|Year : 2018 | Volume
| Issue : 2 | Page : 455-461
Vitamin D receptor gene polymorphism in immune thrombocytopenic purpura
Mohamed Abdelhafez1, Enas S Esaa2, Mohamed Sakr1
1 Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
|Date of Submission||20-Nov-2016|
|Date of Acceptance||16-Jan-2017|
|Date of Web Publication||27-Aug-2018|
6 El-Geish Street, Queissna, Menoufia
Source of Support: None, Conflict of Interest: None
The aim of this study was to assess the association of vitamin D receptor (VDR) gene polymorphism BsmI in cases of primary immune thrombocytopenic purpura (ITP).
Recently, several studies have demonstrated the role of VDR polymorphisms in the development of autoimmune diseases. Vitamin D affects both innate and adaptive immune responses, which have been held responsible in ITP pathogenesis.
Patient and methods
VDR polymorphism BsmI (rs1544410) was detected by PCR followed by restriction fragment length polymorphism analysis. DNA samples were extracted from the peripheral blood of 40 ITP patients and 60 geographically and ethnically matched healthy controls.
A statistically significant difference was found in the BsmI polymorphism between ITP patients and controls (χ2 = 8.77, P = 0.01). The BsmI polymorphism B allele was higher in ITP patients compared with controls but with a statistically insignificant difference (χ2 = 2.125, P = 0.145). The bb genotype played a protective role in ITP incidence.
This is the first published report on VDR gene polymorphisms in adult ITP patients. The BsmI genotype was associated with increased risk for ITP incidence with no obvious effect on bleeding severity, platelet count, or site of bleeding.
Keywords: immune thrombocytopenia, polymorphism, vitamin D receptor
|How to cite this article:|
Abdelhafez M, Esaa ES, Sakr M. Vitamin D receptor gene polymorphism in immune thrombocytopenic purpura. Menoufia Med J 2018;31:455-61
|How to cite this URL:|
Abdelhafez M, Esaa ES, Sakr M. Vitamin D receptor gene polymorphism in immune thrombocytopenic purpura. Menoufia Med J [serial online] 2018 [cited 2018 Sep 24];31:455-61. Available from: http://www.mmj.eg.net/text.asp?2018/31/2/455/239753
| Introduction|| |
Vitamin D is a steroid hormone precursor that undergoes chemical conversion in the liver and kidney: the first reaction produces 25-hydroxyvitamin D, an objective indicator of vitamin D status, and the second produces the main bioactive form, 1,25-dihydroxyvitamin D . Vitamin D has been shown to exert various anti-inflammatory and immune-modulatory effects, along with its major role in bone mineral homeostasis . Vitamin D directly acts on immune cells by promoting monocyte differentiation and by inhibiting lymphocyte proliferation and production of immunoglobulins and cytokines, such as interleukin-2, interferon-γ, and interleukin-12 ,. It also inhibits dendritic cell differentiation and maturation , and reduces the expression of major histocompatibility complex class II molecules on both immune and nonimmune cells ,. Vitamin D inhibits T helper (Th) 1 and Th17 responses ,, whereas it promotes the expressions of Th2 cytokines  and enhances the ability of T regulatory cells to suppress T-cell proliferation ,. As a consequence, both cell-mediated immune response and B cells proliferation and autoantibodies production would directly be downregulated by vitamin D ,,. Such actions result in an overall protective effect of vitamin D against immune-mediated diseases. In humans, vitamin D status has been associated with susceptibility to several immune-mediated disorders including chronic infections (tuberculosis) and autoimmune diseases ,,,,,,,, and administration of vitamin D supplements has been reported to reduce the risk to develop such diseases ,,,.
The pleiotropic effects of vitamin D are exerted via the vitamin D receptor (VDR), which belongs to the steroid receptor superfamily and is widely expressed in many cell types including lymphocytes, macrophages, and several endocrine cells . The VDR gene, located on chromosome 12q12–q14, shows an extensive polymorphism that influences its function. Four major single nucleotide polymorphisms (SNPs) have been intensively studied – namely, FokI in exon 2, BsmI and ApaI in intron 8, and TaqI in exon 9 – clustered in several haplotype blocks of extensive linkage disequilibrium. BsmI (rs1544410), ApaI (rs7975232), and TaqI (rs731236) SNPs are in strong linkage disequilibrium with each other, whereas no significant linkage disequilibrium with the FokI site was observed. The ApaI (G/T substitution), BsmI (A/G substitution), and TaqI (T/C substitution) polymorphisms do not produce any structural change on the VDR protein ,. On the other hand, the FokI (T/C substitution) polymorphism introduces a second start codon in the VDR gene and yields two potential initiation sites with actual structural change on the VDR protein, suggesting a potential functional consequence.
