laboratory of Genetics and Molecular Biology of Centro Universitário Feevale. This genotyping method detects the presence of three possible alleles in the APOE gene, called E*2, E*3 E and*4, and their combination results in the possible existence of three homozygous genotypes (E*2/ E*2, E*3/ E*3 and E*4/ E*4), and three different heterozygous ones (E*2/ E*3, E*2/ E*4 and E*3/ E*4) in the sample.

Environment-related quality of life assessment method

The World Health Organization has developed a tool to evaluate quality of life through a multicentric project called WHOQOL-100. The Portuguese version of this tool has been developed at the Department of Psychiatry and Forensics of Universidade Federal do Rio Grande do Sul (UFRGS) and published by Fleck et al.¹³

The WHOQOL-100 consists of 6 domains, of which one - Domain V (Environment) - was selected for the present study. This domain evaluates the following aspects: physical safety and protection; home environment; financial resources; availability and quality of social and health care; opportunity to acquire new information and skills; participation in and opportunities of recreation and leisure activities; physical environment (pollution, noise, traffic, climate); and transportation.

Behavioral stress assessment method: the Lipp stress symptom inventory for adults (ISSL)

According to Lipp,¹² this inventory aims at objectively identifying whether the individual has stress symptoms and if they are predominantly physical or psychological. This inventory also establishes which stress phase the individual currently presents: alarm, resistance, near exhaustion and exhaustion. The alarm phase identifies the moment when the individual is getting ready to face the problem or flee from it, preserving his existence. At the second phase, resistance, the individual is trying to adapt in order to survive and find balance and sensations of weariness and fatigue appear. The third phase is that of almost exhaustion, when the individual cannot deal with unremitting stressor events and starts to get ill. When the situation becomes even worse, the fourth and last phase appears, exhaustion, in which all of the individual's adaptive energy has been spent and which determines the onset of the most severe diseases.

Statistical methods

The WHOQOL domain V score, as well as the separate assessment of each aspect, were carried out according to the test instructions (available at http://www.ufrgs.br/psiq/whoqol85.html). Thus, the final scores of each volunteer varied from 0 to 20 for each aspect and also in Domain V, in general.

To assess the genetic and environmental influence separately, t test and chi-square test were used. To assess genetic and environmental influence together, the multivariate logistic regression was used. The regression model used in the study was the "backward stepwise" model, after the removal of the least significant variable for each analysis, starting with the interactions. The simple variables included in the model were stress levels (codified as '1' - exhaustion or near exhaustion and '0' - no stress or resistance), WHOQOL domain V scores codified according to the 50^th percentile, as '1' for values < 13.05, and '0' for values > 13.05) and APOE genotypes as two dummy variables (E*2 allele carriers and E*4 allele carriers). The tested interactions were all the possible ones among the simple variables included in the model (a total of five). All tests were carried out with the software SPSS for Windows, release 11.0.

Ethical implications

The present project was submitted to and approved by the Ethics Committee of Centro Universitário Feevale, # 2.02.02.06.346, and sample collection were started only after project approval. All volunteers signed the Free and Informed Consent Form before study enrollment.

RESULTS

Table 1 shows that stress levels differ significantly between FM patients and controls (P < 0.001). Most patients (62.5%) are at the "Exhaustion" or "Near Exhaustion" level, whereas this group corresponds to 8.6% of the control sample; moreover, almost half of the control individuals (48.9%) showed no stress, when compared to only 5% of the FM patients in the same category.

The mean WHOQOL questionnaire scores for both groups are shown in Figure 1 and it is possible to observe that there was a statistically significant difference between patients and controls (P < 0.001, Figure 1), with controls presenting a better environmental domain quality (14.43 ± 1.96) when compared to patients (11.48 ± 2.15).

Table 2 shows the analysis of APOE polymorphism influence on FM susceptibility. Therefore, the frequencies of the three alleles (E*2, E*3 and E*4) and of four genotypes were compared between patient and control samples. This univariate analysis showed that, as there is no statistically significant difference, it was not possible to prove the isolated influence of this gene on the disease.

