Clinical significance of vitamin D deficiency and receptor gene polymorphism in systemic lupus erythematosus patients

The Egyptian Rheumatologist xxx (2016) xxx–xxx

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Original Article

Clinical significance of vitamin D deficiency and receptor gene polymorphism in systemic lupus erythematosus patients Kamel H. Gado a, Tarek H. Gado a, Rasha M. Abdel Samie a, Noha M. Khalil a,⇑, Safa L. Emam a, Hanan H. Fouad b,c a b c

Internal Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt Medical Biochemistry Department, Faculty of Medicine, Cairo University, Cairo, Egypt Pharmacology Department, Faculty of Pharmacy, University of Hail, Saudi Arabia

a r t i c l e

i n f o

Article history: Received 28 October 2016 Accepted 5 November 2016 Available online xxxx Keywords: SLE Vitamin D VDR FokI and BsmI polymorphism SLEDAI Damage index

a b s t r a c t Introduction: The vitamin D receptor (VDR) gene is a candidate for susceptibility to autoimmune disorders. Aim of the work: To study the frequency of vitamin D deficiency in Egyptian systemic lupus erythematosus (SLE) patients and investigate the association of BsmI and FokI VDR gene polymorphisms with disease susceptibility, activity and damage. Patients and methods: Forty-five SLE patients and 40 controls were enrolled. SLE Disease Activity Index (SLEDAI) and Systemic Lupus International Collaborating Clinics (SLICC) damage index were assessed for the patients. Serum vitamin D levels were measured in all subjects. Genotyping for the VDR BsmI and FokI gene polymorphisms was performed by polymerase chain reaction and restriction fragment length polymorphism for only 34 patients and 16 controls. Results: The mean age of SLE patients was 28.8 ± 7.9 years and disease duration 11.3 ± 9.8 years. Vitamin D level was significantly lower in patients than control (p < 0.001) and significantly correlated with C3 and C4 levels (p < 0.001) and inversely with SLEDAI (p < 0.001), SLICC (p = 0.005), anti-ds DNA (p < 0.001) and ESR (p = 0.011). There were no significant differences in genotype and allelic frequencies of FokI and BsmI polymorphisms between patients and controls. There was a significant relation of FokI polymorphisms with serum vitamin D level (p = 0.002), SLEDAI (p = 0.021) and SLICC (p = 0.002). BsmI polymorphisms showed significant associations with neuropsychiatric damage, low complement, fever and mucosal ulcers. Conclusions: VDR FokI polymorphism in SLE patients is significantly related to low vitamin D level in SLE patients and both are associated with increasing disease activity and damage denoting important implications in this disease. Ó 2016 Publishing services provided by Elsevier B.V. on behalf of Egyptian Society of Rheumatic Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).

1. Introduction Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disorder characterized by generation of autoantibodies against nuclear antigens and deposition of immune complexes in various organs resulting in chronic inflammation and tissue damage [1]. Although the underlying cause still remains unclear, it is thought to result from interactions between environmental factors,

Peer review under responsibility of Egyptian Society of Rheumatic Diseases. ⇑ Corresponding author at: Kasr Al Ainy Street, Internal Medicine Hospital, Faculty of Medicine, Cairo University, Cairo 12111, Egypt. E-mail address: [email protected] (N.M. Khalil).

disease- prone genetic background and a variety of pathogen eliciting innate and adaptive immune responses [2]. The possible involvement of vitamin D deficiency in the development of autoimmune diseases has provided new insights into the function of this vitamin. The immunomodulatory effects of vitamin D include down regulating the T helper cell (Th1) immune responses, and reducing Th induction of immunoglobulin production by B cells, thus altering the cytokine profile toward the Th2 phenotype and preserving innate immune response [3]. Each of these immunologic properties has great potential implications for SLE patients [4]. Lower vitamin D levels were significantly associated with increased cardiovascular risk, higher disease activity and damage in Egyptian SLE patients [5].

