Novel association of genetic variants in non-coding regulatory regions with HIV-1 infection

Introduction: Phenome-wide association studies (PheWAS) using electronic medical record (EMR)-linked biobanks have been used not only to identify and replicate known associations of genetic variants with disease phenotypes but have also resulted in the discovery of potentially novel genotype-phenotype relationships. The natriuretic peptide (NP) system plays an important role in a broad range of disease processes including cardiovascular and inflammatory diseases. We hypothesized that performing a PheWAS using previously known functional genetic variants of the NP system may result in novel disease associations that could provide mechanistic insights in an unbiased manner. Methods: We scanned for associations between 9 single-nucleotide polymorphisms (SNPs) in the NP system and 27 EMR-derived chronic disease phenotypes in 3,025 individuals participating in a case-control study of peripheral arterial disease. The EMR phenotypes were identified using two or more ICD-9-CM diagnosis codes based on the AHRQ Clinical Classifications Software (CCS). The relationship of SNPs and phenotypes were modeled using logistic regression adjusting for gender. Results: We identified rs5065, a SNP located in the stop codon of exon 3 of the NPPA gene, to be the strongest associated SNP with rheumatoid arthritis (RA) (OR=0.78, p=0.0008, q-value=0.11). The SNP leads to the extension of atrial natriuretic peptide (ANP) by 2 additional arginines at the C terminus. Cardiovascular disease is known to be the leading cause of death in patients with RA and ANP plays an important immunomodulatory role by inhibiting inducible nitric oxide synthase, reducing TNF-α production and attenuating prostaglandin E2 production in macrophages. Circulating NPs have been used to screen for occult cardiac disease and are associated with mortality in RA. This study demonstrates for the first time the importance of the relationship between genetic variation in the NP system and RA. Conclusions: PheWAS was successfully used as a tool to identify a novel association of functional genetic variation in the NPPA gene with RA. The observation is hypothesis generating and further replication studies are required to determine the role of rs5065 in cardiovascular outcomes of RA.

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The Effect of RANTES Chemokine Genetic Variants on Early HIV-1 Plasma RNA Among African American Injection Drug Users

JAIDS Journal of Acquired Immune Deficiency Syndromes ◽

10.1097/01.qai.0000134741.49208.03 ◽

2005 ◽

Vol 38 (5) ◽

pp. 584-589 ◽

Cited By ~ 19

Author(s):

Priya Duggal ◽

Cheryl A Winkler ◽

Ping An ◽

Xiao-Fang Yu ◽

Homayoon Farzadegan ◽

...

Keyword(s):

African American ◽

Genetic Variants ◽

Injection Drug Users ◽

Drug Users ◽

Injection Drug ◽

Plasma Rna ◽

Hiv 1

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Prevalence of etravirine resistance associated mutations in HIV-1 strains isolated from infected individuals failing efavirenz: Comparison between subtype B and non-B genetic variants

Journal of Medical Virology ◽

10.1002/jmv.23232 ◽

2012 ◽

Vol 84 (4) ◽

pp. 551-554 ◽

Cited By ~ 3

Author(s):

João Pereira-Vaz ◽

Vitor Duque ◽

Branca Pereira ◽

Vanda Mota ◽

Célia Morais ◽

...

Keyword(s):

Genetic Variants ◽

Subtype B ◽

Hiv 1

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Genome-Wide Association Study of Human Immunodeficiency Virus (HIV)-1 Coreceptor Usage in Treatment-Naive Patients from An AIDS Clinical Trials Group Study

Open Forum Infectious Diseases ◽

10.1093/ofid/ofu018 ◽

2014 ◽

Vol 1 (1) ◽

Cited By ~ 4

Author(s):

Timothy J. Henrich ◽

Paul J. McLaren ◽

Suhas S. P. Rao ◽

Nina H. Lin ◽

Emily Hanhauser ◽

...

Keyword(s):

Genetic Variants ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Coreceptor Usage ◽

