|Ahead of print publication
The increased erythrocyte membrane n-6/n-3 fatty acids ratio and inflammatory markers in patients with psoriasis
Serap Ozer Yaman1, Asım Orem1, Fulya Balaban Yucesan1, Savas Yayli2, Sadık Ozturk3, Sevgi Bahadir1
1 Department of Medical Biochemistry, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
2 Dermatology and Venereology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
3 Department of Dermatology and Venereology, Trabzon Vakfıkebir Health Ministry Hospital, Trabzon, Turkey
Serap Ozer Yaman,
Department of Medical Biochemistry, Karadeniz Technical University, Faculty of Medicine, Trabzon
Source of Support: None, Conflict of Interest: None
Background: Psoriasis is a common chronic, recurrent inflammatory skin disorder. Omega-3 fatty acids exhibit low inflammatory effects, while n-6 fatty acids display high inflammatory effects. The purpose of this preliminary study was to determine erythrocyte membrane n-6/n-3 fatty acid ratio values and their relationship with plasma inflammatory mediators in patients with psoriasis.
Methods: The study groups consisted of thirty patients with psoriasis and 36 healthy controls. Analyses of fatty acids in the erythrocyte membrane were performed using gas chromatography and a flame ionization detector. Serum sample inflammation parameters (C-reactive protein [CRP]), erythrocyte sedimentation rate (ESR), and interleukin-6 (IL-6) were also analyzed.
Results: The erythrocyte membrane n-6/n-3 fatty acid ratio was significantly higher in the psoriatic group compared to the healthy control group (P = 0.004). CRP, ESR, and IL-6 levels were also higher (P < 0.05) in the psoriatic group. The n-6/n-3 ratio was positively correlated with CRP and IL-6 levels in the psoriatic group (rho = 0.687, P= 0.0001 and rho = 0.542, P= 0.002, respectively). ROC curve analyses of CRP, ESR, IL6, and n6/n3 ratio values in patients with psoriasis performed similarly.
Conclusion: This preliminary study indicates that erythrocyte membrane n6/n3 fatty acid ratio was increased and showed correlations with plasma CRP and IL-6 in patients with psoriasis. Receiver operating characteristic analysis indicates that the n6/n3 ratio (area underthe curve = 0.699) may be a suitable inflammatory marker for further exploration in psoriasis. Erythrocyte membrane n-6/n-3 fatty acid ratio may be used as one of the pro-inflammatory markers in psoriasis.
Keywords: Biomarker, C-reactive protein, inflammation, interleukin-6, n-6/n-3 fatty acid ratio, psoriasis
|How to cite this URL:|
Yaman SO, Orem A, Yucesan FB, Yayli S, Ozturk S, Bahadir S. The increased erythrocyte membrane n-6/n-3 fatty acids ratio and inflammatory markers in patients with psoriasis. Indian J Rheumatol [Epub ahead of print] [cited 2019 Dec 6]. Available from: http://www.indianjrheumatol.com/preprintarticle.asp?id=267922
| Introduction|| |
Psoriasis is a chronic, recurrent inflammatory skin disease involving keratinocyte hyperproliferation. Numerous studies have shown that it is a multisystem disease associated with metabolic syndrome, hypertension, and cardiovascular disease (CVD)., The release of inflammatory molecules may play an important role in this association or the pathogeneses of the disease. Significant changes in the metabolism of arachidonic acid (AA) have been observed in psoriasis, and the role of eicosanoids has become important.
The fatty acids n-3 and n-6, polyunsaturated fatty acids (PUFAs) that regulate the functions of biological membranes, also play an important role in the production of eicosanoids in the membranes of inflammatory cells. Prostaglandins (PGs) and leukotrienes (LTs) are composed of omega fatty acids, which may play a role in promoting or suppressing inflammatory processes. The n-6 PUFA AA is a precursor to a number of potent pro-inflammatory mediators, including well-described PGs, thromboxanes, LTs, and related metabolites. These exhibit inflammatory effects on their own, as well as regulate the production of other mediators, including inflammatory cytokines. Omega-3 PUFAs reduce AA-derived eicosanoid products by exhibiting anti-inflammatory effects., However, the consumption of long-chain n-3 PUFAs can result in decrease in the amount of AA in the cell membranes and thus in the production of eicosanoids with less inflammatory effects. The omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), also reduce production of the classic inflammatory cytokines – tumor necrosis factor, interleukin (IL)-1beta, and IL-6.,
The n-6/n-3 ratio has thus been shown to be a good indicator for observing n-6/n-3 balance and its relationship with inflammation status. The ratio of n-6-to-n-3 fatty acids in the cell membranes plays an important role in inflammation., Increased levels of omega-6 PUFAs and a very high n-6/n-3 ratio may play an important role in the pathogenesis of many diseases, including CVD, cancer, and inflammatory and autoimmune diseases. Increased PUFA is generally considered anti-inflammatory because it promotes elimination and reduction of inflammation. The cell population most commonly used for this purpose is red blood cells (RBCs), which are easily available and reflect long-term fatty acid status for at least 2–3 months.
