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1. Genome-wide analyses characterize shared heritability among cancers and identify novel cancer susceptibility regions

Author

Lindström, Sara, Wang, Lu, Feng, Helian, Majumdar, Arunabha, Huo, Sijia, Macdonald, James, Harrison, Tabitha, Turman, Constance, Chen, Hongjie, Mancuso, Nicholas, Bammler, Theo, Consortium, Breast Cancer Association, Gallinger, Steve, Gruber, Stephen B, Gunter, Marc J, Le Marchand, Loic, Moreno, Victor, Offit, Kenneth, Study, Genetics And Epidemiology Of Colorectal Cancer Consortium Colorectal Transdisciplinary Study Colon Cancer Family Registry, De Vivo, Immaculata, O’Mara, Tracy A, Spurdle, Amanda B, Tomlinson, Ian, Consortium, Endometrial Cancer Association, Fitzgerald, Rebecca, Gharahkhani, Puya, Gockel, Ines, Jankowski, Janusz, Macgregor, Stuart, Schumacher, Johannes, Barnholtz-Sloan, Jill, Bondy, Melissa L, Houlston, Richard S, Jenkins, Robert B, Melin, Beatrice, Wrensch, Margaret, Brennan, Paul, Christiani, David C, Johansson, Mattias, Mckay, James, Aldrich, Melinda C, Amos, Christopher I, Landi, Maria Teresa, Tardon, Adonina, Consortium, International Lung Cancer, Bishop, D Timothy, Demenais, Florence, Goldstein, Alisa M, Iles, Mark M, Kanetsky, Peter A, Law, Matthew H, Consortium, Ovarian Cancer Association, Amundadottir, Laufey T, Stolzenberg-Solomon, Rachael, Wolpin, Brian M, Consortium, Pancreatic Cancer Cohort, Klein, Alison, Petersen, Gloria, Risch, Harvey, Consortium, The PRACTICAL Consortium Pancreatic Cancer Case-Control, Chanock, Stephen J, Purdue, Mark P, Scelo, Ghislaine, Pharoah, Paul, Kar, Siddhartha, Hung, Rayjean J, Pasaniuc, Bogdan, and Kraft, Peter

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Human Genome, Genetics, Digestive Diseases, Prevention, Clinical Research, Urologic Diseases, Cancer, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Male, Humans, Genome-Wide Association Study, Genetic Predisposition to Disease, Neoplasms, Risk Factors, Transcriptome, Polymorphism, Single Nucleotide, Breast Cancer Association Consortium, Colorectal Transdisciplinary Study (CORECT), Colon Cancer Family Registry Study (CCFR), Genetics And Epidemiology Of Colorectal Cancer Consortium, Endometrial Cancer Association Consortium, International Lung Cancer Consortium, Ovarian Cancer Association Consortium, Pancreatic Cancer Cohort Consortium, Pancreatic Cancer Case-Control Consortium (Panc4), The PRACTICAL Consortium, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundThe shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from 12 cancer genome-wide association studies (GWAS) to quantify pairwise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci.MethodsWe collected GWAS summary statistics for 12 solid cancers based on 376 759 participants with cancer and 532 864 participants without cancer of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies to discover novel cancer susceptibility loci. Finally, we assessed the extent of variant-specific pleiotropy among cancers at known and newly identified cancer susceptibility loci.ResultsWe observed widespread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and transcriptome-wide association studies, we identified 15 novel cancer susceptibility loci. Additionally, we identified multiple variants at 77 distinct loci with strong evidence of being associated with at least 2 cancer types by testing for pleiotropy at known cancer susceptibility loci.ConclusionsOverall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer-specific and thus tissue-specific. The increase in statistical power associated with larger sample sizes in cross-disease analysis allows for the identification of novel susceptibility regions. Future studies incorporating data on multiple cancer types are likely to identify additional regions associated with the risk of multiple cancer types.

Published
2023

2. Discovery of genomic loci associated with sleep apnea risk through multi-trait GWAS analysis with snoring.

Author

Campos, Adrian, Ingold, Nathan, Huang, Yunru, Mitchell, Brittany, Kho, Pik-Fang, Han, Xikun, García-Marín, Luis, Ong, Jue-Sheng, Law, Matthew, Martin, Nicholas, Dong, Xianjun, Cuellar-Partida, Gabriel, MacGregor, Stuart, Aslibekyan, Stella, Rentería, Miguel, and Yokoyama, Jennifer

Subjects
GWAS, genetics, sleep apnea, snoring, Humans, Genome-Wide Association Study, Snoring, Phenotype, Sleep Apnea Syndromes, Genomics, Polymorphism, Single Nucleotide
Abstract

STUDY OBJECTIVES: Despite its association with severe health conditions, the etiology of sleep apnea (SA) remains understudied. This study sought to identify genetic variants robustly associated with SA risk. METHODS: We performed a genome-wide association study (GWAS) meta-analysis of SA across five cohorts (NTotal = 523 366), followed by a multi-trait analysis of GWAS (multi-trait analysis of genome-wide association summary statistics [MTAG]) to boost power, leveraging the high genetic correlation between SA and snoring. We then adjusted our results for the genetic effects of body mass index (BMI) using multi-trait-based conditional and joint analysis (mtCOJO) and sought replication of lead hits in a large cohort of participants from 23andMe, Inc (NTotal = 1 477 352; Ncases = 175 522). We also explored genetic correlations with other complex traits and performed a phenome-wide screen for causally associated phenotypes using the latent causal variable method. RESULTS: Our SA meta-analysis identified five independent variants with evidence of association beyond genome-wide significance. After adjustment for BMI, only one genome-wide significant variant was identified. MTAG analyses uncovered 49 significant independent loci associated with SA risk. Twenty-nine variants were replicated in the 23andMe GWAS adjusting for BMI. We observed genetic correlations with several complex traits, including multisite chronic pain, diabetes, eye disorders, high blood pressure, osteoarthritis, chronic obstructive pulmonary disease, and BMI-associated conditions. CONCLUSION: Our study uncovered multiple genetic loci associated with SA risk, thus increasing our understanding of the etiology of this condition and its relationship with other complex traits.

Published
2023

3. The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions

Author

Rahmioglu, Nilufer, Mortlock, Sally, Ghiasi, Marzieh, Møller, Peter L, Stefansdottir, Lilja, Galarneau, Geneviève, Turman, Constance, Danning, Rebecca, Law, Matthew H, Sapkota, Yadav, Christofidou, Paraskevi, Skarp, Sini, Giri, Ayush, Banasik, Karina, Krassowski, Michal, Lepamets, Maarja, Marciniak, Błażej, Nõukas, Margit, Perro, Danielle, Sliz, Eeva, Sobalska-Kwapis, Marta, Thorleifsson, Gudmar, Topbas-Selcuki, Nura F, Vitonis, Allison, Westergaard, David, Arnadottir, Ragnheidur, Burgdorf, Kristoffer S, Campbell, Archie, Cheuk, Cecilia SK, Clementi, Caterina, Cook, James, De Vivo, Immaculata, DiVasta, Amy, Dorien, O, Donoghue, Jacqueline F, Edwards, Todd, Fontanillas, Pierre, Fung, Jenny N, Geirsson, Reynir T, Girling, Jane E, Harkki, Paivi, Harris, Holly R, Healey, Martin, Heikinheimo, Oskari, Holdsworth-Carson, Sarah, Hostettler, Isabel C, Houlden, Henry, Houshdaran, Sahar, Irwin, Juan C, Jarvelin, Marjo-Riitta, Kamatani, Yoichiro, Kennedy, Stephen H, Kepka, Ewa, Kettunen, Johannes, Kubo, Michiaki, Kulig, Bartosz, Kurra, Venla, Laivuori, Hannele, Laufer, Marc R, Lindgren, Cecilia M, MacGregor, Stuart, Mangino, Massimo, Martin, Nicholas G, Matalliotaki, Charoula, Matalliotakis, Michail, Murray, Alison D, Ndungu, Anne, Nezhat, Camran, Olsen, Catherine M, Opoku-Anane, Jessica, Padmanabhan, Sandosh, Paranjpe, Manish, Peters, Maire, Polak, Grzegorz, Porteous, David J, Rabban, Joseph, Rexrode, Kathyrn M, Romanowicz, Hanna, Saare, Merli, Saavalainen, Liisu, Schork, Andrew J, Sen, Sushmita, Shafrir, Amy L, Siewierska-Górska, Anna, Słomka, Marcin, Smith, Blair H, Smolarz, Beata, Szaflik, Tomasz, Szyłło, Krzysztof, Takahashi, Atsushi, Terry, Kathryn L, Tomassetti, Carla, Treloar, Susan A, Vanhie, Arne, Vincent, Katy, Vo, Kim C, Werring, David J, Zeggini, Eleftheria, Zervou, Maria I, and Adachi, Sosuke

Subjects
Biological Sciences, Genetics, Contraception/Reproduction, Clinical Research, Endometriosis, Prevention, Pain Research, Chronic Pain, Infertility, 2.1 Biological and endogenous factors, Aetiology, Female, Humans, Genetic Predisposition to Disease, Genome-Wide Association Study, Pain, Comorbidity, DBDS Genomic Consortium, FinnGen Study, FinnGen Endometriosis Taskforce, Celmatix Research Team, 23andMe Research Team, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention.

Published
2023

4. Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers.

Author

Zhang, Yan Dora, Hurson, Amber N, Zhang, Haoyu, Choudhury, Parichoy Pal, Easton, Douglas F, Milne, Roger L, Simard, Jacques, Hall, Per, Michailidou, Kyriaki, Dennis, Joe, Schmidt, Marjanka K, Chang-Claude, Jenny, Gharahkhani, Puya, Whiteman, David, Campbell, Peter T, Hoffmeister, Michael, Jenkins, Mark, Peters, Ulrike, Hsu, Li, Gruber, Stephen B, Casey, Graham, Schmit, Stephanie L, O'Mara, Tracy A, Spurdle, Amanda B, Thompson, Deborah J, Tomlinson, Ian, De Vivo, Immaculata, Landi, Maria Teresa, Law, Matthew H, Iles, Mark M, Demenais, Florence, Kumar, Rajiv, MacGregor, Stuart, Bishop, D Timothy, Ward, Sarah V, Bondy, Melissa L, Houlston, Richard, Wiencke, John K, Melin, Beatrice, Barnholtz-Sloan, Jill, Kinnersley, Ben, Wrensch, Margaret R, Amos, Christopher I, Hung, Rayjean J, Brennan, Paul, McKay, James, Caporaso, Neil E, Berndt, Sonja I, Birmann, Brenda M, Camp, Nicola J, Kraft, Peter, Rothman, Nathaniel, Slager, Susan L, Berchuck, Andrew, Pharoah, Paul DP, Sellers, Thomas A, Gayther, Simon A, Pearce, Celeste L, Goode, Ellen L, Schildkraut, Joellen M, Moysich, Kirsten B, Amundadottir, Laufey T, Jacobs, Eric J, Klein, Alison P, Petersen, Gloria M, Risch, Harvey A, Stolzenberg-Solomon, Rachel Z, Wolpin, Brian M, Li, Donghui, Eeles, Rosalind A, Haiman, Christopher A, Kote-Jarai, Zsofia, Schumacher, Fredrick R, Al Olama, Ali Amin, Purdue, Mark P, Scelo, Ghislaine, Dalgaard, Marlene D, Greene, Mark H, Grotmol, Tom, Kanetsky, Peter A, McGlynn, Katherine A, Nathanson, Katherine L, Turnbull, Clare, Wiklund, Fredrik, Breast Cancer Association Consortium (BCAC), Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON), Colon Cancer Family Registry (CCFR), Transdisciplinary Studies of Genetic Variation in Colorectal Cancer (CORECT), Endometrial Cancer Association Consortium (ECAC), Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), Melanoma Genetics Consortium (GenoMEL), Glioma International Case-Control Study (GICC), International Lung Cancer Consortium (ILCCO), Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Consortium, International Consortium of Investigators Working on Non-Hodgkin’s Lymphoma Epidemiologic Studies (InterLymph), Ovarian Cancer Association Consortium (OCAC), Oral Cancer GWAS, Pancreatic Cancer Case-Control Consortium (PanC4), Pancreatic Cancer Cohort Consortium (PanScan), and Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL)

Subjects
Breast Cancer Association Consortium, Barrett’s and Esophageal Adenocarcinoma Consortium, Colon Cancer Family Registry, Transdisciplinary Studies of Genetic Variation in Colorectal Cancer, Endometrial Cancer Association Consortium, Genetics and Epidemiology of Colorectal Cancer Consortium, Melanoma Genetics Consortium, Glioma International Case-Control Study, International Lung Cancer Consortium, Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Consortium, International Consortium of Investigators Working on Non-Hodgkin’s Lymphoma Epidemiologic Studies, Ovarian Cancer Association Consortium, Oral Cancer GWAS, Pancreatic Cancer Case-Control Consortium, Pancreatic Cancer Cohort Consortium, Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome, Renal Cancer GWAS, Testicular Cancer Consortium, Animals, Humans, Neoplasms, Genetic Predisposition to Disease, Incidence, Risk Assessment, Risk Factors, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Models, Genetic, Female, Male, Genome-Wide Association Study, Human Genome, Prevention, Cancer, Prostate Cancer, Genetics, Urologic Diseases, 2.1 Biological and endogenous factors
Abstract

Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.

