HIV policy: the path forward--a joint position paper of the HIV Medicine Association of the Infectious Diseases Society of America and the American College of Physicians.

Executive Summary The American College of Physicians (ACP) and the Infectious Diseases Society of America (IDSA) have jointly published 3 policy statements on AIDS, the first in 1986 [1], the second in 1988 [2], and the third in 1994 [3]. In 2001, the IDSA created the HIV Medicine Association (HIVMA), and this updated policy paper is a collaboration between the ACP and the HIVMA of the IDSA. Since the last statement, many new developments call for the need to reexamine and update our policies relating to HIV infection. First, there have been major advances in treatment for HIV infection that have transformed HIV/AIDS from a terminal illness to a chronic disease for many of those who have access to potent therapies and expert medical care [4]. Second, there has been a profound expansion and intensification of the global HIV pandemic, particularly in sub-Saharan Africa, coupled with significant US leadership and resources aimed at providing prevention and care services to affected populations in developing countries. Third, the concerns that were prevalent in the mid-1990s regarding the possibility of HIV transmission in health care settings have ultimately proven to be unfounded as the result of the adoption of universal precautions in those settings. In this article, we emphasize the public health and clinical imperatives for earlier identification of persons with HIV infection; the urgent need to expand access to state-of-the-art HIV care and treatment for infected individuals; the need for access to comprehensive prevention and education for those living with and those at risk for HIV infection; and the need for stronger national leadership to respond to the HIV epidemic in the United States and in the developing world. In December 2008, the ACP and HIVMA released a guidance statement on screening for HIV infection in health care settings that recommended that clinicians adopt routine screening for HIV infection and encourage patients to be tested. Also included in the guidance statement is a recommendation that clinicians determine the need for additional screening on an individual basis

Risk of Ovarian Cancer and Inherited Variants in Relapse-Associated Genes

Background: We previously identified a panel of genes associated with outcome of ovarian cancer. The purpose of the current study was to assess whether variants in these genes correlated with ovarian cancer risk. Methods and Findings: Women with and without invasive ovarian cancer (749 cases, 1,041 controls) were genotyped at 136 single nucleotide polymorphisms (SNPs) within 13 candidate genes. Risk was estimated for each SNP and for overall variation within each gene. At the gene-level, variation within MSL1 (male-specific lethal-1 homolog) was associated with risk of serous cancer (p = 0.03); haplotypes within PRPF31 (PRP31 pre-mRNA processing factor 31 homolog) were associated with risk of invasive disease (p = 0.03). MSL1 rs7211770 was associated with decreased risk of serous disease (OR 0.81, 95 % CI 0.66–0.98; p = 0.03). SNPs in MFSD7, BTN3A3, ZNF200, PTPRS, and CCND1A were inversely associated with risk (p,0.05), and there was increased risk at HEXIM1 rs1053578 (p = 0.04, OR 1.40, 95 % CI 1.02–1.91). Conclusions: Tumor studies can reveal novel genes worthy of follow-up for cancer susceptibility. Here, we found that inherited markers in the gene encoding MSL1, part of a complex that modifies the histone H4, may decrease risk of invasiv

Polymorphisms in NF-κB Inhibitors and Risk of Epithelial Ovarian Cancer

<p>Abstract</p> <p>Background</p> <p>The nuclear factor-κB (NF-κB) family is a set of transcription factors with key roles in the induction of the inflammatory response and may be the link between inflammation and cancer development. This pathway has been shown to influence ovarian epithelial tissue repair. Inhibitors of κB (IκB) prevent NF-κB activation by sequestering NF-κB proteins in the cytoplasm until IκB proteins are phosphorylated and degraded.</p> <p>Methods</p> <p>We used a case-control study to evaluate the association between single nucleotide polymorphisms (SNPs) in <it>NFKBIA </it>and <it>NFKBIB </it>(the genes encoding IκBα and IκBβ, respectively) and risk of epithelial ovarian cancer. We queried 19 tagSNPs and putative-functional SNPs among 930 epithelial ovarian cancer cases and 1,037 controls from two studies.</p> <p>Results</p> <p>The minor allele for one synonymous SNP in <it>NFKBIA</it>, rs1957106, was associated with decreased risk (p = 0.03).</p> <p>Conclusion</p> <p>Considering the number of single-SNP tests performed and null gene-level results, we conclude that <it>NFKBIA </it>and <it>NFKBIB </it>are not likely to harbor ovarian cancer risk alleles. Due to its biological significance in ovarian cancer, additional genes encoding NF-κB subunits, activating and inhibiting molecules, and signaling molecules warrant interrogation.</p

