Modulating influence on HIV/AIDS by interacting<i>RANTES</i>gene variants

An, Ping; Nelson, George W.; Wang, Lihua; Donfield, Sharyne; Goedert, James J.; Phair, John P.; Vlahov, David; Buchbinder, Susan; Farrar, William L.; Modi, William S.; O’Brien, Stephen J.; Winkler, Cheryl A.

doi:10.1073/pnas.142313799

Cited by 175 publications

(205 citation statements)

References 37 publications

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“…In the context of haplotypes involving these SNPs, the -28G/-403G haplotype has been associated with near-fatal asthma in Chinese children [23]. In addition, the -403A/-28G haplotype has been shown to be associated with a slower rate of CD4+ T-cell depletion in HIV-1-infected Japanese subjects [1], and haplotypes that included 375C displayed a strong dominant association with rapid progression to AIDS among HIV-1-infected individuals in African-American, European-American and combined cohorts [21]. Therefore, the present authors believe that the genetic association observed in the present study is due to the functional consequences that these functional SNPs have on CCL5 transcriptional activity, although the possibility that they act as markers of another important genetic abnormality without themselves being functionally relevant cannot be excluded.…”

Section: Discussionmentioning

confidence: 98%

“…Three common SNPs of functional relevance have been identified in the regulatory region of CCL5 (-403G.A, -28C.G and 375T.C); these three SNPs influence transcriptional activity in vitro and subsequent CCL5 expression in human cell lines [1,20,21]. These SNPs were associated with increased levels of CCL5 [2,22], as well as increased blood eosinophil counts [23].…”

Section: Discussionmentioning

confidence: 99%

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Functional single nucleotide polymorphisms of the CCL5 gene and nonemphysematous phenotype in COPD patients

Hizawa¹,

Makita²,

Nasuhara³

et al. 2008

European Respiratory Journal

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It was previously reported that the gain-of-function -28 guanine allele of the promoter single nucleotide polymorphism (SNP; cytosine to guanine substitution of nucleotide -28 (-28C.G)) in the CC chemokine ligand 5 gene (CCL5) was associated with susceptibility to late-onset asthma in patients who developed asthma at age o40 yrs. The clinical diagnosis of chronic obstructive pulmonary disease (COPD) includes emphysema and small airway disease, and upregulation of CCL5 has been described in the airways of patients with COPD. It was hypothesised that CCL5 has a genetic impact upon the variable expression of emphysema in patients with COPD.Patients with COPD were studied (n5267). All of the patients underwent pulmonary highresolution computed tomography (CT), and visual scoring (CT score) was performed to determine emphysema severity. Three SNPs of CCL5 were genotyped, including -403G.A, -28C.G and 375T.C.A significant difference was found in CT score according to CCL5 genotype; the -28G allele was inversely associated with CT score. When the analysis was confined to 180 patients with bronchial reversibility of ,15%, even stronger evidence for this association was noted.Functional single nucleotide polymorphisms in the CC chemokine ligand 5 gene were associated with milder emphysema. Together with previous findings, the present study may identify the CC chemokine ligand 5 gene as part of a common pathway in the pathogenesis of lateonset asthma and chronic obstructive pulmonary disease with milder emphysema.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Functional single nucleotide polymorphisms of the CCL5 gene and nonemphysematous phenotype in COPD patients

Hizawa¹,

Makita²,

Nasuhara³

et al. 2008

European Respiratory Journal

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“…The transcriptional activity of two promoter SNPs (rs2280788: À28*C/G and rs2107538: À403*G/A) and an SNP in intron 1 (rs2280789: Int1.1*T/C) has been investigated. 7,21,22 An et al 22 showed that transcription activity was mainly regulated by the Int1.1 genotype. Int1.1*C allele strongly downregulates the transcriptional activity of RANTES, whereas the À403*G/A SNP has no effect on transcription and the À28*G allele shows a modest upregulation.…”

Section: Association Of Rantes With T1dmentioning

confidence: 99%

“…Int1.1*C allele strongly downregulates the transcriptional activity of RANTES, whereas the À403*G/A SNP has no effect on transcription and the À28*G allele shows a modest upregulation. 22 We have investigated the SNP rs2306630, which, according to the HAPMAP data, is a perfect proxy of the Int1.1 SNP (where the Int1.1*C allele could be tagged by the rs2306630*G allele and the Int1.1*T allele corresponds to the rs2306630*A allele). We observed that the haplotype 2, which is tagged by the rs2306630*A allele, is associated with a lower protein level of RANTES.…”

Section: Association Of Rantes With T1dmentioning

confidence: 99%

“…Three RANTES singlenucleotide polymorphisms (SNPs) in the promoter (rs2280788: À28*C/G and rs2107538: À403*G/A) and in the first intron (rs2280789: Int1.1*T/C) have been shown in different studies to modify the transcriptional activity of RANTES. 7,21,22 However, establishing which of these SNPs has functional consequences is complicated by the high linkage disequilibrium (LD) between them.…”

