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Cerhan J.R.,Mayo Medical School | Berndt S.I.,U.S. National Cancer Institute | Vijai J.,Sloan Kettering Cancer Center | Ghesquieres H.,Center Leon Berard | And 133 more authors.
Nature Genetics | Year: 2014

Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P = 2.33 × 10 '21), rs2523607 at 6p21.33 (HLA-B; P = 2.40 × 10 '10), rs79480871 at 2p23.3 (NCOA1; P = 4.23 × 10 '8) and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P = 9.98 × 10 '13 and 3.63 × 10 '11, respectively). These data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL. © 2014 Nature America, Inc. All rights reserved.


Berndt S.I.,U.S. National Cancer Institute | Skibola C.F.,University of California at Berkeley | Skibola C.F.,University of Alabama at Birmingham | Joseph V.,Sloan Kettering Cancer Center | And 140 more authors.
Nature Genetics | Year: 2013

Genome-wide association studies (GWAS) have previously identified 13 loci associated with risk of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL). To identify additional CLL susceptibility loci, we conducted the largest meta-analysis for CLL thus far, including four GWAS with a total of 3,100 individuals with CLL (cases) and 7,667 controls. In the meta-analysis, we identified ten independent associated SNPs in nine new loci at 10q23.31 (ACTA2 or FAS (ACTA2/FAS), P = 1.22 × 10-14), 18q21.33 (BCL2, P = 7.76 × 10-11), 11p15.5 (C11orf21, P = 2.15 × 10 -10), 4q25 (LEF1, P = 4.24 × 10-10), 2q33.1 (CASP10 or CASP8 (CASP10/CASP8), P = 2.50 × 10-9), 9p21.3 (CDKN2B-AS1, P = 1.27 × 10-8), 18q21.32 (PMAIP1, P = 2.51 × 10 -8), 15q15.1 (BMF, P = 2.71 × 10-10) and 2p22.2 (QPCT, P = 1.68 × 10-8), as well as an independent signal at an established locus (2q13, ACOXL, P = 2.08 × 10-18). We also found evidence for two additional promising loci below genome-wide significance at 8q22.3 (ODF1, P = 5.40 × 10-8) and 5p15.33 (TERT, P = 1.92 × 10-7). Although further studies are required, the proximity of several of these loci to genes involved in apoptosis suggests a plausible underlying biological mechanism. © 2013 Nature America, Inc. All rights reserved.


PubMed | Karolinska Institutet, New York University, Dalian Maritime University, Stanford University and 41 more.
Type: | Journal: Nature communications | Year: 2015

Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P=3.95 10(-15)) and HLA-B (rs2922994, P=2.43 10(-9)) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility.


PubMed | Karolinska Institutet, Genome Institute of Singapore, Dalian Maritime University, Stanford University and 48 more.
Type: Comparative Study | Journal: American journal of human genetics | Year: 2014

Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non-HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 10(-20)) near CXCR5; 11q24.3 (rs4937362, p = 6.76 10(-11)) near ETS1; 3q28 (rs6444305, p = 1.10 10(-10)) in LPP; 18q21.33 (rs17749561, p = 8.28 10(-10)) near BCL2; and 8q24.21 (rs13254990, p = 1.06 10(-8)) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DR1 multiallelic amino acids at positions 11, 13, 28, and 30 that were associated with FL risk (pomnibus = 4.20 10(-67) to 2.67 10(-70)). Additional independent signals included rs17203612 in HLA class II (odds ratio [OR(per-allele)] = 1.44; p = 4.59 10(-16)) and rs3130437 in HLA class I (OR(per-allele) = 1.23; p = 8.23 10(-9)). Our findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk.


PubMed | Karolinska Institutet, Lyon, Harvard University, New York University and 58 more.
Type: Journal Article | Journal: Nature genetics | Year: 2014

Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P = 2.33 10(-21)), rs2523607 at 6p21.33 (HLA-B; P = 2.40 10(-10)), rs79480871 at 2p23.3 (NCOA1; P = 4.23 10(-8)) and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P = 9.98 10(-13) and 3.63 10(-11), respectively). These data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL.