Genetically Determined Height and Risk of Non-hodgkin Lymphoma

Although the evidence is not consistent, epidemiologic studies have suggested that taller adult height may be associated with an increased risk of some non-Hodgkin lymphoma (NHL) subtypes. Height is largely determined by genetic factors, but how these genetic factors may contribute to NHL risk is unknown. We investigated the relationship between genetic determinants of height and NHL risk using data from eight genome-wide association studies (GWAS) comprising 10,629 NHL cases, including 3,857 diffuse large B-cell lymphoma (DLBCL), 2,847 follicular lymphoma (FL), 3,100 chronic lymphocytic leukemia (CLL), and 825 marginal zone lymphoma (MZL) cases, and 9,505 controls of European ancestry. We evaluated genetically predicted height by constructing polygenic risk scores using 833 height-associated SNPs. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for association between genetically determined height and the risk of four NHL subtypes in each GWAS and then used fixed-effect meta-analysis to combine subtype results across studies. We found suggestive evidence between taller genetically determined height and increased CLL risk (OR = 1.08, 95% CI = 1.00–1.17, p = 0.049), which was slightly stronger among women (OR = 1.15, 95% CI: 1.01–1.31, p = 0.036). No significant associations were observed with DLBCL, FL, or MZL. Our findings suggest that there may be some shared genetic factors between CLL and height, but other endogenous or environmental factors may underlie reported epidemiologic height associations with other subtypes

Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia

Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P=5.04 × 10−13), 1q42.13 (rs41271473, P=1.06 × 10−10), 4q24 (rs71597109, P=1.37 × 10−10), 4q35.1 (rs57214277, P=3.69 × 10−8), 6p21.31 (rs3800461, P=1.97 × 10−8), 11q23.2 (rs61904987, P=2.64 × 10−11), 18q21.1 (rs1036935, P=3.27 × 10−8), 19p13.3 (rs7254272, P=4.67 × 10−8) and 22q13.33 (rs140522, P=2.70 × 10−9). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response

Genetic overlap between autoimmune diseases and non-Hodgkin lymphoma subtypes

Epidemiologic studies show an increased risk of non-Hodgkin lymphoma (NHL) in patients with autoimmune disease (AD), due to a combination of shared environmental factors and/or genetic factors, or a causative cascade: chronic inflammation/antigen-stimulation in one disease leads to another. Here we assess shared genetic risk in genome-wide-association-studies (GWAS). Secondary analysis of GWAS of NHL subtypes (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and ADs (rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis). Shared genetic risk was assessed by (a) description of regional genetic of overlap, (b) polygenic risk score (PRS), (c)"diseasome", (d)meta-analysis. Descriptive analysis revealed few shared genetic factors between each AD and each NHL subtype. The PRS of ADs were not increased in NHL patients (nor vice versa). In the diseasome, NHLs shared more genetic etiology with ADs than solid cancers (p = .0041). A meta-analysis (combing AD with NHL) implicated genes of apoptosis and telomere length. This GWAS-based analysis four NHL subtypes and three ADs revealed few weakly-associated shared loci, explaining little total risk. This suggests common genetic variation, as assessed by GWAS in these sample sizes, may not be the primary explanation for the link between these ADs and NHLs

Lupus-related single nucleotide polymorphisms and risk of diffuse large B-cell lymphoma

Objective: Determinants of the increased risk of diffuse large B-cell lymphoma (DLBCL) in SLE are unclear. Using data from a recent lymphoma genome-wide association study (GWAS), we assessed whether certain lupus-related single nucleotide polymorphisms (SNPs) were also associated with DLBCL. Methods: GWAS data on European Caucasians from the International Lymphoma Epidemiology Consortium (InterLymph) provided a total of 3857 DLBCL cases and 7666 general-population controls. Data were pooled in a random-effects meta-analysis. Results: Among the 28 SLE-related SNPs investigated, the two most convincingly associated with risk of DLBCL included the CD40 SLE risk allele rs4810485 on chromosome 20q13 (OR per risk allele=1.09, 95% CI 1.02 to 1.16, p=0.0134), and the HLA SLE risk allele rs1270942 on chromosome 6p21.33 (OR per risk allele=1.17, 95% CI 1.01 to 1.36, p=0.0362). Of additional possible interest were rs2205960 and rs12537284. The rs2205960 SNP, related to a cytokine of the tumour necrosis factor superfamily TNFSF4, was associated with an OR per risk allele of 1.07, 95% CI 1.00 to 1.16, p=0.0549. The OR for the rs12537284 (chromosome 7q32, IRF5 gene) risk allele was 1.08, 95% CI 0.99 to 1.18, p=0.0765. Conclusions: These data suggest several plausible genetic links between DLBCL and SLE