Relationship of serum and dietary vitamin D with high cardiometabolic risk in Mexican systemic lupus erythematosus patients: A cross-sectional study.

Objetive: Serum and dietary vitamin D could influence clinical disease activity and cardiometabolic outcomes in systemic lupus erythematosus (SLE). This study aimed to assess the relationship of serum and dietary vitamin D with cardiometabolic risk in Mexican SLE patients and healthy subjects (HS).Methods: 224 SLE patients and 201 HS were included in this cross-sectional study. Serum calcidiol was measured using a competitive enzyme-linked immunosorbent assay (ELISA). Vitamin D dietary intake was assessed by collecting three 24h food records. Dietary patterns (DPs) were identified using principal component analysis (PCA). Cardiometabolic status was analyzed through biochemical measurements and cardiometabolic indexes.Results: Calcidiol deficiency (<20 ng/mL) was associated with 1.66-fold higher risk of excess weight by body mass index (BMI) (≥25 kg/m2) (p = .02), 2.25-fold higher risk to low high-density lipoprotein-cholesterol (HDL-C) (<40 mg/dL) (p < .001), and 1.74-fold higher risk to high triglycerides (TG) ≥150 mg/dL (p = .02). Inadequate vitamin D dietary intake was associated with 1.92-fold higher risk of presenting non-healthy waist circumference (WC) (>80 cm) (p < .01), 2.05-fold higher risk of android waist to hip ratio (WHR ≥85) (p < .01), and 1.72-fold higher risk to excess weight (p = .02). Non-adherence to a DP rich in vitamin D food sources was associated with higher WC, WHR, triglycerides, and lower high-density lipoprotein-cholesterol (HDL-C); furthermore, in HS, non-adherence to the DP rich in vitamin D food sources provided 2.11-fold higher risk to calcidiol deficiency.In Cconclusion: A pattern of Calcidiol deficiency, inadequate vitamin D dietary intake, and non-adherence to a DP rich in vitamin D food sources was related to high cardiometabolic risk in SLE patients and HS.

Genetic risk score for insulin resistance based on gene variants associated to amino acid metabolism in young adults.

Circulating concentration of arginine, alanine, aspartate, isoleucine, leucine, phenylalanine, proline, tyrosine, taurine and valine are increased in subjects with insulin resistance, which could in part be attributed to the presence of single nucleotide polymorphisms (SNPs) within genes associated with amino acid metabolism. Thus, the aim of this work was to develop a Genetic Risk Score (GRS) for insulin resistance in young adults based on SNPs present in genes related to amino acid metabolism. We performed a cross-sectional study that included 452 subjects over 18 years of age. Anthropometric, clinical, and biochemical parameters were assessed including measurement of serum amino acids by high performance liquid chromatography. Eighteen SNPs were genotyped by allelic discrimination. Of these, ten were found to be in Hardy-Weinberg equilibrium, and only four were used to construct the GRS through multiple linear regression modeling. The GRS was calculated using the number of risk alleles of the SNPs in HGD, PRODH, DLD and SLC7A9 genes. Subjects with high GRS (≥ 0.836) had higher levels of glucose, insulin, homeostatic model assessment- insulin resistance (HOMA-IR), total cholesterol and triglycerides, and lower levels of arginine than subjects with low GRS (p < 0.05). The application of a GRS based on variants within genes associated to amino acid metabolism may be useful for the early identification of subjects at increased risk of insulin resistance.

Analysis of Potential Vitamin D Molecule Biomarkers: Association of Calcitriol and Its Hydroxylation Efficiency Ratio with Cardiovascular Disease Risk in Rheumatoid Arthritis Patients.

