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Caroline T. Tiemessen - One of the best experts on this subject based on the ideXlab platform.

  • Influence of intragenic CCL3 haplotypes and CCL3L copy number in HIV-1 infection in a sub-Saharan African population
    Genes & Immunity, 2013
    Co-Authors: Maria Paximadis, Ashraf Coovadia, D B Schramm, G E Gray, G Sherman, L Kuhn, Caroline T. Tiemessen
    Abstract:

    Two CCL3 haplotypes (HapA1 and Hap-A3) and two polymorphic positions shared by the haplotypes (Hap-2SNP (single nucleotide polymorphism)) were investigated together with CCL3L copy number (CN), for their role in HIV-1 disease. Hap-A1 was associated with protection from in utero HIV-1 infection: exposed uninfected (EU) infants had higher representation of wild type (WT)/Hap-A1 than infected infants (excluding intrapartum (IP)-infected infants), which maintained significance post maternal Nevirapine (mNVP) and viral load (MVL) correction ( P =0.04; odds ratio (OR)=0.33). Mother–infant pair analyses showed the protective effect of Hap-A1 is dependent on its presence in the infant. Hap-A3 was associated with increased IP transmission: WT/Hap-A3 was increased in IP-transmitting vs non-transmitting (NT) mothers, and remained significant post mNVP and MVL correction ( P =0.02; OR=3.50). This deleterious effect of Hap-A3 seemed dependent on its presence in the mother. Hap-2SNP was associated with lower CD4 count in the NT mothers ( P =0.03). CCL3 Hap-A1 was associated with high CCL3L CN in total ( P =0.001) and EU infants ( P =0.006); the effect was not additive, however, having either Hap-A1 or high CCL3L CN was more significantly ( P =0.0008) associated with protection from in utero infection than Hap-A1 ( P =0.028) or high CCL3L CN ( P =0.002) alone. Linkage disequilibrium between Hap-A1 and high CCL3L CN appears unlikely given that a Nigerian population showed an opposite relationship.

  • identification of new variants within the two functional genes ccl3 and ccl3l encoding the ccl3 mip 1α chemokine implications for hiv 1 infection
    International Journal of Immunogenetics, 2009
    Co-Authors: Maria Paximadis, Louise Kuhn, N Mohanlal, Glenda E Gray, Caroline T. Tiemessen
    Abstract:

    The CC chemokine CCL3 is encoded by two functional genes, namely CCL3 and CCL3L, and has been identified as a key chemokine in HIV-1 susceptibility and disease progression. The complete CCL3 and CCL3L genes and core promoters of 43 African mother-infant pairs (86 samples) and 28 Caucasian adults in South Africa were sequenced and extensively analysed for genetic variations. Africans were found to be more polymorphic in both genes with 25 single nucleotide polymorphisms (SNPs) in the CCL3 gene and 14 gene copy number single nucleotide polymorphisms (gcnSNPs) in the CCL3L gene, compared to nine CCL3 SNPs and eight CCL3L gcnSNPs in Caucasians. A total of 14 polymorphisms across the two genes were newly identified in this study, most (12/14) of which were exclusive to the African population. In addition, two indels were identified and characterized in the CCL3 and CCL3L genes of a small number of individuals. Of the numerous unique intragenic haplotypes found in the two genes, none were shared by the two population groups. A newly identified five-SNP CCL3 haplotype (Hap-C1) found in a high frequency in Caucasians, however, seems to be evolutionarily related to the most prevalent newly identified African seven-SNP CCL3 haplotype (Hap-A1). Hap-A1 also includes an SNP in the core promoter region and previous CCL3 haplotypes that have been reported to be associated with HIV-1 infection appear to be smaller haplotypes within Hap-A1. We thus propose Hap-A1 as a likely candidate for influencing levels of CCL3 production and in turn outcomes of HIV-1 infection.

  • Host CCL3L1 Gene Copy Number in Relation to HIV-1-Specific CD4 + and CD8 + T-Cell Responses and Viral Load in South African Women
    Journal of acquired immune deficiency syndromes (1999), 2008
    Co-Authors: Sharon Shalekoff, Louise Kuhn, Diana B. Schramm, Samantha L. Donninger, Stephen Meddows-taylor, Ashraf Coovadia, Gayle G. Sherman, Glenda Gray, Caroline T. Tiemessen
    Abstract:

    HIV-specific T-cell responses play an important role in control of infection. Because CCL3 has immune modulatory and antiviral activities, we hypothesized that host CCL3 genotype (CCL3L1 gene duplications) would influence the development of effective HIV-specific immune responses. Copy numbers of CCL3L1 were determined for 71 HIV-infected women, and HIV-specific CD4 and CD8 T-cell responses to overlapping peptide pools spanning the HIV-1 subtype C genome were simultaneously measured by an interferon-gamma and interleukin-2 whole-blood flow cytometric assay. Host CCL3L1 copy number correlated negatively with viral load (r=-0.239, P=0.045), as did magnitudes of Gag CD4 (r=-0.362, P=0.002) and CD8 (r=-0.261, P=0.028) T-cell responses. Patients with a Gag CD4 response (P=0.002) or dominant Gag CD8 (P=0.006) response had significantly lower viral loads than those whose dominant response targeted another region of the genome, whereas a dominant Nef-specific CD8 T-cell response was associated with higher HIV viral load. CCL3L1 copy number greater than or equal to the population median of 5 was significantly associated with increased magnitude of CD4 Gag responses (P=0.017), and women who had CD4 and CD8 Gag-specific responses had significantly lower viral loads (P=0.004) and higher CCL3L1 copy number (P=0.015) than those women with only CD8 Gag-specific responses.

