Osteopontin (OPN) regulates the immune response at multiple levels. Physiologically, it regulates the host response to infections by driving T helper (Th) polarization and acting on both innate and adaptive immunity; pathologically, it contributes to the development of immune-mediated and inflammatory diseases. In some cases, the mechanisms of these effects have been described, but many aspects of the OPN function remain elusive. This is in part ascribable to the fact that OPN is a complex molecule with several posttranslational modifications and it may act as either an immobilized protein of the extracellular matrix or a soluble cytokine or an intracytoplasmic molecule by binding to a wide variety of molecules including crystals of calcium phosphate, several cell surface receptors, and intracytoplasmic molecules. This review describes the OPN structure, isoforms, and functions and its role in regulating the crosstalk between innate and adaptive immunity in autoimmune diseases.

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Osteopontin Bridging Innate and Adaptive Immunity in Autoimmune Diseases

BACKGROUND Pre-eclampsia has a clear familial component, suggesting that the condition may be partly attributable to genetic susceptibility. The search for susceptibility genes has led to a drastic increase in the number of published studies associating genetic factors with pre-eclampsia. However, attempts to replicate these findings have yielded inconsistent results. This meta-analysis assessed the pooled effect of each genetic variant that is reproducibly associated with pre-eclampsia. METHODS Studies that assessed the association between genes and pre-eclampsia were searched in PubMed, Embase and Web of Science. We selected all genetic variants that were significantly associated with pre-eclampsia in an initial study and were subsequently independently reproduced in at least one additional study. All studies that assessed these reproduced variants were then included. The association between genetic variants and pre-eclampsia was calculated at the allele level, and the main measure of effect was a pooled odds ratio in a random-effects model. RESULTS The literature search yielded 2965 articles, of which 542 investigated genetic associations in pre-eclampsia. We identified 22 replicated genetic variants, of which 7 remained significantly associated with pre-eclampsia following meta-analysis. These variants were in or near the following genes: ACE, CTLA4, F2, FV, LPL and SERPINE1. CONCLUSIONS This meta-analysis identified seven genetic variants associated with pre-eclampsia. Importantly, many of these variants are also risk factors for developing cardiovascular disease, revealing that pre-eclampsia and cardiovascular disease have shared genetic risk factors. The contribution of the identified genetic variants in the pathogenesis of pre-eclampsia should be the focus of future studies.

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Genetic variants in pre-eclampsia: a meta-analysis

Laboratory red blood cell (RBC) measurements are clinically important, heritable and differ among ethnic groups. To identify genetic variants that contribute to RBC phenotypes in African Americans (AAs), we conducted a genome-wide association study in up to ~16 500 AAs. The alpha-globin locus on chromosome 16pter [lead SNP rs13335629 in ITFG3 gene; P < 1E-13 for hemoglobin (Hgb), RBC count, mean corpuscular volume (MCV), MCH and MCHC] and the G6PD locus on Xq28 [lead SNP rs1050828; P < 1E - 13 for Hgb, hematocrit (Hct), MCV, RBC count and red cell distribution width (RDW)] were each associated with multiple RBC traits. At the alpha-globin region, both the common African 3.7 kb deletion and common single nucleotide polymorphisms (SNPs) appear to contribute independently to RBC phenotypes among AAs. In the 2p21 region, we identified a novel variant of PRKCE distinctly associated with Hct in AAs. In a genome-wide admixture mapping scan, local European ancestry at the 6p22 region containing HFE and LRRC16A was associated with higher Hgb. LRRC16A has been previously associated with the platelet count and mean platelet volume in AAs, but not with Hgb. Finally, we extended to AAs the findings of association of erythrocyte traits with several loci previously reported in Europeans and/or Asians, including CD164 and HBS1L-MYB. In summary, this large-scale genome-wide analysis in AAs has extended the importance of several RBC-associated genetic loci to AAs and identified allelic heterogeneity and pleiotropy at several previously known genetic loci associated with blood cell traits in AAs.