The purposes of this preliminary study were (i) to analyze the n-6/n-3 fatty acid ratio in the erythrocyte membrane in patients with psoriasis and (ii) to assess its relationship with well-known inflammatory biomarkers such as C-reactive protein (CRP) and IL-6.
| Methods|| |
Since our study was planned as a preliminary study, the sample size was not calculated beforehand. Approximately 100 patients were registered and prescreened. After these screenings, thirty patients with psoriasis (14 females and 16 males, age: 40.4 ± 12.4 years) and 36 control participants (20 females and 16 males, age: 37.0 ± 9.5 years) were included in the study. The diagnosis of psoriasis was made by a consultant dermatologist. The majority of the patients admitted to the dermatology polyclinic were inactive during the disease period. Patients with psoriasis were only on topical treatments or phototherapy. The last systemic therapies of all patients, including methotrexate and cyclosporine, were given at least 3 months ago. Participants' health status was evaluated by means of detailed medical history and physical examinations. At the first visit, exclusion criteria were involved smoking, alcohol or drug abuse, coronary heart disease, diabetes mellitus, obesity (body mass index [BMI] >30 kg/m2), and other systemic diseases. Participants who consumed lipid-lowering medications, dietary supplements, and antioxidants were also excluded. Clinical severity of the current disease was assessed using the psoriasis area and severity index (PASI), which determines the affected body surface area together with erythema, infiltration, and scaling.
Blood samples were drawn after overnight fasting and placed into two separate tubes, one for serum and another for plasma-containing ethylenediaminetetraacetic acid. Blood samples were centrifuged for 10 min at 1800 g. Serum specimens were separated and stored at −80°C until analysis. The following data were determined using an automatic analyzer: erythrocyte sedimentation rate (ESR) was measured using capillary kinetic photometric assay (Alifax Test1 THL, Polverara, Italy), CRP was determined using immunoturbidimetric assay (Roche Cobas 6000), and white blood cell (WBC) count was measured using electrical impedance methods (Beckman Coulter LH780, Mishima, Japan). These parameters were run after daily quality control procedures at the Clinical Biochemistry Laboratory as approved by the Turkish Ministry of Health.
Serum IL-6 levels were determined using an enzyme-linked immunosorbent assay kit (Abcam, Cat. No ab46027, Cambridge, UK) in line with the manufacturer's instructions. Absorbance of samples was measured at 450 nm using a VERSA max tunable microplate reader (designed by Molecular Devices, California, USA). Results were expressed as pg/mL.
Fatty acid analysis
Following centrifugation, the plasma and buffy coat were removed. Erythrocyte membranes were isolated from RBCs with some modifications to the method described by Hamaguchi and Cleve. Plasma was carefully separated, and the RBC pellet was washed three times with an equal volume of 0.9% NaCI-5 mM Tris-SO4(pH = 7.4). Lipid extraction and preparation of fatty acid methyl esters (FAMEs) in the erythrocyte membranes were performed using the method described by Sattler et al. with some modifications. Lipids were extracted using a freeze dryer (Telstar, Darmsmat, Germany). The fatty acid composition of the erythrocyte membrane was determined by means of a gas chromatographic (GC) method (Agilent Technologies 6890N, Waldbronn, Germany) using a flame ionization detector (FID). Experimental conditions for GC-FID were as follows: column: DB-23 capillary column 60.0 m × 250 μm × 0.20 μm nominal; inlet temperature: 250°C; injection volume: 1 μL; carrier gas: helium; head pressure: 230 kPa constant pressure (33 cm/s at 50°C); and oven temperature: 50°C for 1 min, 25°C/min to 175°C, hold at 175°C for 10 min, 5°C/min to 230°C, and hold at 230°C for 15 min. Individual FAMEs were identified by comparing retention times with authentic standards (Supelco 37-component FAME mixture, 47885-U, Sigma-Aldrich Co., Dorset, UK). Values were expressed as weight percentage of total identified fatty acids.