http://dx.doi.org/10.1016/j.ejr.2016.11.003 1110-1164/Ó 2016 Publishing services provided by Elsevier B.V. on behalf of Egyptian Society of Rheumatic Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article in press as: Gado KH et al. Clinical significance of vitamin D deficiency and receptor gene polymorphism in systemic lupus erythematosus patients. The Egyptian Rheumatologist (2016), http://dx.doi.org/10.1016/j.ejr.2016.11.003

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K.H. Gado et al. / The Egyptian Rheumatologist xxx (2016) xxx–xxx

Vitamin D (1, 25 dihydroxyvitamin D3) exerts many of its actions through interaction with vitamin D receptor (VDR) [6]. The wide distribution and expression of VDR in most immune cells such as peripheral lymphocytes, macrophages, monocytes, dendritic cells, natural killer cells and T and B lymphocytes [7,8] as well as its effect on cell proliferation and differentiation makes vitamin D a possible candidate for regulation of immune response [8]. The VDR gene, located on chromosome 12 and composed of 9 exons has emerged as a candidate gene for susceptibility to autoimmune disorders [9]. The VDR gene contains more than 470 single nucleotide polymorphisms (SNPs), a number of which modulate the uptake of 1, 25(OH)2D3 uptake. The most frequently studied VDR polymorphisms include FokI situated in exon 2, BsmI located in intron 8, TaqI and ApaI with the latter being situated in exon 9 and intron 9 [10]. The role of VDR polymorphisms in the development of SLE and its clinical manifestations have been demonstrated with conflicting results. The aim of the present study was to assess vitamin D status in Egyptian patients with SLE and to investigate whether BsmI and FokI VDR gene polymorphisms could be susceptibility markers for the disease activity and severity.

2. Patients and methods This cross-sectional case-control study was conducted on 45 SLE (38 females and 7 males) patients fulfilling the fulfilled the Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for SLE [11] and 40 age and sex matched healthy controls. All subjects were recruited from Internal Medicine and Rheumatology outpatient clinics of Kasr Al Ainy University Hospitals. All the patients provided an informed consent and the study was approved by the local ethical committee conforming to the 1995 Helsinki declaration. Patients with hepatic dysfunction or disease, renal disease (other than SLE), malignancy or those taking drugs known to affect vitamin D metabolism (such as anticonvulsants, cimetidine, antituberculosis agents, theophylline, orlistat and drugs for AIDS) were excluded. All subjects were subjected to full medical history including age, body mass index (BMI), history of photosensitivity and dress code, concurrent diseases (such as diabetes or hypertension), post menopausal history as well as history of pregnancy and lactation. Detailed drug history was obtained from all patients and included duration and daily doses of medications as well as calcium and vitamin D supplementations. The disease activity was assessed in SLE patients by the SLE Disease Activity Index (SLEDAI) [12] and organ damage was assessed by Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR DI) [13]. All subjects underwent routine laboratory investigations which included complete blood picture (CBC), Erythrocyte sedimentation rate (ESR), serum calcium (total and ionized), serum phosphorous, alkaline phosphatase, serum creatinine and glomerular filtration rate (GFR), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and complete urine analysis with 24 h urinary protein. Specific laboratory investigations for SLE patients included antinuclear antibody (ANA), anti-double stranded deoxyribonucleic acid (anti-dsDNA) with titer, serum complement components 3 and 4 (C3 and C4). The level of serum 25-hydroxyvitamin D [25(OH) D3] was quantitatively measured by enzyme linked immunosorbent assay (ELISA) for all subjects. A serum level P30 ng/ml was considered normal, between 10 and 30 ng/ml as insufficiency and < 10 ng/ml as deficiency.