Published
2020

5. Overlapping genetic architecture between Parkinson disease and melanoma

Author

Dube, Umber, Ibanez, Laura, Budde, John P, Benitez, Bruno A, Davis, Albert A, Harari, Oscar, Iles, Mark M, Law, Matthew H, Brown, Kevin M, and Cruchaga, Carlos

Subjects
Biomedical and Clinical Sciences, Neurosciences, Neurodegenerative, Aging, Biotechnology, Prevention, Cancer, Human Genome, Parkinson's Disease, Brain Disorders, Clinical Research, Genetics, 2.1 Biological and endogenous factors, Aetiology, Neurological, Case-Control Studies, Genome-Wide Association Study, Humans, Melanoma, Multifactorial Inheritance, Parkinson Disease, Skin Neoplasms, 23andMe Research Team, Melanoma-Meta-analysis Consortium, Genetic correlation, Parkinson disease, Polygenic, Shared genetic architecture, TWAS, Clinical Sciences, Neurology & Neurosurgery
Abstract

Epidemiologic studies have reported inconsistent results regarding an association between Parkinson disease (PD) and cutaneous melanoma (melanoma). Identifying shared genetic architecture between these diseases can support epidemiologic findings and identify common risk genes and biological pathways. Here, we apply polygenic, linkage disequilibrium-informed methods to the largest available case-control, genome-wide association study summary statistic data for melanoma and PD. We identify positive and significant genetic correlation (correlation: 0.17, 95% CI 0.10-0.24; P = 4.09 × 10-06) between melanoma and PD. We further demonstrate melanoma and PD-inferred gene expression to overlap across tissues (correlation: 0.14, 95% CI 0.06 to 0.22; P = 7.87 × 10-04) and highlight seven genes including PIEZO1, TRAPPC2L, and SOX6 as potential mediators of the genetic correlation between melanoma and PD. These findings demonstrate specific, shared genetic architecture between PD and melanoma that manifests at the level of gene expression.

Published
2020

6. Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study

Author

Haycock, Philip C, Burgess, Stephen, Nounu, Aayah, Zheng, Jie, Okoli, George N, Bowden, Jack, Wade, Kaitlin Hazel, Timpson, Nicholas J, Evans, David M, Willeit, Peter, Aviv, Abraham, Gaunt, Tom R, Hemani, Gibran, Mangino, Massimo, Ellis, Hayley Patricia, Kurian, Kathreena M, Pooley, Karen A, Eeles, Rosalind A, Lee, Jeffrey E, Fang, Shenying, Chen, Wei V, Law, Matthew H, Bowdler, Lisa M, Iles, Mark M, Yang, Qiong, Worrall, Bradford B, Markus, Hugh Stephen, Hung, Rayjean J, Amos, Chris I, Spurdle, Amanda B, Thompson, Deborah J, O’Mara, Tracy A, Wolpin, Brian, Amundadottir, Laufey, Stolzenberg-Solomon, Rachael, Trichopoulou, Antonia, Onland-Moret, N Charlotte, Lund, Eiliv, Duell, Eric J, Canzian, Federico, Severi, Gianluca, Overvad, Kim, Gunter, Marc J, Tumino, Rosario, Svenson, Ulrika, van Rij, Andre, Baas, Annette F, Bown, Matthew J, Samani, Nilesh J, van t’Hof, Femke NG, Tromp, Gerard, Jones, Gregory T, Kuivaniemi, Helena, Elmore, James R, Johansson, Mattias, Mckay, James, Scelo, Ghislaine, Carreras-Torres, Robert, Gaborieau, Valerie, Brennan, Paul, Bracci, Paige M, Neale, Rachel E, Olson, Sara H, Gallinger, Steven, Li, Donghui, Petersen, Gloria M, Risch, Harvey A, Klein, Alison P, Han, Jiali, Abnet, Christian C, Freedman, Neal D, Taylor, Philip R, Maris, John M, Aben, Katja K, Kiemeney, Lambertus A, Vermeulen, Sita H, Wiencke, John K, Walsh, Kyle M, Wrensch, Margaret, Rice, Terri, Turnbull, Clare, Litchfield, Kevin, Paternoster, Lavinia, Standl, Marie, Abecasis, Gonçalo R, SanGiovanni, John Paul, Li, Yong, Mijatovic, Vladan, Sapkota, Yadav, Low, Siew-Kee, Zondervan, Krina T, Montgomery, Grant W, Nyholt, Dale R, van Heel, David A, Hunt, Karen, Arking, Dan E, Ashar, Foram N, Sotoodehnia, Nona, Woo, Daniel, and Rosand, Jonathan

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Clinical Research, Cancer, Prevention, Genetics, Aetiology, 2.1 Biological and endogenous factors, Adult, Aged, Aged, 80 and over, Cardiovascular Diseases, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Germ-Line Mutation, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Neoplasms, Polymorphism, Single Nucleotide, Risk Assessment, Telomere, Telomere Homeostasis, Telomeres Mendelian Randomization Collaboration, Public Health and Health Services, Oncology and carcinogenesis
Abstract

ImportanceThe causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.ObjectiveTo conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.Data sourcesGenomewide association studies (GWAS) published up to January 15, 2015.Study selectionGWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available.Data extraction and synthesisSummary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.Main outcomes and measuresOdds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.ResultsSummary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]).Conclusions and relevanceIt is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

Published
2017

7. Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study.

Author

Telomeres Mendelian Randomization Collaboration, Haycock, Philip C, Burgess, Stephen, Nounu, Aayah, Zheng, Jie, Okoli, George N, Bowden, Jack, Wade, Kaitlin Hazel, Timpson, Nicholas J, Evans, David M, Willeit, Peter, Aviv, Abraham, Gaunt, Tom R, Hemani, Gibran, Mangino, Massimo, Ellis, Hayley Patricia, Kurian, Kathreena M, Pooley, Karen A, Eeles, Rosalind A, Lee, Jeffrey E, Fang, Shenying, Chen, Wei V, Law, Matthew H, Bowdler, Lisa M, Iles, Mark M, Yang, Qiong, Worrall, Bradford B, Markus, Hugh Stephen, Hung, Rayjean J, Amos, Chris I, Spurdle, Amanda B, Thompson, Deborah J, O'Mara, Tracy A, Wolpin, Brian, Amundadottir, Laufey, Stolzenberg-Solomon, Rachael, Trichopoulou, Antonia, Onland-Moret, N Charlotte, Lund, Eiliv, Duell, Eric J, Canzian, Federico, Severi, Gianluca, Overvad, Kim, Gunter, Marc J, Tumino, Rosario, Svenson, Ulrika, van Rij, Andre, Baas, Annette F, Bown, Matthew J, Samani, Nilesh J, van t'Hof, Femke NG, Tromp, Gerard, Jones, Gregory T, Kuivaniemi, Helena, Elmore, James R, Johansson, Mattias, Mckay, James, Scelo, Ghislaine, Carreras-Torres, Robert, Gaborieau, Valerie, Brennan, Paul, Bracci, Paige M, Neale, Rachel E, Olson, Sara H, Gallinger, Steven, Li, Donghui, Petersen, Gloria M, Risch, Harvey A, Klein, Alison P, Han, Jiali, Abnet, Christian C, Freedman, Neal D, Taylor, Philip R, Maris, John M, Aben, Katja K, Kiemeney, Lambertus A, Vermeulen, Sita H, Wiencke, John K, Walsh, Kyle M, Wrensch, Margaret, Rice, Terri, Turnbull, Clare, Litchfield, Kevin, Paternoster, Lavinia, Standl, Marie, Abecasis, Gonçalo R, SanGiovanni, John Paul, Li, Yong, Mijatovic, Vladan, Sapkota, Yadav, Low, Siew-Kee, Zondervan, Krina T, Montgomery, Grant W, Nyholt, Dale R, van Heel, David A, Hunt, Karen, Arking, Dan E, Ashar, Foram N, Sotoodehnia, Nona, and Woo, Daniel

Subjects
Telomeres Mendelian Randomization Collaboration, Telomere, Humans, Neoplasms, Cardiovascular Diseases, Genetic Predisposition to Disease, Risk Assessment, Germ-Line Mutation, Polymorphism, Single Nucleotide, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Genome-Wide Association Study, Mendelian Randomization Analysis, Telomere Homeostasis, Polymorphism, Single Nucleotide, and over, Prevention, Clinical Research, Cancer, Genetics, Rare Diseases, 2.1 Biological and endogenous factors, Oncology and Carcinogenesis, Public Health and Health Services
Abstract

ImportanceThe causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.ObjectiveTo conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.Data sourcesGenomewide association studies (GWAS) published up to January 15, 2015.Study selectionGWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available.Data extraction and synthesisSummary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.Main outcomes and measuresOdds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.ResultsSummary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]).Conclusions and relevanceIt is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

Published
2017

8. Development and validation of a risk score for chronic kidney disease in HIV infection using prospective cohort data from the D:A:D study.

Author

Mocroft, Amanda, Lundgren, Jens D, Ross, Michael, Law, Matthew, Reiss, Peter, Kirk, Ole, Smith, Colette, Wentworth, Deborah, Neuhaus, Jacqueline, Fux, Christoph A, Moranne, Olivier, Morlat, Phillipe, Johnson, Margaret A, Ryom, Lene, D:A:D study group, Royal Free Hospital Clinic Cohort, INSIGHT study group, SMART study group, and ESPRIT study group

Subjects
D:A:D study group, Royal Free Hospital Clinic Cohort, INSIGHT study group, SMART study group, ESPRIT study group, Kidney, Humans, HIV, HIV Infections, HIV Seropositivity, Anti-HIV Agents, CD4 Lymphocyte Count, Incidence, Risk, Risk Assessment, Prospective Studies, Age Factors, Comorbidity, Sex Factors, Adult, Middle Aged, Female, Male, Renal Insufficiency, Chronic, Clinical Decision-Making, Renal Insufficiency, Chronic, General & Internal Medicine, Medical and Health Sciences
Abstract

BackgroundChronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice.Methods and findingsA total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with ≥3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR ≤ 60 ml/min/1.73 m2. Poisson regression was used to develop a risk score, externally validated on two independent cohorts. In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1:393 chance of developing CKD in the next 5 y in the low risk group (risk score < 0, 33 events), rising to 1:47 and 1:6 in the medium (risk score 0-4, 103 events) and high risk groups (risk score ≥ 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria.ConclusionsBoth traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.

Published
2015

9. Circulating microRNAs in Sera Correlate with Soluble Biomarkers of Immune Activation but Do Not Predict Mortality in ART Treated Individuals with HIV-1 Infection: A Case Control Study

Author

Murray, Daniel D, Suzuki, Kazuo, Law, Matthew, Trebicka, Jonel, Neuhaus, Jacquie, Wentworth, Deborah, Johnson, Margaret, Vjecha, Michael J, Kelleher, Anthony D, and Emery, Sean

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, Biotechnology, Clinical Research, Infectious Diseases, Genetics, HIV/AIDS, Aetiology, 2.1 Biological and endogenous factors, Infection, Good Health and Well Being, Adult, Anti-HIV Agents, Antiretroviral Therapy, Highly Active, Biomarkers, CD4-Positive T-Lymphocytes, Female, Genetic Association Studies, HIV Infections, HIV-1, Humans, Male, MicroRNAs, Middle Aged, INSIGHT ESPRIT and SMART Study Groups, General Science & Technology
Abstract

IntroductionThe use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals.Materials and methodsA set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed.ResultsNone of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR-145 correlated with nadir CD4+ T cell count.DiscussionNo associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection.

Published
2015

10. Investigation of Shared Genetic Risk Factors Between Parkinson's Disease and Cancers

Author

Sugier, Pierre-Emmanuel, Lucotte, Elise A., Domenighetti, Cloé, Law, Matthew H., Iles, Mark M., Brown, Kevin, Amos, Christopher, McKay, James D., Hung, Rayjean J., Karimi, Mojgan, Bacq-Daian, Delphine, Boland-Augé, Anne, Olaso, Robert, Deleuze, Jean-François, Lesueur, Fabienne, Ostroumova, Evgenia, Kesminiene, Ausrele, de Vathaire, Florent, Guénel, Pascal, consortium, The Epithyr, Sreelatha, Ashwin Ashok Kumar, Schulte, Claudia, Grover, Sandeep, May, Patrick, Bobbili, Dheeraj Reddy, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Singleton, Andrew B., Hernandez, Dena G., Edsall, Connor, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Rogaeva, Ekaterina, Lang, Anthony E., Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Harlin, Marie-Christine, Mutez, Eugénie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimios, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza Maria, Petrucci, Simona, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotaka, Nakayama, Akiyoshi, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, van de Warrenburg, Bart P. C., Bloem, Bastiaan R., Aasly, Jan, Toft, Mathias, Pihlstrøm, Lasse, Guedes, Leonor Correia, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Fairen, Monica, Wirdefeldt, Karin, Pedersen, Nancy, Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Rödström, Emil Ygland, Clarke, Carl E., Morrison, Karen E., Tan, Manuela, Krainc, Dimitri, Burbulla, Lena F., Farrer, Matt J., Krüger, Rejko, Gasser, Thomas, Sharma, Manu, Landoulsi, Zied, consortium, Courage-PD, Truong, Thérèse, Elbaz, Ales, JPND Courage-PD [sponsor], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], and Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center]

Subjects
Male, Lung Neoplasms, Parkinson's disease, Neurology [D14] [Human health sciences], RESEARCH ARTICLES, RESEARCH ARTICLE, SDG 3 - Good Health and Well-being, genetics [Parkinson Disease], Risk Factors, pleiotropy, Humans, cancer, ddc:610, genetics [Genetic Predisposition to Disease], Ovarian Neoplasms, Neurologie [D14] [Sciences de la santé humaine], Prostatic Neoplasms, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], genetic correlation, parkinson's disease, polygenic risk score, epidemiology [Melanoma], Neurology, genetics [Melanoma], genetics [Polymorphism, Single Nucleotide], Female, epidemiology [Parkinson Disease], Genetics & genetic processes [F10] [Life sciences], Neurology (clinical), Génétique & processus génétiques [F10] [Sciences du vivant], Genome-Wide Association Study
Abstract

BackgroundEpidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties.ObjectiveWe used results from genome-wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors.MethodsWe used individual data for participants of European ancestry from the Courage-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta-Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross-phenotypes polygenic risk score (PRS) analyses.ResultsWe confirmed a previously reported positive genetic correlation of PD with melanoma (Gcorr = 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (Gcorr = 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly driven by rs183211 located in an intron of the NSF gene (17q21.31).ConclusionsWe show evidence in favor of a contribution of pleiotropic genes to the association between PD and specific cancers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Published
2023

11. ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival: A comprehensive analysis from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas

Author

Johnatty, Sharon E, Beesley, Jonathan, Gao, Bo, Chen, Xiaoqing, Lu, Yi, Law, Matthew H, Henderson, Michelle J, Russell, Amanda J, Hedditch, Ellen L, Emmanuel, Catherine, Fereday, Sian, Webb, Penelope M, Group, Australian Ovarian Cancer Study, Goode, Ellen L, Vierkant, Robert A, Fridley, Brooke L, Cunningham, Julie M, Fasching, Peter A, Beckmann, Matthias W, Ekici, Arif B, Hogdall, Estrid, Kjaer, Susanne K, Jensen, Allan, Hogdall, Claus, Brown, Robert, Paul, Jim, Lambrechts, Sandrina, Despierre, Evelyn, Vergote, Ignace, Lester, Jenny, Karlan, Beth Y, Heitz, Florian, du Bois, Andreas, Harter, Philipp, Schwaab, Ira, Bean, Yukie, Pejovic, Tanja, Levine, Douglas A, Goodman, Marc T, Camey, Michael E, Thompson, Pamela J, Lurie, Galina, Shildkraut, Joellen, Berchuck, Andrew, Terry, Kathryn L, Cramer, Daniel W, Norris, Murray D, Haber, Michelle, MacGregor, Stuart, deFazio, Anna, and Chenevix-Trench, Georgia

Subjects
Genetics, Ovarian Cancer, Rare Diseases, Human Genome, Cancer, Aetiology, 2.1 Biological and endogenous factors, ATP Binding Cassette Transporter, Subfamily B, ATP Binding Cassette Transporter, Subfamily B, Member 1, Antineoplastic Combined Chemotherapy Protocols, Carboplatin, Carcinoma, Ovarian Epithelial, Disease Progression, Disease-Free Survival, Drug Resistance, Multiple, Drug Resistance, Neoplasm, Female, Humans, Kaplan-Meier Estimate, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Paclitaxel, Pharmacogenetics, Polymorphism, Single Nucleotide, Proportional Hazards Models, Ovarian cancer, Polymorphisms, Outcome, Chemotherapy, ABCB1, Australian Ovarian Cancer Study Group, Oncology and Carcinogenesis, Paediatrics and Reproductive Medicine, Oncology & Carcinogenesis
Abstract

ObjectiveABCB1 encodes the multi-drug efflux pump P-glycoprotein (P-gp) and has been implicated in multi-drug resistance. We comprehensively evaluated this gene and flanking regions for an association with clinical outcome in epithelial ovarian cancer (EOC).MethodsThe best candidates from fine-mapping analysis of 21 ABCB1 SNPs tagging C1236T (rs1128503), G2677T/A (rs2032582), and C3435T (rs1045642) were analysed in 4616 European invasive EOC patients from thirteen Ovarian Cancer Association Consortium (OCAC) studies and The Cancer Genome Atlas (TCGA). Additionally we analysed 1,562 imputed SNPs around ABCB1 in patients receiving cytoreductive surgery and either 'standard' first-line paclitaxel-carboplatin chemotherapy (n=1158) or any first-line chemotherapy regimen (n=2867). We also evaluated ABCB1 expression in primary tumours from 143 EOC patients.ResultFine-mapping revealed that rs1128503, rs2032582, and rs1045642 were the best candidates in optimally debulked patients. However, we observed no significant association between any SNP and either progression-free survival or overall survival in analysis of data from 14 studies. There was a marginal association between rs1128503 and overall survival in patients with nil residual disease (HR 0.88, 95% CI 0.77-1.01; p=0.07). In contrast, ABCB1 expression in the primary tumour may confer worse prognosis in patients with sub-optimally debulked tumours.ConclusionOur study represents the largest analysis of ABCB1 SNPs and EOC progression and survival to date, but has not identified additional signals, or validated reported associations with progression-free survival for rs1128503, rs2032582, and rs1045642. However, we cannot rule out the possibility of a subtle effect of rs1128503, or other SNPs linked to it, on overall survival.

Published
2013

12. Phase 2 gene therapy trial of an anti-HIV ribozyme in autologous CD34+ cells

Author

Mitsuyasu, Ronald T, Merigan, Thomas C, Carr, Andrew, Zack, Jerome A, Winters, Mark A, Workman, Cassy, Bloch, Mark, Lalezari, Jacob, Becker, Stephen, Thornton, Lorna, Akil, Bisher, Khanlou, Homayoon, Finlayson, Robert, McFarlane, Robert, Smith, Don E, Garsia, Roger, Ma, David, Law, Matthew, Murray, John M, von Kalle, Christof, Ely, Julie A, Patino, Sharon M, Knop, Alison E, Wong, Philip, Todd, Alison V, Haughton, Margaret, Fuery, Caroline, Macpherson, Janet L, Symonds, Geoff P, Evans, Louise A, Pond, Susan M, and Cooper, David A

Subjects
Biomedical and Clinical Sciences, Immunology, HIV/AIDS, Clinical Trials and Supportive Activities, Pediatric AIDS, Gene Therapy, Genetics, Clinical Research, Pediatric, Infectious Diseases, 6.2 Cellular and gene therapies, Evaluation of treatments and therapeutic interventions, Development of treatments and therapeutic interventions, 5.2 Cellular and gene therapies, 6.1 Pharmaceuticals, Infection, Adult, Antigens, CD34, Base Sequence, Double-Blind Method, Female, Genetic Therapy, HIV Infections, HIV-1, Humans, Male, Placebos, RNA, Catalytic, Viral Load, Medical and Health Sciences, Biomedical and clinical sciences, Health sciences
Abstract

Gene transfer has potential as a once-only treatment that reduces viral load, preserves the immune system and avoids lifetime highly active antiretroviral therapy. This study, which is to our knowledge the first randomized, double-blind, placebo-controlled, phase 2 cell-delivered gene transfer clinical trial, was conducted in 74 HIV-1-infected adults who received a tat-vpr-specific anti-HIV ribozyme (OZ1) or placebo delivered in autologous CD34+ hematopoietic progenitor cells. There were no OZ1-related adverse events. There was no statistically significant difference in viral load between the OZ1 and placebo group at the primary end point (average at weeks 47 and 48), but time-weighted areas under the curve from weeks 40-48 and 40-100 were significantly lower in the OZ1 group. Throughout the 100 weeks, CD4+ lymphocyte counts were higher in the OZ1 group. This study indicates that cell-delivered gene transfer is safe and biologically active in individuals with HIV and can be developed as a conventional therapeutic product.

Published
2009

13. The association between genetically elevated polyunsaturated fatty acids and risk of cancer

Author

Haycock, Philip C, Borges, Maria Carolina, Burrows, Kimberley, Lemaitre, Rozenn N, Burgess, Stephen, Khankari, Nikhil K, Tsilidis, Konstantinos K, Gaunt, Tom R, Hemani, Gibran, Zheng, Jie, Truong, Therese, Birmann, Brenda M, OMara, Tracy, Spurdle, Amanda B, Iles, Mark M, Law, Matthew H, Slager, Susan L, Saberi Hosnijeh, Fatemeh, Mariosa, Daniela, Cotterchio, Michelle, Cerhan, James R, Peters, Ulrike, Enroth, Stefan, Gharahkhani, Puya, Le Marchand, Loic, Williams, Ann C, Block, Robert C, ACCC, CCFR-CORECT-GECCO, EPITHYR, InterLymph, MMAC, ECAC, ILCCO, PRACTICAL Consortium, PanScan, PanC4, Amos, Christopher I, Hung, Rayjean J, Zheng, Wei, Gunter, Marc J, Smith, George Davey, Relton, Caroline, Martin, Richard M, Fatty Acids in Cancer Mendelian Randomization Collaboration, Burgess, Stephen [0000-0001-5365-8760], and Apollo - University of Cambridge Repository

Subjects
Fatty Acid Desaturases, Esophageal Neoplasms, Delta-5 desaturase, Inflammatory Bowel Diseases, Polymorphism, Single Nucleotide, Omega 6, Cancer risk, Omega 3, Fatty Acids, Omega-3, Mendelian randomization, Fatty Acids, Unsaturated, Delta-6 desaturase, Humans, Polyunsaturated fatty acids, Esophageal Squamous Cell Carcinoma, Colorectal Neoplasms
Abstract

BACKGROUND: The causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain. METHODS: Using a Mendelian randomization (MR) framework, we assessed the causal relevance of PUFAs for risk of cancer in European and East Asian ancestry individuals. We defined the primary exposure as PUFA desaturase activity, proxied by rs174546 at the FADS locus. Secondary exposures were defined as omega 3 and omega 6 PUFAs that could be proxied by genetic polymorphisms outside the FADS region. Our study used summary genetic data on 10 PUFAs and 67 cancers, corresponding to 562,871 cases and 1,619,465 controls, collected by the Fatty Acids in Cancer Mendelian Randomization Collaboration. We estimated odds ratios (ORs) for cancer per standard deviation increase in genetically proxied PUFA exposures. FINDINGS: Genetically elevated PUFA desaturase activity was associated (P

Published
2023

14. Incidence of hypertension in people with HIV who are treated with integrase inhibitors versus other antiretroviral regimens in the RESPOND cohort consortium

Author

Byonanebye, Dathan M., Polizzotto, Mark N., Neesgaard, Bastian, Sarcletti, Mario, Matulionyte, Raimonda, Braun, Dominique L., Castagna, Antonella, de Wit, Stéphane, Wit, Ferdinand, Fontas, Eric, Vehreschild, J. rg Janne, Vesterbacka, Jan, Greenberg, Lauren, Hatleberg, Camilla, Garges, Harmony, Gallant, Joel, Volny Anne, Alain, Öllinger, Angela, Mozer-Lisewska, Iwona, Surial, Bernard, Spagnuolo, Vincenzo, Necsoi, Coca, van der Valk, Marc, Mocroft, Amanda, Law, Matthew, Ryom, Lene, Petoumenos, Kathy, Hillebregt, M., Rose, N., Hutchinson, J., Zangerle, R., Appoyer, H., Delforge, M., Stephan, C., Bucht, M., Chkhartishvili, N., Chokoshvili, O., Mussini, C., Borghi, V., Pradier, C., Dollet, K., Caissotti, C., Casabona, J., Miro, J. M., Smith, C., Lampe, F., Johnson, M., Burns, F., Chaloner, C., Lazzarin, A., Poli, A., Sönnerborg, A., Falconer, K., Svedhem, V., Günthard, H., Ledergerber, B., Bucher, H., Scherrer, A., Wasmuth, J. C., Rockstroh, J., Fätkenheuer, G., Stecher, M., Schulze, N., Franke, B., Rooney, J., McNicholl, I., Vannappagari, V., Wandeler, G., Lundgren, J., Kowalska, J., Raben, D., Mocroft, A., Peters, L., Williams, E. D., Necsoi, C., D’Arminio Monforte, A., Bruguera, A., Dedes, Nikos, Mendao, Luis, Larsen, J. F., Jaschinski, N., Jakobsen, M. L., Bruun, T., Bojesen, A., Hansen, E. V., Traytel, A. K., Elsing, T. W., Kristensen, D., Weide, T., Bansi-Matharu, L., Pelchen-Matthews, A., Infectious diseases, AII - Infectious diseases, APH - Aging & Later Life, APH - Digital Health, APH - Personalized Medicine, and APH - Global Health

Subjects
Adult, Aged, 80 and over, HIV, antiretroviral agents, hypertension, integrase inhibitors, Adolescent, Anti-HIV Agents, Health Policy, Incidence, virus diseases, 610 Medicine & health, HIV Infections, Integrase Inhibitors, Infectious Diseases, Anti-Retroviral Agents, Hypertension, Humans, Reverse Transcriptase Inhibitors, Pharmacology (medical), HIV Integrase Inhibitors
Abstract

OBJECTIVE To compare the incidence of hypertension in people living with HIV receiving integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) versus non-nucleoside reverse transcriptase inhibitors (NNRTIs) or boosted protease inhibitors (PIs) in the RESPOND consortium of HIV cohorts. METHODS Eligible people with HIV were aged ���18��years who initiated a new three-drug ART regimen for the first time (baseline), did not have hypertension, and had at least two follow-up blood pressure (BP) measurements. Hypertension was defined as two consecutive systolic BP measurements ���140��mmHg and/or diastolic BP ���90��mmHg or initiation of antihypertensives. Multivariable Poisson regression was used to determine adjusted incidence rate ratios (aIRRs) of hypertension, overall and in those who were ART na��ve or experienced at baseline. RESULTS Overall, 4606 people living with HIV were eligible (INSTIs��3164, NNRTIs��807, PIs��635). The median baseline systolic BP, diastolic BP, and age were 120 (interquartile range [IQR] 113-130) mmHg, 78 (70-82) mmHg, and 43 (34-50) years, respectively. Over 8380.4 person-years (median follow-up 1.5 [IQR 1.0-2.7]��years), 1058 (23.0%) participants developed hypertension (incidence rate 126.2/1000 person-years, 95% confidence interval [CI] 118.9-134.1). Participants receiving INSTIs had a higher incidence of hypertension than those receiving NNRTIs (aIRR 1.76; 95% CI 1.47-2.11), whereas the incidence was no different in those receiving PIs (aIRR 1.07; 95% CI 0.89-1.29). The results were similar when the analysis was stratified by ART status at baseline. CONCLUSION Although unmeasured confounding and channelling bias cannot be excluded, INSTIs were associated with a higher incidence of hypertension than were NNRTIs, but rates were similar to those of PIs overall, in ART-na��ve and ART-experienced participants within RESPOND.

