RESUMO
Systemic lupus erythematosus (SLE) patients present a high prevalence of cardiometabolic risk, associated with worse clinical manifestations and mortality. Folate, an essential micronutrient that participates in vital immune cellular functions, could positively affect the cardiometabolic and disease risk in SLE, through the methylenetetrahydrofolate reductase (MTHFR) enzyme, which participates in the folate metabolism, where single nucleotide variants (SNVs) have been described as a potential genetic risk factor for SLE. The aim of this study was to determine the association of the c.+677 C>T (rs1801133) and c.+1298 A>C (rs1801131) MTHFR genetic variants with cardiometabolic risk and clinical disease variables in SLE patients. A case-control study was conducted on 394 unrelated Mexican-mestizo women: 199 with SLE according to the 1997 SLE-ACR criteria and 196 control subjects (CS). Folic acid and homocysteine levels were evaluated by immunoassays. Genotyping of MTHFR genetic variants was carried out by allelic discrimination. No significant differences were found for folic acid (p = .15) and homocysteine serum levels (p = .59) between groups. According to the CC c.+677 MTHFR genotype, this was associated with low cardiovascular disease (CVD) risk by the Castelli index (OR = 0.42; p = .03) in SLE patients. The TC (OR = 1.3; p = .03) and the TA (OR = 1.6; p < .01) haplotypes from c.+677 C>T plus c.+1298 MTHFR were associated with SLE risk, while the CC MTHFR haplotype (OR = 0.5; p = .01) was found as a non-risk factor for the disease. In conclusion, the TC and the TA MTHFR haplotypes are associated with disease risk; meanwhile, the CC c.+677 MTHFR genotype confers lower cardiometabolic risk in Mexican-mestizo SLE patients.
Assuntos
Ácido Fólico , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico , Metilenotetra-Hidrofolato Redutase (NADPH2) , Polimorfismo de Nucleotídeo Único , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/complicações , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Feminino , Estudos Transversais , Estudos de Casos e Controles , Adulto , México/epidemiologia , Pessoa de Meia-Idade , Ácido Fólico/sangue , Homocisteína/sangue , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/epidemiologia , Fatores de Risco Cardiometabólico , Genótipo , Fatores de Risco , Adulto JovemRESUMO
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.
Assuntos
Lúpus Eritematoso Sistêmico , Deficiência de Vitamina D , Vitamina D , Humanos , Lúpus Eritematoso Sistêmico/sangue , Estudos Transversais , Feminino , Masculino , Adulto , Vitamina D/sangue , México/epidemiologia , Pessoa de Meia-Idade , Deficiência de Vitamina D/epidemiologia , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/complicações , Índice de Massa Corporal , Dieta , Fatores de Risco Cardiometabólico , Circunferência da Cintura , Calcifediol/sangue , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Estudos de Casos e Controles , Triglicerídeos/sangue , Adulto Jovem , HDL-Colesterol/sangueRESUMO
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.
Assuntos
Doenças Cardiovasculares , Hiperuricemia , Nefropatias , Lúpus Eritematoso Sistêmico , Humanos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Hidroxicloroquina/uso terapêutico , Hiperuricemia/complicações , Estudos Transversais , Nefropatias/complicações , Fatores de Risco , Doenças Cardiovasculares/etiologiaRESUMO
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.
Assuntos
Lúpus Eritematoso Sistêmico , Micronutrientes , Animais , Humanos , Micronutrientes/uso terapêutico , Epigênese Genética , Metilação de DNA , DietaRESUMO
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.
Assuntos
Calcitriol , Vitamina D , Fatores Imunológicos/farmacologia , Receptores X de Retinoides , Vitamina D/metabolismo , Vitamina D/farmacologia , Vitaminas/farmacologiaRESUMO
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 (ORâ¯>â¯2) to present Castelli scoreâ¯≥â¯4.5, HDL-Câ¯<â¯40â¯mg/dL and LDL-Câ¯≥â¯100â¯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 (ORâ¯>â¯2) to present a Castelli scoreâ¯≥â¯4.5, Kannel scoreâ¯≥â¯3, TG/HDL-C ratioâ¯≥â¯3 and HDL-Câ¯<â¯40â¯mg/dL. In conclusion, SLE patients have high cardiometabolic risk to CVD related to disease evolution time, and clinical activity.
Assuntos
Doenças Cardiovasculares/epidemiologia , Dislipidemias/epidemiologia , Lúpus Eritematoso Sistêmico/patologia , Adulto , Glicemia/análise , Índice de Massa Corporal , Proteína C-Reativa/análise , Antígenos CD36/sangue , Colesterol/sangue , Estudos Transversais , Dislipidemias/patologia , Feminino , Glucose/metabolismo , Humanos , Lipoproteínas LDL/sangue , Pessoa de Meia-Idade , Obesidade/epidemiologia , Fatores de RiscoRESUMO
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.
