Host Genomic Influences on HIV/AIDS

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

Gene Discovery and Data Sharing in Genome Wide Association Analyses: Lessons Form AIDS Genetic Restriction Genes

As genome wide association studies plus whole genome sequence analyses for complex human disease determinants are expanding, it seems useful to develop strategies to facilitate large data sharing, rapid replication and validation of provocative statistical associations that straddle the threshold for genome wide significance. At this conference, we shall announce GWATCH, (Genome Wide Association Tracks Chromosome Highway) a web based data release platform that can freely display and inspect unabridged genome tracked association data without compromising privacy or Informed Consent constrictions, allowing for rapid discovery and replication opportunities. We illustrate the utility with HIV-AIDS resistance genes screened in combined large multicenter cohort studies GWAS (MACS, HGDS, MHGS, ALLIVE, LSOCA HOMER) developed and studied over the last decades

Risk Factors for Symptomatic Hyperlactatemia and Lactic Acidosis Among Combination Antiretroviral Therapy-Treated Adults in Botswana: Results from a Clinical Trial

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

The Principal Genetic Determinants for Nasopharyngeal Carcinoma in China Involve the HLA Class I Antigen Recognition Groove

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

A High-Resolution SNP Array-Based Linkage Map Anchors a New Domestic Cat Draft Genome Assembly and Provides Detailed Patterns of Recombination

High-resolution genetic and physical maps are invaluable tools for building accurate genome assemblies, and interpreting results of genome-wide association studies (GWAS). Previous genetic and physical maps anchored good quality draft assemblies of the domestic cat genome, enabling the discovery of numerous genes underlying hereditary disease and phenotypes of interest to the biomedical science and breeding communities. However, these maps lacked sufficient marker density to order thousands of shorter scaffolds in earlier assemblies, which instead relied heavily on comparative mapping with related species. A high-resolution map would aid in validating and ordering chromosome scaffolds from existing and new genome assemblies. Here, we describe a high-resolution genetic linkage map of the domestic cat genome based on genotyping 453 domestic cats from several multi-generational pedigrees on the Illumina 63K SNP array. The final maps include 58,055 SNP markers placed relative to 6637 markers with unique positions, distributed across all autosomes and the X chromosome. Our final sex-averaged maps span a total autosomal length of 4464 cM, the longest described linkage map for any mammal, confirming length estimates from a previous microsatellite-based map. The linkage map was used to order and orient the scaffolds from a substantially more contiguous domestic cat genome assembly (Felis catusv8.0), which incorporated ∼20 × coverage of Illumina fragment reads. The new genome assembly shows substantial improvements in contiguity, with a nearly fourfold increase in N50 scaffold size to 18 Mb. We use this map to report probable structural errors in previous maps and assemblies, and to describe features of the recombination landscape, including a massive (∼50 Mb) recombination desert (of virtually zero recombination) on the X chromosome that parallels a similar desert on the porcine X chromosome in both size and physical location

Genetic Variants in Nuclear-Encoded Mitochondrial Genes Influence AIDS Progression

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 nuclearencoded mitochondrial genes found in the current study add support to the idea that mitochondrial function plays a role in AIDS pathogenesis

Affinities of the Saw-Billed Hermit (Ramphodon naevius) Determined by Cytochrome-B Sequence Data

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Mitochondrial Haplogroups Are Associated With Risk of Neuroretinal Disorder in HIV-Positive Patients

Although highly active antiretroviral therapy has improved survivorship dramatically and decreased the incidence of cytomegalovirus retinitis among patients with AIDS, other ophthalmic complications continue to occur. One complication observed in ∼12% of HIV-infected patients is a presumed neuroretinal disorder (NRD), manifested as decreased contrast sensitivity and associated with vague subjective complaints of hazy vision. Pathologically, patients with AIDS even without ocular opportunistic infections have loss of optic nerve axons, suggestive of mitochondrial dysfunction. We explored whether variation in mitochondrial DNA was associated with time to NRD in HIV-infected patients in the Longitudinal Study of Ocular Complications of AIDS cohort. Within the Western European, or “N”, mitochondrial DNA macrohaplogroup, haplogroup J, was associated with 80% decrease in the risk of progression to NRD during the study (hazard ratio = 0.20, P = 0.039) and suggested an independent association with protection against NRD in a cross-section of all patients taken at enrollment (1.5% vs. 8.9% in patients with vs. without haplogroup J, respectively, P = 0.05). These data suggest that mitochondrial genotype may influence propensity to develop HIV-associated NRD in patients with AIDS