  • host CCL3L1 gene copy number in relation to hiv 1 specific cd4 and cd8 t cell responses and viral load in south african women
    Journal of Acquired Immune Deficiency Syndromes, 2008
    Co-Authors: Sharon Shalekoff, Louise Kuhn, Diana B. Schramm, Samantha L. Donninger, Ashraf Coovadia, Gayle G. Sherman, Glenda Gray, Stephen Meddowstaylor, Caroline T. Tiemessen
    Abstract:

    HIV-specific T-cell responses play an important role in control of infection. Because CCL3 has immune modulatory and antiviral activities, we hypothesized that host CCL3 genotype (CCL3L1 gene duplications) would influence the development of effective HIV-specific immune responses. Copy numbers of CCL3L1 were determined for 71 HIV-infected women, and HIV-specific CD4 and CD8 T-cell responses to overlapping peptide pools spanning the HIV-1 subtype C genome were simultaneously measured by an interferon-gamma and interleukin-2 whole-blood flow cytometric assay. Host CCL3L1 copy number correlated negatively with viral load (r=-0.239, P=0.045), as did magnitudes of Gag CD4 (r=-0.362, P=0.002) and CD8 (r=-0.261, P=0.028) T-cell responses. Patients with a Gag CD4 response (P=0.002) or dominant Gag CD8 (P=0.006) response had significantly lower viral loads than those whose dominant response targeted another region of the genome, whereas a dominant Nef-specific CD8 T-cell response was associated with higher HIV viral load. CCL3L1 copy number greater than or equal to the population median of 5 was significantly associated with increased magnitude of CD4 Gag responses (P=0.017), and women who had CD4 and CD8 Gag-specific responses had significantly lower viral loads (P=0.004) and higher CCL3L1 copy number (P=0.015) than those women with only CD8 Gag-specific responses.

  • African infants' CCL3 gene copies influence perinatal HIV transmission in the absence of maternal nevirapine.
    AIDS (London England), 2007
    Co-Authors: Louise Kuhn, Diana B. Schramm, Samantha L. Donninger, Stephen Meddows-taylor, Ashraf Coovadia, Gayle G. Sherman, Glenda Gray, Caroline T. Tiemessen
    Abstract:

    Background Individuals with more copies of CCL3L1 (CCR5 ligand) than their population median have been found to be less susceptible to HIV infection. We investigated whether maternal or infant CCL3L1 gene copy numbers are associated with perinatal HIV transmission when single-dose nevirapine is given for prevention.

Hemant Kulkarni - One of the best experts on this subject based on the ideXlab platform.

  • Influence of Variations in CCL3L1 and CCR5 on Tuberculosis in a Northwestern Colombian Population
    The Journal of infectious diseases, 2011
    Co-Authors: Manju Mamtani, John Castiblanco, Robert Maldonado, Racquel Sanchez, Srinivas Mummidi, Veron Ramsuran, Minh Hieu Pham, Kazi Begum, Maria Soledad Valera, Hemant Kulkarni
    Abstract:

    We investigated the association of polymorphisms in CCR5, the major human immunodeficiency virus (HIV)-1 coreceptor, and copy number of its potent ligand CCL3L1 with tuberculosis in 298 individuals from Colombia. The CCR5-HHD haplotype, a known genetic determinant of increased susceptibility to HIV-AIDS, and a high copy number of CCL3L1, a known genetic determinant of enhanced CCL3/CCL3L1 chemokine expression, each associated with presence of tuberculosis. Furthermore, CCR5-HHD was associated with higher CCR5 gene and surface expression. These results substantiate the strong link between the pro-inflammatory effects of CCR5 and its ligands with active tuberculosis and suggest that chemokine-chemokine receptor genetic determinants may influence tuberculosis in addition to HIV/AIDS.