Published
2022

15. Risk for non-AIDS-defining and AIDS-defining cancer of early versus delayed initiation of antiretroviral therapy

Author

Chammartin, Frédérique, Lodi, Sara, Logan, Roger, Ryom, Lene, Mocroft, Amanda, Kirk, Ole, d’Arminio Monforte, Antonella, Reiss, Peter, Phillips, Andrew, El-Sadr, Wafaa, Hatleberg, Camilla I., Pradier, Christian, Bonnet, Fabrice, Law, Matthew, De Wit, Stéphane, Sabin, Caroline, Lundgren, Jens D., and Bucher, Heiner C.

Subjects
adult, anti-HIV agents, CD4 lymphocyte count, female, HIV infections, humans, incidence, male, middle aged, neoplasms, prospective studies, risk factors, time-to-treatment, viral load
Abstract

ackground: Immediate initiation of antiretroviral therapy (ART) regardless of CD4 cell count reduces risk for AIDS and non-AIDS-related events in asymptomatic, HIV-positive persons and is the standard of care. However, most HIV-positive persons initiate ART when their CD4 count decreases below 500 × 109 cells/L. Consequences of delayed ART on risk for non-AIDS-defining and AIDS-defining cancer, one of the most common reasons for death in HIV, are unclear. Objective: To estimate the long-term risk difference for cancer with the immediate ART strategy. Design: Multinational prospective cohort study. Setting: The D:A:D (Data collection on Adverse events of anti-HIV Drugs) study, which included HIV-positive persons from Europe, Australia, and the United States. Participants: 8318 HIV-positive persons with at least 1 measurement each of CD4 cell count and viral load while ART-naive (study period, 2006 to 2016). Measurements: The parametric g-formula was used, with adjustment for baseline and time- dependent confounders (CD4 cell count and viral load), to assess the 10-year risk for non-AIDS- defining and AIDS-defining cancer of immediate versus deferred (at CD4 counts < 350 and < 500 × 109 cells/L) ART initiation strategies. Results: During 64 021 person-years of follow-up, 231 cases of non-AIDS-defining cancer and 272 of AIDS- defining cancer occurred among HIV-positive persons with a median age of 36 years (interquartile range, 29 to 43 years). With immediate ART, the 10-year risk for non-AIDS- defining cancer was 2.97% (95% CI, 2.37% to 3.50%) and that for AIDS-defining cancer was 2.50% (CI, 2.37% to 3.38%). Compared with immediate ART initiation, the 10-year absolute risk differences when deferring ART to CD4 counts less than 500 × 109 cells/L and less than 350 × 109 cells/L were 0.12 percentage point (CI, -0.01 to 0.26 percentage point) and 0.29 percentage point (CI, -0.03 to 0.73 percentage point), respectively, for non-AIDS-defining cancer and 0.32 percentage point (CI, 0.21 to 0.44 percentage point) and 1.00 percentage point (CI, 0.67 to 1.44 percentage points), respectively, for AIDS-defining cancer. Limitation: Potential residual confounding due to observational study design. Conclusion: In this young cohort, effects of immediate ART on 10-year risk for cancer were small, and further supportive data are needed for non-AIDS-defining cancer. Primary Funding Source: Highly Active Antiretroviral Therapy Oversight Committee.

Published
2021

16. Uptake and Discontinuation of Integrase Inhibitors (INSTIs) in a Large Cohort Setting

Author

Greenberg, Lauren, Ryom, Lene, Wandeler, Gilles, Grabmeier-Pfistershammer, Katharina, Öllinger, Angela, Neesgaard, Bastian, Stephan, Christoph, Calmy, Alexandra, Rauch, Andri, Castagna, Antonella, Spagnuolo, Vincenzo, Johnson, Margaret, Stingone, Christof, Mussini, Cristina, De Wit, Stéphane, Necsoi, Coca, Campins, Antoni A., Pradier, Christian, Stecher, Melanie, Wasmuth, Jan-Christian, Monforte, Antonella dʼArminio, Law, Matthew, Puhr, Rainer, Chkhartishvilli, Nikoloz, Tsertsvadze, Tengiz, Garges, Harmony, Thorpe, David, Lundgren, Jens D., Peters, Lars, Bansi-Matharu, Loveleen, Mocroft, Amanda, RESPOND Study Group, Greenberg, L., Ryom, L., Wandeler, G., Grabmeier-Pfistershammer, K., Ollinger, A., Neesgaard, B., Stephan, C., Calmy, A., Rauch, A., Castagna, A., Spagnuolo, V., Johnson, M., Stingone, C., Mussini, C., De Wit, S., Necsoi, C., Campins, A. A., Pradier, C., Stecher, M., Wasmuth, J. -C., Monforte, A. D., Law, M., Puhr, R., Chkhartishvilli, N., Tsertsvadze, T., Garges, H., Thorpe, D., Lundgren, J. D., Peters, L., Bansi-Matharu, L., and Mocroft, A.

Subjects
Adult, Male, Integrase Inhibitors/adverse effects, medicine.medical_specialty, animal structures, Anti-HIV Agents, Integrase Inhibitors/therapeutic use, HIV Infections/drug therapy, Integrase inhibitor, 610 Medicine & health, HIV Infections, Integrase Inhibitors, 030312 virology, Anti-HIV Agents/administration & dosage, Integrase Inhibitors/administration & dosage, Cohort Studies, 03 medical and health sciences, chemistry.chemical_compound, Internal medicine, Medicine, Humans, Pharmacology (medical), ddc:616, 0303 health sciences, business.industry, Elvitegravir, Proportional hazards model, HIV, toxicity, Hepatitis C, Middle Aged, Raltegravir, medicine.disease, Discontinuation, dolutegravir, Europe, Infectious Diseases, chemistry, Anti-HIV Agents/therapeutic use, Toxicity, Dolutegravir, Anti-HIV Agents/adverse effects, elvitegravir, Female, raltegravir, business, medicine.drug
Abstract

BACKGROUND: Despite increased integrase strand transfer inhibitor (INSTI) use, limited large-scale, real-life data exists on INSTI uptake and discontinuation. SETTING: International multicohort collaboration. METHODS: RESPOND participants starting dolutegravir (DTG), elvitegravir (EVG), or raltegravir (RAL) after January 1, 2012 were included. Predictors of INSTI used were assessed using multinomial logistic regression. Kaplan-Meier and Cox proportional hazards models describe time to and factors associated with discontinuation. RESULTS: Overall, 9702 persons were included; 5051 (52.1%) starting DTG, 1933 (19.9%) EVG, and 2718 (28.0%) RAL. The likelihood of starting RAL or EVG vs DTG decreased over time and was higher in Eastern and Southern Europe compared with Western Europe. At 6 months after initiation, 8.9% (95% confidence interval: 8.3% to 9.5%) had discontinued the INSTI (6.4% DTG, 7.4% EVG, and 14.0% RAL). The main reason for discontinuation was toxicity (44.2% DTG, 42.5% EVG, 17.3% RAL). Nervous system toxicity accounted for a higher proportion of toxicity discontinuations on DTG (31.8% DTG, 23.4% EVG, 6.6% RAL). Overall, treatment simplification was highest on RAL (2.7% DTG, 1.6% EVG, and 19.8% RAL). Factors associated with a higher discontinuation risk included increasing year of INSTI initiation, female gender, hepatitis C coinfection, and previous non-AIDS-defining malignancies. Individuals in Southern and Eastern Europe were less likely to discontinue. Similar results were seen for discontinuations after 6 months. CONCLUSIONS: Uptake of DTG vs EVG or RAL increased over time. Discontinuation within 6 months was mainly due to toxicity; nervous system toxicity was highest on DTG. Discontinuation was highest on RAL, mainly because of treatment simplification.

Published
2020

17. Early mortality after late initiation of antiretroviral therapy in the TREAT Asia HIV Observational Database of IeDEA Asia-Pacific

Author

Rupasinghe, Dhanushi, Kiertiburanakul, Sasisopin, Kamarulzaman, Adeeba, Zhang, Fujie, Kumarasamy, Nagalingeswaran, Chaiwarith, Romanee, Merati, Tuti Parwati, Duy, Cuong Do, Khusuwan, Suwimon, Avihingsanon, Anchalee, Lee, Man Po, Ly, Penh Sun, Yunihastuti, Evy, Nguyen, Van Kinh, Ditangco, Rossana, Chan, Yu-Jian, Pujari, Sanjay, Ng, Oon Tek, Choi, Jun Yong, Sim, Benedict Lim Heng, Tanuma, Junko, Sangle, Shashikala, Ross, Jeremy, and Law, Matthew

Subjects
Adult, Male, Anti-HIV Agents, Cause of Death, Humans, Alanine Transaminase, Female, HIV Infections, Mortality, Poverty, Article, CD4 Lymphocyte Count, Time-to-Treatment
Abstract

Early mortality among those still initiating antiretroviral therapy (ART) with advanced stages of HIV infection in resource-limited settings remains high despite recommendations for universal HIV treatment. We investigated risk factors associated with early mortality in people living with HIV (PLHIV) starting ART at low CD4 levels in the Asia-Pacific.PLHIV enrolled in the Therapeutics, Research, Education and AIDS Training in Asia (TREAT Asia) HIV Observational Database (TAHOD) who initiated ART with a CD4 count 100 cells/μL between 2003 and 2018 were included in the study. Early mortality was defined as death within 1 year of ART initiation. PLHIV in follow-up for1 year were censored at 12 months. Competing risk regression was used to analyse risk factors with loss to follow-up as a competing risk.A total of 1813 PLHIV were included in the study, of whom 74% were male. With 73 (4%) deaths, the overall first-year mortality rate was 4.27 per 100 person-years (PY). Thirty-eight deaths (52%) were AIDS-related, 10 (14%) were immune reconstituted inflammatory syndrome (IRIS)-related, 13 (18%) were non-AIDS-related and 12 (16%) had an unknown cause. Risk factors included having a body mass index (BMI) 18.5 [sub-hazard ratio (SHR) 2.91; 95% confidence interval (CI) 1.60-5.32] compared to BMI 18.5-24.9, and alanine aminotransferase (ALT) ≥ 5 times its upper limit of normal (ULN) (SHR 6.14; 95% CI 1.62-23.20) compared to ALT 5 times its ULN. A higher CD4 count (51-100 cells/μL: SHR 0.28; 95% CI 0.14-0.55; and 100 cells/μL: SHR 0.12; 95% CI 0.05-0.26) was associated with reduced hazard for mortality compared to CD4 count ≤ 25 cells/μL.Fifty-two per cent of early deaths were AIDS-related. Efforts to initiate ART at CD4 counts50 cell/μL are associated with improved short-term survival rates, even in those with late stages of HIV disease.

Published
2019

18. Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways

Author

Duffy, David L, Zhu, Gu, Xin, Li, Sanna, Marianna, Iles, Mark M, Jacobs, Leonie C, Evans, David M, Yazar, Seyhan, Beesley, Jonathan, Law, Matthew H, Kraft, Peter, Visconti, Alessia, Taylor, John C, Lui, Fan, Wright, Margaret J, Henders, Anjali K, Bowdler, Lisa, Glass, Dan, Ikram, Arfan M, Uitterlinden, André G, Madden, Pamela A, Heath, Andrew C, Nelson, Elliot C, Green, Adele C, Chanock, Stephen, Barrett, Jennifer H, Brown, Matthew A, Hayward, Nicholas K, Macgregor, Stuart, Sturm, Richard A, Hewitt, Alex W, Kayser, Manfred, Hunter, David J, Newton Bishop, Julia A, Spector, Timothy D, Montgomery, Grant W, Mackey, David A, Smith, George Davey, Nijsten, Tamar E, Bishop, D Timothy, Bataille, Veronique, Falchi, Mario, Han, Jiali, Martin, Nicholas, G, Lee, Je, Brossard, M, Moses, Ek, Song, F, Kumar, R, Easton, Df, Pharoah, Pdp, Swerdlow, Aj, Kypreou, Kp, Harland, M, Randerson-Moor, J, Akslen, La, Andresen, Pa, Avril, Mf, Azizi, E, Scarrà, Gb, Brown, Km, Dębniak, T, Elder, De, Fang, S, Friedman, E, Galan, P, Ghiorzo, P, Gillanders, Em, Goldstein, Am, Gruis, Na, Hansson, J, Helsing, P, Hočevar, M, Höiom, V, Ingvar, C, Kanetsky, Pa, Chen, Wv, Landi, Mt, Lang, J, Lathrop, Gm, Lubiński, J, Mackie, Rm, Mann, Gj, Molven, A, Novaković, S, Olsson, H, Puig, S, Puig-Butille, Ja, Radford-Smith, Gl, van der Stoep, N, van Doorn, R, Whiteman, Dc, Craig, Je, Schadendorf, D, Simms, La, Burdon, Kp, Nyholt, Dr, Pooley, Ka, Orr, N, Stratigos, Aj, Cust, Ae, Ward, Sv, Schulze, Hj, Dunning, Am, Demenais, F, Amos, Ci., Apollo - University of Cambridge Repository, Dermatology, Genetic Identification, Epidemiology, Internal Medicine, and Consortium, Melanoma Gwas

Subjects
0301 basic medicine, Skin Neoplasms, Medizin, General Physics and Astronomy, Genome-wide association study, Receptors, G-Protein-Coupled, 0302 clinical medicine, Guanine Nucleotide Exchange Factors, lcsh:Science, skin and connective tissue diseases, Melanoma, Telomerase, Genetics, 0303 health sciences, Nevus, Pigmented, Stem Cell Factor, Multidisciplinary, Microfilament Proteins, Nuclear Proteins, RNA-Binding Proteins, Genetic Pleiotropy, Microphthalmia-associated transcription factor, 3. Good health, 030220 oncology & carcinogenesis, Cytochrome P-450 CYP1B1, Interferon Regulatory Factors, Medical genetics, PPARGC1B, Dock8, medicine.medical_specialty, Science, Telomere-Binding Proteins, Single-nucleotide polymorphism, Nerve Tissue Proteins, Biology, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Histone Deacetylases, White People, Group VI Phospholipases A2, 03 medical and health sciences, Genetic predisposition, Pigmented Nevus, medicine, Nevus, Humans, Genetic Predisposition to Disease, neoplasms, 030304 developmental biology, General Chemistry, medicine.disease, Repressor Proteins, MicroRNAs, 030104 developmental biology, Cutaneous melanoma, RNA, lcsh:Q, Carrier Proteins, IRF4, Genome-Wide Association Study
Abstract

The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, United Kingdom, and United States, comprising a total of 52,506 phenotyped individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs at a genome-wide level of significance in KITLG, DOCK8, and a broad region of 9q32. In a bivariate analysis combining the nevus results with those from a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level of significance. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis via genes we can show to be expressed under control of the MITF melanocytic cell lineage regulator.

