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1.  Host genomic influences on HIV/AIDS 
Genome Biology  2013;14(1):201.
The AIDS era has seen multiple advances in the power of genetics research; scores of host genetic protective factors have been nominated and several have translated to the bedside. We discuss how genomics may inform HIV/AIDS prevention, treatment and eradication.
doi:10.1186/gb-2013-14-1-201
PMCID: PMC3663097  PMID: 23369251
2.  A genome wide study of genetic adaptation to high altitude in feral Andean Horses of the páramo 
Background
Life at high altitude results in physiological and metabolic challenges that put strong evolutionary pressure on performance due to oxidative stress, UV radiation and other factors dependent on the natural history of the species. To look for genes involved in altitude adaptation in a large herbivore, this study explored genome differentiation between a feral population of Andean horses introduced by the Spanish in the 1500s to the high Andes and their Iberian breed relatives.
Results
Using allelic genetic models and Fst analyses of ~50 K single nucleotide polymorphisms (SNPs) across the horse genome, 131 candidate genes for altitude adaptation were revealed (Bonferoni of p ≤ 2 × 10–7). Significant signals included the EPAS1 in the hypoxia-induction-pathway (HIF) that was previously discovered in human studies (p = 9.27 × 10-8); validating the approach and emphasizing the importance of this gene to hypoxia adaptation. Strong signals in the cytochrome P450 3A gene family (p = 1.5 ×10-8) indicate that other factors, such as highly endemic vegetation in altitude environments are also important in adaptation. Signals in tenuerin 2 (TENM2, p = 7.9 × 10-14) along with several other genes in the nervous system (gene categories representation p = 5.1 × 10-5) indicate the nervous system is important in altitude adaptation.
Conclusions
In this study of a large introduced herbivore, it becomes apparent that some gene pathways, such as the HIF pathway are universally important for high altitude adaptation in mammals, but several others may be selected upon based on the natural history of a species and the unique ecology of the altitude environment.
doi:10.1186/1471-2148-13-273
PMCID: PMC3878729  PMID: 24344830
hypoxia; Equus; Hypoxia Inducing Factor; Adaptation; Genomes wide association
3.  Risk Factors for Symptomatic Hyperlactatemia and Lactic Acidosis Among Combination Antiretroviral Therapy-Treated Adults in Botswana: Results from a Clinical Trial 
Abstract
Nucleoside analogue reverse transcriptase inhibitors are an integral component of combination antiretroviral treatment regimens. However, their ability to inhibit polymerase-γ has been associated with several mitochondrial toxicities, including potentially life-threatening lactic acidosis. A total of 650 antiretroviral-naive adults (69% female) initiated combination antiretroviral therapy (cART) and were intensively screened for toxicities including lactic acidosis as part of a 3-year clinical trial in Botswana. Patients were categorized as no lactic acidosis symptoms, minor symptoms but lactate <4.4 mmol/liter, and symptoms with lactate ≥4.4 mmol/liter [moderate to severe symptomatic hyperlactatemia (SH) or lactic acidosis (LA)]. Of 650 participants 111 (17.1%) developed symptoms and/or laboratory results suggestive of lactic acidosis and had a serum lactate drawn; 97 (87.4%) of these were female. There were 20 events, 13 having SH and 7 with LA; all 20 (100%) were female (p<0.001). Cox proportional hazard analysis limited to the 451 females revealed that having a higher baseline BMI was predictive for the development of SH/LA [aHR=1.17 per one-unit increase (1.08–1.25), p<0.0001]. Ordered logistic regression performed among all 650 patients revealed that having a lower baseline hemoglobin [aOR=1.28 per one-unit decrease (1.1–1.49), p=0.002] and being randomized to d4T/3TC-based cART [aOR=1.76 relative to ZDV/3TC (1.03–3.01), p=0.04] were predictive of the symptoms and/or the development of SH/LA. cART-treated women in sub-Saharan Africa, especially those having higher body mass indices, should receive additional monitoring for SH/LA. Women presently receiving d4T/3TC-based cART in such settings also warrant more intensive monitoring.
doi:10.1089/aid.2011.0303
PMCID: PMC3399551  PMID: 22540188
4.  The Principal Genetic Determinants for Nasopharyngeal Carcinoma in China Involve the HLA Class I Antigen Recognition Groove 
PLoS Genetics  2012;8(11):e1003103.