Ellen J.M.,All Childrens Hospital | Greenberg L.,Health Studies Sector | Willard N.,Johns Hopkins University | Korelitz J.,Health Studies Sector | And 7 more authors.
JAMA Pediatrics | Year: 2015

Importance: With the emphasis on structural-level interventions that target social determinants of human immunodeficiency virus (HIV) transmission to curb the HIV epidemic, there is a need to develop evaluation models that can detect changes in individual factors associated with HIV-related structural changes.Objective: To describe whether structural changes developed and achieved by community coalitions are associated with an effect on individual factors associated with the risk of contracting HIV.Design, Setting, And Participants: In this serial cross-sectional survey design, datawere collected from 8 cities during 4 rounds of annual surveys from March 13, 2007, through July 29, 2010. Study recruitment took place at venues where the population of focus was known to congregate, such as clubs, bars, community centers, and low-income housing. The convenience sample of at-risk youth (persons aged 12-24 years) included 5337 individuals approached about the survey and 3142 (58.9%) who were screened for eligibility. Of the 2607 eligible participants, 2559 (98.2%) ultimately agreed to participate.Interventions: Achievement of locally identified structural changes that targeted public and private entities (eg, federal agencies, homeless shelters, and school systems) with the goal of fostering changes in policy and practice to ultimately facilitate positive behavioral changes aimed at preventing HIV.Main Outcomes And Measures: Number of sexual partners, partner characteristics, condom use, and history of sexually transmitted infections and HIV testing.Results: Exposure to structural changes was not statistically significantly associated with any of the outcome measures, although some results were in the direction of a positive structural change effect (eg, a 10-unit increase in a structural change score had an odds ratio of 0.88 [95%CI, 0.76-1.03; P = .11] for having an older sexual partner and an odds ratio of 0.91 [95% CI, 0.60-1.39; P= .39] for using a condom half the time or less with a casual partner).Conclusions And Relevance This study evaluated a broad representation of at-risk individuals and assessed the effect of numerous structural changes related to various HIV risk factors. No structural changes as measured in this study were associated with a statistically significant reduction in risk behaviors. These null findings underscore the need for a long-term approach in evaluating structural interventions and the development of more nuanced methods of quantifying and comparing structural-change initiatives and determining the appropriate strategies for evaluating effect. © 2015 American Medical Association. All rights reserved.


Hamilton C.D.,Global Health | Hamilton C.D.,Duke University | Swaminathan S.,National Institute for Research in Tuberculosis | Christopher D.J.,Christian Medical College | And 10 more authors.
Clinical Infectious Diseases | Year: 2015

Progress in tuberculosis clinical research is hampered by a lack of reliable biomarkers that predict progression from latent to active tuberculosis, and subsequent cure, relapse, or failure. Regional Prospective Observational Research in Tuberculosis (RePORT) International represents a consortium of regional cohorts (RePORT India, RePORT Brazil, and RePORT Indonesia) that are linked through the implementation of a Common Protocol for data and specimen collection, and are poised to address this critical research need. Each RePORT network is designed to support local, in-country tuberculosis-specific data and specimen biorepositories, and associated research. Taken together, the expected results include greater global clinical research capacity in high-burden settings, and increased local access to quality data and specimens for members of each network and their domestic and international collaborators. Additional networks are expected to be added, helping to spur tuberculosis treatment and prevention research around the world. © 2015 The Author.


PubMed | Center for Infectious Disease Research, Boston University, Instituto Goncalo Moniz, Health Studies Sector and 2 more.
Type: | Journal: Tuberculosis (Edinburgh, Scotland) | Year: 2017

RePORT International is a collaborative research network of investigators from multiple countries and institutions with the goal of establishing a bio-repository of specimens and clinical data for the study of active TB and latent TB infection (LTBI). During the first meeting of RePORT International in Boston, Massachusetts, the results of research pertinent to TB control and eradication were presented, including advances in the research of Mycobacterium tuberculosis (MTB) persistence and drug resistance, TB diagnostics, drug and vaccine development.


PubMed | National Institute of Infectious Diseases Evandro Chagas Fiocruz, Johns Hopkins University, Christian Medical College, Health Studies Sector and 5 more.
Type: | Journal: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America | Year: 2015

Progress in tuberculosis clinical research is hampered by a lack of reliable biomarkers that predict progression from latent to active tuberculosis, and subsequent cure, relapse, or failure. Regional Prospective Observational Research in Tuberculosis (RePORT) International represents a consortium of regional cohorts (RePORT India, RePORT Brazil, and RePORT Indonesia) that are linked through the implementation of a Common Protocol for data and specimen collection, and are poised to address this critical research need. Each RePORT network is designed to support local, in-country tuberculosis-specific data and specimen biorepositories, and associated research. Taken together, the expected results include greater global clinical research capacity in high-burden settings, and increased local access to quality data and specimens for members of each network and their domestic and international collaborators. Additional networks are expected to be added, helping to spur tuberculosis treatment and prevention research around the world.

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