  • reply to experimental aspects of copy number variant assays at CCL3L1
    Nature Medicine, 2009
    Co-Authors: Hemant Kulkarni, John Castiblanco, Chisato Shimizu, Una Aluyen, Robert Maldonado, Andrew Carrillo, Madeline Griffin, Amanda Lipsitt, Lisa Beachy, Ludmila Shostakovichkoretskaya
    Abstract:

    Reply to: “ CCL3L1 and HIV/AIDS susceptibility” and “Experimental aspects of copy number variant assays at CCL3L1 ”

  • Role of CCL3L1-CCR5 Genotypes in the Epidemic Spread of HIV-1 and Evaluation of Vaccine Efficacy
    PloS one, 2008
    Co-Authors: Hemant Kulkarni, Matthew J Dolan, Vincent C. Marconi, Brian K. Agan, Carole P. Mcarthur, George E. Crawford, Robert A. Clark, Sunil K. Ahuja
    Abstract:

    Abstract Background:Polymorphisms in CCR5, the major coreceptor for HIV, and CCL3L1, a potent CCR5 ligand and HIV-suppressivechemokine, are determinants of HIV-AIDS susceptibility. Here, we mathematically modeled the potential impact of thesegenetic factors on the epidemic spread of HIV, as well as on its prevention.Methods and Results:Ro, the basic reproductive number, is a fundamental concept in explaining the emergence andpersistence of epidemics. By modeling sexual transmission among HIV+/HIV2 partner pairs, we find that Ro estimates, andconcordantly, the temporal and spatial patterns of HIV outgrowth are highly dependent on the infecting partners’ CCL3L1-CCR5 genotype. Ro was least and highest when the infected partner possessed protective and detrimental CCL3L1-CCR5genotypes, respectively. The modeling data indicate that in populations such as Pygmies with a high CCL3L1 gene dose andprotective CCR5 genotypes, the spread of HIV might be minimal. Additionally, Pc, the critical vaccination proportion, anestimate of the fraction of the population that must be vaccinated successfully to eradicate an epidemic was ,1 only whenthe infected partner had a protective CCL3L1-CCR5 genotype. Since in practice Pc cannot be .1, to prevent epidemicspread, population groups defined by specific CCL3L1-CCR5 genotypes might require repeated vaccination, or as our modelssuggest, a vaccine with an efficacy of .70%. Further, failure to account for CCL3L1-CCR5-based genetic risk might confoundestimates of vaccine efficacy. For example, in a modeled trial of 500 subjects, misallocation of CCL3L1-CCR5 genotype of only25 (5%) subjects between placebo and vaccine arms results in a relative error of ,12% from the true vaccine efficacy.Conclusions:CCL3L1-CCR5 genotypes may impact on the dynamics of the HIV epidemic and, consequently, the observedheterogeneous global distribution of HIV infection. As Ro is lowest when the infecting partner has beneficial CCL3L1-CCR5genotypes, we infer that therapeutic vaccines directed towards reducing the infectivity of the host may play a role in haltingepidemic spread. Further, CCL3L1-CCR5 genotype may provide critical guidance for optimizing the design and evaluation ofHIV-1 vaccine trials and prevention programs.

  • CCL3L1-CCR5 Genotype Improves the Assessment of AIDS Risk in HIV-1-Infected Individuals
    PloS one, 2008
    Co-Authors: Hemant Kulkarni, Jose F Camargo, Vincent C. Marconi, Brian K. Agan, George E. Crawford, Robert J. O'connell, Judith Delmar, Kenneth R. Phelps, Robert A. Clark
    Abstract:

    Whether vexing clinical decision-making dilemmas can be partly addressed by recent advances in genomics is unclear. For example, when to initiate highly active antiretroviral therapy (HAART) during HIV-1 infection remains a clinical dilemma. This decision relies heavily on assessing AIDS risk based on the CD4+ T cell count and plasma viral load. However, the trajectories of these two laboratory markers are influenced, in part, by polymorphisms in CCR5, the major HIV coreceptor, and the gene copy number of CCL3L1, a potent CCR5 ligand and HIV-suppressive chemokine. Therefore, we determined whether accounting for both genetic and laboratory markers provided an improved means of assessing AIDS risk. In a prospective, single-site, ethnically-mixed cohort of 1,132 HIV-positive subjects, we determined the AIDS risk conveyed by the laboratory and genetic markers separately and in combination. Subjects were assigned to a low, moderate or high genetic risk group (GRG) based on variations in CCL3L1 and CCR5. The predictive value of the CCL3L1-CCR5 GRGs, as estimated by likelihood ratios, was equivalent to that of the laboratory markers. GRG status also predicted AIDS development when the laboratory markers conveyed a contrary risk. Additionally, in two separate and large groups of HIV+ subjects from a natural history cohort, the results from additive risk-scoring systems and classification and regression tree (CART) analysis revealed that the laboratory and CCL3L1-CCR5 genetic markers together provided more prognostic information than either marker alone. Furthermore, GRGs independently predicted the time interval from seroconversion to CD4+ cell count thresholds used to guide HAART initiation. The combination of the laboratory and genetic markers captures a broader spectrum of AIDS risk than either marker alone. By tracking a unique aspect of AIDS risk distinct from that captured by the laboratory parameters, CCL3L1-CCR5 genotypes may have utility in HIV clinical management. These findings illustrate how genomic information might be applied to achieve practical benefits of personalized medicine.