Published
2018

19. Cell-type–specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes

Author

Zhang, Tongwu, Choi, Jiyeon, Kovacs, Michael A., Shi, Jianxin, Mai, Xu, Goldstein, Alisa M., Trower, Adam J., Bishop, D. Timothy, Iles, Mark M., Duffy, David L., Macgregor, Stuart, Amundadottir, Laufey T., Law, Matthew H., Loftus, Stacie K., Pavan, William J., Brown, Kevin M., Lee, Je, Brossard, M, Martin, Ng, Moses, Ek, Song, F, Barrett, Jh, Kumar, R, Easton, Df, Pharoah, Pdp, Swerdlow, Aj, Kypreou, Kp, Taylor, Jc, Harland, M, Randerson-Moor, J, Akslen, La, Andresen, Pa, Avril, Mf, Azizi, E, Bianchi Scarrà, G, Dȩbniak, T, Duffy, Dl, Elder, De, Fang, S, Friedman, E, Galan, P, Ghiorzo, P, Gillanders, Em, Goldstein, Am, Gruis, Na, Hansson, J, Helsing, P, Hočevar, M, Höiom, V, Ingvar, C, Kanetsky, Pa, Chen, Wv, Landi, Mt, Lang, J, Lathrop, Gm, Lubiński, J, Mackie, Rm, Mann, Gj, Molven, A, Montgomery, Gw, Novaković, S, Olsson, H, Puig, S, Puig-Butille, Ja, Wu, W, Qureshi, Aa, Radford-Smith, Gl, van der Stoep, N, van Doorn, R, Whiteman, Dc, Craig, Je, Schadendorf, D, Simms, La, Burdon, Kp, Nyholt, Dr, Pooley, Ka, Orr, N, Stratigos, Aj, Cust, Ae, Ward, Sv, Hayward, Nk, Han, J, Schulze, Hj, Dunning, Am, Bishop, Jan, Demenais, F, Amos, Ci, Macgregor, S, Iles, Mm, Barnabas, Bb, Bouffard, Gg, Brooks, Sy, Coleman, H, Dekhtyar, L, Guan, X, Ho, Sl, Legaspi, R, Maduro, Ql, Masiello, Ca, Mcdowell, Jc, Montemayor, C, Mullikin, Jc, Park, M, Riebow, Nl, Schandler, K, Schmidt, B, Sison, C, Smith, R, Stantripop, S, Thomas, Jw, Thomas, Pj, Vemulapalli, M, and Young, Ac.

Subjects
0301 basic medicine, Hemeproteins, Linkage disequilibrium, Quantitative Trait Loci, Single-nucleotide polymorphism, Genome-wide association study, Biology, Quantitative trait locus, Melanocyte, Polymorphism, Single Nucleotide, Linkage Disequilibrium, 03 medical and health sciences, Heme-Binding Proteins, 0302 clinical medicine, Genetics, medicine, Basic Helix-Loop-Helix Transcription Factors, Humans, Genetic Predisposition to Disease, Melanoma, Genetics (clinical), Cells, Cultured, Genetic association, Research, medicine.disease, Repressor Proteins, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Expression quantitative trait loci, Interferon Regulatory Factors, Melanocytes, Carrier Proteins
Abstract

Most expression quantitative trait locus (eQTL) studies to date have been performed in heterogeneous tissues as opposed to specific cell types. To better understand the cell-type–specific regulatory landscape of human melanocytes, which give rise to melanoma but account for cis-eQTL SNPs prior to linkage disequilibrium (LD) pruning and 4997 eGenes (FDR < 0.05). Melanocyte eQTLs differed considerably from those identified in the 44 GTEx tissue types, including skin. Over a third of melanocyte eGenes, including key genes in melanin synthesis pathways, were unique to melanocytes compared to those of GTEx skin tissues or TCGA melanomas. The melanocyte data set also identified trans-eQTLs, including those connecting a pigmentation-associated functional SNP with four genes, likely through cis-regulation of IRF4. Melanocyte eQTLs are enriched in cis-regulatory signatures found in melanocytes as well as in melanoma-associated variants identified through genome-wide association studies. Melanocyte eQTLs also colocalized with melanoma GWAS variants in five known loci. Finally, a transcriptome-wide association study using melanocyte eQTLs uncovered four novel susceptibility loci, where imputed expression levels of five genes (ZFP90, HEBP1, MSC, CBWD1, and RP11-383H13.1) were associated with melanoma at genome-wide significant P-values. Our data highlight the utility of lineage-specific eQTL resources for annotating GWAS findings, and present a robust database for genomic research of melanoma risk and melanocyte biology.

Published
2018

20. Association between exposure to antiretroviral drugs and the incidence of hypertension in HIV-positive persons: the D:A:D Study

Author

Hatleberg, Camilla Ingrid, Ryom, DR Lene, Monforte, Antonella d’Arminio, Fontas, Eric, Reiss, Peter, Kirk, Ole, Sadr, Wafaa El, Phillips, Andrew, de Wit, Stephane, Dabis, Francois, Weber, Rainer, Law, Matthew, Lundgren, Jens Dilling, and Sabin, Caroline

Subjects
Adult, Male, Anti-HIV Agents, Risk Factors, Incidence, Hypertension, Humans, Regression Analysis, Female, HIV Infections, Article
Abstract

This article presents findings indicating that cumulative exposure to antiretroviral drugs is not associated with a clinically relevant increased risk of hypertension in HIV-positive individuals. Increased risk of hypertension is mainly linked to traditional cardiovascular disease risk factors. OBJECTIVES: Previous studies have suggested that hypertension in HIV-positive individuals is associated primarily with traditional risk factors such as older age, diabetes and dyslipidemia. However, controversy remains as to whether exposure to antiretroviral (ARV) drugs poses additional risk, and we investigated this question in the D:A:D cohort. METHODS: The incidence of hypertension (systolic blood pressure (BP) >140 and/or diastolic BP >90 mmHg and/or initiation of antihypertensive treatment) was determined overall and in strata defined by demographic, metabolic- and HIV-related factors, including cumulative exposure to each individual ARV drug. Predictors of hypertension were identified using uni- and multivariable Poisson regression models. RESULTS: Of 33,278 included persons, 7636 (22.9%) developed hypertension over 223,149 person years (Incidence rate: 3.42 [95% CI 3.35–3.50]/100 PYRS). In univariable analyses, cumulative exposure to most ARV drugs was associated with an increased risk of hypertension. After adjustment for demographic, metabolic and HIV-related factors, only associations for nevirapine (rate ratio 1.07 [95% CI 1.04–1.13]/5 years) and indinavir/ritonavir (1.12 [1.04–1.20]/5 years) remained statistically significant, although effects were small. The strongest independent predictors of hypertension were male gender, older age, black African ethnicity, diabetes, dyslipidemia, use of lipid-lowering drugs, high BMI, renal impairment and a low CD4 count. CONCLUSION: We did not find evidence for any strong independent association between exposure to any of the individual ARV drugs and the risk of hypertension. Findings provide reassurance that screening policies and preventative measures for hypertension in HIV-positive persons should follow algorithms used for the general population.

Published
2018

21. Predictors of estimated glomerular filtration rate progression, stabilization or improvement after chronic renal impairment in HIV-positive individuals

Author

Ryom, Lene, Mocroft, Amanda, Kirk, Ole, Reiss, Peter, Ross, Michael, Smith, Colette, Moranne, Olivier, Morlat, Philippe, Fux, Christoph, Sabin, Caroline, Phillips, Andrew, Law, Matthew, Lundgren, Jens, study group, D:A:D, Centre Hospitalier Universitaire de Nice (CHU Nice), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Aide à la Décision pour une Médecine Personnalisé - Laboratoire de Biostatistique, Epidémiologie et Recherche Clinique - EA 2415 (AIDMP), Université Montpellier 1 (UM1)-Université de Montpellier (UM), Service de médecine interne et maladies infectieuses [Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Saint-André, Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), AII - Infectious diseases, APH - Aging & Later Life, Global Health, and AII - Amsterdam institute for Infection and Immunity

Subjects
Adult, Male, medicine.medical_specialty, endocrine system, Anti-HIV Agents, Immunology, 030232 urology & nephrology, Urology, Renal function, HIV Infections, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Antiretroviral Therapy, Highly Active, Diabetes mellitus, medicine, Humans, Immunology and Allergy, Prospective Studies, 030212 general & internal medicine, Renal Insufficiency, Chronic, Adverse effect, Prospective cohort study, Chronic renal impairment, Aged, business.industry, Middle Aged, Prognosis, medicine.disease, 3. Good health, Atazanavir, Discontinuation, Infectious Diseases, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Ritonavir, business, Glomerular Filtration Rate, medicine.drug
Abstract

OBJECTIVES: The objectives of this analysis were to investigate predictors of progression, stabilization or improvement in estimated glomerular filtration rate (eGFR) after development of chronic renal impairment (CRI) in HIV-positive individuals. DESIGN: Prospective observational study. METHODS: The Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) study participants progressing to CRI defined as confirmed, at least 3 months apart, and eGFR 70 ml/min per 1.73 m or less were included in the analysis. The median of all eGFRs measured 24-36 months post-CRI was compared with the median eGFR defining CRI, and changes were grouped into improvement (>+10 ml/min per 1.73 m), stabilization (-10 to +10 ml/min per 1.73 m) and progression (

Published
2017

22. Trends in CD4 count response to first-line antiretroviral treatment in HIV-positive patients from Asia, 2003–2013: TAHOD-LITE

Author

De La Mata, Nicole L., Ly, Penh Sun, Ng, Oon Tek, Van Nguyen, Kinh, Merati, Tuti Parwati, Pham, Thuy Thanh, Lee, Man Po, Choi, Jun Yong, Sohn, Annette H., Law, Matthew G., and Kumarasamy, Nagalingeswaran

Subjects
Adult, Male, Asia, Time Factors, Anti-HIV Agents, HIV Infections, Middle Aged, Viral Load, Article, Drug Administration Schedule, CD4 Lymphocyte Count, Antiretroviral Therapy, Highly Active, Humans, Female
Abstract

Antiretroviral treatment (ART) guidelines have changed over the past decade, recommending earlier initiation and more tolerable regimens. The study objective was to examine the CD4 response to ART, depending on the year of ART initiation, in HIV-positive patients in the Asia-Pacific. We included HIV-positive adult patients who initiated ART between 2003 and 2013 in our regional cohort from eight urban referral centres in seven countries within Asia. We used mixed-effects linear regression models to evaluate differences in CD4 response by year of ART initiation during 36 months of follow-up, adjusted a priori for other covariates. Overall, 16,962 patients were included. Patients initiating in 2006-9 and 2010-13 had an estimated mean CD4 cell count increase of 8 and 15 cells/µl, respectively, at any given time during the 36-month follow-up, compared to those in 2003-5. The median CD4 cell count at ART initiation also increased from 96 cells/µl in 2003-5 to 173 cells/µl in 2010-13. Our results suggest that the CD4 response to ART is modestly higher for those initiating ART in more recent years. Moreover, fewer patients are presenting with lower absolute CD4 cell counts over time. This is likely to reduce their risk of opportunistic infections and future non-AIDS defining cancers.