Rheumatoid arthritis (RA) is a multifactorial autoimmune disease in which hypovitaminosis D by calcidiol quantification has been associated with disease severity. However, other vitamin D molecules could be implicated in RA pathophysiology and its comorbidities such as cardiovascular disease (CVD), which impacts the severity and mortality of RA patients. This study aimed to assess the relationship between calcidiol, calcitriol, its hydroxylation efficiency ratio, and the soluble vitamin D receptor (sVDR) and clinical and CVD risk variables to propose potential vitamin D molecule biomarkers for RA. A cross-sectional study of females was conducted on 154 RA patients and 201 healthy subjects (HS). Calcidiol, calcitriol, and the sVDR were measured in blood serum, and vitamin D hydroxylation efficiency was estimated using the calcitriol/calcidiol ratio score. CVD risk was calculated by the high-sensitivity C-reactive protein (hs-CRP) cutoff values. Disease activity was evaluated with the Disease Activity Score for 28 standard joints (DAS28-CRP). Results: The hydroxylation efficiency ratio and calcitriol serum levels were higher in RA patients with hypovitaminosis D (p < 0.001). Moreover, RA patients had a higher probability of a high hydroxylation efficiency ratio (OR = 2.02; p = 0.02), calcitriol serum levels (OR = 2.95; p < 0.001), and sVDR serum levels (OR = 5.57; p < 0.001) than HS. This same pattern was also observed in RA patients with high CVD risk using CRP serum levels; they showed a higher hydroxylation efficiency ratio (OR = 4.51; p = 0.04) and higher calcitriol levels (OR = 5.6; p < 0.01). Calcitriol correlates positively with the sVDR (r = 0.21, p = 0.03), CRP (r = 0.28, p < 0.001), and cardiometabolic indexes (p < 0.001) also showed discrimination capacity for CVD risk in RA patients with CRP ≥ 3 mg/L (AUC = 0.72, p < 0.01). In conclusion, hypovitaminosis D in RA patients was characterized by a pattern of a higher hydroxylation efficiency ratio and higher calcitriol and sVDR serum levels. Notably, higher calcitriol serum levels and a higher vitamin D hydroxylation efficiency ratio were associated with higher CVD risk in RA patients.

Nutritional Approaches to Modulate Cardiovascular Disease Risk in Systemic Lupus Erythematosus: A Literature Review.

Systemic lupus erythematosus (SLE) is a chronic pathology characterized by a bimodal mortality pattern attributed to clinical disease activity and cardiovascular disease (CVD). A complex interaction between traditional CVD risk factors such as obesity, dyslipidemia, smoking, insulin resistance, metabolic syndrome, and hypertension, as well as the presence of non-traditional CVD risk factors such as hyperhomocysteinemia, pro-inflammatory cytokines, and C-reactive protein levels, has been suggested as a cause of the high prevalence of CVD in SLE patients. On the other hand, environmental factors, such as nutritional status, could influence the disease's prognosis; several nutrients have immunomodulators, antioxidants, and anti-cardiometabolic risk properties which could reduce SLE severity and organ damage by decreasing the development of traditional and non-traditional CVD risk factors. Therefore, this critical literature review discusses the therapeutic potential of nutritional approaches that could modulate the development of the main comorbidities related to CVD risk in SLE patients.

Methyl Donor Micronutrients: A Potential Dietary Epigenetic Target in Systemic Lupus Erythematosus Patients.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by an aberrant immune response and persistent inflammation. Its pathogenesis remains unknown; however, a complex interaction between environmental, genetic, and epigenetic factors has been suggested to cause disease onset. Several studies have demonstrated that epigenetic alterations, such as DNA hypomethylation, miRNA overexpression, and altered histone acetylation, may contribute to SLE onset and the disease's clinical manifestations. Epigenetic changes, especially methylation patterns, are modifiable and susceptible to environmental factors such as diet. It is well known that methyl donor nutrients, such as folate, methionine, choline, and some B vitamins, play a relevant role in DNA methylation by participating as methyl donors or coenzymes in one-carbon metabolism. Based on this knowledge, this critical literature review aimed to integrate the evidence in animal models and humans regarding the role of nutrients in epigenetic homeostasis and their impact on immune system regulation to suggest a potential epigenetic diet that could serve as adjuvant therapy in SLE.

Nutritional, biochemical, and clinical determinants of hyperuricemia in systemic lupus erythematosus patients: Relationship with clinical and renal disease activity.