Assuntos
Doenças Autoimunes/sangue , Doenças Autoimunes/genética , Autoimunidade/genética , Calcifediol/sangue , Polimorfismo de Nucleotídeo Único , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Calcifediol/deficiência , Colestanotriol 26-Mono-Oxigenase/genética , Família 2 do Citocromo P450/genética , Frequência do Gene , Genética Populacional/métodos , Haplótipos , Humanos , Receptores de Calcitriol/genética , Fatores de Risco , Proteína de Ligação a Vitamina D/genéticaRESUMO
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 -173Gâ¯>â¯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.
Assuntos
Artrite Reumatoide/genética , Citocinas/genética , Haplótipos/genética , Oxirredutases Intramoleculares/genética , Leucócitos Mononucleares/metabolismo , Fatores Inibidores da Migração de Macrófagos/genética , Regiões Promotoras Genéticas/genética , Células Th17/metabolismo , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético/genéticaRESUMO
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.
Assuntos
Interleucina-6/imunologia , Oxirredutases Intramoleculares/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Fatores Inibidores da Migração de Macrófagos/imunologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia , Fator de Necrose Tumoral alfa/imunologia , Adulto , Estudos de Casos e Controles , Citocinas/imunologia , Feminino , Humanos , Interleucina-17/imunologia , Interleucina-6/sangue , Oxirredutases Intramoleculares/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Lúpus Eritematoso Sistêmico/sangue , Fatores Inibidores da Migração de Macrófagos/farmacologia , Pessoa de Meia-Idade , Cultura Primária de Células , Proteínas Recombinantes/farmacologia , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Fator de Necrose Tumoral alfa/sangueRESUMO
The presence of childhood obesity predisposes to the development of cardiovascular and metabolic diseases, such as coronary artery disease and type 2 diabetes mellitus, in adulthood. The polymorphisms described in PAI-1 gene have been linked with obesity and metabolic syndrome in several populations. The aim of this study was to investigate the association of the -844 G/A (rs2227631), -675 4G/5G (rs1799889) and HindIII C/G (rs757716)PAI-1 polymorphisms with obesity and dyslipidemia in a sample of Mexican children. A cross-sectional study was performed in 222 children with an age range between 6-11 years; 104 children were classified as obese and 118 children with normal-weight. The PAI-1 polymorphisms were analyzed by PCR-RFLP. Linkage disequilibrium (LD) and haplogenotype analysis among the three polymorphisms were determined. The results showed significant associations with obesity of the -844 G/A genotype and the A allele (OR= 2.75, p<0.001 and OR= 1.76, p=0.01, respectively). The -844 G/A polymorphism was found in LD with -675 4G/5G PAI-1 polymorphism (D'= 0.77). We found that G-4G-C/A-5G-G is a risk haplogenotype for obesity [OR=2.6; 95% confidence interval (CI) 1.17-4.22; p= 0.01] and with marginal association with hypertriglyceridemia(OR= 2.6; 95% CI 1.04-6.35; p= 0.05). The G-4G-C/A-5G-G PAI-1 haplogenotype may be a genetic marker of susceptibility for obesity and hypertriglyceridemia in Mexican children.
Assuntos
Hipertrigliceridemia/genética , Obesidade Infantil/genética , Inibidor 1 de Ativador de Plasminogênio/genética , Criança , Estudos Transversais , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , MéxicoRESUMO
Macrophage migration inhibitory factor (MIF) and tumor necrosis factor alpha (TNFα) play a pivotal role in rheumatoid arthritis (RA). MIF is considered a relevant cytokine because it appears before TNFα in the inflammatory cascade thus stimulating TNFα production and MIF's relationship with traditional synthetic disease modifying antirheumatic drugs (sDMARDs) is unknown. In this cross-sectional study, we investigated the association of MIF and TNFα serum levels with methotrexate (MTX) and in combination with chloroquine (CLQ) and sulfasalazine (SSZ) in RA patients classified according to the ACR/EULAR 2010 criteria. Patients were divided into three groups: MTX-monotherapy group (n = 40), MTX combination therapy groups: MTX + CLQ (n = 41), and MTX + CLQ + SSZ (n = 42). MIF and TNFα serum levels were determined by ELISA. We found high levels of ESR, CRP, RF, and anti-CCP in all therapy groups. Furthermore, we subclassified 97 patients with established RA (≥2 years of disease duration) and found that TNFα serum levels were lower in the combination therapy group (MTX + CLQ + SSZ) in comparison with the monotherapy MTX group (16.7 pg/mL versus 13.6 pg/mL, p = 0.02). However, we did not find differences between sDMARD therapies in MIF serum levels. We did find a significant reduction in MIF serum levels in patients treated with oral steroids compared with patients without oral steroids (1.7 ng/mL versus 4.3 ng/mL, p < 0.001). In conclusion, this study supports the role of sDMARDs in modifying TNFα serum levels and oral steroids MIF serum levels. Nevertheless, we found that MIF serum levels are not modified by sDMARD treatment.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Oxirredutases Intramoleculares/sangue , Fatores Inibidores da Migração de Macrófagos/sangue , Fator de Necrose Tumoral alfa/sangue , Adulto , Idoso , Artrite Reumatoide/diagnóstico , Biomarcadores/sangue , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