Section: Introductionmentioning

confidence: 99%

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Genetic variants of RANTES are associated with serum RANTES level and protection for type 1 diabetes

et al. 2006

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RANTES (regulated on activation, normal T-cell expressed and secreted) is a T-helper type 1 (Th1) chemokine that promotes T-cell activation and proliferation. RANTES is genetically associated with asthma, sarcoidosis and multiple sclerosis. The concentration of RANTES is increased at inflammation sites in different autoimmune diseases. Type 1 diabetes (T1D) is a Th1-mediated disease with complex genetic predisposition. We tested RANTES as a candidate gene for association with T1D using three single-nucleotide polymorphism (SNP) variants (rs4251719, rs2306630 and rs2107538) to capture haplotype information. The minor alleles of all SNPs were transmitted less frequently to T1D offspring (transmission rates 37.3% (P ¼ 0.002), 38.7% (P ¼ 0.007) and 41.0% (P ¼ 0.01)) and were less frequently present in patients compared to controls (P ¼ 0.009, 0.03 and 0.04, respectively). A similar protective effect was observed for the haplotype carrying three minor alleles (transmission disequilibrium test (TDT): P ¼ 0.003; odds ratio (OR) ¼ 0.55; confidence interval (CI): 0.37-0.83; case/control: P ¼ 0.03; OR ¼ 0.74; CI: 0.55-0.98). Both patients and controls carrying the protective haplotype express significantly lower serum levels of RANTES compared to non-carriers. Subsequently, we tested a cohort of 310 celiac disease patients, but failed to detect association. RANTES SNPs are significantly associated with RANTES serum concentration and development of T1D. The rs4251719*A-rs2306630*A-rs2107538*A haplotype associated with low RANTES production confers protection from T1D. Our data imply that RANTES is associated with T1D both genetically and functionally, and contributes to diabetesprone Th1 cytokine profile.

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Effects of RANTES and MBL2 gene polymorphisms in sickle cell disease clinical outcomes: Association of the g.In1.1T>C RANTES variant with protection against infections

et al. 2009

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An adult patient affected by b 0 -thalassemia major underwent allogeneic bone marrow transplant (BMT) from a matched related donor. Forty days after transplant, allogeneic engraftment failure and autologous b 0 -thalassemic bone marrow recovery were documented. Red blood cell transfusions were required until 118 days post-transplant. Thereafter, the haemoglobin (Hb) levels stabilized over 11.8 gr/dl throughout the ongoing 34-month follow-up, abolishing the need for transfusion support. The Hb electrophoresis showed 100% Hb Fetal (HbF). This unexplained case suggests full HbF production may occur in an adult patient with b 0 -thalassemia major.Homozygous b-thalassemia is a severe disorder caused by inheritance of two b-thalassemia alleles. The gene mutations produce absent or insufficient synthesis of b-globin chains leading to excess a-globin chain accumulation and precipitation in early erythroid cells [1]. Concurrent genetic factors (hereditary persistence of fetal hemoglobin(HbF), a-gene mutations, and db-thalassemia determinants) are known to modify the globin chain imbalance [1,2].To date, the only cure for thalassemia major is stem cell transplantation [3]. Here, we report an atypical case of sustained and full HbF production after graft failure in an adult b 0 -thalassemic patient.On September 2005, an 18-year-old patient affected by b 0 -thalassemia major was referred to our center for bone marrow transplant (BMT) from an HLA identical sibling. The thalassemia Major diagnosis was evident by 2 years of age when the blood transfusion therapy was started and regularly administered every 2-3 weeks. After splenectomy, performed when the patient was 6 years old, the transfusion requirement was reduced to one red blood cell unit every 2-3 months. Such behavior was maintained during the following years without any transfusion-free period. The iron-chelation therapy was never administered.At the time of presentation to our Institution, the patient presented typical thalassemic facies and hepatomegaly (over 4 cm below the ribs). The complete blood counts showed: low Hb level (9.7 g/dl), low red blood cell count (3.59 3 10 12 /l), a mean corpuscular volume of 82 fl, a mild increase of reticulocyte count (4.07%), increased white cell count (3.901 3 10 12 /l), abundant circulating nucleated red cells (80% of total nucleated cells), and an elevated platelet count (803 3 10 9 /l). The bone marrow exhibited marked hypercellularity. The Hb profile showed predominantly HbF (73.6%), and the genetic analysis detected a double mutation in the b-globin locus: the homozygous mutation IVS-I-1 of the b-globin gene and the homozygous mutation for T variant at position 2158 upstream of the Gg-globin gene. High-performance liquid chromatography (HPLC) analyses detected the lack of b-chain synthesis (b 0%) and 2.47% of the a/non a imbalance.Chronic hepatitis C was documented by a HCV-RNA test. Liver biopsy showed mild fibrosis (1/6 degree) and marked iron overload ([3/4] histological score). The liver iron concentration was marked ...

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Modulating influence on HIV/AIDS by interactingRANTESgene variants

Abstract: RANTES (regulated on activation normal T cell expressed and

Cited by 175 publications

References 37 publications

Functional single nucleotide polymorphisms of the CCL5 gene and nonemphysematous phenotype in COPD patients

Functional single nucleotide polymorphisms of the CCL5 gene and nonemphysematous phenotype in COPD patients

Genetic variants of RANTES are associated with serum RANTES level and protection for type 1 diabetes

Effects of RANTES and MBL2 gene polymorphisms in sickle cell disease clinical outcomes: Association of the g.In1.1T>C RANTES variant with protection against infections

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