Certain SNPs of the VDR gene may result in reduced vitamin D function and have been associated with a range of autoimmune diseases such as systemic lupus erythematosus ,, multiple sclerosis ,, type 1 diabetes ,, and Grave's , and Behcet's disease .
Concerning immune thrombocytopenia, there are no published reports available in the literature on the association of VDR gene polymorphisms in adult immune thrombocytopenic purpura (ITP) patients.
Primary ITP is a complex, chronic, often cell-specific, autoimmune disease that is still not fully understood. It is defined currently as isolated thrombocytopenia (peripheral blood platelet count <100 × 109/l) in the absence of conditions known to cause thrombocytopenia . According to population-based studies, the overall incidence of ITP ranges from 3.2 to 12.1 per 105 adults each year, with prevalence ranges from 9.5 to 23.6 per 105 persons. The incidence of ITP increases with age . The improved understanding of the innate and adaptive immune systems, however, allows us to understand and appreciate some of the complex interactions between platelets, the immune system, and the development of ITP. Immune-mediated platelet destruction and/or insufficient platelet production in ITP occurs by a complex process involving multiple components of the immune system .
The present study aimed to assess the association of VDR gene polymorphism BsmI in cases of primary ITP.
| Patients and Methods|| |
This was a case–control study. It included 40, consecutive, primary, adult, female ITP cases diagnosed according to the guidelines of the American Society of Hematology 2011 . Patients were enrolled during their admission to inpatient wards or routine follow-up at the hematology clinic, Menoufia University Hospitals, during the period from April 2014 to March 2016 inclusive. Sixty, unrelated, healthy controls matched for age and sex were included as a control group. Patients were invited to participate with no attempt to select them by known or perceived risk factors.
Informed required consents were obtained from the patients and controls in advance. All investigations were performed in accordance with the Menoufia University, Health and Human Ethical Clearance Committee guidelines for Clinical Research. The Local Ethics Committee approved the study protocol.
For all ITP patients and controls, we carried out full history taking, including family history; physical examination with emphasis on bleeding symptoms, severity, and site; abdominal ultrasound imaging; and laboratory investigations such as complete blood count with peripheral blood smear, direct antiglobulin test, virology screen, stool test for Helicobacter pylori antigen, antinuclear antibodies, and antiphospholipid antibodies, pregnancy test, and bone marrow examination when needed.
The VRD BsmI polymorphism (rs1544410) was detected by PCR followed by restriction fragment length polymorphism analysis.
One milliliter peripheral venous blood samples were collected in sterile tubes containing EDTA for DNA extraction.
DNA was extracted from whole-blood samples using QIA amp Blood Genomic DNA Kit that depends on the spin column method, according to the protocol supplied by the manufacturer (Qiagen GmbH, Hilden, Germany). For determining DNA concentration, 1 OD unit measured at 260 nm corresponds to 50 μg/ml of DNA. DNA purity was determined by measuring the A260/A280 ratio. The ratio of 1.8–1.9 corresponds to pure double-stranded DNA. DNA sample aliquots were stored at −20°C until use.