Aiming at evaluating whether the isolated factors investigated in the study (stress, environmental quality and APOE polymorphism) had any influence on FM when assessed together, a multivariate logistic regression was carried out, which included interaction variables. Table 3 shows the parameters of each model tested by the backward modeling technique. Based on these data, it is possible to observe that the parameters related to the different models are practically not modified after the removal of the interaction variables, and that all regressions performed are highly significant (P < 0.001). Therefore, the 5^th model was chosen, as it contains the lowest confidence intervals for the odds ratio (OR) values. Thus, Table 4 demonstrates the most adequate regression model, with the interpretation of the identified interaction. These data confirmed the influence of the environment on the disease, as we identified individuals with the assessed domain scores < 13.05 (50^th percentile), that is, individuals with bad environmental quality had a 57.7-higher chance of developing FM (P = 0.001). Similarly, the association between FM and stress was confirmed by this analysis (OR = 197.2; P = 0.001), but no interaction between stress levels and environment was identified. This analysis demonstrated that the presence of the two rare APOE alleles (E*2 and E*4) is not related, individually, with the chance of developing FM, but that there is a significant interaction between the presence of the E*2 allele and stress levels (P = 0.028). Therefore, the calculation of OR estimated in each group demonstrated that in the group of women who were E*2-allele carriers and had high stress levels, the chance of developing the disease was 1.06, whereas in the group of non-carriers, but who still had high stress levels, this chance increased to 265.1, thus demonstrating the protective role of the E*2 allele presence.

DISCUSSION

The present study aimed at investigating the association between stress levels, environmental quality, APOE gene variation and how these variables interacted to influence FM susceptibility. As FM is a multifactorial etiology syndrome that remains poorly understood, the increase in the number of studies on its bases, physiological as well as genetic and environmental ones, is of utmost importance.

The use of Lipp Stress Symptom Inventory for Adults (ISSL) showed a high stress level among patients. Although the association between fibromyalgia and stress has been pointed out in the literature^3,4, to date no study had investigated this association in Brazilian patients. The present study demonstrated a very high number (95%) of women with FM that presented some level of stress, when compared to 51.2% in the control sample. These figures are much higher than those identified in other Brazilian studies. Moreira et al.¹⁶, when investigating infertile women, identified that almost 62% presented some level of stress. Santos and Alves Jr.,¹⁷ when evaluating Master's Degree students in the state of Sergipe, Brazil, identified a value of 40.7%, although with a significant variation between the genders: 80% of the women and 18% of the men. Another study that demonstrated that stress is more frequently observed in women is the one performed by Calais et al.¹⁸, in a sample of young individuals from the city of Campinas, state of Sao Paulo, Brazil, showing that 79% of young female individuals had stress, when compared to 52% of young male individuals. Therefore, the data demonstrated that the association between stress and FM is quite strong, as to date, the highest frequency of stress found in Brazilian studies was that observed in our sample.

However, some studies have shown that women are much more prone to stress and as our sample consists of women only, that could have been a confounding factor. To test this hypothesis, our sample was compared to a control sample that also consisted exclusively of women, whose identified stress frequency (51.2%) was within a variation range that had been previously identified by other studies with healthy women, of around 36%.^16,17

Regarding stress levels, a disturbing proportion of our patient sample was at the two upper stress levels - exhaustion and near exhaustion 67.5%), when compared to 8.6% in our control sample. These figures are higher than all data found in the Brazilian literature: among infertile women, this frequency was 12.7%,¹⁶ whereas in healthy women this frequency was zero or close to zero in young individuals,^17,18 7.4% among adult women,¹⁶ up to 15% and 23% in adult individuals living in Sao Paulo (capital and countryside, respectively).¹⁹ Therefore, we realize that the stress data identified by the present analysis are within the variation range already identified for healthy individuals, but are much higher than any previously recorded value, when related to FM patients. This fact demonstrates the important association between the disease and stress, but unfortunately, it is not possible to suggest a cause-and-effect relation, as both possibilities are likely: FM can increase the chance of developing stress, as well as stress onset can increase the chance of developing FM. That is a hypothesis that must be further tested with longitudinal and prospective studies.

The existing literature demonstrates that FM is a multifactorial disease and thus, the WHOQOL domain V was chosen to assess the association between the environment and the chance of disease onset. As the type of question used in this tool allows it to be adapted for a past period of time, this method was used to perform a retrospective investigation and, therefore, the questionnaire was applied to patients based on the period prior to the disease development. This approach allowed the final results on the environment to be correlated with the disease onset, and not as a consequence of the disease. Hence, it was possible to detect a significantly lower environmental quality in patients, when compared to the control sample (P < 0.001). Evidently, as in any other retrospective study, there is a possibility that the patients were not capable of consistently answering the questionnaire, based on their healthy life period, but were influenced by the disease. On the other hand, a subjective analysis of the researchers that applied the tool demonstrated that the patients tended to be excessively optimistic regarding the period prior to symptom onset, as they compared their lives with the current period. Nevertheless, the data demonstrated a strong association between environment and FM, and the values observed for patients and controls are within the variation range found in the literature.^20-23