BACKGROUND: Cardiovascular disease (CVD) results from a combination of abnormalities in lipoprotein metabolism, oxidative stress, chronic inflammation, and susceptibility to thrombosis. Atherosclerosis is the major cause of CVD. CD36 has been shown to play a critical role in the development of atherosclerotic lesions by its capacity to bind and promote endocytosis of oxidized low-density lipoprotein (oxLDL) and is implicated in the formation of foam cells. The purpose of this research was to evaluate whether there is an association of sCD36 and oxLDL levels with cardiovascular risk factors in young subjects. METHODS: A total of 188 subjects, 18 to 25 years old, 133 normal-weight and 55 obese subjects from the state of Guerrero, Mexico were recruited in the study. The lipid profile and glucose levels were measured by enzymatic colorimetric assays. Enzyme-linked immunosorbant assays (ELISA) for oxLDL and sCD36 were performed. Statistical analyses of data were performed with Wilcoxon- Mann Whitney and chi-square tests as well as with multinomial regression. RESULTS: TC, LDL-C, TG, oxLDL and sCD36 levels were higher in obese subjects than in normal-weight controls, as well as, monocyte and platelet counts (P < 0.05). Obese subjects had 5.8 times higher risk of sCD36 in the third tertil (>97.8 ng/mL) than normal-weight controls (P = 0.014), and 7.4 times higher risk of oxLDL levels in third tertile (>48 U/L) than control group. The subjects with hypercholesterolemia, hypertriglyceridemia, fasting impaired LDL-C had a higher risk of oxLDL levels in the third tertile (>48 U/L) than the control group (P < 0.05). CONCLUSIONS: Circulating CD36 and oxLDL levels are associated with cardiovascular risk factors in young subjects and may be potential early markers for cardiovascular disease (CVD).
Assuntos
Antígenos CD36/sangue , Doenças Cardiovasculares/sangue , Lipoproteínas LDL/sangue , Obesidade/sangue , Adulto , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Feminino , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/epidemiologia , Hipertensão/sangue , Hipertensão/epidemiologia , Masculino , México/epidemiologia , Obesidade/diagnóstico , Obesidade/epidemiologia , Razão de Chances , Prevalência , Prognóstico , Fatores de Risco , Regulação para Cima , Adulto JovemRESUMO
Several studies have found that obesity and increased adiposity mainly in the abdominal region, are associated with low-grade inflammation, insulin resistance (IR), impaired glucose homeostasis and comorbidities such as type 2 diabetes mellitus (T2D) and cardiovascular disease. The macrophage migration inhibitory factor (MIF), is a proinflammatory cytokine involved in autoimmune and inflammatory diseases. However, currently it is suggested that MIF is involved in the inflammatory process associated with obesity and the metabolic control of the complications associated with obesity. Different studies show consistently, increased serum levels of MIF in subjects with obesity, type 2 diabetes and diabetics with microvascular complications (nephropathy, retinopathy and diabetic foot syndrome). The relationship of the MIF to the regulation of glucose metabolism and apoptosis of pancreatic beta cells, and the association of some functional polymorphisms in the promoter of the MIF gene with obesity and diabetes. This review summarizes, the knowledge based on clinical and epidemiological studies on the role of MIF in obesity and type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2/etiologia , Fatores Inibidores da Migração de Macrófagos/fisiologia , Obesidade/etiologia , Diabetes Mellitus Tipo 2/sangue , Humanos , Fatores Inibidores da Migração de Macrófagos/sangue , Obesidade/sangueRESUMO
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.
RESUMO
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.
Assuntos
Resistência à Insulina , Adulto Jovem , Humanos , Adolescente , Adulto , Resistência à Insulina/genética , Estudos Transversais , Estratificação de Risco Genético , Alanina , ArgininaRESUMO
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.
Assuntos
Doenças Cardiovasculares , Hipertensão , Lúpus Eritematoso Sistêmico , Síndrome Metabólica , Humanos , Doenças Cardiovasculares/etiologia , Fatores de Risco , Lúpus Eritematoso Sistêmico/epidemiologia , Hipertensão/complicações , Síndrome Metabólica/complicaçõesRESUMO
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.