Analysis of polymorphisms
The analysis was performed using 1× Taq PCR master mix (Taq PCR Master Mix Kit; Qiagen GmbH), which contained 200 mol/l of each dNTP, 5ml of 109 reaction buffer, 1.25 U Taq gold polymerase, and 4 mmol/l MgCl2. For a 25 μl reaction volume, 12.5 μl master mix was used and then DNA and PCR primers (Promega, Madison, Wisconsin, USA) were added. The volume of the reaction mixture was increased to a final volume of 25 μl with the addition of dH2O. The BsmI PCR primers were as follows: forward: 5'-CAACCAAGACTACAAGTACCGC GTCAGTGA-3' and reverse: 5'-AACCAGCGG GAAGAGGTCAAGGG-3'. Amplification was performed using a PTC-100 thermal cycler (MJ Research Inc., Watertown, Massachusetts, USA) with 65°C as the annealing temperature. Restriction fragment length polymorphism was used to identify VDR genotypes. Amplified PCR products (10 ml) were digested (37°C for 20 h) with 4 U BsmI restriction enzyme (New England Biolabs, 75-77 Knowl Piece, Wilbury Way, Hitchin, Herts SG4 0TY) in 20 μl reaction volume; The EC 360 Submarine Gel electrophoresis system was used (Maxicell, EC 360; MEC Apparatus Cooperation, St Petersburg, Florida, USA). The PCR products were visualized using 2% agarose gel containing ethidium bromide under ultraviolet transillumination.
Capital letters represented absence and lowercase letters represented presence of a BsmI restriction site (B/b). Genotype was determined according to fragment length – that is, homozygote AA (bb) individuals = 822 bp product, heterozygote GA (Bb) individuals = 822, 650, and 172 bp products, and homozygote GG (BB) individuals = 650 and 172 bp products [Figure 4].
|Figure 4: Vitamin D receptor BsmI genotypes in immune thrombocytopenic purpura patients.|
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A SNP resulting in A–G substitution in the VDR gene intron 8 led to the generation of a BsmI restriction site. Homozygous individuals with alleles containing nucleotide A at this position showed one band at 822 bp and were designated as having bb BsmI genotype. Homozygous individuals with alleles containing G at this position showed two bands of 650 and 172 bp and were designated as BB. Individuals with heterozygote status showed three bands 825, 650, and 172 bp and were designated as Bb. For quality control, genotyping of 10% of the samples was repeated and interpreted blindly by two different observers, which proved to be identical to the initial results.
The included patients in our study were divided in two groups – ITP cases and healthy controls. The ITP group was further divided according to bleeding severity to mild and moderate following (modified Buchanan and Adix and, Imbach 2013) , and International working group for ITP .
Data were analyzed using statistical package for social sciences, version 18 (SPSS Inc., Chicago, Illinois, USA). Quantitative data are expressed as mean ± SD. Qualitative data are expressed as frequencies and percentages. For qualitative data, the c2-test with Yates correction or Fisher's exact test was used when appropriate. P value was significant if less than 0.05; strength of associations was assessed by computing odds ratio and their 95% confidence intervals. The Kolmogrov–Smirnov test was used to explore normality of data. The Student t-test and one-way analysis of variance test were used to compare between quantitative data of two and more than two groups, respectively.
Bonferroni's correction was used for the obtained P value by multiplying the observed (uncorrected) P value by the number of comparisons or tests.
The significance of association between the observed and expected number of the genotypes for a population in the Hardy–Weinberg equilibrium was analyzed using Pearson's two-sided c2-test.
| Results|| |
Demographics and baseline characteristics of ITP patients are summarized in [Table 1] and [Table 2]. This study included 40, adult, female ITP patients (age range: 20–43 years, mean ± SD: 30.52 ± 5.66586) and 60, adult, female controls matched for age (range: 20–40 years, mean ± SD: 29.51 ± 5.84399). There was a highly statistically significant difference between the ITP group and the control group regarding hemoglobin level and platelet count.
|Table 1: Differences between immune thrombocytopenic purpura cases and healthy controls regarding the studied variables|
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|Table 2: Demographics and baseline characteristics of immune thrombocytopenic purpura patients|
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In our study, there was a statistically significant difference between ITP patients and controls with regard to distribution of BsmI genotype frequencies (P = 0.01) with no statistically significant differences regarding the distribution of the BsmI genotype allele (P = 0.145). Moreover, there was no statistically significant differences between mutant and corecessive BsmI genotype variants in the ITP group and the control group (P = 0.15) and between codominant and recessive BsmI genotype variants (P = 0.08) [Table 3].
|Table 3: Distribution of the vitamin D receptor BsmI genotype and allele in immune thrombocytopenic purpura patients and healthy controls|
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This study showed no significant differences between BsmI genotype and hemoglobin level (P = 0.69) and platelet count (P = 0.32) [Figure 1], [Figure 2], [Figure 3].