Nasopharyngeal carcinoma (NPC) is an epithelial malignancy facilitated by Epstein-Barr Virus infection. Here we resolve the major genetic influences for NPC incidence using a genome-wide association study (GWAS), independent cohort replication, and high-resolution molecular HLA class I gene typing including 4,055 study participants from the Guangxi Zhuang Autonomous Region and Guangdong province of southern China. We detect and replicate strong association signals involving SNPs, HLA alleles, and amino acid (aa) variants across the major histocompatibility complex-HLA-A, HLA –B, and HLA -C class I genes (PHLA-A-aa-site-62 = 7.4×10−29; P HLA-B-aa-site-116 = 6.5×10−19; P HLA-C-aa-site-156 = 6.8×10−8 respectively). Over 250 NPC-HLA associated variants within HLA were analyzed in concert to resolve separate and largely independent HLA-A, -B, and -C gene influences. Multivariate logistical regression analysis collapsed significant associations in adjacent genes spanning 500 kb (OR2H1, GABBR1, HLA-F, and HCG9) as proxies for peptide binding motifs carried by HLA- A*11:01. A similar analysis resolved an independent association signal driven by HLA-B*13:01, B*38:02, and B*55:02 alleles together. NPC resistance alleles carrying the strongly associated amino acid variants implicate specific class I peptide recognition motifs in HLA-A and -B peptide binding groove as conferring strong genetic influence on the development of NPC in China.
Author Summary
NPC is a deadly throat cancer in China that is dependent on EBV infection. Here, we performed a 1 M SNP genome-wide association study using a large cohort of Chinese study participants at risk for NPC. Although several putative gene regions show significant associations, the strongest statistical signals involved scores of variants within the HLA region on chromosome 6. HLA poses a formidable association-genetics challenge because of extensive linkage disequilibrium, rather low allele frequencies, and multiple physically close interacting genes of diverse function. We examined over 250 NPC-HLA associated variants detected with sequence-based nucleotide alleles and amino acid variants. The multiple associations were collapsed to implicate causal signals by multivariate logistical regression to resolve allele association interaction. One operative variant was identified as the HLA-A*11:01 allele motif, specifically in the peptide binding groove, which recognizes invading antigens; a second involved two aa sites with HLA-B tracking B*13:01 and B*55:02 alleles. We synthesize these new and previous discoveries to help resolve the important gene influences on this disease.
doi:10.1371/journal.pgen.1003103
PMCID: PMC3510037  PMID: 23209447
5.  AGA President’s Symposium 2011: The Application of Genomics to Biodiversity 
Journal of Heredity  2011;102(6):782-783.
doi:10.1093/jhered/esr106
PMCID: PMC3247804  PMID: 22013020
6.  Genome-wide Association Study Implicates PARD3B-based AIDS Restriction 
The Journal of Infectious Diseases  2011;203(10):1491-1502.
Background. Host genetic variation influences human immunodeficiency virus (HIV) infection and progression to AIDS. Here we used clinically well-characterized subjects from 5 pretreatment HIV/AIDS cohorts for a genome-wide association study to identify gene associations with rate of AIDS progression.
Methods.  European American HIV seroconverters (n = 755) were interrogated for single-nucleotide polymorphisms (SNPs) (n = 700,022) associated with progression to AIDS 1987 (Cox proportional hazards regression analysis, co-dominant model).
Results.  Association with slower progression was observed for SNPs in the gene PARD3B. One of these, rs11884476, reached genome-wide significance (relative hazard = 0.3; P =3. 370 × 10−9) after statistical correction for 700,022 SNPs and contributes 4.52% of the overall variance in AIDS progression in this study. Nine of the top-ranked SNPs define a PARD3B haplotype that also displays significant association with progression to AIDS (hazard ratio, 0.3; P = 3.220 × 10−8). One of these SNPs, rs10185378, is a predicted exonic splicing enhancer; significant alteration in the expression profile of PARD3B splicing transcripts was observed in B cell lines with alternate rs10185378 genotypes. This SNP was typed in European cohorts of rapid progressors and was found to be protective for AIDS 1993 definition (odds ratio, 0.43, P = .025).
Conclusions. These observations suggest a potential unsuspected pathway of host genetic influence on the dynamics of AIDS progression.
doi:10.1093/infdis/jir046
PMCID: PMC3080910  PMID: 21502085
7.  Effect of host genetics on CMV retinitis occurrence in patients with AIDS 
The Journal of infectious diseases  2010;202(4):606-613.
Background
Cytomegalovirus (CMV) retinitis is a common opportunistic infection among patients with AIDS and still causes visual morbidity despite the wide spread usage of highly active antiretroviral therapy (HAART). The ubiquitous CMV pathogen contains a human interleukin-10 (IL-10) homolog in its genome and utilizes it to evade host immune reactions through an IL-10 receptor mediated immune-suppression pathway.