Only 34 SLE patients and 16 age- and sex- matched controls were genotyped for the VDR BsmI and FokI gene polymorphisms based on the polymerase chain reaction and restriction fragment length polymorphism (PCR/RFLP) due to financial constraints. Statistical analysis The data was coded and entered using the statistical package SPSS version 15. The data was summarized using descriptive statistics: mean, standard deviation, minimal and maximum values for quantitative variables and number and percentage for qualitative values. Statistical differences between the groups were tested using the Chi-Square test for qualitative variables, independent sample t-test for quantitative normally distributed variables; while the non-parametrical Mann-Whitney test was used for quantitative variables which were not normally distributed. Correlations were done to test for linear relations between quantitative variables. 3. Results The age, BMI and laboratory data of the SLE patients and their age- and sex- matched controls are shown in Table 1. There were no significant differences between SLE patients and controls as regard sex and post menopausal status (5 patients and 4 control) (p = 0.81 and 0.4 respectively). The mean disease duration of the patients was 11.3 ± 9.8 years. Patients suffered from peripheral vascular damage (40%), followed by cardiac, neuropsychiatric, musculoskeletal and skin damage (33.3%, 20%, 15.5%, and 15.5% respectively). Only one patient suffered pulmonary damage (2.2%) and none suffered from malignancy. Serum levels of vitamin D were significantly lower in SLE patients (12 ± 2.28 ng/ml) compared to the controls (21.13 ± 3.2 ng/ml) (p < 0.001). Table 2 shows comparison between SLE patients and the controls as regard the vitamin D status. There was a significant difference between SLE patients with vitamin D deficiency and insufficiency as regards the total and ionized calcium (p = 0.009 and 0.039 respectively). Patients with deficiency showed higher mean anti-ds DNA titer (90.2 ± 37.8 IU/ml) compared to those with insufficiency (61.5 ± 10.2 IU/ml) (p < 0.001). The daily and cumulative doses of steroids were non-significantly higher in vitamin D deficient compared to insufficient patients. The cumulative doses of HCQ, AZA and cyclophosphamide tended to be higher in vitamin D insufficient patients. Vitamin D deficient patients had significantly greater SLEDAI and damage scores than insufficient patients (p = 0.001 and p = 0.035 respectively) (Fig. 1). As regard gender, post-menopausal status, photosensitivity, dress code and vitamin D supplementation, no significant differences were observed between patients with vitamin D deficiency or insufficiency. A significant difference was found between vitamin D deficient and insufficient patients as regard

Table 1 The age, body mass index and laboratory investigations in systemic lupus erythematosus patients and control. Variable mean ± SD

SLE patients (n = 45)

Controls (n = 40)

p

Age (years) BMI Hb (g/dl) TLC (103/lL) Creatinine (mg/dl) Calcium (mg/dl) Ionized 25(OH)D3 (ng/ml)

28.8 ± 7.9 22 ± 2.7 8.2 ± 1.9 6.3 ± 2.2 1.4 ± 1.4 7.6 ± 0.9 3.7 ± 0.6 12 ± 2.3

30.4 ± 9.6 22.5 ± 1.95 12.4 ± 1.2 6.3 ± 0.9 0.8 ± 0.21 9.1 ± 0.21 4.96 ± 0.2 21.1 ± 3.2

0.4 0.38 <0.001 0.62 <0.001 <0.001 <0.001 <0.001

SLE: systemic lupus erythematosus, BMI: body mass index, Hb: haemoglobin, TLC: total leucocytic count. Significance is considered at p value < 0.05

Please cite this article in press as: Gado KH et al. Clinical significance of vitamin D deficiency and receptor gene polymorphism in systemic lupus erythematosus patients. The Egyptian Rheumatologist (2016), http://dx.doi.org/10.1016/j.ejr.2016.11.003

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K.H. Gado et al. / The Egyptian Rheumatologist xxx (2016) xxx–xxx Table 2 Vitamin D status in systemic lupus erythematosus patients and controls. Vitamin D status n (%)

SLE patients (n = 45)

Deficiency (<10 ng/ml) Insufficiency (10–30 ng/ml)