|Figure 1: Vitamin D receptor BsmI genotype and studied variables in the immune thrombocytopenic purpura group.|
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|Figure 2: Association between the BsmI gene allele and the studied variables in the immune thrombocytopenic purpura group, codominant pattern (BB + Bb) versus recessive homozygote (bb).|
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|Figure 3: Association between the BsmI gene allele and the studied variables in the immune thrombocytopenic purpura group, mutant homozygote (BB) versus corecessive pattern (Bb + bb).|
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Regarding bleeding severity, there was no statistically significant differences with respect to BsmI genotype frequency (P = 0.08) and allele (P = 0.206) [Table 4]. There was a statistically significant difference between BB versus Bb + bb genotype variants regarding degree of bleeding severity (P = 0.014) with no significant differences between BB + Bb versus bb genotype variants (P = 0.12) [Table 4].
|Table 4: Distribution of vitamin D receptor genotyping BsmI in immune thrombocytopenic purpura patients regarding bleeding severity|
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For site of bleeding, the BsmI genotype and its variants showed no statistically significant differences apart from oral bleeding where BB + Bb is in statistical significant differences when compared with bb genotype (P = 0.04) and BB when compared with Bb + bb (P = 0.03) [Table 5], [Table 6], [Table 7].
|Table 5: Distribution of vitamin D receptor BsmI genotyping in immune thrombocytopenic purpura patients regarding site of bleeding|
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|Table 6: Association between BsmI genotype variant and site of bleeding in the immune thrombocytopenic purpura group, codominant pattern (BB + Bb) versus recessive homozygote (bb)|
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|Table 7: Association between the BsmI genotype variant and site of bleeding in the immune thrombocytopenic purpura group, mutant homozygote (BB) versus corecessive pattern (Bb + bb)|
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| Discussion|| |
As ITP had been testified to be a heterogeneous disease, studies in terms of gene polymorphisms in ITP are being carried out extensively, and new findings and opinions are continually being published,[28-30] which are helpful to better understand the pathogenesis of ITP and would be of value in choosing therapeutic regimens.
Several cells involved in the immune system express VDR and key vitamin D metabolizing enzymes, which could explain the suppressive effects of vitamin D on immunity .
Most of the biological activities of vitamin D are mediated by the VDR gene. Genetic variation in the VDR gene could lead to significant receptor dysfunction, which could affect calcium metabolism, cell proliferation, and immune response. Polymorphisms in the VDR gene have been associated with bad health outcomes involving low bone density, cardiovascular disease, cancers, autoimmunity, and infections. VDR polymorphisms have been reported to be associated with a wide range of autoimmune diseases (such as rheumatoid arthritis, systemic sclerosis, type 1 diabetes mellitus, multiple sclerosis, inflammatory bowel diseases, and autoimmune gastritis).
BsmI is located in the intron between exons 8 and 9, which may affect VDR mRNA stability. Since 1996, when Berg et al. first reported that the VDR BsmI polymorphism could affect osteoporosis in postmenopausal women,  to date, a large number of studies regarding the association between BsmI gene polymorphism and autoimmune diseases have been published.
Despite an extensive literature study, no study has so far reported the relationship between VDR polymorphisms and adult ITP. This is the first report on VDR gene BsmI polymorphisms in adult ITP.
In the present study, there was a statistically significant difference between the ITP group and the control group regarding BsmI genotype frequency with no statistically significant difference regarding the BsmI allele.
The heterozygous pattern Bb genotype was the most common among patients and least common among controls. The frequency of the B allele in the present study was higher, although insignificantly, in ITP patients than in controls. The b allele was higher, although insignificantly, in controls than in patients.
In our study, there was no statistically significant difference between BsmI genotype and its variants and clinical parameters of ITP presentations (platelet count, bleeding severity, site of bleeding) apart from oral bleeding where it was common in B+ ve allele and not in BB.