  • CCL3L1 ccr5 genotype improves the assessment of aids risk in hiv 1 infected individuals
    PLOS ONE, 2008
    Co-Authors: Hemant Kulkarni, Jose F Camargo, Vincent C. Marconi, Brian K. Agan, Robert J Oconnell, Judith Delmar
    Abstract:

    Background Whether vexing clinical decision-making dilemmas can be partly addressed by recent advances in genomics is unclear. For example, when to initiate highly active antiretroviral therapy (HAART) during HIV-1 infection remains a clinical dilemma. This decision relies heavily on assessing AIDS risk based on the CD4+ T cell count and plasma viral load. However, the trajectories of these two laboratory markers are influenced, in part, by polymorphisms in CCR5, the major HIV coreceptor, and the gene copy number of CCL3L1, a potent CCR5 ligand and HIV-suppressive chemokine. Therefore, we determined whether accounting for both genetic and laboratory markers provided an improved means of assessing AIDS risk. Methods and Findings In a prospective, single-site, ethnically-mixed cohort of 1,132 HIV-positive subjects, we determined the AIDS risk conveyed by the laboratory and genetic markers separately and in combination. Subjects were assigned to a low, moderate or high genetic risk group (GRG) based on variations in CCL3L1 and CCR5. The predictive value of the CCL3L1-CCR5 GRGs, as estimated by likelihood ratios, was equivalent to that of the laboratory markers. GRG status also predicted AIDS development when the laboratory markers conveyed a contrary risk. Additionally, in two separate and large groups of HIV+ subjects from a natural history cohort, the results from additive risk-scoring systems and classification and regression tree (CART) analysis revealed that the laboratory and CCL3L1-CCR5 genetic markers together provided more prognostic information than either marker alone. Furthermore, GRGs independently predicted the time interval from seroconversion to CD4+ cell count thresholds used to guide HAART initiation. Conclusions The combination of the laboratory and genetic markers captures a broader spectrum of AIDS risk than either marker alone. By tracking a unique aspect of AIDS risk distinct from that captured by the laboratory parameters, CCL3L1-CCR5 genotypes may have utility in HIV clinical management. These findings illustrate how genomic information might be applied to achieve practical benefits of personalized medicine.

Manju Mamtani - One of the best experts on this subject based on the ideXlab platform.

  • Influence of Variations in CCL3L1 and CCR5 on Tuberculosis in a Northwestern Colombian Population
    The Journal of infectious diseases, 2011
    Co-Authors: Manju Mamtani, John Castiblanco, Robert Maldonado, Racquel Sanchez, Srinivas Mummidi, Veron Ramsuran, Minh Hieu Pham, Kazi Begum, Maria Soledad Valera, Hemant Kulkarni
    Abstract:

    We investigated the association of polymorphisms in CCR5, the major human immunodeficiency virus (HIV)-1 coreceptor, and copy number of its potent ligand CCL3L1 with tuberculosis in 298 individuals from Colombia. The CCR5-HHD haplotype, a known genetic determinant of increased susceptibility to HIV-AIDS, and a high copy number of CCL3L1, a known genetic determinant of enhanced CCL3/CCL3L1 chemokine expression, each associated with presence of tuberculosis. Furthermore, CCR5-HHD was associated with higher CCR5 gene and surface expression. These results substantiate the strong link between the pro-inflammatory effects of CCR5 and its ligands with active tuberculosis and suggest that chemokine-chemokine receptor genetic determinants may influence tuberculosis in addition to HIV/AIDS.

  • Association of CCR2-CCR5 Haplotypes and CCL3L1 Copy Number with Kawasaki Disease, Coronary Artery Lesions, and IVIG Responses in Japanese Children
    PloS one, 2010
    Co-Authors: Manju Mamtani, Chisato Shimizu, Tomoyo Matsubara, Susumu Furukawa, Teiji Akagi, Yoshihiro Onouchi, Akira Hata, Akihiro Fujino, Sunil K. Ahuja
    Abstract:

    Author(s): Mamtani, Manju; Matsubara, Tomoyo; Shimizu, Chisato; Furukawa, Susumu; Akagi, Teiji; Onouchi, Yoshihiro; Hata, Akira; Fujino, Akihiro; He, Weijing; Ahuja, Sunil K; Burns, Jane C | Abstract: The etiology of Kawasaki Disease (KD) is enigmatic, although an infectious cause is suspected. Polymorphisms in CC chemokine receptor 5 (CCR5) and/or its potent ligand CCL3L1 influence KD susceptibility in US, European and Korean populations. However, the influence of these variations on KD susceptibility, coronary artery lesions (CAL) and response to intravenous immunoglobulin (IVIG) in Japanese children, who have the highest incidence of KD, is unknown.We used unconditional logistic regression analyses to determine the associations of the copy number of the CCL3L1 gene-containing duplication and CCR2-CCR5 haplotypes in 133 Japanese KD cases [33 with CAL and 25 with resistance to IVIG] and 312 Japanese controls without a history of KD. We observed that the deviation from the population average of four CCL3L1 copies (i.e., four copies) was associated with an increased risk of KD and IVIG resistance (adjusted odds ratio (OR)=2.25, p=0.004 and OR=6.26, p=0.089, respectively). Heterozygosity for the CCR5 HHF*2 haplotype was associated with a reduced risk of both IVIG resistance (OR=0.21, p=0.026) and CAL development (OR=0.44, p=0.071).The CCL3L1-CCR5 axis may play an important role in KD pathogenesis. In addition to clinical and laboratory parameters, genetic markers may also predict risk of CAL and resistance to IVIG.