Genome Wide ◽

Immunodeficiency Virus ◽

Treatment Naïve ◽

Host Genetic ◽

Aids Clinical Trials ◽

Hiv 1

Abstract Objectives. We conducted a genome-wide association study to explore whether common host genetic variants (>5% frequency) were associated with presence of virus able to use CXCR4 for entry. Methods. Phenotypic determination of human immunodeficiency virus (HIV)-1 coreceptor usage was performed on pretreatment plasma HIV-1 samples from treatment-naive participants in AIDS Clinical Trials Group A5095, a study of initial antiretroviral regimens. Associations between genome-wide single-nucleotide polymorphisms (SNPs), CCR5 Δ32 genotype, and human leukocyte antigen (HLA) class I alleles and viral coreceptor usage were explored. Results. Viral phenotypes were obtained from 593 patients with available genome-wide SNP data. Forty-four percent of subjects had virus capable of using CXCR4 for entry as determined by phenotyping. Overall, no associations, including those between polymorphisms in genes encoding viral coreceptors and their promoter regions or in HLA genes previously associated with HIV-1 disease progression, passed the statistical threshold for genome-wide significance (P < 5.0 × 10−8) in any comparison. However, the presence of viruses able to use CXCR4 for entry was marginally associated with the CCR5 Δ32 genotype in the nongenome-wide analysis. Conclusions. No human genetic variants were significantly associated with virus able to use CXCR4 for entry at the genome-wide level. Although the sample size had limited power to definitively exclude genetic associations, these results suggest that host genetic factors, including those that influence coreceptor expression or the immune pressures leading to viral envelope diversity, are either rare or have only modest effects in determining HIV-1 coreceptor usage.

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Novel association of five HLA alleles with HIV-1 progression in Spanish long-term non progressor patients

PLoS ONE ◽

10.1371/journal.pone.0220459 ◽

2019 ◽

Vol 14 (8) ◽

pp. e0220459

Author(s):

Eva Ramírez de Arellano ◽

Francisco Díez-Fuertes ◽

Francisco Aguilar ◽

Humberto Erick de la Torre Tarazona ◽

Susana Sánchez-Lara ◽

...

Keyword(s):

Hla Alleles ◽

Novel Association ◽

Hiv 1

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Cis-regulatory genetic variants in the CCR5 gene and natural HIV-1 control in black South Africans

Clinical Immunology ◽

10.1016/j.clim.2019.05.009 ◽

2019 ◽

Vol 205 ◽

pp. 16-24

Author(s):

Gemma W. Koor ◽

Maria Paximadis ◽

Anabela C.P. Picton ◽

Fidan Karatas ◽

Shayne A. Loubser ◽

...

Keyword(s):

Genetic Variants ◽

Ccr5 Gene ◽

South Africans ◽

Black South Africans ◽

Hiv 1

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Impact of APOL1 Genetic Variants on HIV-1 Infection and Disease Progression

Frontiers in Immunology ◽

10.3389/fimmu.2019.00053 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 5

Author(s):

Ping An ◽

Gregory D. Kirk ◽

Sophie Limou ◽

Elizabeth Binns-Roemer ◽

Jeffrey B. Kopp ◽

...

Keyword(s):

Disease Progression ◽

Genetic Variants ◽

Hiv 1

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Population Genetic Analysis of the Protease Locus of Human Immunodeficiency Virus Type 1 Quasispecies Undergoing Drug Selection, Using a Denaturing Gradient-Heteroduplex Tracking Assay

Journal of Virology ◽

10.1128/jvi.75.14.6729-6736.2001 ◽

2001 ◽

Vol 75 (14) ◽

pp. 6729-6736 ◽

Cited By ~ 11

Author(s):

Laurence Doukhan ◽

Eric Delwart

Keyword(s):

Genetic Diversity ◽

Genetic Variants ◽

Population Genetic ◽

Protease Gene ◽

Plasma Viremia ◽

Viral Quasispecies ◽

Immunodeficiency Virus ◽

Pcr Products ◽

Hiv 1

ABSTRACT Monitoring the evolution of human immunodeficiency virus type 1 (HIV-1) drug resistance requires measuring the frequency of closely related genetic variants making up the complex viral quasispecies found in vivo. In order to resolve both major and minor (≥2%) protease gene variants differing by one or more nucleotide substitutions, we analyzed PCR products derived from plasma viral quasispecies by using a combination of denaturing gradient gel electrophoresis and DNA heteroduplex tracking assays. Correct population sampling of the high level of genetic diversity present within viral quasispecies could be documented by parallel analysis of duplicate, independently generated PCR products. The composition of genetically complex protease gene quasispecies remained constant over short periods of time in the absence of treatment and while plasma viremia fell >100-fold following the initiation of protease inhibitor ritonavir monotherapy. Within a month of initiating therapy, a strong reduction in the genetic diversity of plasma viral populations at the selected protease locus was associated with rising plasma viremia and the emergence of drug resistance. The high levels of protease genetic diversity seen before treatment reemerged only months later. In one patient, reduction in genetic diversity at the protease gene was observed concomitantly with an increase in diversity at the envelope gene (E. L. Delwart, P. Heng, A. Neumann, and M. Markowitz, J. Virol. 72:2416-2421, 1998), indicating that opposite population genetic changes can take place in different HIV-1 loci. The rapid emergence of drug-resistant HIV-1 was therefore associated with a strong, although only transient, reduction in genetic diversity at the selected locus. The denaturing gradient-heteroduplex tracking assay is a simple method for the separation and quantitation of very closely related, low-frequency, genetic variants within complex viral populations.

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