21 24

Controls (n = 40) (46.7) (53.3)

0 40

p (0) (100)

<0.001

SLE: systemic lupus erythematosus

Figure 1. Disease activity and damage in systemic lupus erythematosus patients according to their vitamin D status.

arthritis, fever, low C3 and C4 (p = 0.017, p = 0.001, p = 0.036 respectively). Vitamin D deficiency was more sensitive (85%) but less specific (72%) for prediction of concurrent disease activity (positive predictive value 82.1 and negative predictive value 76.5). Correlation of serum vitamin D levels with clinical, laboratory parameters as well as markers of SLE disease activity revealed a highly significant inverse correlation with the disease duration, SLEDAI and damage scores (p = 0.03, p < 0.001 and p = 0.005 respectively). Vitamin D levels also inversely correlated with anti-ds DNA and ESR (p < 0.001 and p = 0.01 respectively). A significant correlation was found with the total calcium, ionized calcium, C3 and C4 levels (p = 0.002, p = 0.004, p < 0.001 and p < 0.001 respectively). No significant correlation with the age or BMI was observed. Table 3 shows the distribution of VDR Bsm I (BB, Bb, bb) and FokI (FF, Ff and ff) genotypes in 34 SLE patients and 16 controls. No statistically significant differences were observed. There was an increased frequency of the F allele in patients with SLE but these differences were not significant with OR for VDR F allele versus f allele = 2.2 (95% CI 0.89–5.2; p = 0.11). The frequency of the b allele was higher in SLE patients than in controls but these differences

were also non significant with OR for the VDR B allele versus b allele = 0.85 (95% CI 0.35–2.08; p = 0.73). Vitamin D levels, disease activity and damage according to VDR FokI and BsmI genotypic frequency in SLE patients are presented in Table 4. Vitamin D was significantly lower in patients with FF genotype (10.8 ± 1.5 ng/ml) compared to ff and Ff genotypes (16.5 ± 2.1 ng/ml and 13.3 ± 1.9 ng/ml respectively; p = 0.001). Vitamin D levels tended to be lower in patients with BB genotype compared to bb and Bb genotypes (p = 0.06). There were no significant differences in the SLEDAI or DI according to the BsmI genotypes. Patients with VDR FF genotype significantly had a higher disease activity and damage index compared to the other genotypes (p = 0.02 and p = 0.002, respectively) (Fig. 2). The VDR FokI polymorphisms showed significant associations with fever (p = 0.001) and low complement (p = 0.005). A significant association was found between VDR BsmI (BB, Bb, and bb) polymorphism and the neuropsychiatric damage (p = 0.005). There was also a statistically significant association of the VDR BsmI polymorphisms with mucosal ulcers, hypocomplementemia and fever with (p = 0.002, p = 0.02 and 0.04 respectively). 4. Discussion In this study we have confirmed significantly lower vitamin D levels among all SLE cases compared to the control. Vitamin D insufficiency was present in 53.3% and deficiency in 46.7% while all the control had insufficiency. Although our population resides in areas with a lot of sunny days yet many contributing factors lead to low vitamin D levels as in most middle east countries and include the dark skin pigment, the limited dietary intake of vitamin D and the religious and cultural practice of wearing clothes that almost cover the entire body [14]. Also Fragoso et al. explained this to be a result from modern life activities, which make us avoid sun exposure and consequently reduce vitamin D synthesis [15]. Our results are concordant to a study by Emam et al. which revealed low vitamin D level in 85% of SLE patients and 60% of the control [16]. This was also concordant with results of Damanhouri [17] who found that in Saudi SLE patients vitamin D inadequacy and deficiency was significantly higher than in the control: 98.8% versus 55% and 89.7% versus 20% respectively. In disagreement, Stockton et al. found no significant difference in vitamin D levels between Australian SLE patients and control [18]. The authors explained