Published
2017

23. Safety and Efficacy of Autologous CD34+ Hematopoietic Progenitor Cells Transduced with an Anti-Tat Ribozyme in a Multi-Center, Randomized, Placebo-Controlled, Phase II Gene Therapy Trial for the Human Immunodeficiency Virus

Author

Mitsuyasu, Ronald T, Merigan, Thomas C, Carr, Andrew, Zack, Jerome A, Winters, Mark A, Workman, Cassy, Bloch, Mark, Lalezari, Jacob, Becker, Stephen, Thornton, Lorna, Akil, Bisher, Khanlou, Homayoon, Finlayson, Robert, McFarlane, Robert, Smith, Don E, Garsia, Roger, Ma, David, Law, Matthew, Murray, John M., von Kalle, Christof, Ely, Julie A, Patino, Sharon M, Knop, Alison E, Wong, Philip, Todd, Alison V, Haughton, Margaret, Fuery, Caroline, Macpherson, Janet L, Symonds, Geoff P, Evans, Louise A, Pond, Susan M, and Cooper, David A

Subjects
Adult, Male, Base Sequence, Antigens, CD34, HIV Infections, Genetic Therapy, Viral Load, Article, Placebos, Double-Blind Method, HIV-1, Humans, Female, RNA, Catalytic
Abstract

Gene transfer has potential as a once-only treatment that reduces viral load, preserves the immune system and avoids lifetime highly active antiretroviral therapy. This study, which is to our knowledge the first randomized, double-blind, placebo-controlled, phase 2 cell-delivered gene transfer clinical trial, was conducted in 74 HIV-1-infected adults who received a tat-vpr-specific anti-HIV ribozyme (OZ1) or placebo delivered in autologous CD34+ hematopoietic progenitor cells. There were no OZ1-related adverse events. There was no statistically significant difference in viral load between the OZ1 and placebo group at the primary end point (average at weeks 47 and 48), but time-weighted areas under the curve from weeks 40-48 and 40-100 were significantly lower in the OZ1 group. Throughout the 100 weeks, CD4+ lymphocyte counts were higher in the OZ1 group. This study indicates that cell-delivered gene transfer is safe and biologically active in individuals with HIV and can be developed as a conventional therapeutic product.

Published
2009

24. Effects of CD4 monitoring frequency on clinical endpoints in clinically stable HIV-infected patients with viral suppression

Author

Ahn, Jin Young, Boettiger, David, Law, Matthew, Kumarasamy, Nagalingeswaran, Yunihastuti, Evy, Chaiwarith, Romanee, Lee, Man Po, Sim, Benedict LH, Oka, Shinichi, Wong, Wingwai, Kamarulzaman, Adeeba, Kantipong, Pacharee, Phanuphak, Praphan, Ng, Oon Tek, Kiertiburanakul, Sasisopin, Zhang, Fujie, Pujari, Sanjay, Ditangco, Rossana, Ratanasuwan, Winai, Merati, Tuti Parwati, Saphonn, Vonthanak, Sohn, Annette H., and Choi, Jun Yong

Subjects
Adult, Cohort Studies, Male, Anti-HIV Agents, HIV-1, Humans, Female, HIV Infections, Middle Aged, Article, CD4 Lymphocyte Count
Abstract

Current treatment guidelines for HIV infection recommend routine CD4 lymphocyte (CD4) count monitoring in patients with viral suppression. This may have a limited impact on influencing care as clinically meaningful CD4 decline rarely occurs during viral suppression.In a regional HIV observational cohort in the Asia-Pacific region, patients with viral suppression (2 consecutive viral loads400 copies/mL) and a CD4 count ≥200 cells per microliter who had CD4 testing 6 monthly were analyzed. Main study end points were occurrence of 1 CD4 count200 cells per microliter (single CD4200) and 2 CD4 counts200 cells per microliter within a 6-month period (confirmed CD4200). A comparison of time with single and confirmed CD4200 with biannual or annual CD4 assessment was performed by generating a hypothetical group comprising the same patients with annual CD4 testing by removing every second CD4 count.Among 1538 patients, the rate of single CD4200 was 3.45/100 patient-years and of confirmed CD4200 was 0.77/100 patient-years. During 5 years of viral suppression, patients with baseline CD4 200-249 cells per microliter were significantly more likely to experience confirmed CD4200 compared with patients with higher baseline CD4 [hazard ratio, 55.47 (95% confidence interval: 7.36 to 418.20), P0.001 versus baseline CD4 ≥500 cells/μL]. Cumulative probabilities of confirmed CD4200 was also higher in patients with baseline CD4 200-249 cells per microliter compared with patients with higher baseline CD4. There was no significant difference in time to confirmed CD4200 between biannual and annual CD4 measurement (P = 0.336).Annual CD4 monitoring in virally suppressed HIV patients with a baseline CD4 ≥250 cells per microliter may be sufficient for clinical management.

Published
2015

25. Tenofovir-based Antiretroviral Therapy in Hepatitis B Virus/HIV Co-infection: Results from the TREAT Asia HIV Observational Database

Author

Boettiger, David C, Kerr, Stephen, Ditangco, Rossana, Chaiwarith, Romanee, Li, Patrick CK, Merati, Tuti Parwati, Pham, Thuy Thi Thanh, Kiertiburanakul, Sasisopin, Kumarasamy, Nagalingeswaran, Vonthanak, Saphonn, Lee, Christopher KC, Van Kinh, Nguyen, Pujari, Sanjay, Wong, Wing Wai, Kamarulzaman, Adeeba, Zhang, Fujie, Yunihastuti, Evy, Choi, Jun Yong, Oka, Shinichi, Ng, Oon Tek, Kantipong, Pacharee, Mustafa, Mahiran, Ratanasuwan, Winai, Durier, Nicolas, and Law, Matthew

Subjects
Male, Hepatitis B virus, Databases, Factual, Coinfection, HIV Infections, Hepatitis B, Kidney Function Tests, Antiviral Agents, Article, CD4 Lymphocyte Count, Cohort Studies, Treatment Outcome, Liver Function Tests, Risk Factors, Antiretroviral Therapy, Highly Active, HIV-1, Humans, Reverse Transcriptase Inhibitors, Drug Therapy, Combination, Female, Mortality, Tenofovir, Biomarkers
Abstract

The World Health Organization recommends HBV-HIV-coinfected individuals start antiretroviral therapy containing tenofovir. Here we describe first-line tenofovir use and treatment outcomes in coinfected patients in Asia.HBV surface antigen positive patients enrolled in the TREAT Asia HIV Observational Database who started first-line antiretroviral therapy were included. Logistic regression adjusted for period of treatment initiation was used to determine factors associated with tenofovir use. Generalized estimating equations were used to evaluate factors associated with alanine transaminase levels and CD4(+) T-cell count on treatment.There were 548 eligible patients, of whom 149 (27.2%) started tenofovir. Patients treated in high/high-middle income countries (odds ratio 4.4 versus low/low-middle, 95% CI 2.6, 7.4; P0.001) and those with elevated baseline alanine transaminase (odds ratio 4.2 versus normal, 95% CI 2.4, 7.2; P0.001) were more likely to receive tenofovir. Hepatitis C antibody positive patients (odds ratio 0.4 versus negative, 95% CI 0.2, 0.8; P=0.008) were less likely. In those starting antiretroviral therapy with elevated alanine transaminase, mean reduction after tenofovir initiation was 11.2 IU/l (95% CI 0.9, 21.6; P=0.034) lower compared with those using a non-tenofovir-based regimen although this did not significantly increase the chance of alanine transaminase normalization. Tenofovir use was not associated with a superior CD4(+) T-cell response.HBV-HIV-coinfected patients in Asia are most likely to receive tenofovir if they are treated in a high/high-middle income country, have elevated alanine transaminase levels and are hepatitis C antibody negative. Compared to other antiretroviral therapies, tenofovir-based regimens more effectively reduce liver inflammation in HBV-HIV-coinfection but do not result in superior CD4(+) T-cell recovery.

Published
2015

26. Estimated mortality of adult HIV-infected patients starting treatment with combination antiretroviral therapy

Author

Boulle, Andrew, Balestre, Eric, Gsponer, Thomas, Musick, Beverly Sue, Shepherd, Bryan E, Law, Matthew, Egger, Matthias, International Epidemiologic Databases To Evaluate AIDS (IeDEA) C, Johnson, Leigh Francis, and Yiannoutsos, Constantin Theodore

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Asia, Adolescent, Anti-HIV Agents, 030231 tropical medicine, HIV Infections, 610 Medicine & health, Dermatology, HIV Clinical Care, Young Adult, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, Antiretroviral Therapy, Highly Active, medicine, Humans, Hiv infected patients, 030212 general & internal medicine, Young adult, Risk factor, Survival analysis, Estimation, business.industry, Clinical Care (General), Mortality rate, Age Factors, virus diseases, Middle Aged, Survival Analysis, Antiretroviral therapy, CD4 Lymphocyte Count, 3. Good health, AIDS, Epidemiology (General), Latin America, Infectious Diseases, Africa, Vital Status, Female, Epidemiologic Methods, business, Supplement
Abstract

Objective To provide estimates of mortality among HIV-infected patients starting combination antiretroviral therapy. Methods We report on the death rates from 122 925 adult HIV-infected patients aged 15 years or older from East, Southern and West Africa, Asia Pacific and Latin America. We use two methods to adjust for biases in mortality estimation resulting from loss from follow-up, based on double-sampling methods applied to patient outreach (Kenya) and linkage with vital registries (South Africa), and apply these to mortality estimates in the other three regions. Age, gender and CD4 count at the initiation of therapy were the factors considered as predictors of mortality at 6, 12, 24 and >24 months after the start of treatment. Results Patient mortality was high during the first 6 months after therapy for all patient subgroups and exceeded 40 per 100 patient years among patients who started treatment at low CD4 count. This trend was seen regardless of region, demographic or disease-related risk factor. Mortality was under-reported by up to or exceeding 100% when comparing estimates obtained from passive monitoring of patient vital status. Conclusions Despite advances in antiretroviral treatment coverage many patients start treatment at very low CD4 counts and experience significant mortality during the first 6 months after treatment initiation. Active patient tracing and linkage with vital registries are critical in adjusting estimates of mortality, particularly in low- and middle-income settings.

Published
2012
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27. Incidence and risk factors for new-onset diabetes in HIV-infected patients: the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study

Author

de Wit, Stephane, Sabin, Caroline A., Weber, Rainer, Worm, Signe Westring, Reiss, Peter, Cazanave, Charles, El-Sadr, Wafaa, D'Arminio Monforte, Antonella, Fontas, Eric, Law, Matthew G., Friis-Møller, Nina, Phillips, Andrew, University of Zurich, De Wit, S, AII - Amsterdam institute for Infection and Immunity, APH - Amsterdam Public Health, and Infectious diseases

Subjects
Adult, Male, Anti-HIV Agents, 2902 Advanced and Specialized Nursing, Incidence, HIV Infections, 610 Medicine & health, Article, Cohort Studies, 10234 Clinic for Infectious Diseases, 2712 Endocrinology, Diabetes and Metabolism, Risk Factors, 2724 Internal Medicine, Multivariate Analysis, Diabetes Mellitus, Humans, Drug Therapy, Combination, Female, Prospective Studies
Abstract

OBJECTIVE - The aims of this study were to determine the incidence of diabetes among HIV-infected patients in the Data Collection on Adverse Events of Anti-HIV Drugs (D-A:D) cohort, to identify demographic, HIV-related, and combination antiretroviral therapy (cART)-related factors associated with the onset of diabetes, and to identify possible mechanisms for any relationships found. RESEARCH DESIGN AND METHODS - D:A:D is a prospective observational study of 33,389 HIV-infected patients; diabetes is a study end point. Poisson regression models were used to assess the relation between diabetes and exposure to cART after adjusting for known risk factors for diabetes, CD4 count, lipids, and lipodystrophy. RESULTS - Over 130,151 person-years of follow-up (PYFU), diabetes was diagnosed in 744 patients (incidence rate of 5.72 per 1,000 PYFU [95% CI 5.31-6.13]). The incidence of diabetes increased with cumulative exposure to cART, an association that remained significant after adjustment for potential risk factors for diabetes. The strongest relationship with diabetes was exposure to stavudine; exposures to zidovudine and didanosine were also associated with an increased risk of diabetes. Time-updated measurements of total cholesterol, HDL cholesterol, and triglycerides were all associated with diabetes. Adjusting for each of these variables separately reduced the relationship between cART and diabetes slightly. Although lipodystrophy was significantly associated with diabetes, adjustment for this did not modify the relationship between cART and diabetes. CONCLUSION - Stavudine and zidovudine are significantly associated with diabetes after adjustment for risk factors for diabetes and lipids. Adjustment for lipodystrophy did not modify the relationship, suggesting that the two thymidine analogs probably directly contribute to insulin resistance, potentially through mitochondrial toxicity

Published
2008

28. Predictors of deferral of treatment for hepatitis C infection in Australian clinics

Author

Gidding, Heather F., Law, Matthew G., Janaki Amin, Macdonald, Graeme A., Sasadeusz, Joe J., Jones, Tracey L., Strasser, Simone I., Jacob George, and Dore, Gregory J.

Subjects
Adult, Male, Patient Selection, Australia, Hepatitis C, Chronic, Middle Aged, Prognosis, Antiviral Agents, Drug Administration Schedule, Cohort Studies, Risk Factors, General & Internal Medicine, Humans, Patient Compliance, Female, Retrospective Studies
Abstract

Objective: To determine uptake of treatment for hepatitis C virus (HCV) infection and predictors of deferral of treatment for HCV by using prospectively collected data from the Australian Chronic Hepatitis C Observational Study (ACHOS). Design, patients and setting: Cohort study involving interview and medical record review at enrolment and routine follow-up clinic visits of patients with chronic HCV and compensated liver disease attending a national network of 24 HCV clinics between April 2008 and December 2009. Eligible patients were those who had not been previously treated, were enrolled within 6 months of their first clinic visit, were eligible for treatment and had been enrolled for at least 6 months. Main outcome measure: Predictors of patients undergoing HCV treatment within the first 6 months of assessment. Results: 1239 patients were enrolled in ACHOS, of whom 406 met the criteria for inclusion in the subcohort for this study. Among this subcohort, 171 (42%) received treatment within 6 months of their first clinic visit. Current injecting drug use (odds ratio [OR], 0.26; 95% CI, 0.08-0.77), past and current treatment for drug dependency (OR, 0.34; 95% CI, 0.18-0.67, and OR, 0.42; 95% CI, 0.22-0.81, respectively) and alcohol use above 20 g/day (OR, 0.20; 95% CI, 0.08-0.46) were independent predictors of deferral of treatment. At least one of these factors applied to 41% of the subcohort. Clinical factors, including HCV genotype, HCV RNA level, and stage of liver disease were not associated with deferral of treatment for HCV. Conclusion: Factors related to drug and alcohol use, rather than clinical factors, influenced uptake of treatment for HCV. Further support for patients with drug and alcohol dependency is required to optimise treatment uptake.

