Host determinants of HIV-1 control in African Americans

We performed a whole-genome association study of human immunodeficiency virus type 1 (HIV-1) set point among a cohort of African Americans (n = 515), and an intronic single-nucleotide polymorphism (SNP) in the HLA-B gene showed one of the strongest associations. We use a subset of patients to demonstrate that this SNP reflects the effect of the HLA-B*5703 allele, which shows a genome-wide statistically significant association with viral load set point (P = 5.6 x 10(-10)). These analyses therefore confirm a member of the HLA-B*57 group of alleles as the most important common variant that influences viral load variation in African Americans, which is consistent with what has been observed for individuals of European ancestry, among whom the most important common variant is HLA-B*5701

A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A

Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979-1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this populatio

The Characterization of Twenty Sequenced Human Genomes

We present the analysis of twenty human genomes to evaluate the prospects for identifying rare functional variants that contribute to a phenotype of interest. We sequenced at high coverage ten “case” genomes from individuals with severe hemophilia A and ten “control” genomes. We summarize the number of genetic variants emerging from a study of this magnitude, and provide a proof of concept for the identification of rare and highly-penetrant functional variants by confirming that the cause of hemophilia A is easily recognizable in this data set. We also show that the number of novel single nucleotide variants (SNVs) discovered per genome seems to stabilize at about 144,000 new variants per genome, after the first 15 individuals have been sequenced. Finally, we find that, on average, each genome carries 165 homozygous protein-truncating or stop loss variants in genes representing a diverse set of pathways

Copy Number Variation of KIR Genes Influences HIV-1 Control

The authors that the number of activating and inhibitory KIR genes varies between individuals and plays a role in the regulation of immune mechanisms that determine HIV-1 control

Genome-Wide Analyses of HIV-1 Host Genetics

<p>HIV has presented some of the greatest biomedical challenges in recent decades, and an understanding of how the virus behaves when it is in the human body is critical to addressing many of these challenges. One avenue through which to do this is the study of host genetics, which investigates the human genetic variants that modify the interactions between the HIV-1 virus and the human body. In my graduate work, I performed several different investigations that have furthered our understanding of the human genetic variants that either modulate the response to HIV-1 infection or play a role in the acquisition of an HIV-1 infection. This work took place at a time of transition in human genetics, and spanned both the era of genome-wide association studies as well as the beginning of the sequencing and rare variant eras. </p><p>The earliest HIV-1 host genetics findings were made through candidate gene studies, which reflected the state of human genetics research in the 1990s and early 2000s. The draft sequence of the human genome was released in 2001, and HIV host genetics, as well as human genetics in general, has changed considerably since then. Chapter 1 describes the basics of HIV-1 biology and the HIV-1 epidemic, as well as some crucial findings in HIV-1 host genetics. This chapter also gives a brief recent history of human genetics and describes some of the current challenges in the field. </p><p>Chapters 2 and 3 describe the identification of human genetic variants that associate with viral load set point. Chapter 2 describes a copy number variable region (CNV) in the KIR region of the genome that associates with a change in set point, and Chapter 3 describes an allele of HLA-B (HLA-B*5703) that is the largest determinant of viral control in an African American population. Both chapters use data from genotyping chips as a starting point.</p><p>In the past several years, the cost to sequence a genome has plummeted, and it is now possible for a single group to sequence and align an entire human genome in just a few weeks. This "next-generation" sequencing has dramatically changed the field of human genetics, and Chapter 4 will discuss this new technology and provide an early analysis of the patterns of variation that are observed across multiple human genomes. Notably, this new technology allows for an unprecedented amount of variant discovery, including the possibility of identifying low frequency and rare variants. </p><p>Chapter 5 describes two different projects that make use of next-generation sequencing technology to investigate variants that influence HIV-1 disease acquisition and progression. Both projects are extreme phenotype whole-genome sequencing projects. For the first project, we have sequenced individuals who have hemophilia and were highly exposed to contaminated blood products but who remained uninfected. For the second project, we have sequenced African American individuals whose disease progressed very quickly or very slowly. I compare the variants in these individuals to the variants in control populations and describe follow-up genotyping results. I have not identified a causative variant in either of these studies, although a list of candidate variants is still being pursued. These analyses have shown that there is substantial heterogeneity in the genetic basis for both phenotypes. </p><p>Overall, my work has identified two common variants that are playing a role in modulating HIV-1 infection, as well as provided the first assessment of the patterns of variation across a set of unrelated human genomes. This thesis also describes some of the early attempts to apply the next-generation sequencing technique to HIV-1 host genetics. In the Conclusion, I discuss the future of HIV-1 host genetics research and the clinical applications of human genetics.</p>Dissertatio

Word of Mouth: Communicating with Patients Who Have Dementia or Language Difficulties (Slides)

The main purpose of this optional symposium is to help develop "EQ" emotional quotient skills to assist in clinical decision making and conduct with regards to the doctor-patient relationship and interactions, focusing on patient interactions and communication. Upon completion of this session, participants should be able to: (1) identify common heuristic decisionmaking errors with relevance to neuro-ophthalmology, (2) employ skills to avert making medical errors, (3) demonstrate empathy when delivering bad news, and (4) communicate efficiently with patients who have specific challenges with communication

A genome-wide association study of variants associated with acquisition of Staphylococcus aureus bacteremia in a healthcare setting

BACKGROUND: Humans vary in their susceptibility to acquiring Staphylococcus aureus infection, and research suggests that there is a genetic basis for this variability. Several recent genome-wide association studies (GWAS) have identified variants that may affect susceptibility to infectious diseases, demonstrating the potential value of GWAS in this arena. METHODS: We conducted a GWAS to identify common variants associated with acquisition of S. aureus bacteremia (SAB) resulting from healthcare contact. We performed a logistic regression analysis to compare patients with healthcare contact who developed SAB (361 cases) to patients with healthcare contact in the same hospital who did not develop SAB (699 controls), testing 542,410 SNPs and adjusting for age (by decade), sex, and 6 significant principal components from our EIGENSTRAT analysis. Additionally, we evaluated the joint effect of the host and pathogen genomes in association with severity of SAB infection via logistic regression, including an interaction of host SNP with bacterial genotype, and adjusting for age (by decade), sex, the 6 significant principal components, and dialysis status. Bonferroni corrections were applied in both analyses to control for multiple comparisons. RESULTS: Ours is the first study that has attempted to evaluate the entire human genome for variants potentially involved in the acquisition or severity of SAB. Although this study identified no common variant of large effect size to have genome-wide significance for association with either the risk of acquiring SAB or severity of SAB, the variant (rs2043436) most significantly associated with severity of infection is located in a biologically plausible candidate gene (CDON, a member of the immunoglobulin family) and may warrant further study. CONCLUSIONS: The genetic architecture underlying SAB is likely to be complex. Future investigations using larger samples, narrowed phenotypes, and advances in both genotyping and analytical methodologies will be important tools for identifying causative variants for this common and serious cause of healthcare-associated infection