Methods
Effects of IL-10R1, IL-10 and previously described AIDS restriction gene variants are investigated on the development of CMV retinitis in the Longitudinal Study of the Ocular Complications of AIDS (LSOCA) cohort (n=1284).
Results
In Europen Americans (n=750), a haplotype carrying an amino acid changing variation in the cytoplasmic domain (S420L) of IL-10R1 can be protective (OR = 0.14, CI: 0.02–0.94, P = 0.04) against, whereas another haplotype carrying an amino acid changing variation in the extracellular domain (I224V) of IL-10R1 can be more susceptible (OR = 6.21, CI: 1.22–31.54, P = 0.03) to CMV retinitis. In African Americans (n=534), potential effects of IL-10 variants are observed.
Conclusion
Host genetics may have a role in the occurrence of CMV retinitis in patients infected with HIV.
doi:10.1086/654814
PMCID: PMC2932829  PMID: 20617924
AIDS; CMV retinitis; HIV-1; host genetics; interleukin-10 receptor
8.  Effect of host genetics on incidence of HIV neuroretinal disorder in patients with AIDS 
Approximately 10 to 15% of patients with AIDS but without ocular opportunistic infections will have a presumed neuroretinal disorder (HIV-NRD), manifested by reduced contrast sensitivity and abnormal visual fields. The loss of contrast sensitivity often is sufficient to impair reading speed. To evaluate the effect of host genetics on HIV-NRD, we explored validated AIDS restriction gene variants CCR5Δ32, CCR2-64I, CCR5 P1, SDF-3`A, IL-10-5`A, RANTES -403A, RANTES -28G, RANTES-In1.1C, CX3CR1-249I, CX3CR1-280M, IFNG-179T, MDR1-3435T, and MCP-1364G, each of which has been implicated previously to influence HIV-1 infection, AIDS progression, therapy response, and antiviral drug metabolism, and an IL-10 receptor gene, IL-10R1, in the Longitudinal Study of the Ocular Complications of AIDS (LSOCA) cohort. In European Americans (cases=55, controls=290), IL-10-5`A variant and its promoter haplotype (HR=2.09, CI: 1.19–3.67, P = 0.01); in African Americans (cases=54, controls=180) RANTES-In1.1C and the associated haplotype (HR=2.72, CI: 1.48–5.00, P = 0.001), showed increased HIV-NRD susceptibility. While sample sizes are small and P values do not pass a strict Bonferroni correction, our results suggest that, in European Americans, an IL-10-related pathway, and, in African Americans, chemokine receptor ligand polymorphisms in RANTES are risk factors for HIV- NRD development. Clearly, further studies are warrented.
doi:10.1097/QAI.0b013e3181deaf4d
PMCID: PMC2908809  PMID: 20531015
AIDS; HIV-1; host genetics; HIV-neuroretinal disorder
9.  Genetic Variants in Nuclear-Encoded Mitochondrial Genes Influence AIDS Progression 
PLoS ONE  2010;5(9):e12862.
Background
The human mitochondrial genome includes only 13 coding genes while nuclear-encoded genes account for 99% of proteins responsible for mitochondrial morphology, redox regulation, and energetics. Mitochondrial pathogenesis occurs in HIV patients and genetically, mitochondrial DNA haplogroups with presumed functional differences have been associated with differential AIDS progression.
Methodology/Principal Findings
Here we explore whether single nucleotide polymorphisms (SNPs) within 904 of the estimated 1,500 genes that specify nuclear-encoded mitochondrial proteins (NEMPs) influence AIDS progression among HIV-1 infected patients. We examined NEMPs for association with the rate of AIDS progression using genotypes generated by an Affymetrix 6.0 genotyping array of 1,455 European American patients from five US AIDS cohorts. Successfully genotyped SNPs gave 50% or better haplotype coverage for 679 of known NEMP genes. With a Bonferroni adjustment for the number of genes and tests examined, multiple SNPs within two NEMP genes showed significant association with AIDS progression: acyl-CoA synthetase medium-chain family member 4 (ACSM4) on chromosome 12 and peroxisomal D3,D2-enoyl-CoA isomerase (PECI) on chromosome 6.
Conclusions
Our previous studies on mitochondrial DNA showed that European haplogroups with presumed functional differences were associated with AIDS progression and HAART mediated adverse events. The modest influences of nuclear-encoded mitochondrial genes found in the current study add support to the idea that mitochondrial function plays a role in AIDS pathogenesis.
doi:10.1371/journal.pone.0012862
PMCID: PMC2943476  PMID: 20877624
10.  Association of Y chromosome haplogroup I with HIV progression, and HAART outcome 
Human genetics  2009;125(3):281-294.