29. Gastroesophageal reflux GWAS identifies risk loci that also associate with subsequent severe esophageal diseases

Author

An, Jiyuan, Gharahkhani, Puya, Law, Matthew H, Ong, Jue-Sheng, Han, Xikun, Olsen, Catherine M, Neale, Rachel E, Lai, John, Vaughan, Tom L, Gockel, Ines, Thieme, René, Böhmer, Anne C, Jankowski, Janusz, Fitzgerald, Rebecca C, Schumacher, Johannes, Palles, Claire, BEACON, 23andMe Research Team, Whiteman, David C, and MacGregor, Stuart

Subjects
Male, Genetic Loci, Gastroesophageal Reflux, Humans, Female, Genetic Predisposition to Disease, Esophageal Diseases, Polymorphism, Single Nucleotide, humanities, digestive system diseases, 3. Good health, Genome-Wide Association Study
Abstract

Gastroesophageal reflux disease (GERD) is caused by gastric acid entering the esophagus. GERD has high prevalence and is the major risk factor for Barrett's esophagus (BE) and esophageal adenocarcinoma (EA). We conduct a large GERD GWAS meta-analysis (80,265 cases, 305,011 controls), identifying 25 independent genome-wide significant loci for GERD. Several of the implicated genes are existing or putative drug targets. Loci discovery is greatest with a broad GERD definition (including cases defined by self-report or medication data). Further, 91% of the GERD risk-increasing alleles also increase BE and/or EA risk, greatly expanding gene discovery for these traits. Our results map genes for GERD and related traits and uncover potential new drug targets for these conditions.

30. Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways

Author

Duffy, David L, Zhu, Gu, Li, Xin, Sanna, Marianna, Iles, Mark M, Jacobs, Leonie C, Evans, David M, Yazar, Seyhan, Beesley, Jonathan, Law, Matthew H, Kraft, Peter, Visconti, Alessia, Taylor, John C, Lui, Fan, Wright, Margaret J, Henders, Anjali K, Bowdler, Lisa, Glass, Dan, Ikram, Arfan M, Uitterlinden, André G, Madden, Pamela A, Heath, Andrew C, Nelson, Elliot C, Green, Adele C, Chanock, Stephen, Barrett, Jennifer H, Brown, Matthew A, Hayward, Nicholas K, MacGregor, Stuart, Sturm, Richard A, Hewitt, Alex W, Melanoma GWAS Consortium, Kayser, Manfred, Hunter, David J, Newton Bishop, Julia A, Spector, Timothy D, Montgomery, Grant W, Mackey, David A, Smith, George Davey, Nijsten, Tamar E, Bishop, D Timothy, Bataille, Veronique, Falchi, Mario, Han, Jiali, and Martin, Nicholas G

Subjects
Skin Neoplasms, Telomere-Binding Proteins, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Histone Deacetylases, White People, Receptors, G-Protein-Coupled, Group VI Phospholipases A2, Guanine Nucleotide Exchange Factors, Humans, Genetic Predisposition to Disease, skin and connective tissue diseases, Melanoma, Telomerase, Nevus, Pigmented, Stem Cell Factor, Microfilament Proteins, Nuclear Proteins, RNA-Binding Proteins, Genetic Pleiotropy, 3. Good health, Repressor Proteins, MicroRNAs, Cytochrome P-450 CYP1B1, Interferon Regulatory Factors, RNA, Carrier Proteins, Genome-Wide Association Study
Abstract

The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B, DOCK8, and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis.

31. Cancers in the TREAT Asia HIV Observational Database (TAHOD): a retrospective analysis of risk factors

Author

Petoumenos, Kathy, Hui, Eugenie, Kumarasamy, Nagalingeswaran, Kerr, Stephen J, Choi, Jun Yong, Chen, Yi-Ming A, Merati, Tuti, Zhang, Fujie, Lim, Poh-Lian, Sungkanuparph, Somnuek, Pujari, Sanjay, Ponnampalavanar, Sasheela, Ditangco, Rosanna, Lee, Christopher KC, Grulich, Andrew, Law, Matthew G, and Asia HIV Observational Database, Treat

Subjects
Adult, Male, medicine.medical_specialty, Asia, Databases, Factual, MEDLINE, Human immunodeficiency virus (HIV), HIV Infections, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Retrospective survey, Risk Factors, Internal medicine, Neoplasms, Retrospective analysis, Medicine, Humans, 030212 general & internal medicine, Retrospective Studies, Observational database, business.industry, Public health, Research, Public Health, Environmental and Occupational Health, virus diseases, Cancer, Retrospective cohort study, Middle Aged, medicine.disease, 3. Good health, Surgery, Infectious Diseases, 030220 oncology & carcinogenesis, Female, business
Abstract

Background This retrospective survey describes types of cancers diagnosed in HIV-infected subjects in Asia, and assesses risk factors for cancer in HIV-infected subjects using contemporaneous HIV-infected controls without cancer. Methods TREAT Asia HIV Observational Database (TAHOD) sites retrospectively reviewed clinic medical records to determine cancer diagnoses since 2000. For each diagnosis, the following data were recorded: date, type, stage, method of diagnosis, demographic data, medical history, and HIV-related information. For risk factor analyses, two HIV-infected control subjects without cancer diagnoses were also selected. Cancers were grouped as AIDS-defining cancers (ADCs), and non-ADCs. Non-ADCs were further categorized as being infection related (NADC-IR) and unrelated (NADC-IUR). Results A total of 617 patients were included in this study: 215 cancer cases and 402 controls from 13 sites. The majority of cancer cases were male (71%). The mean age (SD) for cases was 39 (10.6), 46 (11.5) and 44 (13.7) for ADCs, NADC-IURs and NADCs-IR, respectively. The majority (66%) of cancers were ADCs (16% Kaposi sarcoma, 40% non-Hodgkin's lymphoma, and 9% cervical cancer). The most common NADCs were lung (6%), breast (5%) and hepatocellular carcinoma and Hodgkin's lymphoma (2% each). There were also three (1.4%) cases of leiomyosarcoma reported in this study. In multivariate analyses, individuals with CD4 counts above 200 cells/mm3 were approximately 80% less likely to be diagnosed with an ADC (p < 0.001). Older age (OR: 1.39, p = 0.001) and currently not receiving antiretroviral treatment (OR: 0.29, p = 0.006) were independent predictors of NADCs overall, and similarly for NADCs-IUR. Lower CD4 cell count and higher CDC stage (p = 0.041) were the only independent predictors of NADCs-IR. Conclusions The spectrum of cancer diagnoses in the Asia region currently does not appear dissimilar to that observed in non-Asian HIV populations. One interesting finding was the cases of leiomyosarcoma, a smooth-muscle tumour, usually seen in children and young adults with AIDS, yet overall quite rare. Further detailed studies are required to better describe the range of cancers in this region, and to help guide the development of screening programmes.

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32. Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers

Author

Montserrat Garcia-Closas, Ellen L. Goode, Mark M. Iles, Brian M. Wolpin, Stephen J. Chanock, Susan L. Slager, Li Hsu, Clare Turnbull, Ccfr, Michael Hoffmeister, Peter T. Campbell, Maria Teresa Landi, Paul D.P. Pharoah, Amber N. Hurson, Melissa L. Bondy, Roger L. Milne, Peter A. Kanetsky, Simon A. Gayther, Christopher A. Haiman, Nicola J. Camp, Mark A. Jenkins, Margaret Wrensch, Bcac, Ulrike Peters, Jill S. Barnholtz-Sloan, Richard S. Houlston, PanScan, Haoyu Zhang, Christopher I. Amos, Ben Kinnersley, GenoMEL, Florence Demenais, Rosalind A. Eeles, Katherine A. McGlynn, Practical, John K. Wiencke, Gicc, Katherine L. Nathanson, Stolzenberg-Solomon R, Brenda M. Birmann, Rayjean J. Hung, Donghui Li, David C. Whiteman, Ghislaine Scelo, Sonja I. Berndt, Alison P. Klein, Sarah V. Ward, Per Hall, D. Timothy Bishop, Tracy A. O'Mara, Kirsten B. Moysich, Corect, Laufey T. Amundadottir, Marjanka K. Schmidt, Ian Tomlinson, Ocac, Yan Zhang, Gloria M. Petersen, Ali Amin Al Olama, Puya Gharahkhani, Deborah J. Thompson, Paul Brennan, Douglas F. Easton, Celeste Leigh Pearce, InterLymph, Jacques Simard, Mark H. Greene, Zsofia Kote-Jarai, Nilanjan Chatterjee, Ecac, Marlene Danner Dalgaard, Mark P. Purdue, Beatrice Melin, Graham Casey, Rajesh Kumar, Jenny Chang-Claude, Thomas A. Sellers, Stephen B. Gruber, Beacon, James D. McKay, Tecac, Stephanie L. Schmit, Tom Grotmol, Kyriaki Michailidou, Immaculata De Vivo, Joellen M. Schildkraut, Eric J. Jacobs, Fredrik Wiklund, Amanda B. Spurdle, Nathaniel Rothman, Parichoy Pal Choudhury, Peter Kraft, Panc, Renal Cancer Gwas, Neil E. Caporaso, Joe Dennis, Matthew Law, Fredrick R. Schumacher, Harvey A. Risch, Stuart MacGregor, Andrew Berchuck, Ilcco, Oral Cancer Gwas, Zhang, Yan Dora [0000-0002-5302-3690], Hurson, Amber N. [0000-0001-7831-6660], Easton, Douglas F. [0000-0003-2444-3247], Milne, Roger L. [0000-0001-5764-7268], Simard, Jacques [0000-0001-6906-3390], Michailidou, Kyriaki [0000-0001-7065-1237], Dennis, Joe [0000-0003-4591-1214], Schmidt, Marjanka K. [0000-0002-2228-429X], Gharahkhani, Puya [0000-0002-4203-5952], Whiteman, David [0000-0003-2563-9559], Jenkins, Mark [0000-0002-8964-6160], Peters, Ulrike [0000-0001-5666-9318], Schmit, Stephanie L. [0000-0001-5931-1194], O’Mara, Tracy A. [0000-0002-5436-3232], Spurdle, Amanda B. [0000-0003-1337-7897], Thompson, Deborah J. [0000-0003-1465-5799], Tomlinson, Ian [0000-0003-3037-1470], Landi, Maria Teresa [0000-0003-4507-329X], Law, Matthew H. [0000-0002-4303-8821], Iles, Mark M. [0000-0002-2603-6509], Demenais, Florence [0000-0001-8361-0936], Kumar, Rajiv [0000-0002-6093-0395], MacGregor, Stuart [0000-0001-6731-8142], Bishop, D. Timothy [0000-0002-8752-8785], Houlston, Richard [0000-0002-5268-0242], Barnholtz-Sloan, Jill [0000-0001-6190-9304], Kinnersley, Ben [0000-0003-1783-6296], Amos, Christopher I. [0000-0002-8540-7023], Hung, Rayjean J. [0000-0002-4486-7496], Brennan, Paul [0000-0002-0518-8714], Birmann, Brenda M. [0000-0002-7550-5498], Camp, Nicola J. [0000-0002-4788-1998], Kraft, Peter [0000-0002-4472-8103], Pharoah, Paul D. P. [0000-0001-8494-732X], Gayther, Simon A. [0000-0001-7937-5443], Amundadottir, Laufey T. [0000-0003-1859-8971], Jacobs, Eric J. [0000-0002-8458-7659], Klein, Alison P. [0000-0003-2737-8399], Eeles, Rosalind A. [0000-0002-3698-6241], Schumacher, Fredrick R. [0000-0002-3073-7463], Greene, Mark H. [0000-0003-1852-9239], Kanetsky, Peter A. [0000-0002-5567-9618], Nathanson, Katherine L. [0000-0002-6740-0901], Wiklund, Fredrik [0000-0002-4623-0544], Chanock, Stephen J. [0000-0002-2324-3393], Garcia-Closas, Montserrat [0000-0003-1033-2650], Apollo - University of Cambridge Repository, Hurson, Amber N [0000-0001-7831-6660], Easton, Douglas F [0000-0003-2444-3247], Milne, Roger L [0000-0001-5764-7268], Schmidt, Marjanka K [0000-0002-2228-429X], Schmit, Stephanie L [0000-0001-5931-1194], O'Mara, Tracy A [0000-0002-5436-3232], Spurdle, Amanda B [0000-0003-1337-7897], Thompson, Deborah J [0000-0003-1465-5799], Law, Matthew H [0000-0002-4303-8821], Iles, Mark M [0000-0002-2603-6509], Bishop, D Timothy [0000-0002-8752-8785], Amos, Christopher I [0000-0002-8540-7023], Hung, Rayjean J [0000-0002-4486-7496], Birmann, Brenda M [0000-0002-7550-5498], Camp, Nicola J [0000-0002-4788-1998], Pharoah, Paul DP [0000-0001-8494-732X], Gayther, Simon A [0000-0001-7937-5443], Amundadottir, Laufey T [0000-0003-1859-8971], Jacobs, Eric J [0000-0002-8458-7659], Klein, Alison P [0000-0003-2737-8399], Eeles, Rosalind A [0000-0002-3698-6241], Schumacher, Fredrick R [0000-0002-3073-7463], Greene, Mark H [0000-0003-1852-9239], Kanetsky, Peter A [0000-0002-5567-9618], Nathanson, Katherine L [0000-0002-6740-0901], and Chanock, Stephen J [0000-0002-2324-3393]

Subjects
Male, 0301 basic medicine, Oncology, Multifactorial Inheritance, 45/43, General Physics and Astronomy, Diseases, Genome-wide association study, 0302 clinical medicine, Risk Factors, Neoplasms, 631/208/68, lcsh:Science, Cancer genetics, Multidisciplinary, 692/699, Incidence, article, 030220 oncology & carcinogenesis, Medical genetics, Female, Medical Genetics, medicine.medical_specialty, Science, Biology, Polymorphism, Single Nucleotide, Risk Assessment, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Genetic predisposition, Animals, Humans, Genetic Predisposition to Disease, Lung cancer, Genetic association, Medicinsk genetik, Cancer och onkologi, Models, Genetic, 45, Cancer, General Chemistry, Heritability, medicine.disease, 030104 developmental biology, Sample size determination, Relative risk, Cancer and Oncology, lcsh:Q, Ovarian cancer, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence., In cancer many gene variants may contribute to disease etiology, but the impact of a given gene variant may have varied effect size. Here, the authors analyse summary statistics of genome-wide association studies from fourteen cancers, and show the utility of polygenic risk scores may vary depending on cancer type.