Systemic lupus erythematosus (SLE) is the prototypical autoimmune disease considered as an independent risk factor for mortality by cardiovascular disease. Currently, uric acid is described as a novel biomarker associated with cardiometabolic risk. However, nutritional and serum determinants that influence hyperuricemia development in autoimmune diseases have not been fully elucidated. This study aimed to assess the nutritional, biochemical, and cardiometabolic determinants of hyperuricemia and its relationship with clinical variables in SLE patients. A cross-sectional study was conducted in 167 SLE patients and 195 control subjects (CS). Nutrient intake, anthropometry, biochemical, and cardiometabolic indexes were evaluated. In SLE patients, adequate protein (OR = 0.4; p = 0.04) and carbohydrate (OR = 0.2; p = 0.01) intakes were associated with a lower risk of hyperuricemia. SLE patients with hyperuricemia presented a higher risk of clinical (OR = 2.2; p = 0.03) and renal activity (OR = 3.4; p < 0.01), as well as triglycerides ≥150 mg/dL (OR = 3.6; p < 0.01), hs-CRP ≥1 mg/L (OR = 3.1; p < 0.01), Kannel score ≥3 (OR = 2.5; p = 0.02), and BMI ≥25 kg/m2 (OR = 2.2; p = 0.02). Oppositely, serum levels of HDL-C ≥40 mg/dL (OR = 0.2; p < 0.01) were associated with a lower risk of hyperuricemia. According to the pharmacotherapy administered, prednisone treatment was associated with a high risk of hyperuricemia (OR = 4.7; p < 0.001). In contrast, the hydroxychloroquine treatment was associated with a lower risk of hyperuricemia (OR = 0.4; p = 0.02). In conclusion, SLE patients with hyperuricemia presented a high risk of clinical and renal activity as well as worse cardiometabolic status. Notably, an adequate intake of protein, carbohydrates, healthy HDL-C serum levels, and hydroxychloroquine treatment could be determinants of lower risk of hyperuricemia.

Association of - 717 A > G (rs2794521) CRP polymorphism with high cardiovascular risk by C-reactive protein in systemic lupus erythematosus patients.

INTRODUCTION: Systemic lupus erythematosus (SLE) is an autoimmune disease where genetic factors have been related to SLE susceptibility and disease severity. CRP polymorphisms have been associated with high C-reactive protein (CRP) serum levels, cardiovascular disease (CVD), and high clinical disease activity in SLE patients; however, the evidence is still inconclusive. OBJECTIVE: This study was aimed to assess the association of the - 717 A > G, - 409 G > A, + 1444 C > T, and + 1846 C > T CRP polymorphisms with genetic susceptibility, clinical disease activity, and CVD risk in Mexican-mestizo SLE patients. METHODS: A comparative cross-sectional study was conducted on 369 unrelated women: 183 with SLE according to the 1997 SLE-ACR criteria and 186 healthy subjects (HS). The clinical disease activity was assessed by the Mex-SLEDAI score; CRP and lipid profile were quantified by turbidimetry and colorimetric-enzymatic assays, respectively. The CRP polymorphisms genotyping was carried out by allelic discrimination. RESULTS: SLE patients with - 717 AA genotype had higher CRP serum levels than SLE carriers of AG and GG genotypes (AA = 5 mg/L vs. AG = 3.2 mg/L vs. GG = 2.4 mg/L; p = 0.01), and the AA genotype was associated with high CVD risk by CRP in SLE patients (OR = 3; CI: 1.2-7.6; p < 0.01). CONCLUSIONS: The - 717 A > G CRP polymorphism is a risk factor for high CRP levels and high CVD risk in Mexican-mestizo SLE patients. Key Points • Cardiovascular disease is one of the major causes of death in SLE patients due to the higher prevalence of traditional and non-traditional cardiovascular risk factors. • C-reactive protein is a liver-derived acute-phase protein suggested as one powerful independent risk predictor factor for cardiovascular disease. • Single nucleotide polymorphisms in CRP have been suggested as genetic susceptibility factors that could modify the SLE pathophysiology outcomes. • Mexican-mestizo SLE patients carrying the -717 A>G CRP AA genotype had 3-fold high cardiovascular disease risk than SLE patients with AG or GG genotypes.

Vitamin D Receptor (VDR) Genetic Variants: Relationship of FokI Genotypes with VDR Expression and Clinical Disease Activity in Systemic Lupus Erythematosus Patients.