The host genetic basis of differential outcomes in HIV infection, progression, viral load set point and highly active retroviral therapy (HAART) responses was examined for the common Y haplogroups in European Americans and African Americans. Accelerated progression to acquired immune deficiency syndrome (AIDS) and related death in European Americans among Y chromosome haplogroup I (Y-I) subjects was discovered. Additionally, Y-I haplogroup subjects on HAART took a longer time to HIV-1 viral suppression and were more likely to fail HAART. Both the accelerated progression and longer time to viral suppression results observed in haplogroup Y-I were significant after false-discovery-rate corrections. A higher frequency of AIDS-defining illnesses was also observed in haplogroup Y-I. These effects were independent of the previously identified autosomal AIDS restriction genes. When the Y-I haplogroup subjects were further subdivided into six I subhaplogroups, no one subhaplogroup accounted for the effects on HIV progression, viral load or HAART response. Adjustment of the analyses for population stratification found significant and concordant haplogroup Y-I results. The Y chromosome haplogroup analyses of HIV infection and progression in African Americans were not significant. Our results suggest that one or more loci on the Y chromosome found on haplogroup Y-I have an effect on AIDS progression and treatment responses in European Americans.
doi:10.1007/s00439-008-0620-7
PMCID: PMC2885350  PMID: 19169712
11.  Mitochondrial DNA Haplogroups influence lipoatrophy after Highly Active Anti-retroviral Therapy 
Although highly active retroviral therapy (HAART) has been extremely effective in lowering AIDS incidence among patients infected with HIV, certain drugs included in HAART can cause serious mitochondrial toxicities. One of the most frequent adverse events is lipoatrophy, which is the loss of subcutaneous fat in the face, arms, buttocks and/or legs as an adverse reaction to nucleoside reverse transcriptase inhibitors (NRTIs). The clinical symptoms of lipoatrophy resemble those of inherited mitochondrial diseases, which suggests that host mitochondrial genotype may play a role in susceptibility. We analyzed the association between mitochondrial haplogroup and severity of lipoatrophy in HIV-infected European American patients on HAART in the Multicenter AIDS cohort Study (MACS) and found that mitochondrial haplogroup H was strongly associated with increased atrophy (arms: p = 0.007, OR = 1.77, 95% CI = 1.17–2.69 legs: p = 0.037, OR = 1.54 95% CI = 1.03–2.31, and buttocks: p = 0.10, OR = 1.41 95% CI = 0.94–2.12). We also saw borderline significance for haplogroup T as protective against lipoatrophy (p = 0.05, OR = 0.52, 95% CI = 0.20–1.00). These data suggest that mitochondrial DNA haplogroup may influence the propensity for lipoatrophy in patients receiving NRTIs.
doi:10.1097/QAI.0b013e3181a324d6
PMCID: PMC2742970  PMID: 19339895
lipoatrophy; mitochondrial haplogroup; NRTI; mitochondrial toxicity
12.  Mitochondrial DNA Haplogroups influence AIDS Progression 
AIDS (London, England)  2008;22(18):2429-2439.
Objective
Mitochondrial function plays a role in both AIDS progression and highly active antiretroviral therapy (HAART) toxicity, therefore we sought to determine whether mitochondrial (mt) DNA variation revealed novel AIDS Restriction Genes (ARGs), particularly as mtDNA single nucleotide polymorphisms (SNPs) are known to influence regulation of oxidative phosphorylation, reactive oxygen species (ROS) production, and apoptosis.
Design
Retrospective cohort study.
Methods
We performed an association study of mtDNA haplogroups among 1833 European American HIV-1 patients from five US cohorts, the Multicenter AIDS Cohort Study (MACS), the San Francisco City Clinic Study (SFCC), Hemophilia Growth and Development Study (HGDS), the Multicenter Hemophilia Cohort Study (MHCS), and the AIDS Linked to Intravenous Experiences (ALIVE) cohort to determine whether the mtDNA haplogroup correlated with AIDS progression rate.
Results
MtDNA haplogroups J and U5a were elevated among HIV-1 infected people who display accelerated progression to AIDS and death. Haplogroups Uk, H3, and IWX appeared to be highly protective against AIDS progression.
Conclusions
The associations found in our study appear to support a functional explanation by which mtDNA variation among haplogroups influencing ATP production, ROS generation, and apoptosis is correlated to AIDS disease progression, however repeating these results in cohorts with different ethnic backgrounds would be informative. These data suggest that mitochondrial genes are important indicators of AIDS disease progression in HIV-1 infected persons.
doi:10.1097/QAD.0b013e32831940bb
PMCID: PMC2699618  PMID: 19005266
Mitochondria; AIDS; HIV-1; apoptosis; disease

Results 1-12 (12)