  • association of ccr2 ccr5 haplotypes and CCL3L1 copy number with kawasaki disease coronary artery lesions and ivig responses in japanese children
    PLOS ONE, 2010
    Co-Authors: Manju Mamtani, Sunil K. Ahuja, Chisato Shimizu, Tomoyo Matsubara, Susumu Furukawa, Teiji Akagi, Yoshihiro Onouchi, Akira Hata, Akihiro Fujino, Jane C Burns
    Abstract:

    Author(s): Mamtani, Manju; Matsubara, Tomoyo; Shimizu, Chisato; Furukawa, Susumu; Akagi, Teiji; Onouchi, Yoshihiro; Hata, Akira; Fujino, Akihiro; He, Weijing; Ahuja, Sunil K; Burns, Jane C | Abstract: BackgroundThe etiology of Kawasaki Disease (KD) is enigmatic, although an infectious cause is suspected. Polymorphisms in CC chemokine receptor 5 (CCR5) and/or its potent ligand CCL3L1 influence KD susceptibility in US, European and Korean populations. However, the influence of these variations on KD susceptibility, coronary artery lesions (CAL) and response to intravenous immunoglobulin (IVIG) in Japanese children, who have the highest incidence of KD, is unknown.Methodology/principal findingsWe used unconditional logistic regression analyses to determine the associations of the copy number of the CCL3L1 gene-containing duplication and CCR2-CCR5 haplotypes in 133 Japanese KD cases [33 with CAL and 25 with resistance to IVIG] and 312 Japanese controls without a history of KD. We observed that the deviation from the population average of four CCL3L1 copies (i.e., four copies) was associated with an increased risk of KD and IVIG resistance (adjusted odds ratio (OR)=2.25, p=0.004 and OR=6.26, p=0.089, respectively). Heterozygosity for the CCR5 HHF*2 haplotype was associated with a reduced risk of both IVIG resistance (OR=0.21, p=0.026) and CAL development (OR=0.44, p=0.071).Conclusions/significanceThe CCL3L1-CCR5 axis may play an important role in KD pathogenesis. In addition to clinical and laboratory parameters, genetic markers may also predict risk of CAL and resistance to IVIG.

  • Association of copy number variation in the FCGR3B gene with risk of autoimmune diseases
    Genes & Immunity, 2010
    Co-Authors: Manju Mamtani, Juan-manuel Anaya, W He, S K Ahuja
    Abstract:

    Copy number variation (CNV) in the human genome is an important determinant of susceptibility to autoimmune diseases. Many autoimmune diseases share similar clinical and pathogenic features. Thus, CNVs of genes involved in immunity may serve as shared determinants of multiple autoimmune diseases. Here, we determined the association between CNV in the gene encoding FCGR3B with the risk of developing autoimmune diseases and whether the observed associations are modified by the CNV in CCL3L1 (CC chemokine ligand 3-like 1), a gene encoding a potent chemokine. In a cross-sectional study of 774 subjects, we estimated FCGR3B and CCL3L1 gene copy number in 146, 158 and 61 subjects with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and primary Sjögren's syndrome (SS), respectively, and 409 healthy controls. The median gene dose of FCGR3B in the study population was two. FCGR3B copy number < or >2 was associated with an increased risk of SLE and primary SS but not RA. This association was mostly evident in subjects who also had two copies of CCL3L1 . Thus, our data suggest that epistatic interactions between CNV of FCGR3B and CCL3L1 , two immune response genes, may influence phenotypically related autoimmune diseases.

  • CCL3L1 and ccr5 influence cell mediated immunity and affect hiv aids pathogenesis via viral entry independent mechanisms
    Nature Immunology, 2007
    Co-Authors: Matthew J Dolan, Juan-manuel Anaya, Manju Mamtani, Hemant Kulkarni, Jose F Camargo, Alison Smith, Toshiyuki Miura, Frederick Hecht, Florencia Pereyra
    Abstract:

    CCL3L1 and CCR5 influence cell-mediated immunity and affect HIV-AIDS pathogenesis via viral entry-independent mechanisms

John A L Armour - One of the best experts on this subject based on the ideXlab platform.