Vitamin D (VD) deficiency is more frequent in systemic lupus erythematosus (SLE) patients than in control subjects (CS); genetic variants in the VD receptor (VDR) could contribute to the clinical disease activity. This study was aimed to determine the association of the VDR variants FokI (rs2228570), BsmI (rs1544410), ApaI (rs7975232), and TaqI (rs731236) with susceptibility to the disease, VD status, VDR mRNA expression, and clinical disease activity in SLE patients. A cross-sectional study was conducted in 194 SLE and 196 CS Mexican women. Immunoassays quantified serum calcidiol and calcitriol. Genotyping was performed by allelic discrimination assays and mRNA VDR expression by qPCR. The FokI variant was not in linkage disequilibrium with BsmI, ApaI, and TaqI VDR variants. SLE patient carriers of the TT FokI genotype showed higher clinical disease activity scores. Notably, the mRNA VDR expression was higher in SLE patients vs. CS, in active vs. inactive SLE patients, and in participants of both study groups with vitamin D deficiency, higher calcitriol levels, and TT FokI genotype carriers. In conclusion, the TT FokI VDR genotype was related to high VDR expression and clinical disease activity in systemic lupus erythematosus patients.

CRP Serum Levels Are Associated with High Cardiometabolic Risk and Clinical Disease Activity in Systemic Lupus Erythematosus Patients.

Systemic lupus erythematosus (SLE) patients have a higher frequency of cardiovascular risk factors such as high C-reactive protein (CRP) levels than the general population. CRP is considered a cardiovascular disease marker that could be related to SLE clinical disease activity. This study aimed to assess the association between CRP with cardiometabolic risk and clinical disease activity in SLE patients. A comparative cross-sectional study was conducted in 176 female SLE patients and 175 control subjects (CS) with median ages of 38 and 33 years, respectively; SLE patients were classified by the 1997 SLE-ACR criteria, and the clinical disease activity by the Mexican-SLEDAI (Mex-SLEDAI). CRP and lipid profile (triglycerides, cholesterol, HDL-C, and LDL-C) were quantified by turbidimetry and colorimetric-enzymatic assays, respectively. SLE patients had higher CRP levels than CS (SLE: 5 mg/L vs. CS = 1.1 mg/L; p < 0.001). In SLE patients, CRP levels ≥ 3 mg/L were associated with a higher risk of cardiometabolic risk status assessed by LAP index (OR = 3.01; IC: 1.04−8.7; p = 0.04), triglycerides/HDL-C index (OR = 5.2; IC: 2.1−12.8; p < 0.001), Kannel index (OR = 3.1; IC: 1.1−8.1; p = 0.03), Castelli index (OR = 6.6; IC: 2.5−17.8; p < 0.001), and high clinical disease activity (OR = 2.5: IC: 1.03−6.2; p = 0.04; and ß coefficient = 5.8; IC: 2.5−9.4; R2 = 0.15; p = 0.001). In conclusion, high CRP levels were associated with high cardiometabolic risk and clinical disease activity in SLE patients.

Functional effects of vitamin D: From nutrient to immunomodulator.

Vitamin D can be obtained from the endogenous synthesis in the epidermis by exposure to UVB light, and from foods and supplements in the form of ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). The main metabolite used to measure vitamin D serum status is calcidiol [25(OH)D]. However, its active metabolite calcitriol [1α,25(OH)2D] performs pleiotropic effects in the cardiovascular, neurological, and adipose tissue as well as immune cells. Calcitriol exerts its effects through genomic mechanisms modulated by the nuclear vitamin D receptor (VDR)/retinoid X receptor (RXR) complex, to bind to vitamin D response elements (VDRE) in target genes of several cells such as activated T and B lymphocytes, neutrophils, macrophages, and dendritic cells; besides of its genomic mechanisms, VDR performs novel non-genomic mechanisms that involve its membrane expression and soluble form; highlighting that vitamin D could be an immunomodulatory nutrient that plays a key role during physiological and pathological events. Therefore, the aim of this comprehensive literature review was to describe the most relevant findings of vitamin D dietary sources, absorption, synthesis, metabolism, and factors that influence its serum status, signaling pathways, and biological effects of this immunonutrient in the health and disease.

Influence of Diet and Levels of Zonulin, Lipopolysaccharide and C-Reactive Protein on Cardiometabolic Risk Factors in Young Subjects.