The association between the WHOQOL domain V scores and other diseases, although not assessed retrospectively, has been investigated by several studies carried out worldwide. However, few studies have identified a significant association between the domain V scores and some disease or characteristic. The association between decreased environmental quality and Parkinson's disease has been identified by Valeikiene et al.,²³ although Schestatsky et al.²⁴ did not identify any difference between patients and their caregivers. One investigation with automobile factory workers from Malaysia demonstrated that the domain V scores were positively correlated with work control, social support, physical health, psychological status and social relations, and negatively correlated with work demand, stress, anxiety and depression.²² On the other hand, this domain scores were not significantly associated with treatment adherence for type 2 diabetes mellitus,²⁵ osteoarthritis,²³ successful aging process,²⁶ physical exercises in radiotherapy patients,²¹ narcolepsy²⁷ and systemic lupus erythematosus.²⁸ Most of these studies determined significant associations between the investigated diseases and the scores of other WHOQOL domains, demonstrating that the tool is efficient, but that apparently, the environment is not associated with these characteristics. Thus, this analysis specifically demonstrated the importance of the association between the environment and FM, as we found a significant association that is not always found in the literature, and had not been investigated regarding this disease in any previous international study.

The last objective of the present study was to assess whether the variation in the apolipoprotein E gene could be associated with FM onset. This gene was chosen due to its role in stress response and also due to the pain threshold modification, demonstrated in both human studies and animal models.^8-11

Additionally, a brief literature review showed that the polymorphism found in this gene is linked to the increased susceptibility to several diseases, such as Alzheimer's,^29,30 Parkinson's,³¹ cholelithiasis,³² atherosclerosis,³³ bone density,³⁴ rheumatoid arthritis,³⁵ depression in elderly,³⁶ schizophrenia and bipolar disorder,³⁷ among others. Still, to date, no study had tried to determine the association between the APOE gene and FM susceptibility in any population, although other genes have been associated with the disease, such as the 5HT2A serotonin receptor⁶ and the HLA region.³⁸ The present study data did not demonstrate a significant association between the presence of the gene rare alleles (E*2 and E*4) and FM susceptibility (Table 3). However, when a multivariate analysis was performed, seeking to detect an association between FM, the APOE gene, environmental quality and stress levels, a significant interaction was identified between the presence of the E*2 allele and stress levels (Table 4).

There have been no studies in the literature that can be compared with this analysis. Moreover, caution is necessary when interpreting these data due to limitations inherent to the Lipp questionnaire and the low statistical power caused by the small sample size, which results in an excessive increase in identified OR values. Therefore, although our data suggest an interaction between stress and APOE gene, caution is necessary when interpreting them, especially regarding the magnitude of the estimated OR values.

Firstly, as the applied stress inventory is adequate to detect current symptoms, or at most, of the previous days, it has the limitation of not being able to be applied retrospectively. Therefore, it becomes impossible to establish a causal relation for the strong association between stress and fibromyalgia, so that either of the two characteristics can trigger the other. Therefore, the protective role of the E*2 allele presence can be interpreted as protection against the disease onset in women with high stress levels or as protection against high-stress level development in patients with fibromyalgia. The only way to test these hypotheses would be to carry out a prospective study, which must be greatly encouraged regarding future research on this subject. Additionally, there is obviously a possibility that the present data reflect a type I error, caused by the small sample size.

In spite of the discussed limitations, the importance of the present study lies mainly in the fact that it is the first one to investigate the association between the APOE gene and fibromyalgia. The data shown here have demonstrated a significant influence of the E*2 allele, of which presence acts as a protective factor for the association between stress and fibromyalgia. However, determining which of the two events was the causative agent was not the objective of the present study. Moreover, a review of apo E physiological role demonstrates that it has influence on stress physiology, at least in animal models, which supports the influence identified in our sample. However, we believe that interaction identified in the present study can be used as a basis for hypothesis investigation in larger samples, thus contributing to the increase in knowledge on fibromyalgia etiology.

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

Roze Mary Ribas Becker^I; Vanessa Kappel da Silva^II; Fernanda da Silva Machado^II; Adriana Freitag dos Santos^III; Daiane Cristine Meireles^III; Michelle Mergener^IV; Geraldine Alves dos Santos^V; Fabiana Michelsen de Andrade^VI

Publication Dates

• Publication in this collection
  07 Jan 2011
• Date of issue
  Dec 2010

History

• Received
  05 Mar 2009
• Accepted
  04 Oct 2010