  • CCL3L1 copy number, CCR5genotype and susceptibility to tuberculosis
    BMC Medical Genetics, 2014
    Co-Authors: Danielle Carpenter, Marie-anne Shaw, Carmen Taype, Jon Goulding, Mike Levin, Brian Eley, Suzanne Anderson, John A L Armour
    Abstract:

    Background Tuberculosis is a major infectious disease and functional studies have provided evidence that both the chemokine MIP-1α and its receptor CCR5 play a role in susceptibility to TB. Thus by measuring copy number variation of CCL3L1 , one of the genes that encode MIP-1α, and genotyping a functional promoter polymorphism -2459A > G in CCR5 (rs1799987) we investigate the influence of MIP-1α and CCR5, independently and combined, in susceptibility to clinically active TB in three populations, a Peruvian population (n = 1132), a !Xhosa population (n = 605) and a South African Coloured population (n = 221). The three populations include patients with clinically diagnosed pulmonary TB, as well as other, less prevalent forms of extrapulmonary TB. Methods and results Copy number of CCL3L1 was measured using the paralogue ratio test and exhibited ranges between 0–6 copies per diploid genome (pdg) in Peru, between 0–12 pdg in !Xhosa samples and between 0–10 pdg in South African Coloured samples. The CCR5 promoter polymorphism was observed to differ significantly in allele frequency between populations (*A; Peru f = 0.67, !Xhosa f = 0.38, Coloured f = 0.48). Conclusions The case–control association studies performed however find, surprisingly, no evidence for an influence of variation in genes coding for MIP-1α or CCR5 individually or together in susceptibility to clinically active TB in these populations.

  • CCL3L1 copy number, CCR5 genotype and susceptibility to tuberculosis
    BMC medical genetics, 2014
    Co-Authors: Danielle Carpenter, Marie-anne Shaw, Carmen Taype, Jon Goulding, Brian Eley, Michael Levin, Suzanne T. Anderson, John A L Armour
    Abstract:

    Background Tuberculosis is a major infectious disease and functional studies have provided evidence that both the chemokine MIP-1α and its receptor CCR5 play a role in susceptibility to TB. Thus by measuring copy number variation of CCL3L1, one of the genes that encode MIP-1α, and genotyping a functional promoter polymorphism -2459A > G in CCR5 (rs1799987) we investigate the influence of MIP-1α and CCR5, independently and combined, in susceptibility to clinically active TB in three populations, a Peruvian population (n = 1132), a !Xhosa population (n = 605) and a South African Coloured population (n = 221). The three populations include patients with clinically diagnosed pulmonary TB, as well as other, less prevalent forms of extrapulmonary TB.

  • Association analysis of the CCL3L1 copy number locus by paralogue ratio test in Norwegian rheumatoid arthritis patients and healthy controls
    Genes and immunity, 2012
    Co-Authors: Gry B. N. Nordang, Danielle Carpenter, John A L Armour, Marte K. Viken, T K Kvien, Benedicte A. Lie
    Abstract:

    Genotyping of multiallelic copy number variants (CNVs) is technically difficult and can lead to inaccurate conclusions. This is reflected by inconsistent results published for the CNV C-C chemokine ligand 3-like 1 (CCL3L1) and its contribution to rheumatoid arthritis (RA) susceptibility. In order to draw robust conclusions about CCL3L1 involvement in RA, we have performed association analysis (CNVtools) using genotyping by the paralogue ratio test of a Norwegian RA case-control material (N=1877). We also analyzed the associations after stratification for anti-citrullinated peptide antibody (ACPA) status. Clear clusters representing specific copy number classes were evident, but significant differential bias was observed resulting in a systematic trend toward slightly higher apparent copy number for cases relative to controls. Controlling for bias revealed no significant differences in copy number distribution either between all patients and controls, or after ACPA stratification. Our results do not support involvement of the CCL3L1 CNV in RA susceptibility.

  • CCL3L1 copy number and susceptibility to malaria
    Infection genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases, 2012
    Co-Authors: Danielle Carpenter, John A L Armour, Anna Färnert, Ingegerd Rooth, Marie-anne Shaw
    Abstract:

    Copy number variation can contribute to the variation observed in susceptibility to complex diseases. Here we present the first study to investigate copy number variation of the chemokine gene CCL3L1 with susceptibility to malaria. We present a family-based genetic analysis of a Tanzanian population (n=922), using parasite load, mean number of clinical infections of malaria and haemoglobin levels as phenotypes. Copy number of CCL3L1 was measured using the paralogue ratio test (PRT) and the dataset exhibited copy numbers ranging between 1 and 10 copies per diploid genome (pdg). Association between copy number and phenotypes was assessed. Furthermore, we were able to identify copy number haplotypes in some families, using microsatellites within the copy variable region, for transmission disequilibrium testing. We identified a high level of copy number haplotype diversity and find some evidence for an association of low CCL3L1 copy number with protection from anaemia.