A western diet and increased intestinal permeability may contribute to systemic inflammation and the development of cardio-metabolic alterations. The aim of this study was to assess the relationship between diet, biomarkers of intestinal permeability, and chronic low-grade inflammation on the cardiometabolic profile. A cross-sectional study was carried out in 238 young subjects aged 18-29 years, divided into two groups: with <3 cardiometabolic risk factors (CRF) and ≥3 risk factors. Anthropometric parameters, biochemical profile, and serum levels of zonulin, lipopolysaccharide (LPS), and high-sensitivity C-reactive protein (hs-CRP) were measured, and the macronutrient intake was evaluated. Interaction models showed elevated glucose levels in the presence of high biomarker levels: zonulin ≥51.6 ng/mL plus LPS ≥ 1.35 EU/mL (ß = 1.1, p = 0.006), and LPS ≥1.35 EU/mL plus hs-CRP ≥ 4.3 mg/L (ß = 1.2, p = 0.007). In addition, triglyceride levels increased in the presence of LPS ≥ 1.35 EU/mL and hs-CRP ≥ 4.3 mg/L (ß = 3.9, p = 0.01). Despite having increased biomarker levels, a higher consumption of water (≥2100 mL), polyunsaturated fatty acids (≥6.0 g), or fiber (≥30 g) decreased triglyceride (ß = -9.6, p = 0.03), total cholesterol (ß = -5.1, p = 0.01), and LDL-C levels (ß = -7.7, p = 0.01). These findings suggest that the increased consumption of water, PUFA and fiber may improve lipid profile in subjects with intestinal permeability dysfunction or low-grade systemic inflammation.

Macrophage migration inhibitory factor: A promising oncogenic serological biomarker for oral squamous cell carcinoma.

There are few reports in oral squamous cell carcinoma (OSCC) that indicate the expression of macrophage migration inhibitory factor (MIF) in tissues, serum, or saliva of patients with OSCC. The aim of this study was to evaluate the mRNA expression and protein of MIF in tissues and serum, respectively, in OSCC patients and its association with the TNM stage. A cross-sectional study was performed. Serum and tissues of 25 patients with OSCC and 25 healthy control subjects (HCS) were included to evaluate the MIF mRNA expression and protein serum levels by real-time PCR and ELISA, respectively. Serum MIF levels were significantly higher in OSCC compared with control subjects. Furthermore, in the OSCC group, MIF was significantly increased in accordance with tumor disease stage (TNM III-IV), as well as in poorly differentiated tumors. The mRNA showed significantly higher levels in HCS, as well as in more differentiated tumors. The results of this study suggest that MIF could be an indicator of severity and progression of OSCC. Further studies are required to explore the role of MIF as a serological biomarker for OSCC.

Presence of Adenovirus-36 DNA in Adipose Tissue of Women: Relationship with Adipocyte Morphology and the Expression of C/EBPß and HIF-1α.

BACKGROUND: Human adenovirus 36 (HAd36) infection has been associated with obesity. Experiments using 3T3-L1 adipocyte cultured cells and human adipose stem cells (hASCc) have shown that HAd36 stimulates the expression of genes implicated in cell differentiation and increased lipid accumulation. The presence of HAd36 in adipose tissue of overweight and obese women has also been confirmed. This study aims to analyze the presence of HAd36 DNA in the adipose tissue of women undergoing surgery for weight reduction and its relationship with obesity through changes in adipocyte morphology as well as the expression of C/EBPß and HIF-1α. METHODS: Fifty-two subcutaneous adipose tissue biopsies were collected. The anthropometric parameters measured were weight, height, skin folds, body circumferences, and body fat percentage. Biochemical measures were performed for glucose, cholesterol, triglycerides, cholesterol HDL-c, and LDL-c. The presence of HAd36 DNA was performed by conventional PCR. Adipocyte morphology was analyzed in H&E-stained sections using ImageJ/Fiji software. The expression of genes C/EBPß, HIF-1α and ß-actin was determined using TaqMan probes. RESULTS: HAd36 DNA was detected in 31% of adipose tissue samples. The presence of viral DNA was not significantly associated with anthropometric, clinical, or metabolic measurements, or with changes in adipose tissue morphology. The levels of mRNA expression for C/EBPß and HIF-1α did not show significant differences between positive and negative samples for HAd36 (p>0.05). CONCLUSION: The presence of HAd36 DNA in adipose tissue was identified, but it was not related to morphological changes of adipocytes, or the expression of C/EBPß and HIF-1α. Further studies are needed to confirm these findings.