Table 3 Distribution of frequency of the vitamin D receptor BsmI and FokI gene polymorphisms in systemic lupus erythematosus patients and controls. VDR genotype n (%) BsmI

FokI

SLE patients (n = 34)

Control (n = 16)

OR (95%CI)

p

bb BB Bb BB + Bb

16 3 15 18

(47.1) (8.8) (44.1) (52.9)

8 3 5 8

(50) (18.8) (31.3) (50)

Reference 0.5 (0.08–3.06) 1.5 (0.4–5.6) 1.13 (0.3–3.7)

0.45 0.55 0.85

ff FF Ff FF + Ff

2 18 14 32

(5.9) (52.9) (41.2) (94.1)

4 6 6 12

(25) (37.5) (37.5) (75)

Reference 6 (0.9–41.4) 4.7 (0.7–32.7) 5.3 (0.9–33)

0.14 0.16 0.07

VDR: vitamin D receptor, SLE: systemic lupus erythematosus.

Please cite this article in press as: Gado KH et al. Clinical significance of vitamin D deficiency and receptor gene polymorphism in systemic lupus erythematosus patients. The Egyptian Rheumatologist (2016), http://dx.doi.org/10.1016/j.ejr.2016.11.003

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K.H. Gado et al. / The Egyptian Rheumatologist xxx (2016) xxx–xxx

Table 4 Vitamin D levels, disease activity and damage according to FokI and BsmI genotypic frequency in systemic lupus erythematosus patients. VDR genotype n (%) mean ± SD

Systemic lupus erythematosus patients (n = 34) Vit. D (ng/ml)

p

SLEDAI

p

DI

P

BsmI

bb BB Bb

16 (47.1) 3 (8.8) 15 (44.1)

12.2 ± 2.6 9.3 ± 1.5 12.7 ± 1.8

0.06

13.2 ± 5.2 17.7 ± 7.8 9.9 ± 6.7

0.08

1.9 ± 1.1 2±1 1.7 ± 1.4

0.77

FokI

ff FF Ff

2 (5.9) 18 (52.9) 14 (41.2)

16.5 ± 2.1 10.8 ± 1.5 13.3 ± 1.9

0.001

10 ± 2.8 14.9 ± 6.2 8.8 ± 5.3

0.02

0.5 ± 0.7 2.4 ± 1.2 1.2 ± 0.8

0.002

VDR: vitamin D receptor, Vit. D: vitamin D, SLEDAI: systemic lupus erythematosus disease activity index, DI: damage index.

Figure 2. Disease activity and damage according to VDR FokI and BsmI genotypic frequency in systemic lupus erythematosus patients.

that this difference was because their study was conducted in Brisbane, Queensland where ultraviolet radiation levels are high almost all year round; thus, the higher vitamin D levels may reflect inadequate photo-protection and the mean SLEDAI score of their patients’ revealed mild activity. Similarly, Redlich et al. did not find a significant difference between patients and control [19] possibly attributed to the mild SLE disease activity in those patients. There was a significant negative correlation between vitamin D level and disease duration but, this however, disagrees with another Egyptian study that did not find a significant relation [16]. The finding of a highly significant negative correlation between vitamin D level and SLEDAI in the present study could be attributed to the underlying inflammatory process in SLE patients that possibly enhances vitamin D catabolism [20]. Our observations are consistent with the findings of other studies [16,20–23] and suggests that among other factors, inadequate vitamin D level probably contributes to the development of active disease in SLE patients. On the other hand, previous studies have reported a negative correlation [24,25] while others found none [26,27]. In the present study the disease activity and damage scores were higher in patients with vitamin D deficiency. These findings are in agreement with the results of another Egyptian study [5]. The significant negative correlation between vitamin D level and damage score was consistent with the results of Wu et al. [28] while others found no association [21,26,27,29]. In this study there was a significant correlation between vitamin D level with C3 and C4. These results are in concordance with that of Kim et al. [27] while another study found no significant correlation [21]. In our study there was a significant negative correla-