This study was approved by the Karadeniz Technical University Faculty of Medicine Ethic Council (Submission Number: 2011/117, dated September 26, 2011). All patients gave written informed consent before their enrollment in this study.
Statistical analysis was performed on SPSS version 16.0 software (SPSS Inc., Chicago, USA). Data were expressed as mean ± standard deviation for normally distributed variables and as median (interquartile range [IQR]) values for nonnormally distributed variables. The distribution of variables was assessed using the Kolmogorov–Smirnov test. Comparison of two groups was performed using Student's t-test for normal distribution or Mann–Whitney U-test for nonnormal distribution. Spearman correlation analysis was used to assess the relationships among the parameters considering the skewness of data distribution. Receiver operating characteristic (ROC) curves were analyzed on Medcalc software version 18.104.22.168 (Medcalc software BVBA, Belgium). Diagnostic accuracy for the n-6/n-3 ratio, CRP, ESR, and IL-6 levels in the psoriasis group was assessed using area under the curve analysis. Statistical significance was set at P < 0.05.
| Results|| |
There was no significant difference in age between the patients with psoriasis and the controls (P = 0.229). The median IQR PASI score was 3.85 (2.78–5.18). Significant differences were observed in inflammation parameters between the psoriatic and control groups [Table 1]. CRP, ESR, WBC, and IL-6 values in the psoriatic group were higher than those of the control group (P = 0.0001, P = 0.0001, P = 0.0001, and P = 0.002, respectively). The psoriatic patients were divided into two groups based on median PASI score (3.85 [2.78–5.18]) (median [IQR]). The patient group was classified as Group 1 with a median PASI score < 3.85 and Group 2 with median PASI score ≥3.85. The n-6/n-3 fatty acid ratio and CRP levels were significantly higher, while no difference was observed in IL-6 levels in Group 2 compared to the Group 1 (P = 0.004, P = 0.001, and P = 0.641, respectively) [Table 2].
|Table 1: Demographic and clinic characteristics of patients with psoriasis and control|
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|Table 2: Inflammation parameters in the psoriatic group classified based on Psoriasis area and severity index score|
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Fatty acid compositions in the erythrocyte membrane are given in [Table 3]. The n-6/n-3 PUFA ratio was significantly higher in patients with psoriasis compared to the controls (P = 0.004). The differences in n-3 and n-6 fatty acids between the two groups were calculated as a 12.5% decrease for n-3 and a 9.2% increase for n-6 fatty acids. The difference between the psoriatic and control groups in terms of the n-6 fatty acid linoleic acid was not significant, while the percentages of dihomo-γ-linolenic acid and AA were significantly higher in patients with psoriasis (P = 0.498, P = 0.008, and P = 0.018, respectively). The percentage of the n-3 fatty acid EPA was significantly lower, while no difference was observed in DHA levels, in patients with psoriasis compared to the controls (P = 0.016, and P = 0.777, respectively). The erythrocyte membrane n-6/n-3 ratio was positively correlated with inflammation indices including CRP and IL-6 levels in patients with psoriasis (rho = 0.687, P = 0.0001 and rho = 0.486, P = 0.007, respectively) [Figure 1]. In addition, n-6 fatty acid was positively correlated with CRP and IL-6 in the erythrocyte membrane, whereas n-3 fatty acid was negatively correlated with these inflammation parameters (rho = 0.509, P = 0.004; rho = 0.436, P = 0.016 and rho = −0.582, P = 0.001; rho = −0.421, P = 0.021, respectively). No significant correlation was observed between the ratio and PASI scores (P > 0.05).
|Table 3: Erythrocyte membrane fatty acid compositions in patients with psoriasis and control participants|
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|Figure 1: Correlations between n-6/n-3 ratio, interleukin-6, and C-reactive protein in patients with psoriasis. (a) n-6/n-3 ratio correlated with C-reactive protein, (b) n-6/n-3 ratio correlated with interleukin-6|
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ROC curve analyses of CRP, ESR, IL-6, and n-6/n-3 ratio values in patients with psoriasis and the controls are shown in [Figure 2]. All these parameters were identified as significant inflammatory markers for psoriasis. The significant power of the n-6/n-3 ratio was similar to that observed in CRP, ESR, and IL-6, classic inflammatory markers [Figure 2].