Assuntos
Doenças Cardiovasculares , Lúpus Eritematoso Sistêmico , Humanos , Feminino , Predisposição Genética para Doença , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/etiologia , Estudos Transversais , Fatores de Risco , Genótipo , Polimorfismo de Nucleotídeo Único , Fatores de Risco de Doenças Cardíacas , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/genética , Frequência do Gene , Estudos de Casos e ControlesRESUMO
Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting the synovial membrane, cartilage and bone. PAI-1 is a key regulator of the fibrinolytic system through which plasminogen is converted to plasmin. The plasmin activates the matrix metalloproteinase system, which is closely related with the joint damage and bone destruction in RA. The aim of this study was to investigate the relationship between 4G/5G PAI-1 polymorphism with mRNA expression and PAI-1 plasma protein levels in RA patients. 113 RA patients and 123 healthy subjects (HS) were included in the study. The 4G/5G PAI-1 polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism method; the PAI-1 mRNA expression was determined by real-time PCR; and the soluble PAI-1 (sPAI-1) levels were quantified using an ELISA kit. No significant differences in the genotype and allele frequencies of 4G/5G PAI-1 polymorphism were found between RA patients and HS. However, the 5G/5G genotype was the most frequent in both studied groups: RA (42%) and HS (44%). PAI-1 mRNA expression was slightly increased (0.67 fold) in RA patients with respect to HS (P = 0.0001). In addition, in RA patients, the 4G/4G genotype carriers showed increased PAI-1 mRNA expression (3.82 fold) versus 4G/5G and 5G/5G genotypes (P = 0.0001), whereas the sPAI-1 plasma levels did not show significant differences. Our results indicate that the 4G/5G PAI-1 polymorphism is not a marker of susceptibility in the Western Mexico. However, the 4G/4G genotype is associated with high PAI-1 mRNA expression but not with the sPAI-1 levels in RA patients.
Assuntos
Artrite Reumatoide/genética , Inibidor 1 de Ativador de Plasminogênio/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Artrite Reumatoide/sangue , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , México , Pessoa de Meia-Idade , Inibidor 1 de Ativador de Plasminogênio/sangue , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
BACKGROUND: Several association studies have shown that -844 G/A and HindIII C/G PAI-1 polymorphisms are related with increase of PAI-1 levels, obesity, insulin resistance, glucose intolerance, hypertension and dyslipidemia, which are components of metabolic syndrome. The aim of this study was to analyze the allele and genotype frequencies of these polymorphisms in PAI-1 gene and its association with metabolic syndrome and its components in a sample of Mexican mestizo children. METHODS: This study included 100 children with an age range between 6-11 years divided in two groups: a) 48 children diagnosed with metabolic syndrome and b) 52 children metabolically healthy without any clinical and biochemical alteration. Metabolic syndrome was defined as the presence of three or more of the following criteria: fasting glucose levels ≥ 100 mg/dL, triglycerides ≥ 150 mg/dL, HDL-cholesterol < 40 mg/dL, obesity BMI ≥ 95th percentile, systolic blood pressure (SBP) and diastolic blood pressure (DBP) ≥ 95th percentile and insulin resistance HOMA-IR ≥ 2.4. The -844 G/A and HindIII C/G PAI-1 polymorphisms were analyzed by PCR-RFLP. RESULTS: For the -844 G/A polymorphism, the G/A genotype (OR = 2.79; 95% CI, 1.11-7.08; p = 0.015) and the A allele (OR = 2.2; 95% CI, 1.10-4.43; p = 0.015) were associated with metabolic syndrome. The -844 G/A and A/A genotypes were associated with increase in plasma triglycerides levels (OR = 2.6; 95% CI, 1.16 to 6.04; p = 0.02), decrease in plasma HDL-cholesterol levels (OR = 2.4; 95% CI, 1.06 to 5.42; p = 0.03) and obesity (OR = 2.6; 95% CI, 1.17-5.92; p = 0.01). The C/G and G/G genotypes of the HindIII C/G polymorphism contributed to a significant increase in plasma total cholesterol levels (179 vs. 165 mg/dL; p = 0.02) in comparison with C/C genotype. CONCLUSIONS: The -844 G/A PAI-1 polymorphism is related with the risk of developing metabolic syndrome, obesity and atherogenic dyslipidemia, and the HindIII C/G PAI-1 polymorphism was associated with the increase of total cholesterol levels in Mexican children.
Assuntos
Dislipidemias/genética , Resistência à Insulina/genética , Síndrome Metabólica/genética , Obesidade/genética , Inibidor 1 de Ativador de Plasminogênio/genética , Polimorfismo Genético , Índice de Massa Corporal , Estudos de Casos e Controles , Criança , Colesterol/sangue , Feminino , Genótipo , Humanos , Insulina/sangue , Masculino , Síndrome Metabólica/metabolismo , México , Obesidade/metabolismo , Fatores de Risco , Triglicerídeos/sangueRESUMO
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.