Among controls, the distribution of the BsmI genotype was BB, Bb, and bb at 33.3, 21.7, and 45.0%, respectively. The percentage of BB was similar to values obtained by Saad et al.  (Egypt), Abd-Allah et al.  (Egypt), and El-Beshbishy et al.  (Saudi Arabia), but in contrast to the results of Karray et al.  (Tunisia), Cai et al.  (China), and Carvalho et al.  (White). The percentage of Bb was similar to values obtained by Emerah and El-Shal  (Egypt), Mosaad et al.  (Egypt), and Khalid  (Sudan), but in contrast to the results of Abdeltif et al.  (Morocco), Abbasi et al.  (China), Sakulpipatsin et al.  (Taiwan), Mostowska et al.  (White), and Kizildag et al.  (Turkey). The percentage of bb was similar to the values obtained by Abd-Allah et al. , Mosaad et al. , and Khalid , but in contrast to the results of Karray et al. , Abdeltif et al. , Sakulpipatsin et al. , and Carvalho et al. .
These variations are due to ethnic variations in VDR polymorphisms among populations with gene–gene and gene–environment interactions.
Moreover, in the control group, the BsmI B allele frequency was 44.2%. This result is in agreement with El-Hoseiny et al.  but in contrast to the results of Emerah and El-Shal  and Mansour et al. . The b allele frequency in the control group was 55.8%. This is in agreement with El-Barbary et al.  and Abd-Allah et al.  but not in agreement with Saad et al.  and Mosaad et al. . These differences may be related the size of each study.
Finally, we can recommend that the VDR BsmI polymorphism can be used as a risk marker for primary ITP susceptibility; however, further studies on larger samples and replication of significant findings are necessary to clarify this notice. It is better to assess the levels of 25-hydroxyvitamin D while checking VDR polymorphisms and to take into account all polymorphisms that could influence the expression and activity of the mRNA and that in high linkage disequilibrium with BsmI (ApaI, TaqI polymorphisms). Close follow-up of ITP patients during treatment is highly indicated to study the drawbacks or advantages of BsmI genotype on treatment plan.
| Conclusion|| |
In our study, we found an association of VDR BsmI in ITP patients with no obvious effect on platelet count, bleeding severity, or even site of bleeding.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Baeke F, Takiishi T, Korf H, Gysemans C, Mathieu C. Vitamin D modulator of the immune system. Curr Opin Pharmacol 2010; 10
Willheim M, Thien R, Schrattbauer K, Bajna E, Holub M, Gruber R, et al
. Regulatory effects of 1alpha, 25-dihydroxyvitamin D3 on the cytokine production of human peripheral blood lymphocytes. J Clin Endocrinol Metab 1999; 84
Tokuda N, Mano T, Kasahara M, Levy R. 1,25-Dihydroxyvitamin D3 antagonizes interferon-gamma-induced expression of class II major histocompatibility antigens on thyroid follicular and testicular Leydig cells. Endocrinology 1990; 127
Lemire JM, Archer DC, Beck L, Spiegelberg HL. Immunosuppressive actions of 1,25-dihydroxyvitamin D3: preferential inhibition of Th1 functions. J Nutr 1995; 125
Joshi S, Pantalena LC, Liu XK, Gaffen SL, Liu H, Rohowsky-Kochan C, et al
. 1,25-dihydroxyvitamin D(3) ameliorates Th17 autoimmunity via transcriptional modulation of interleukin-17A. Mol Cell Biol 2011; 31
Boonstra A, Barrat FJ, Crain C, Heath VL, Savelkoul HF, O'Garra A. 1alpha, 25-Dihydroxyvitamin D3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells. J Immunol 2001; 167
Rudensky AY. Regulatory T cells and Foxp3. Immunol Rev 2011; 241
Ardalan MR, Maljaei H, Shoja MM, Piri AR, Khosroshahi HT, Noshad H. Calcitriol started in the donor, expands the population of CD4+ CD25+ T cells in renal transplant recipients. Transplant Proc 2007; 39