|Figure 2: Receiver operating characteristic curve analysis of n-6/n-3 ratio, interleukin-6, C-reactive protein and erythrocyte sedimentation rate levels in patients with psoriasis|
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The patient group has psoriatic arthritis (n = 6, 20%) and osteoarthritis (n = 5, 16.7%), and the rest do not have any chronic disease (n = 19, 63.3%). The median n-6/n-3 ratio of disease groups was 4.66 (3.26–4.80), 4.79 (3.83–4.88), and 5.78 (5.32–6.44), respectively.
| Discussion|| |
The main objective of this study was to evaluate the n-6/n-3 fatty acid ratio in the erythrocyte membrane and its relationship with inflammatory markers in patients with psoriasis. The n-6/n-3 fatty acid ratio was significantly higher in the psoriatic group compared to the control group. Decreasing n-3 fatty acid levels seems to have a more dominant effect on the increased n-6/n-3 ratio. To the best of our knowledge, this is the first study to evaluate the n-6/n-3 fatty acid ratio in this regard in psoriatic patients.
One of the main objectives of this study was to show the relationship between the rate and disease activity. However, it was not found significant relationship between the ratio and PASI score. This may be due to the patient group with insufficient of PASI score distribution. Since the number of patients with a high PASI score is small, we cannot classify patients as active and inactive or mild and severe, and so we divided them into two groups according to the median value of the existing PASI score. Thus, we tried to evaluate the status of the ratio within the current degree of inflammation of the patients [Table 2]. The n-6/n-3 fatty acid ratio was significantly different between Groups 1 and 2. These results suggest that a higher n-6/n-3 fatty acid ratio may be associated with clinical severity of psoriasis (PASI score). It also supports the view that the ratio of fatty acid may play an important role in regulating the inflammatory response in psoriatic patients. Low levels of n-3 and high levels of n-6 PUFAs determined in the psoriatic patients in our study may be associated with pro-inflammatory conditions. As shown in [Figure 1], we also determined a significant association between increased erythrocyte n-6/n-3 fatty acid ratio and CRP and IL-6 levels, indicating that an increased n-6/n-3 fatty acid ratio may affect the inflammatory state in patients with psoriasis. The increase in the n-6/n-3 ratio correlated with levels of inflammatory cytokine IL-6 in our psoriatic group. Levels of n-3 PUFA in the plasma have been reported to be negatively correlated with plasma pro-inflammatory markers, including CRP and IL-6. Our findings show that an increased erythrocyte n-6/n-3 ratio may be associated with higher serum concentrations of pro-inflammatory cytokine. These findings, therefore, support the view that AA and n-3 PUFAs may reflect the inflammatory response in psoriatic patients.
PUFAs are very important components for the biosynthesis of cell membrane biology and lipid mediators. Although intake of n-3 PUFAs is generally associated with a reduced risk of inflammatory diseases, a high intake of n-6 PUFAs may increase this risk. The present study indicates that while erythrocyte membrane n-6 fatty acid, dihomo-γ-linolenic acid and AA, levels were higher in patients with psoriasis, n-3 fatty acid EPA levels were lower than in the control group. Previous studies have investigated levels of erythrocyte PUFAs in psoriatic patients. Silva and Pierre investigated erythrocyte membrane n-6/n-3 fatty acid ratios in a small psoriatic group. They compared erythrocyte membrane fatty acid composition in healthy and various disease populations, including intensive care unit (ICU)-trauma, cancer, geriatric, social phobia, and psoriatic patients (n = 13). However, the focus of their study was to compare erythrocyte fatty acid composition before and after n-3 supplementation in healthy participants and ICU-trauma groups only, not in the other patient groups. Erythrocyte membrane fatty acid ratios in their patient groups were similar to our own results, whereas the fatty acid ratio in their control group was lower than our finding. No inflammatory parameters such as CRP and IL-6 were investigated in the patients in that study, and the relationship between the ratio and inflammation parameters in psoriasis was, therefore, unclear. The study reported no difference in the n-6 fatty acids, linoleic acid and AA, in the erythrocyte membrane between patients with psoriasis and healthy controls. However, the percentage of the n-3 fatty acids, EPA and DHA, was significantly lower in the psoriatic group. Erythrocyte membrane fatty acid ratios in their patient group were similar to our results, while those in the control groups were lower than in our study. Corrocher et al. investigated the associations between the erythrocyte membrane and cation transport systems in psoriatic patients. They reported that erythrocyte membrane fatty acid composition differed between the psoriatic and control groups. However, only AA levels were significantly higher in patients with psoriasis than in the control group. Myśliwiec et al. determined circulating