Association of High Calcitriol Serum Levels and Its Hydroxylation Efficiency Ratio with Disease Risk in SLE Patients with Vitamin D Deficiency.

Vitamin D (calcidiol) deficiency in systemic lupus erythematosus (SLE) is more frequent than in healthy subjects (HS); it is associated with clinical activity and damage in SLE. Although calcidiol is considered the best indicator of the vitamin D serum status, its deficiency could not reflect its hydroxylation efficiency ratio and calcitriol serum status. This study was aimed at assessing the association of calcidiol and calcitriol serum levels and its hydroxylation efficiency ratio with the risk to clinical and renal disease activities in SLE patients. A cross-sectional study was conducted in 308 SLE and HS women; calcidiol and calcitriol serum levels were evaluated by immunoassays. SLE patients showed lower calcidiol serum levels vs. HS (21.2 vs. 24.2 ng/mL; p < 0.001). Active SLE patients presented higher calcidiol/calcitriol ratio scores vs. inactive SLE patients (2.78 vs. 1.92 pg/ng; p = 0.02), and SLE patients with renal disease activity showed a pattern of calcidiol-deficient levels (19.5 vs. 25.3 ng/mL; p < 0.04) with higher calcitriol levels (47 pg/mL vs. 41.5 pg/mL; p = 0.02) and calcidiol/calcitriol ratio scores (2.13 vs. 1.54 pg/ng; p < 0.02) compared to SLE patients without renal disease activity. Calcidiol levels were negatively correlated with calcitriol levels (r = -0.26; p = 0.001) and urine proteins (mg/dL) (r = -0.39; p < 0.01). Regarding calcitriol levels, it was positively correlated with the blood lymphocyte count (r = 0.30; p < 0.001) and negatively correlated with the glomerular filtration rate (r = -0.28; p = 0.001). Moreover, the calcitriol/calcidiol ratio was positively correlated with urine proteins (r = 0.38; p < 0.01). The calcidiol deficiency (OR = 2.27; 95% CI = 1.15-4.49; p < 0.01), high calcitriol levels (T3rd, OR = 4.19, 95% CI = 2.23-7.90; p < 0.001), and a high calcitriol/calcidiol ratio score (T3rd, OR = 5.93, 95% CI: 3.08-11.5; p < 0.001) were associated with the risk for SLE. In conclusion, a pattern of calcidiol deficiency with high calcitriol serum levels and a high vitamin D hydroxylation efficiency ratio was associated with disease risk in SLE patients.

Association of cardiometabolic risk status with clinical activity and damage in systemic lupus erythematosus patients: A cross-sectional study.

Cardiometabolic status is a key factor in mortality by cardiovascular disease (CVD) in systemic lupus erythematosus (SLE). This study evaluated the association of cardiometabolic risk status with clinical activity and damage in SLE patients. A cross-sectional study was conducted in 158 SLE patients and 123 healthy subjects (HS). Anthropometry, glucose, hs-CRP, lipid profile, oxLDL, sCD36, anti-oxLDL antibodies, and cardiometabolic indexes were evaluated. SLE patients had dyslipidemia, higher sCD36, anti-oxLDL antibodies, hs-CRP, and risk (OR > 2) to present Castelli score ≥ 4.5, HDL-C < 40 mg/dL and LDL-C ≥ 100 mg/dL. Disease evolution time was correlated with glucose and BMI, damage with TG, and clinical activity with TG, TG/HDL-C ratio, and Kannel index. Active SLE patients had risk (OR > 2) to present a Castelli score ≥ 4.5, Kannel score ≥ 3, TG/HDL-C ratio ≥ 3 and HDL-C < 40 mg/dL. In conclusion, SLE patients have high cardiometabolic risk to CVD related to disease evolution time, and clinical activity.

Association of Vitamin D Metabolism Gene Polymorphisms with Autoimmunity: Evidence in Population Genetic Studies.