  • Accuracy and differential bias in copy number measurement of CCL3L1 in association studies with three auto-immune disorders
    BMC genomics, 2011
    Co-Authors: Danielle Carpenter, Susan Walker, Natalie J. Prescott, Joost Schalkwijk, John A L Armour
    Abstract:

    Background Copy number variation (CNV) contributes to the variation observed between individuals and can influence human disease progression, but the accurate measurement of individual copy numbers is technically challenging. In the work presented here we describe a modification to a previously described paralogue ratio test (PRT) method for genotyping the CCL3L1/CCL4L1 copy variable region, which we use to ascertain CCL3L1/CCL4L1 copy number in 1581 European samples. As the products of CCL3L1 and CCL4L1 potentially play a role in autoimmunity we performed case control association studies with Crohn's disease, rheumatoid arthritis and psoriasis clinical cohorts.

Sunil K. Ahuja - One of the best experts on this subject based on the ideXlab platform.

  • Association of CCR2-CCR5 Haplotypes and CCL3L1 Copy Number with Kawasaki Disease, Coronary Artery Lesions, and IVIG Responses in Japanese Children
    PloS one, 2010
    Co-Authors: Manju Mamtani, Chisato Shimizu, Tomoyo Matsubara, Susumu Furukawa, Teiji Akagi, Yoshihiro Onouchi, Akira Hata, Akihiro Fujino, Sunil K. Ahuja
    Abstract:

    Author(s): Mamtani, Manju; Matsubara, Tomoyo; Shimizu, Chisato; Furukawa, Susumu; Akagi, Teiji; Onouchi, Yoshihiro; Hata, Akira; Fujino, Akihiro; He, Weijing; Ahuja, Sunil K; Burns, Jane C | Abstract: The etiology of Kawasaki Disease (KD) is enigmatic, although an infectious cause is suspected. Polymorphisms in CC chemokine receptor 5 (CCR5) and/or its potent ligand CCL3L1 influence KD susceptibility in US, European and Korean populations. However, the influence of these variations on KD susceptibility, coronary artery lesions (CAL) and response to intravenous immunoglobulin (IVIG) in Japanese children, who have the highest incidence of KD, is unknown.We used unconditional logistic regression analyses to determine the associations of the copy number of the CCL3L1 gene-containing duplication and CCR2-CCR5 haplotypes in 133 Japanese KD cases [33 with CAL and 25 with resistance to IVIG] and 312 Japanese controls without a history of KD. We observed that the deviation from the population average of four CCL3L1 copies (i.e., four copies) was associated with an increased risk of KD and IVIG resistance (adjusted odds ratio (OR)=2.25, p=0.004 and OR=6.26, p=0.089, respectively). Heterozygosity for the CCR5 HHF*2 haplotype was associated with a reduced risk of both IVIG resistance (OR=0.21, p=0.026) and CAL development (OR=0.44, p=0.071).The CCL3L1-CCR5 axis may play an important role in KD pathogenesis. In addition to clinical and laboratory parameters, genetic markers may also predict risk of CAL and resistance to IVIG.

  • association of ccr2 ccr5 haplotypes and CCL3L1 copy number with kawasaki disease coronary artery lesions and ivig responses in japanese children
    PLOS ONE, 2010
    Co-Authors: Manju Mamtani, Sunil K. Ahuja, Chisato Shimizu, Tomoyo Matsubara, Susumu Furukawa, Teiji Akagi, Yoshihiro Onouchi, Akira Hata, Akihiro Fujino, Jane C Burns
    Abstract:

    Author(s): Mamtani, Manju; Matsubara, Tomoyo; Shimizu, Chisato; Furukawa, Susumu; Akagi, Teiji; Onouchi, Yoshihiro; Hata, Akira; Fujino, Akihiro; He, Weijing; Ahuja, Sunil K; Burns, Jane C | Abstract: BackgroundThe etiology of Kawasaki Disease (KD) is enigmatic, although an infectious cause is suspected. Polymorphisms in CC chemokine receptor 5 (CCR5) and/or its potent ligand CCL3L1 influence KD susceptibility in US, European and Korean populations. However, the influence of these variations on KD susceptibility, coronary artery lesions (CAL) and response to intravenous immunoglobulin (IVIG) in Japanese children, who have the highest incidence of KD, is unknown.Methodology/principal findingsWe used unconditional logistic regression analyses to determine the associations of the copy number of the CCL3L1 gene-containing duplication and CCR2-CCR5 haplotypes in 133 Japanese KD cases [33 with CAL and 25 with resistance to IVIG] and 312 Japanese controls without a history of KD. We observed that the deviation from the population average of four CCL3L1 copies (i.e., four copies) was associated with an increased risk of KD and IVIG resistance (adjusted odds ratio (OR)=2.25, p=0.004 and OR=6.26, p=0.089, respectively). Heterozygosity for the CCR5 HHF*2 haplotype was associated with a reduced risk of both IVIG resistance (OR=0.21, p=0.026) and CAL development (OR=0.44, p=0.071).Conclusions/significanceThe CCL3L1-CCR5 axis may play an important role in KD pathogenesis. In addition to clinical and laboratory parameters, genetic markers may also predict risk of CAL and resistance to IVIG.