tion between the serum vitamin D levels and anti-dsDNA titer which is in concordance with the results of others [16,21,30–32]. anti-dsDNA antibodies are specific for SLE and their levels fluctuate with disease activity [33]. The present study showed a significant negative correlation between vitamin D level and ESR which is in disagreement with the results of another study [16]. In our study vitamin D deficiency was more sensitive but less specific for prediction of concurrent SLE disease activity. Vitamin D deficiency was more specific but less sensitive than antidsDNA for prediction of SLE activity [21]. Kamen et al. suggested that Vitamin D supplementation in SLE patients may have a beneficial effect on the immune system, in addition to the influence on bone metabolism [34]. In the current study there was no significant difference in the vitamin D status between those receiving Vitamin D supplementation and those not. This may indicate that the used dose was inadequate. There was no significant difference in the frequency of VDR BsmI and FokI gene polymorphisms between the SLE patients and control however there was a tendency to a higher frequency of the b and F alleles. Similarly, no difference in the BsmI [4,35–37] or the FokI [4,10,38] genotypes and alleles was found between SLE patients and controls. In contrast, Huang et al. found that the frequency of B allele was significantly more common in Chinese SLE patients [38] while an increased frequency of the F allele was observed in SLE patients compared to the control, but the differences was not significant [10]. Moreover, Xiong et al. found a significantly higher frequency of FF + Ff versus ff genotype [39]. In the present study a significant association between VDR BsmI polymorphisms and few markers of SLE disease activity including

Please cite this article in press as: Gado KH et al. Clinical significance of vitamin D deficiency and receptor gene polymorphism in systemic lupus erythematosus patients. The Egyptian Rheumatologist (2016), http://dx.doi.org/10.1016/j.ejr.2016.11.003

K.H. Gado et al. / The Egyptian Rheumatologist xxx (2016) xxx–xxx

fever, low complement and mucosal ulcers as well as with neuropsychiatric damage was observed. However, there were no associations with SLEDAI or damage scores which are concordant to the results of another study [36]. In the present study, a significant association was present between VDR Fok1 polymorphism, but not BsmI, and the vitamin D status in the patients. In vitamin D deficient patients, 86.7% had FF genotypes while in those with insufficiency 63.2% had Ff genotypes. SLE patients with the FF genotype had a significantly lower vitamin D level. This is in agreement with the results of others [4,40]. It has been suggested that 1,25-dihidroxyvitamin D, an active form of vitamin D, has negative control over its own levels and the levels of its precursor through the VDR [41]. Allele f may be associated with VDR dysfunction allowing increased synthesis of vitamin D precursor which would explain the observation of higher vitamin D levels in individuals with ff genotype [4]. In accordance to the present results, BsmI genotypes were not significantly associated with the vitamin D concentrations in SLE patients [4]. There was a significant association of VDR FokI polymorphisms with the SLEDAI, fever and low complement in the present study. This was in disagreement to the results of Luo et al. [35]. There was also a statistically significant association of VDR FokI polymorphisms and SLE damage index. To the best of our knowledge no other studies were conducted on the association between VDR FokI and organ damage among SLE patients. Collectively, these data suggest that FokI polymorphism could have important consequences for vitamin D metabolism in SLE patients. The present study included a relatively small sample size and due to financial constraints only a small number of SLE patients and controls were genotyped for VDR FokI and BsmI polymorphisms, thus additional studies with a large number of patients are warranted to further explore the observations and findings of the present study and their potential impact. In conclusion, VDR FokI polymorphism in SLE patients is significantly related to low vitamin D level in SLE patients and both are associated with increasing disease activity and damage denoting important implications in this disease.

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Please cite this article in press as: Gado KH et al. Clinical significance of vitamin D deficiency and receptor gene polymorphism in systemic lupus erythematosus patients. The Egyptian Rheumatologist (2016), http://dx.doi.org/10.1016/j.ejr.2016.11.003