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Genome-wide association analysis of red blood cell traits in African Americans: the COGENT Network

Osteopontin (OPN) is a pleiotropic glycoprotein expressed in various cell types in animals and in humans, including bone, immune, smooth muscle, epithelial and endothelial cells. Moreover, OPN is found in kidneys (in the thick ascending limbs of the loop of Henle and in distal nephrons) and urine. The protein plays an important role in mineralization and bone resorption. In addition, OPN is involved in the regulation of immunity and inflammation, angiogenesis and apoptosis. It was demonstrated that OPN and some OPN gene polymorphic variants are associated with the pathogenesis and progression of multiple disorders, such as cancer, autoimmune, neurodegenerative and cardiovascular diseases. Moreover, recent studies suggested that OPN is associated with the pathogenesis of renal failure. In this review, I briefly discussed the role of OPN and its gene polymorphisms in kidney physiology, as well as in various kidney diseases. Most studies reported that OPN expression is elevated in urolithiasis, and also in acute and chronic kidney diseases, and in renal allograft dysfunction. Moreover, it was demonstrated that polymorphic variants of the OPN gene may be associated with renal failure. However, some reports suggested that OPN is essential for tubulogenesis, and that it inhibits calcium oxalate crystal formation and retention, nitric oxide synthesis, cell apoptosis and promotes cell regeneration. Thus, further studies are required to fully understand the role of OPN in kidney physiology and pathology. Eventually, these studies may result in the identification of OPN as a valuable marker for renal dysfunction prognosis and treatment.

The role of osteopontin in kidney diseases.

The association of novel IL-33 polymorphisms with sIL-33 and risk of systemic lupus erythematosus.

Osteopontin (OPN) is a chemokine-like glycoprotein that has a prominent role in regulating inflammation and immunity. OPN polymorphisms and elevated OPN levels are associated with systemic lupus erythematosus (SLE) in several populations. The aim of present study was to evaluate the association between the OPN rs1126616 polymorphism and OPN level with SLE susceptibility. A total of 163 SLE patients and 180 age-, gender- and ethnically matched controls were genotyped for the rs1126616 polymorphism by the polymerase chain reaction-restriction fragment length polymorphism method. Serum OPN levels were assayed by the enzyme-linked immunosorbent assay. There was no association between the OPN rs1126616 C/T polymorphism and SLE. The frequency of the OPN rs1126616 CT genotype was significantly higher in SLE patients with nephritis compared to SLE patients without nephritis and controls. Additionally, the frequency of TT genotypes was higher in SLE patients with nephritis compared to controls. The serum OPN levels were significantly higher in SLE patients compared to controls (50.6±22 vs. 35.6±15.8 ng/ml, P<0.001). Increased serum OPN levels were observed in SLE patients with lupus nephritis and joint symptoms. There was no correlation between OPN levels and the OPN rs1126616 polymorphism. The present data suggest that the CT and TT genotypes of the OPN rs1126616 polymorphism could be a risk factor for lupus nephritis. The OPN level is associated with SLE and certain SLE manifestations. However, there was no association between the OPN rs1126616 C/T polymorphism and SLE susceptibility.

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Association of the osteopontin rs1126616 polymorphism and a higher serum osteopontin level with lupus nephritis.

Purpose
Preeclampsia is an important disorder of pregnancy that carries a severe morbidity and mortality risk for both mother and fetus. A large number of studies have shown that abnormalities in nitric oxide synthesis may contribute to the development of preeclampsia.

Lack of relationship between endothelial nitric oxide synthase gene 4b/a and T-786C polymorphisms with preeclampsia in southeast of Iran.

Background and Objective: Evidence indicates that genetic factors may be involved in the risk of ischemic stroke (IS). The aim of this study was to assess the effect of genetic polymorphisms located in exons or untranslated regions of MTHFR as well as FV genes on ischemic stroke. Materials and Methods: In this case-control study, 106 patients with IS and 157 healthy volunteers (age <50 years) were genotyped for MTHFR C677T, A1298C, C2572A and C4869G, FVL, and prothrombin G20210A polymorphisms. Results: The MTHFR 677CT genotype was more frequent in patients and increased risk of IS with Odds Ratio = 1.9. The MTHFR A1298C and C2572A polymorphisms were not associated with IS in dominant and recessive models. Our findings showed a significant decrease in the MTHFR 4869CG genotype in IS patients, and this variant was associated with a decreased risk of IS in the dominant model. The CAAT haplotype was associated with increased risk, and the GAAC haplotype was associated with decreased risk of IS compared to other haplotypes. There was no relation between FVL G1691A polymorphism and IS risk. Conclusions: The present study showed that the MTHFR 677CT genotype was more frequent and the MTHFR 4869CG genotype was less frequent in young IS patients.

https://www.mdpi.com/1648-9144/55/2/47/pdf

Common Variations in Prothrombotic Genes and Susceptibility to Ischemic Stroke in Young Patients: A Case-Control Study in Southeast Iran.

