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He W.,Veterans Administration Research Center for and 1 Infection | Castiblanco J.,Veterans Administration Research Center for and 1 Infection | Okulicz J.F.,U.S. Army | Ahuja S.K.,Veterans Administration Research Center for and 1 Infection | Ahuja S.K.,University of Texas Health Science Center at San Antonio
Current Opinion in HIV and AIDS | Year: 2010

Purpose of Review: It is unknown whether biomarkers simply correlate with or are causal for HIV-associated outcomes. Mendelian randomization is a genetic epidemiologic approach used to disentangle causation from association. Here, we discuss the potential use of Mendelian randomization for differentiating whether biomarkers are correlating with or causal for HIV-associated outcomes. Recent Findings: Mendelian randomization refers to the random allocation of alleles at the time of gamete formation. In observational epidemiology, this refers to the use of genetic variants to estimate a causal effect between a modifiable risk factor and an outcome of interest. A formal Mendelian randomization study using a genetic marker as a proxy for the biomarker has not been conducted in the HIV field. However, in the postgenomic era, this approach is being used increasingly. Examples are evidence for the causal role of BMI in blood pressure and noncausal role of C-reactive protein in coronary heart disease. We discuss the conceptual framework, uses, and limitations of Mendelian randomization in the context of HIV infection as well as specific biomarkers (IL-6, C-reactive protein) and genetic determinants (e.g., in CCR5, chemokine, and DARC genes) that associate with HIV-related outcomes. Summary: Making the distinction between correlation and causality has particular relevance when a biomarker (e.g., IL-6) is potentially modifiable, in which case a biomarker-guided targeted treatment strategy may be feasible. Although the tenets of Mendelian randomization rest on strong assumptions, and conducting a Mendelian randomization study in HIV infection presents many challenges, it may offer the potential to identify causal biomarkers for HIV-associated outcomes. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Huik K.,University of Tartu | Avi R.,University of Tartu | Uibopuu H.,West Tallinn Hospital Laboratories | Pauskar M.,University of Tartu | And 18 more authors.
Journal of Acquired Immune Deficiency Syndromes | Year: 2014

Background: The influence of the diversity of CCR5 on HIV susceptibility and disease progression has been clearly demonstrated but how the variability of this gene influences the HIV tropism is poorly understood. We investigated whether CCR5 haplotypes are associated with HIV tropism in a Caucasian population. Methods: We evaluated 161 HIV-positive subjects in a crosssectional study. CCR5 haplotypes were derived after genotyping 9 CCR2-CCR5 polymorphisms. The HIV subtype was determined by phylogenetic analysis using the maximum likelihood method and viral tropism by the genotypic tropism assay (geno2pheno). Associations between CCR5 haplotypes and viral tropism were determined using logistic regression analyses. Samples from 500 blood donors were used to evaluate the representativeness of HIV-positives in terms of CCR5 haplotype distribution. Results: The distribution of CCR5 haplotypes was similar in HIVpositive subjects and blood donors. The majority of viruses (93.8%) belonged to HIV-1 CRF06-cpx; 7.5% were X4, and the remaining were R5 tropic. X4 tropic viruses were over represented among people with CCR5 human haplotype E (HHE) compared with those without this haplotype (13.0% vs 1.4%; P = 0.006). People possessing CCR5 HHE had 11 times increased odds (odds ratio = 11.00; 95% confidence interval: 1.38 to 87.38) of having X4 tropic viruses than those with non-HHE. After adjusting for antiretroviral (ARV) therapy, neither the presence of HHE nor the use of ARV was associated with X4 tropic viruses. Conclusions: Our results suggest that CCR5 HHE and ARV treatment might be associated with the presence of HIV-1 X4 tropic viruses. Copyright © 2014 by Lippincott Williams & Wilkins.

Ramsuran V.,HIV Pathogenesis Programme | Ramsuran V.,University of KwaZulu - Natal | Ramsuran V.,Veterans Administration Research Center for and 1 Infection | Ramsuran V.,University of Texas Health Science Center at San Antonio | And 25 more authors.
Clinical Infectious Diseases | Year: 2011