A high prevalence of vitamin D (calcidiol) serum deficiency has been described in several autoimmune diseases, including multiple sclerosis (MS), rheumatoid arthritis (AR), and systemic lupus erythematosus (SLE). Vitamin D is a potent immunonutrient that through its main metabolite calcitriol, regulates the immunomodulation of macrophages, dendritic cells, T and B lymphocytes, which express the vitamin D receptor (VDR), and they produce and respond to calcitriol. Genetic association studies have shown that up to 65% of vitamin D serum variance may be explained due to genetic background. The 90% of genetic variability takes place in the form of single nucleotide polymorphisms (SNPs), and SNPs in genes related to vitamin D metabolism have been linked to influence the calcidiol serum levels, such as in the vitamin D binding protein (VDBP; rs2282679 GC), 25-hydroxylase (rs10751657 CYP2R1), 1α-hydroxylase (rs10877012, CYP27B1) and the vitamin D receptor (FokI (rs2228570), BsmI (rs1544410), ApaI (rs7975232), and TaqI (rs731236) VDR). Therefore, the aim of this comprehensive literature review was to discuss the current findings of functional SNPs in GC, CYP2R1, CYP27B1, and VDR associated to genetic risk, and the most common clinical features of MS, RA, and SLE.

Relationship of Excess Weight with Clinical Activity and Dietary Intake Deficiencies in Systemic Lupus Erythematosus Patients.

Obesity and nutrients intake deficiencies may contribute to the clinical manifestations and inflammatory processes in systemic lupus erythematosus (SLE). The aim of this study was to assess the relationship between nutritional status and dietary intake with clinical variables in Mexican-mestizo SLE patients. A cross-sectional study was conducted in 130 female SLE patients, classified by the 1997 SLE American College of Rheumatology (ACR) criteria; the clinical activity was evaluated by the Mexican-Systemic Lupus Erythematosus-Disease Activity Index (Mex-SLEDAI); body mass index (BMI) by the World Health Organization (WHO) criteria; the energy calculation and nutritional intake were performed by Nutritionist Pro Diet software. SLE patients with excess weight (BMI > 25 kg/m2) showed a higher score of clinical activity (Mex-SLEDAI = 2; p = 0.003), higher clinical activity prevalence (40.9%; p = 0.039) and a significant association for high clinical activity (odds ratio (OR) = 2.52; 95% confidence interval (CI) = 1.08-5.9; p = 0.033), in comparison with patients without excess weight (BMI < 25 kg/m2). In particular, the excess weight increased the Mex-SLEDAI score (ß coefficient = 1.82; R2 = 0.05; p = 0.005). Also, the SLE patients presented a high prevalence (%) of deficient consumption (cut-off point: <67% of dietary adequacy) of vitamin E (100%), iodine (96%), omega 3 (93.44%), biotin (78%), vitamin K (73.33%), iron (67%), vitamin D (63.3%), potassium (59%), folic acid (56.67%), pantothenic acid (43.3%), vitamin A (41.67%) and zinc (32%). In conclusion, in SLE patients the excess weight was associated with increased clinical activity and to the presence of deficiencies in some essential nutrients ingested.

Functional MIF promoter haplotypes modulate Th17-related cytokine expression in peripheral blood mononuclear cells from control subjects and rheumatoid arthritis patients.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by elevated levels of pro-inflammatory cytokines, such as interleukin (IL)-6, IL-17, and macrophage migration inhibitory factor (MIF). MIF induces IL-17 secretion and MIF promoter polymorphisms influence the expression of selected downstream mediators. The aim of this study was to investigate the relationship between known functional MIF haplotypes and Th17-related cytokine secretion profile in peripheral blood mononuclear cells (PBMC) from control subjects (CS) and RA patients stimulated with lipopolysaccharide (LPS) and recombinant human MIF (rhMIF). The -794 CATT5-8 and -173G > C polymorphisms of the MIF gene were determined by conventional PCR and PCR-RFLP, respectively. The most frequent haplotypes of the MIF polymorphism and PBMC were identified from three subjects homozygous for each haplotype and in both study groups, the PBMC were obtained and stimulated with LPS or rhMIF. The secretion of cytokines related to the Th17 profile was determined by a multiplex immunoassay (MAGPIX). LPS stimulation induced the secretion of cytokines related to the Th17 profile in PBMC from CS and RA patients, whereas, rhMIF only stimulated this response in PBMC from RA patients. PBMC from CS carriers of the MIF 7C haplotype showed more IL-17A, IL-17F, IL-22, and IL-23 secretion than non-7C carriers after LPS stimulation. In the case of rhMIF stimulation, the PBMC from CS carriers of the 7C haplotype secreted more IL-17A and IL-23 than non-7C carriers. In conclusion, genetic variants of the MIF promoter modulate the secretion of cytokines related to the Th17 profile in PBMC from CS inducing a differential response in comparison to PBMC from RA patients.