Sutaria N, Liu C, Chen T. Vitamin D status, receptor gene polymorphisms, and supplementation on tuberculosis: a systematic review of case–control studies and randomized controlled trials. J Clin Transl Endocrinol 2014; 1
Adorini L, Penna G. Control of autoimmune diseases by the vitamin D endocrine system. Nat Clin Pract Rheumatol 2008; 4
Pike J. Vitamin D3 receptors: structure and function in transcription. Annu Rev Nutr 1991; 11
Pani M, Knapp M, Donner H, Braun J, Baur M, Badenhoop K. Vitamin D receptor allele combinations influence genetic susceptibility to type 1 diabetes in Germans. Diabetes 2000; 49
Muscogiuri G, Mitri J, Mathieu C, Badenhoop K, Tamer G, Orio F, et al
. Mechanisms in endocrinology: vitamin D as a potential contributor in endocrine health and disease. Eur J Endocrinol 2014; 171
Bellastella G, Maiorino M, Petrizzo M, Bellis A, Capuano A, Esposito K. Vitamin D and autoimmunity: what happens in autoimmune polyendocrine syndromes? J Endocrinol Invest 2015; 38
Dong J, Zhang W, Chen J, Zhang Z, Han S, Qin L. Vitamin D intake and risk of type 1 diabetes: a meta-analysis of observational studies. Nutrients 2013; 5
Xiong J, He Z, Zeng X, Zhang Y, Hu Z. Association of vitamin D receptor gene polymorphisms with systemic lupus erythematosus: a meta-analysis. Clin Exp Rheumatol 2014; 32
Monticielo OA, Brenol JC, Chies JA, Longo MG, Rucatti GG, Scalco R. The role of BsmI
vitamin D receptor gene polymorphisms and serum 25-hydroxyvitamin D in Brazilian patients with systemic lupus erythematosus. Lupus 2012; 21
Garcia-Martin E, Agundez JA, Martinez C, Benito-Leon J, Millan-Pascual J, Calleja P, et al
. Vitamin D3 receptor (VDR) gene rs2228570 (FokI
) and rs731236 (TaqI
) variants are not associated with the risk for multiple sclerosis: results of a new study and a meta-analysis. PLoS One 2013; 8
Huang J, Xie ZF. Polymorphisms in the vitamin D receptor gene and multiple sclerosis risk: a meta-analysis of case–control studies. J Neurol Sci 2012; 313
Tizaoui K, Kaabachi W, Hamzaoui A, Hamzaoui K. Contribution of VDR polymorphisms to type 1 diabetes susceptibility: systematic review of case–control studies and meta analysis. J Steroid Biochem Mol Biol 2014; 143
De Azevedo Silva J, Guimaraes RL, Brandao LA, Araujo J, Segat L, Crovella S. Vitamin D receptor (VDR) gene polymorphisms and age onset in type 1 diabetes mellitus. Autoimmunity 2013; 46
Zhou H, Xu C, Gu M. Vitamin D receptor (VDR) gene polymorphisms and Graves' disease: a meta-analysis. Clin Endocrinol 2009; 70
Tizaoui K, Kaabachi W, Ouled SM, Ben Amor A, Hamzaoui A, Hamzaoui K. Vitamin D receptor TaqI
polymorphisms: a comparative study in patients with Behçet's disease and rheumatoid arthritis in Tunisian population. Cell Immunol 2014; 290
Provan D, Stasi R, Newland A, Blanchette V, Bolton-Maggs P, Bussel JB, et al
. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 2010; 115
Cooper N, Bussel J. The pathogenesis of immune thrombocytopenic purpura. Br J Haematol 2006; 133
McKenzie C, Guo L, Freedman J, Semlpe J. Cellular immune dysfunction in immune thrombocytopenia (ITP). Br J Haematol 2013; 163
Neunert C, Lim W, Crowther M, Cohen A, Solberg L Jr, Crowther MA. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood 2011; 117
Buchanan G, Adix L. Grading of hemorrhage in patients with idiopathic thrombocytopenic purpura. J Pediatr 2002; 141
Neunert CE, Buchanan GR, Imbach P, Bolton-Maggs PH, Bennett CM, Neufeld E, et al
. Bleeding manifestations and management of children with persistent and chronic immune thrombocytopenia: data from the Intercontinental Cooperative ITP Study Group (ICIS). Blood 2013; 121
Rodeghiero F, Michel M, Gernsheimer T, Ruggeri M, Blanchette V, Bussel JB, et al
