Genetic variants in LGALS3 are related to lower galectin-3 serum levels and clinical outcomes in systemic sclerosis patients: A case-control study.

INTRODUCTION: Systemic sclerosis (SSc) is a rare complex disease characterized by vascular damage, autoimmunity, and extensive skin and internal organs fibrosis. Galectin-3 (Gal-3) is encoded by gene LGALS3 (Lectin, Galactoside-Binding, Soluble, 3; 14q22.3) and it has been reported to play a central role in self-tolerance, inflammation, and fibrosis. OBJECTIVE: To investigate associations among LGALS3 single nucleotide polymorphisms (SNPs) and serum levels Gal-3 and SSc susceptibility and their clinical features. METHODS: A case-control study with 88 patients and 151 matched controls was performed. LGALS3 variants were analyzed by the TaqMan real-time polymerase chain reaction (PCR) system whereas Gal-3 serum levels were measured by sandwich enzyme linked immunosorbent assay (ELISA). Associations among genotypes, clinical features, and Gal-3 levels were performed by univariable and multivariable analysis through statistical packages. RESULTS: The LGALS3 rs4652 A/C genotype was more frequent in SSc patients than controls according to overdominant model [OR 1.89 (CI 95% 1.01 - 3.52); p = .046]. Also, LGALS3 rs4652 C/C polymorphic genotype was associated with lower patient Gal-3 levels (p = .03) and control group (p = 0.005), as noted by generalized linear model (GLM). The LGALS3 rs1009977 G/T controls showed higher Gal-3 levels than wild-type and polymorphic genotypes (p = .03); however, in SSc patients, no difference was found. None of the LGALS3 SNPs or Gal-3 levels was associated with clinical manifestations in SSc patients. Considering only the SSc group, GLM analysis pointed LGALS3 rs4652 and rs2075601, pulmonary arterial hypertension (PAH), myopathy, and health assessment questionnaire (HAQ) and scleroderma health assessment questionnaire (SHAQ) as important predictors for Gal-3 levels. CONCLUSION: The LGALS3 rs4652 A/C was more frequent in SSc patients and related to lower Gal-3 levels. These findings were corroborated through a GLM to estimate Gal-3 values. Also, by model equations, Gal-3 levels may be predicted by HAQ, SHAQ, PAH, myopathy, and LGALS3 rs4652 and rs2075601 factors. In these ways, we suggest that galectins may be promising biomarkers to identify susceptibility to SSc as well as to identify HAQ, SHAQ, PAH, and myopathy outcomes.

Galectin-9 gene (LGALS9) polymorphisms are associated with rheumatoid arthritis in Brazilian patients.

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and hyperplasia, as well as cartilage and bone destruction. Several proteins are associated with the pathogenesis of the disease. Galectin-9 belongs to the family of lectins that are involved in various biological processes and have anti-inflammatory activity. OBJECTIVE: To investigate associations between the SNPs of the GAL-9 gene (LGALS9) and serum levels in rheumatoid arthritis patients. We extracted DNA from 356 subjects, 156 RA patients and 200 healthy controls from northeastern Brazil. Three polymorphisms (rs4795835, rs3763959, and rs4239242) in the LGALS9 gene were selected and genotyped using TaqMan SNP genotyping assay. Serum concentrations of galectin-9 were analyzed by ELISA. RESULTS: The rs4239242 TT genotype showed a positive association with RA (p = 0.0032, odds ratio = 0.28), and heterozygous TC were prevalent in the control group compared to RA patients (p = 0.0001, odds ratio = 7.99). Galectin-9 serum levels were significantly increased in RA patients compared to the control group (p<0.0001). Patients in remission had high levels of galectin compared to the moderate activity group (p<0.0001). Regarding the Clinical Disease Activity Index (CDAI), patients in remission or low activity presented high levels of galectin when compared to patients in severity (p<0.0001). Patients performing moderate activity had a significant value compared to patients who were in high disease severity (p = 0.0064). Interestingly, the AG genotype (rs3763959) has been associated with a higher presence of bone erosion in RA patients (p = 0.0436). The SNP rs4239242 TT genotype showed a positive association with RA in comparison to the control group. The AG genotype (rs3763959) has been associated with a higher presence of bone erosion in RA patients.

Galectin-1, -4, and -7 Were Associated with High Activity of Disease in Patients with Rheumatoid Arthritis.

BACKGROUND: Due to the variety of functions that galectins (Gal) possess, it is clear that they participate in the pathogenesis of rheumatoid arthritis (RA). Although some studies demonstrate their functions, there is still no correlation with the clinical data of the disease, having the physiological meaning still unknown. OBJECTIVES: To compare serum levels of Gal-1, -4, and -7 in patients with RA and healthy controls and to correlate them with clinical parameters. METHODS: Serum samples were collected from patients with RA and healthy donors to determine the serum levels of Gal-1, -4, and -7. RESULTS: Serum levels of Gal-1, -4, and -7 were significantly higher in RA patients compared to controls. We evaluated disease activity (CDAI) with serum levels of galectins and found that patients who were high in disease activity had high levels of galectin compared to the moderate activity group. Galectin-4 had higher levels in patients who were in high activity when compared to the group in remission or low activity. Evaluating the activity of the individual disease (DAS28), patients in high individual activity had high levels of Gal-4 when compared to the group in remission or low activity. We also found an association between positive rheumatoid factor and Gal-1 and Gal-4 levels. CONCLUSION: Our results show for the first time the relationship between serum levels of galectin and the clinical parameters of patients with RA. Demonstrating their role in pathogenesis, new studies with galectins are needed to assess how they function as a biomarker in RA.

Reassessing the Role of the Active TGF-ß1 as a Biomarker in Systemic Sclerosis: Association of Serum Levels with Clinical Manifestations.

Objective. To determine active TGF-ß1 (aTGF-ß1) levels in serum, skin, and peripheral blood mononuclear cell (PBMC) culture supernatants and to understand their associations with clinical parameters in systemic sclerosis (SSc) patients. Methods. We evaluated serum samples from 56 SSc patients and 24 healthy controls (HC). In 20 SSc patients, we quantified spontaneous or anti-CD3/CD28 stimulated production of aTGF-ß1 by PBMC. The aTGF-ß1 levels were measured by ELISA. Skin biopsies were obtained from 13 SSc patients and six HC, and TGFB1 expression was analyzed by RT-PCR. Results. TGF-ß1 serum levels were significantly higher in SSc patients than in HC (p < 0.0001). Patients with increased TGF-ß1 serum levels were more likely to have diffuse subset (p = 0.02), digital ulcers (p = 0.02), lung fibrosis (p < 0.0001), positive antitopoisomerase I (p = 0.03), and higher modified Rodnan score (p = 0.046). Most of our culture supernatant samples had undetectable levels of TGF-ß1. No significant difference in TGFB1 expression was observed in the SSc skin compared with HC skin. Conclusion. Raised active TGF-ß1 serum levels and their association with clinical manifestations in scleroderma patients suggest that this cytokine could be a marker of fibrotic and vascular involvement in SSc.