Association of extrapituitary prolactin promoter polymorphism with disease susceptibility and anti-RNP antibodies in Mexican patients with systemic lupus erythematosus.

Introduction: Prolactin (PRL) is a 23-kDa protein that can be synthesized and secreted by pituitary and extrapituitary tissues such as immune cells due to its expression being regulated by two independent promoter regions. The promoter which is responsible for extrapituitary expression contains the single nucleotide polymorphism (SNP) -1149 G/T previously associated with autoimmune diseases in various populations. This study evaluates the relationship of PRL -1149 G/T polymorphism with PRL serum levels and clinical characteristics in systemic lupus erythematosus (SLE) patients from western Mexico. Material and methods: One hundred and sixty-three SLE patients classified according to the 1982 American College of Rheumatology (ACR) SLE classification criteria and 326 unrelated control subjects (CS), both from western Mexico, were included. The PRL -1149 G/T polymorphism was genotyped using the polymerase chain reaction restriction fragment length polymorphism technique, and both PRL serum levels and autoantibodies were measured by enzyme-linked immunosorbent assay (ELISA). Results: We found an association between the PRL -1149 TT genotype and SLE according to the recessive genetic model (OR = 2.26, 95% CI: 1.01-5.08, p = 0.04). The TT genotype was associated with anti-RNP antibodies (p = 0.04) and with higher scores of the Mex-SLEDAI (p = 0.02). Moreover, SLE patients showed elevated PRL serum levels (12.4 ng/ml; p < 0.01), and this condition was associated with renal activity and the presence of anti-RNP antibodies. Conclusions: PRL -1149 TT genotype is associated with susceptibility to SLE in a Mexican-Mestizo population, and high PRL serum levels are associated with anti-RNP antibodies and renal activity.

MIF promotes a differential Th1/Th2/Th17 inflammatory response in human primary cell cultures: Predominance of Th17 cytokine profile in PBMC from healthy subjects and increase of IL-6 and TNF-α in PBMC from active SLE patients.

Macrophage migration Inhibitory Factor (MIF) is a cytokine associated with the pathogenesis of autoimmune inflammatory diseases. There is evidence that MIF functions in a positive-feedback-loop with proinflammatory cytokines and could perpetuate the inflammatory process in Systemic Lupus Erythematosus (SLE).The aim of this study was to assess the effect of recombinant-human-MIF (rhMIF) on the expression of Th1, Th2 and Th17 cytokines in Peripheral Blood Mononuclear Cells (PBMC) from Healthy Subjects (HS) and SLE patients. The PBMC were isolated from SLE patients classified according to the 1997 SLE ACR criteria and HS donors; all subjects included were women from an unrelated Mexican-Mestizo population. The PBMC isolated were stimulated with rhMIF, LPS and ISO-1 in different combinations; Th1, Th2 and Th17cytokine profiles levels were determined by MAGPIX Bio-plex assay in supernatants from cell cultures. We observed in supernatants of PBMCs from HS treated with rhMIF a predominance of Th17 cytokine profile with an increase of IL-17A, IL-17F and IL-21 versus PBMCs from SLE patients, which showed an inflammatory profile represented by increase of IL-6 cytokine. According to SLE remission/activity presented at enrollment in the study (Mex-SLEDAI index), the PBMC from active SLE patients showed higher levels of TNF-α and IL-6 versus PBMC from remission SLE patients. In conclusion, our results suggest that MIF can induce a differential inflammatory response in physiological and pathological conditions with a predominance of a Th17 cytokine profile in PBMC from HS and an increase in TNF-α and IL-6 expression in PBMC from active SLE patients.