fatty acid levels in obese and nonobese psoriatic patients. They reported that serum levels of the n-6 fatty acids, linoleic acid and AA, decreased ignificantly in patients with nonobese psoriasis compared to the control group. In addition, serum levels of the n-3 fatty acid, α-linolenic acid, were lower in obese and nonobese psoriatic patients, while EPA and DHA were lower only in nonobese psoriatic patients. These results suggest that circulating free fatty acids may be affected by daily diet and other factors. However, since the half-life of erythrocytes is greater than that of plasma, they reflect long-term fatty acid uptake better than plasma. Erythrocytes are, therefore, regarded as better indicators of long-term efficacy compared to serum and plasma. Our study group consisted of a nonobese psoriatic group with BMI <30 kg/m2. Similar results have been determined in other clinical conditions characterized by acute phases and other phases involving progression toward chronic states. One study reported decreased levels of serum AA and EPA in patients with acne vulgaris. Other studies have reported increases in percentages of erythrocyte n-6 fatty acids of γ-linolenic acid, AA, docosatetraenoic acid, and docosapentaenoic acid, while α-linolenic acid and DHA levels decreased significantly in patients with acute coronary syndrome. Several reports have demonstrated an association between psoriasis and CVDs, including hypertension, myocardial infarction, heart failure, arrhythmia, and vascular disease.,
One previous study suggested that the optimal ratio of n-6-to-n-3 fatty acids (1:1) may change the pathogenesis of inflammatory diseases. The decreased n-6/n-3 ratio in the erythrocyte phospholipids of patients with psoriasis may contribute to general anti-inflammatory effects and to a lowered risk of the disease. Gil reported that a balanced n-6/n-3 fatty acid ratio in daily diet is very important and suggested that lowering this ratio may be useful in terms of the pathogenesis of chronic diseases such as psoriasis. The studies indicate that the optimal ratio of fatty acid may have effect in severity of inflammatory diseases. According to many studies, it is emphasized that 1:1 ratio of n-6/n-3 fatty acid taken with long-term diet is important for human health. In particular, the ratio of 2–3/1 affects less inflammation in patients with rheumatoid arthritis and a ratio of 5/1 would have beneficial effect on patients with asthma. The decreased n-6/n-3 ratio in the erythrocyte phospholipids of patients with psoriasis may contribute to general anti-inflammatory effects and to a lowered risk of the disease. It has been previously reported that the balance of n-6/n-3 fatty acid ratio in the daily diet is very important and that lowering this ratio may be useful for the pathogenesis of chronic diseases. In view of the above-mentioned data, whether long-term diet enriched with omega-3 has any effect on psoriasis needs to be explored in further studies.
Erythrocyte membrane saturated fatty acid (SFA) fatty acids increased only slightly in our psoriatic group, and this increase did not achieve statistical significance. Levels of the monounsaturated fatty acid (MUFA) oleic acid were higher in patients with psoriasis than in the control group in this study. Similar results were determined in a recent
report by Silva and Pierre, who observed an increase in erythrocyte membrane SFA fatty acids in patients with psoriasis. Myśliwiec et al. reported increased serum SFA fatty acid and MUFA oleic acid levels in obese psoriatic groups.
We performed ROC curve analysis to determine whether the n-6/n-3 fatty acid ratio could be used as one of the inflammatory markers for patients with psoriasis. The n-6/n-3 fatty acid ratio performed similar to established pro-inflammatory markers CRP, ESR, and IL-6 for patients with psoriasis.
The main limitation of this preliminary study is lack of the patients with a wide range PASI scores. Therefore, there was no statistical significance in showing the relationship between n-6/n-3 fatty acid ratio and the severity of psoriasis. In this regard, further studies including more patients with different severity are required. Furthermore, further investigations are required for the role of increased n-6/n-3 fatty acid ratio in the pathogenesis and severity of the inflammatory process in the disease. The role of n-6/n-3 fatty acid ratio in psoriatic arthritis remains unclear. In our study, because of the low number of patients with psoriatic arthritis, its relationship with fatty acid ratio could not be compared. Further studies are needed to examine the relationship of this ratio in patients with psoriatic arthritis. The precise presentation of the findings can be better understood in the longitudinal follow-up of a larger patient group. As this was a preliminary study, the sample size was not calculated beforehand.
| Conclusion|| |
Erythrocyte membrane n6/n3 fatty acid ratio was increased and showed correlations with plasma CRP and IL6 in patients with psoriasis. Erythrocyte membrane n-6/n-3 fatty acid ratio may be used as one of the pro-inflammatory markers in patients with psoriasis.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]