. Standardization of bleeding assessment in immune thrombocytopenia: report from the International Working Group. Blood 2013; 121
Valdivielso JM, Fernandez E. Vitamin D receptor polymorphisms and diseases. Clin Chim Acta 2006; 371
Berg JP, Falch JA, Haug E. Fracture rate, pre- and postmenopausal bone mass and early and late postmenopausal bone loss are not associated with vitamin D receptor genotype in a high-endemic area of osteoporosis. Eur J Endocrinol 1996; 135
Abd-Allah S, Pasha H, Hagrass H, Alghobashy A. Vitamin D status and vitamin D receptor gene polymorphisms and susceptibility to type 1 diabetes in Egyptian children. Gene 2014; 536
El-Beshbishy H, Tawfeek M, Taha I, FadulElahi T, Shaheen A, Sultan I. Association of vitamin D receptor gene BsmI
(A>G) and FokI
(C>T) polymorphism in gestational diabetes among Saudi Women. Pak J Med Sci 2015; 31
Karray EF, Ben-Dhifallaha I, Ben-Abdelghanib K, Ben-Ghorbelc I, Khanfir M, Houman H, et al
. Associations of vitamin D receptor gene polymorphisms FokI
with susceptibility to rheumatoid arthritis and Behcet's disease in Tunisians. Joint Bone Spine 2012; 79
Cai G, Zhang X, Xin L, Wang L, Wang M, Yang X, et al
. Associations between vitamin D receptor gene polymorphisms and ankylosing spondylitis in Chinese Han population: a case–control study. Osteoporos Int 2016; 27
Carvalho C, Marinho A, Leal B, Bettencourt A, Boleixa D, Almeida I, et al
. Association between vitamin D receptor (VDR) gene polymorphisms and systemic lupus erythematosus in Portuguese patients. Lupus 2015; 24
Emerah A, El-Shal A Role of vitamin D receptor gene polymorphisms and serum 25-hydroxyvitamin D level in Egyptian female patients with systemic lupus erythematosus. Mol Biol Rep 2013; 40
Mosaad Y, Hammad E, Fawzy Z, Abdal Aal I, Youssef H, El-Said TO, et al
. Vitamin D receptor gene polymorphism as possible risk factor in rheumatoid arthritis and rheumatoid related osteoporosis. Hum Immunol 2014; 75
Khalid KE. Vitamin D receptor gene polymorphisms in Sudanese children with type 1 diabetes. AIMS Genetics 2016; 3
Abdeltif E, Benrahma H, Charoute H, Barakat H, Kandil M, Rouba H. Vitamin D receptor gene polymorphisms and vitamin D status and susceptibility to type 2 diabetes mellitus in Moroccans patients. Int J Sci Res Publ 2014; 4
Abbasi M, Rezaieyazdi Z, Afshari JT, Hatef M, Sahebari M, Saadati N. Lack of association of vitamin D receptor gene BsmI
polymorphisms in patients with systemic lupus erythematosus. Rheumatol Int 2010; 30
Sakulpipatsin W, Verasertniyom O, Nantiruj K, Totemchokchyakarn K, Lertsrisatit P, Janwityanujit S. Vitamin D receptor gene Bsm
I polymorphisms in Thai patients with systemic lupus erythematosus. Arthritis Res Ther 2006; 8
Mostowska A, Lianeri M, Wudarski M, Olesińska M, Jagodziński PP. Vitamin D receptor gene BsmI
polymorphisms and the risk of systemic lupus erythematosus. Mol Biol Rep 2013; 40
Kizildag S, Dedemoglu F, Anik A, Catli G, Makay B, Abaci A, et al
. Association between vitamin D receptor polymorphism and familial Mediterranean fever disease in Turkish children. Biochem Genet 2016; 54
El-Hoseiny S, Morgan D, Rabie A, Bishay S. Vitamin D receptor (VDR) gene polymorphisms (FokI
) and their relation to vitamin D status in pediatrics beta thalassemia major. Indian J Hematol Blood Transfus 2016; 32
Mansour L, Sedky M, Abdel Khader M, Sabry R, Kamal M, El Sawah H. The role of vitamin D receptor genes (FokI
) polymorphism in osteoporosis. Middle East Fertil Soc J 2010; 15
El-Barbary A, Hussein M, Rageh E, Essa S, Zaytoun H. Vitamin D receptor gene polymorphism in rheumatoid arthritis and its association with atherosclerosis. Egypt Rheumatol Rehabil 2015; 42
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]