Background. The Duffy-null trait and ethnic netropenia are both highly prevalent in Africa. The influence of pre-seroconversion levels of peripheral blood cell counts (PBCs) on the risk of acquiring human immunodeficiency virus (HIV)-1 infection among Africans is unknown. Methods. The triangular relationship among pre-seroconversion PBC counts, host genotypes, and risk of HIV acquisition was determined in a prospective cohort of black South African high-risk female sex workers. Twenty-seven women had seroconversion during follow-up, and 115 remained HIV negative for 2 years, despite engaging in high-risk activity. Results. Pre-seroconversion neutrophil counts in women who subsequently had seroconversion were significantly lower, whereas platelet counts were higher, compared with those who remained HIV negative. Comprising 27% of the cohort, subjects with pre-seroconversion neutrophil counts of <2500 cells/mm3 had a ∼3-fold greater risk of acquiring HIV infection. In a genome-wide association analyses, an African-specific polymorphism (rs2814778) in the promoter of Duffy Antigen Receptor for Chemokines (DARC -46T > C) was significantly associated with neutrophil counts (P = 7.9 × 10-11). DARC -46C/C results in loss of DARC expression on erthyrocytes (Duffy-null) and resistance to Plasmodium vivax malaria, and in our cohort, only subjects with this genotype had pre-seroconversion neutrophil counts of <2500 cells/mm3. The risk of acquiring HIV infection was ∼3-fold greater in those with the trait of Duffy-null-associated low neutrophil counts, compared with all other study participants. Conclusions. Pre-seroconversion neutrophil and platelet counts influence risk of HIV infection. The trait of Duffy-null-associated low neutrophil counts influences HIV susceptibility. Because of the high prevalence of this trait among persons of African ancestry, it may contribute to the dynamics of the HIV epidemic in Africa. © 2011 The Author.

Gornalusse G.G.,Veterans Administration Research Center for and 1 Infection | Gornalusse G.G.,Center for Personalized Medicine | Gornalusse G.G.,University of Texas Health Science Center at San Antonio | Mummidi S.,Veterans Administration Research Center for and 1 Infection | And 61 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

T-cell expression levels of CC chemokine receptor 5 (CCR5) are a critical determinant of HIV/AIDS susceptibility, and manifest wide variations (i) between T-cell subsets and among individuals and (ii) in T-cell activation-induced increases in expression levels. We demonstrate that a unifying mechanism for this variation is differences in constitutive and T-cell activation-induced DNA methylation status of CCR5 cis-regulatory regions (cis-regions). Commencing at an evolutionarily conserved CpG (CpG -41), CCR5 cis-regions manifest lower vs. higher methylation in T cells with higher vs. lower CCR5 levels (memory vs. naïve T cells) and in memory T cells with higher vs. lower CCR5 levels. HIV-related and in vitro induced T-cell activation is associated with demethylation of these cis-regions. CCR5 haplotypes associated with increased vs. decreased gene/surface expression levels and HIV/AIDS susceptibility magnify vs. dampen T-cell activation-associated demethylation. Methylation status of CCR5 intron 2 explains a larger proportion of the variation in CCR5 levels than genotype or T-cell activation. The ancestral, protective CCR5-HHA haplotype bears a polymorphism at CpG -41 that is (i) specific to southern Africa, (ii) abrogates binding of the transcription factor CREB1 to this cis-region, and (iii) exhibits a trend for overrepresentation in persons with reduced susceptibility to HIV and disease progression. Genotypes lacking the CCR5-Δ32 mutation but with hypermethylated cis-regions have CCR5 levels similar to genotypes heterozygous for CCR5-Δ32. In HIV-infected individuals, CCR5 cis-regions remain demethylated, despite restoration of CD4+ counts (≥800 cells per mm3) with antiretroviral therapy. Thus, methylation content of CCR5 cis-regions is a central epigenetic determinant of T-cell CCR5 levels, and possibly HIV-related outcomes.

Chatterjee N.,Thalassaemia Unit | Mishra A.,Thalassaemia Unit | Soni R.,Thalassaemia Unit | Kulkarni H.,Lata Medical Research Foundation | And 6 more authors.
Hemoglobin | Year: 2010

Early detection of β-thalassemia (β-thal) trait is important. Voluntary blood donors represent an important group who are accessible and cooperative for this purpose. However, the usefulness of this population in β-thal trait detection programs has not been studied in India. We conducted a hematological survey of 5,045 blood donors who visited the Bhopal Memorial Hospital & Research Centre, Bhopal in central India. Using robust Bayesian methods, we estimated the prevalence of β-thal trait. The overall prevalence of β-thal trait in the study population was 9.59% [95% confidence interval (95% CI) 8.78-10.4%]. The prevalence of β-thal trait varied across the states of origin and within the state of Madhya Pradesh. We observed a cline effect for β-thal trait prevalence in relation to the latitude (p = 0.024). We conclude that blood donors offer an attractive adjunct to β-thal trait detection in national programs. Our study also offers insights into the β-thal trait gene flow and migration in India. © 2010 Informa Healthcare USA, Inc.

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