  • Role of CCL3L1-CCR5 Genotypes in the Epidemic Spread of HIV-1 and Evaluation of Vaccine Efficacy
    PloS one, 2008
    Co-Authors: Hemant Kulkarni, Matthew J Dolan, Vincent C. Marconi, Brian K. Agan, Carole P. Mcarthur, George E. Crawford, Robert A. Clark, Sunil K. Ahuja
    Abstract:

    Abstract Background:Polymorphisms in CCR5, the major coreceptor for HIV, and CCL3L1, a potent CCR5 ligand and HIV-suppressivechemokine, are determinants of HIV-AIDS susceptibility. Here, we mathematically modeled the potential impact of thesegenetic factors on the epidemic spread of HIV, as well as on its prevention.Methods and Results:Ro, the basic reproductive number, is a fundamental concept in explaining the emergence andpersistence of epidemics. By modeling sexual transmission among HIV+/HIV2 partner pairs, we find that Ro estimates, andconcordantly, the temporal and spatial patterns of HIV outgrowth are highly dependent on the infecting partners’ CCL3L1-CCR5 genotype. Ro was least and highest when the infected partner possessed protective and detrimental CCL3L1-CCR5genotypes, respectively. The modeling data indicate that in populations such as Pygmies with a high CCL3L1 gene dose andprotective CCR5 genotypes, the spread of HIV might be minimal. Additionally, Pc, the critical vaccination proportion, anestimate of the fraction of the population that must be vaccinated successfully to eradicate an epidemic was ,1 only whenthe infected partner had a protective CCL3L1-CCR5 genotype. Since in practice Pc cannot be .1, to prevent epidemicspread, population groups defined by specific CCL3L1-CCR5 genotypes might require repeated vaccination, or as our modelssuggest, a vaccine with an efficacy of .70%. Further, failure to account for CCL3L1-CCR5-based genetic risk might confoundestimates of vaccine efficacy. For example, in a modeled trial of 500 subjects, misallocation of CCL3L1-CCR5 genotype of only25 (5%) subjects between placebo and vaccine arms results in a relative error of ,12% from the true vaccine efficacy.Conclusions:CCL3L1-CCR5 genotypes may impact on the dynamics of the HIV epidemic and, consequently, the observedheterogeneous global distribution of HIV infection. As Ro is lowest when the infecting partner has beneficial CCL3L1-CCR5genotypes, we infer that therapeutic vaccines directed towards reducing the infectivity of the host may play a role in haltingepidemic spread. Further, CCL3L1-CCR5 genotype may provide critical guidance for optimizing the design and evaluation ofHIV-1 vaccine trials and prevention programs.

  • CCL3L1 ccr5 genotype influences durability of immune recovery during antiretroviral therapy of hiv 1 infected individuals
    Nature Medicine, 2008
    Co-Authors: Hemant Kulkarni, Jose F Camargo, Vincent C. Marconi, Brian K. Agan, Sunil K. Ahuja, Gabriel Catano, Robert J Oconnell
    Abstract:

    The basis for the extensive variability seen in the reconstitution of CD4+ T cell counts in HIV-infected individuals receiving highly active antiretroviral therapy (HAART) is not fully known. Here, we show that variations in CCL3L1 gene dose and CCR5 genotype, but not major histocompatibility complex HLA alleles, influence immune reconstitution, especially when HAART is initiated at <350 CD4+ T cells/mm3. The CCL3L1-CCR5 genotypes favoring CD4+ T cell recovery are similar to those that blunted CD4+ T cell depletion during the time before HAART became available (pre-HAART era), suggesting that a common CCL3L1-CCR5 genetic pathway regulates the balance between pathogenic and reparative processes from early in the disease course. Hence, CCL3L1-CCR5 variations influence HIV pathogenesis even in the presence of HAART and, therefore, may prospectively identify subjects in whom earlier initiation of therapy is more likely to mitigate immunologic failure despite viral suppression by HAART. Furthermore, as reconstitution of CD4+ cells during HAART is more sensitive to CCL3L1 dose than to CCR5 genotypes, CCL3L1 analogs might be efficacious in supporting immunological reconstitution.

  • CCL3L1-CCR5 genotype influences durability of immune recovery during antiretroviral therapy of HIV-1-infected individuals.
    Nature medicine, 2008
    Co-Authors: Sunil K. Ahuja, Hemant Kulkarni, Jose F Camargo, Vincent C. Marconi, Brian K. Agan, Gabriel Catano, Robert J. O'connell, Judith Delmar, Joseph J. Eron
    Abstract:

    The basis for the extensive variability seen in the reconstitution of CD4(+) T cell counts in HIV-infected individuals receiving highly active antiretroviral therapy (HAART) is not fully known. Here, we show that variations in CCL3L1 gene dose and CCR5 genotype, but not major histocompatibility complex HLA alleles, influence immune reconstitution, especially when HAART is initiated at