Background:  glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common genetic defects in the world, so that more than 400 million people in worldwide are affected with it, but its prevalence varies from 1-65% in different populations. Clinical manifestation of this defect is acute hemolytic anemia, neonatal hyperbilirubinemia and chronic nonspherocytic haemolytic anaemia. So far, almost 140 mutations have been identified in the gene of G6PD enzyme. Mediterranean is the most common mutation. The purpose of this study is to determine the prevalence of G6PD Mediterranean mutation in the deficient people in the city of Zahedan.Materials and Methods: In this descriptive cross-sectional study, blood samples of 1440 male individuals, who were referred to Zahedan Reference Laboratory for premarital testing, were examined for G6PD deficiency using fluorescent spot test. Genomic DNA from blood of people with G6PD deficiency was extracted by DNA extraction kit. Mediterranean mutation was identified using PCR-RFLP method.Results: 101 out of 1440 subjects had G6PD deficiency. Therefore prevalence of G6PD deficiency in Zahedan city was estimated about 7%. Mediterranean mutation frequency in patients with defect of G6PD was estimated 84.2% (85 out of 101 patients) and 15.8% (16 out of 101 patients) did not have mutation Mediterranean. The frequency of G6PD deficiency was expressed as a percentage of total cases and Mediterranean mutation prevalence was expressed as a percentage of total impaired individuals.Conclusion: The result of this study showed that the frequency of G6PD deficiency in Zahedan city is lower than other cities of sistan and baluchestan province. Dominant mutation in present study was Mediterranean type and its frequency was very similar with prevalence of this mutation in other parts of Iran.

The Prevalence of Mediterranean Mutation of Glucose-6-Phosphate Dehydrogenase (G6PD) in Zahedan

Background: glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common known enzymopathy in human. G6PD deficiency is usually asymptomatic, however, deficient individuals are at increased risk of developing acute hemolytic anemia and hyperbilirubinemia following intake of oxidative agents and fava. The objective of present study was to detect prevalence of G6PD deficiency in admitted males for premarriage tests in Zahedan reference laboratory. Also, we compared blood indices of normal and G6PD deficient individuals. Materials and Methods: This descriptive study was carried out on 1340 admitted males in Zahedan reference laboratory from February 2008 to March 2009. G6PD activity was determined in EDTA containing blood samples by qualitative fluorescence spot test, then G6PD deficiency was confirmed by quantitative spectrophotometric method. Total leukocyte count and RBC indices of G6PD deficient samples and the same number of normal samples were compared. The differences between two groups were compared using Sigmaplot software and t-Student test. A P-value less than 0.05 was considered statistically significant. Results: G6PD deficiency was found in 84 individuals of total 1340 by fluorescence spot test and confirmed in 79 by quantitative method. Therefore, prevalence of G6PD deficiency in Zahedan was estimated to be 5.9%. Comparison of deficient and normal individuals did not show significant difference in WBC count, RBC count, hemoglobin concentration, hematocrit, mean corpuscular hemoglobin (MCH) and RDW-SD. However, mean corpuscular volume (MCV) was significantly high and mean corpuscular hemoglobin concentration (MCHC) and RDW-CV were significantly low in G6PD deficient individuals compared to those with normal enzyme level. Discussion: present study revealed that the prevalence of G6PD deficiency in Zahedan is 5.9%. Severity of G6PD deficiency in quantitative assay indicated that class I and II are probably dominant variants in Zahedan.

Survey of the Prevalence of Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency in Admitted Men for Premarriage Tests in Zahedan-Iran Reference Laboratory

Mehrangiz Noora

Papers

Association of the osteopontin rs1126616 polymorphism and a higher serum osteopontin level with lupus nephritis.

Lack of relationship between endothelial nitric oxide synthase gene 4b/a and T-786C polymorphisms with preeclampsia in southeast of Iran.

Common Variations in Prothrombotic Genes and Susceptibility to Ischemic Stroke in Young Patients: A Case-Control Study in Southeast Iran.

The Prevalence of Mediterranean Mutation of Glucose-6-Phosphate Dehydrogenase (G6PD) in Zahedan

Survey of the Prevalence of Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency in Admitted Men for Premarriage Tests in Zahedan-Iran Reference Laboratory