Published
2020

33. Functional annotation and investigation of the 10q24.33 melanoma risk locus identifies a common variant that influences transcriptional regulation of OBFC1

Author

Massimiliano Scalvenzi, Alessandro Testori, Michiel Vermeulen, Annalaura Montella, Nicola Zambrano, Marijke P. Baltissen, Vito Alessandro Lasorsa, Marianna Avitabile, Kevin M. Brown, Sueva Cantalupo, Flora Cimmino, Antonella Cardinale, Mai Xu, Mark M. Iles, Achille Iolascon, Paola Ghiorzo, Fabrizio Ayala, Ferdinando Bonfiglio, Mariangela Succoio, Matthew Law, Daniela Formicola, Matteo Esposito, Mario Capasso, Cardinale, Antonella, Cantalupo, Sueva, Lasorsa, Vito Alessandro, Montella, Annalaura, Cimmino, Flora, Succoio, Mariangela, Vermeulen, Michiel, Baltissen, Marijke P, Esposito, Matteo, Avitabile, Marianna, Formicola, Daniela, Testori, Alessandro, Bonfiglio, Ferdinando, Ghiorzo, Paola, Scalvenzi, Massimiliano, Ayla, Fabrizio, Zambrano, Nicola, Iles, Mark M, Xu, Mai, Law, Matthew H, Brown, Kevin M, Iolascon, Achille, and Capasso, Mario

Subjects
Genetics, Skin Neoplasms, Single-nucleotide polymorphism, Locus (genetics), General Medicine, Biology, Polymorphism, Single Nucleotide, Minor allele frequency, Humans, Genetic Predisposition to Disease, General Article, Allele, Enhancer, Gene, Transcription factor, Molecular Biology, Melanoma, Genetics (clinical), Epigenomics
Abstract

The 10q24.33 locus is known to be associated with susceptibility to cutaneous malignant melanoma (CMM), but the mechanisms underlying this association have been not extensively investigated. We carried out an integrative genomic analysis of 10q24.33 using epigenomic annotations and in vitro reporter gene assays to identify regulatory variants. We found two putative functional single nucleotide polymorphisms (SNPs) in an enhancer and in the promoter of OBFC1, respectively, in neural crest and CMM cells, one, rs2995264, altering enhancer activity. The minor allele G of rs2995264 correlated with lower OBFC1 expression in 470 CMM tumors and was confirmed to increase the CMM risk in a cohort of 484 CMM cases and 1801 controls of Italian origin. Hi-C and chromosome conformation capture (3C) experiments showed the interaction between the enhancer-SNP region and the promoter of OBFC1 and an isogenic model characterized by CRISPR-Cas9 deletion of the enhancer-SNP region confirmed the potential regulatory effect of rs2995264 on OBFC1 transcription. Moreover, the presence of G-rs2995264 risk allele reduced the binding affinity of the transcription factor MEOX2. Biologic investigations showed significant cell viability upon depletion of OBFC1, specifically in CMM cells that were homozygous for the protective allele. Clinically, high levels of OBFC1 expression associated with histologically favorable CMM tumors. Finally, preliminary results suggested the potential effect of decreased OBFC1 expression on telomerase activity in tumorigenic conditions. Our results support the hypothesis that reduced expression of OBFC1 gene through functional heritable DNA variation can contribute to malignant transformation of normal melanocytes.

Published
2022

34. Gastroesophageal reflux GWAS identifies risk loci that also associate with subsequent severe esophageal diseases

Author

Jue-Sheng Ong, René Thieme, Janusz Jankowski, Jiyuan An, Anne C. Böhmer, Stuart MacGregor, David C. Whiteman, Johannes Schumacher, Claire Palles, Rachel E. Neale, Matthew Law, Puya Gharahkhani, Ines Gockel, John Lai, Catherine M. Olsen, Xikun Han, Beacon, Rebecca C. Fitzgerald, Tom L. Vaughan, Gharahkhani, Puya [0000-0002-4203-5952], Law, Matthew H [0000-0002-4303-8821], Ong, Jue-Sheng [0000-0002-6062-710X], Han, Xikun [0000-0002-3823-7308], Olsen, Catherine M [0000-0003-4483-1888], Böhmer, Anne C [0000-0002-5716-786X], Fitzgerald, Rebecca C [0000-0002-3434-3568], MacGregor, Stuart [0000-0001-6731-8142], and Apollo - University of Cambridge Repository

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Science, General Physics and Astronomy, Genome-wide association study, Disease, Esophageal Diseases, Genome-wide association studies, Polymorphism, Single Nucleotide, Gastroenterology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Gastro-oesophageal reflux disease, Internal medicine, Humans, Medicine, Genetic Predisposition to Disease, Allele, Esophagus, Risk factor, lcsh:Science, Cancer genetics, Multidisciplinary, business.industry, Esophageal disease, Oesophageal cancer, General Chemistry, medicine.disease, humanities, digestive system diseases, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Genetic Loci, 030220 oncology & carcinogenesis, Gastroesophageal Reflux, GERD, Adenocarcinoma, lcsh:Q, Female, business, Genome-Wide Association Study
Abstract

Gastroesophageal reflux disease (GERD) is caused by gastric acid entering the esophagus. GERD has high prevalence and is the major risk factor for Barrett’s esophagus (BE) and esophageal adenocarcinoma (EA). We conduct a large GERD GWAS meta-analysis (80,265 cases, 305,011 controls), identifying 25 independent genome-wide significant loci for GERD. Several of the implicated genes are existing or putative drug targets. Loci discovery is greatest with a broad GERD definition (including cases defined by self-report or medication data). Further, 91% of the GERD risk-increasing alleles also increase BE and/or EA risk, greatly expanding gene discovery for these traits. Our results map genes for GERD and related traits and uncover potential new drug targets for these conditions., Gastroesophageal reflux disease (GERD) is a major risk factor for Barret’s esophagus (BE) and esophageal adenocarcinoma (EA). Here, An et al. report 25 genetic loci for GERD, many of which associate with BE and EA or with other traits such as BMI.

Published
2019

35. A comprehensive re-assessment of the association between vitamin D and cancer susceptibility using Mendelian randomization

Author

Upekha E Liyanage, Amanda B. Spurdle, K. E. Huber, Anna H. Wu, J. Fah Sathirapongsasuti, Douglas A. Corley, C. Tian, Anne Böhmer, David A. Hinds, A. Auton, Xikun Han, Matt Buas, M. Agee, Rebecca C. Fitzgerald, Puya Gharahkhani, Yvonne Romero, S. L. Elson, Ines Gockel, Johannes Schumacher, Leslie Bernstein, Nigel C. Bird, Thomas L. Vaughan, E. S. Noblin, P. Fontanillas, Laura J. Hardie, Brian J. Reid, V. Vacic, M. H. McIntyre, Jiyuan An, Andrew Berchuck, Claire Palles, Weimin Ye, K. Bryc, S. J. Pitts, Jue-Sheng Ong, Geoffrey Liu, R. K. Bell, Rachel E. Neale, Marilie D. Gammon, J. L. Mountain, C. A. M. Northover, Catherine M. Olsen, C. H. Wilson, Janusz Jankowski, Matthew Law, A. Kleinman, Suzanne C. Dixon-Suen, J. Y. Tung, Aaron P. Thrift, Wong-Ho Chow, Paul Pharoah, Jean-Cluade Dusingize, Suyash Shringarpure, Mark M. Iles, Wei Zheng, N. A. Furlotte, Penelope M. Webb, B. Alipanahi, O. V. Sazonova, Stuart MacGregor, David Whiteman, J. F. Shelton, Harvey A. Risch, N. K. Litterman, Tracy A. O'Mara, Nicholas J. Shaheen, Ong, Jue-Sheng [0000-0002-6062-710X], Dixon-Suen, Suzanne C [0000-0003-3714-8386], Han, Xikun [0000-0002-3823-7308], Gockel, Ines [0000-0001-7423-713X], Böhmer, Anne [0000-0002-5716-786X], O'Mara, Tracy [0000-0002-5436-3232], Spurdle, Amanda [0000-0003-1337-7897], Law, Matthew H [0000-0002-4303-8821], Iles, Mark M [0000-0002-2603-6509], Pharoah, Paul [0000-0001-8494-732X], Zheng, Wei [0000-0003-1226-070X], Thrift, Aaron P [0000-0002-0084-5308], Olsen, Catherine [0000-0003-4483-1888], Gharahkhani, Puya [0000-0002-4203-5952], Webb, Penelope M [0000-0003-0733-5930], MacGregor, Stuart [0000-0001-6731-8142], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Science, General Physics and Astronomy, Sunburn, Single-nucleotide polymorphism, General Biochemistry, Genetics and Molecular Biology, Article, Cancer prevention, 03 medical and health sciences, 0302 clinical medicine, Cancer epidemiology, Risk Factors, Internal medicine, Neoplasms, Mendelian randomization, Vitamin D and neurology, medicine, Humans, Genetic Predisposition to Disease, 030212 general & internal medicine, Risk factor, Vitamin D, Child, Cancer genetics, Multidisciplinary, business.industry, Pigmentation, Case-control study, Cancer, Mendelian Randomization Analysis, General Chemistry, medicine.disease, Confidence interval, 030104 developmental biology, Case-Control Studies, Multivariate Analysis, business
Abstract

Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer; however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89; 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16; 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible., Studies of the genetic association between vitamin D and cancer risk have typically been underpowered. Here the authors analyse this using Mendelian Randomisation with more than 70 vitamin D variants obtained from the UK Biobank and large-scale data from various consortia, confirming null associations between vitamin D and most cancers.

Published
2020

36. Neural crest-derived tumor neuroblastoma and melanoma share 1p13.2 as susceptibility locus that shows a long-range interaction with the SLC16A1 gene

Author

Mark M. Iles, Massimiliano Scalvenzi, Annalaura Montella, Zalman Vaksman, Mario Capasso, Daniela Formicola, Stefania Staibano, Alessandro Testori, Vito Alessandro Lasorsa, Hakon Hakonarson, Matteo Esposito, Sueva Cantalupo, Jan Koster, Paola Ghiorzo, Fabrizio Ayala, Sharon J. Diskin, Marcella Devoto, Antonella Cardinale, Marianna Avitabile, Flora Cimmino, Maria Fiammetta Romano, Maria Valeria Corrias, Mariangela Succoio, Nicola Zambrano, Virginia Andreotti, Matthew Law, Kevin M. Brown, Achille Iolascon, Avitabile, Marianna, Succoio, Mariangela, Testori, Alessandro, Cardinale, Antonella, Vaksman, Zalman, Lasorsa, Vito Alessandro, Cantalupo, Sueva, Esposito, Matteo, Cimmino, Flora, Montella, Annalaura, Formicola, Daniela, Koster, Jan, Andreotti, Virginia, Ghiorzo, Paola, Romano, Maria Fiammetta, Staibano, Stefania, Scalvenzi, Massimiliano, Ayala, Fabrizio, Hakonarson, Hakon, Corrias, Maria Valeria, Devoto, Marcella, Law, Matthew H, Iles, Mark M, Brown, Kevin, Diskin, Sharon, Zambrano, Nicola, Iolascon, Achille, Capasso, Mario, Oncogenomics, and CCA - Cancer biology and immunology

Subjects
0301 basic medicine, Male, Monocarboxylic Acid Transporters, Cancer Research, Neuroblastoma, malignant cutaneous melanoma, neural crest cells, GWAS, Skin Neoplasms, Adrenal Gland Neoplasms, Genome-wide association study, Locus (genetics), Biology, medicine.disease_cause, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Cell Movement, medicine, Humans, Genetic Predisposition to Disease, Allele, Melanoma, Cancer Biomarkers and Molecular Epidemiology, Symporters, Neural crest, Cell Differentiation, General Medicine, Cell cycle, medicine.disease, 030104 developmental biology, Chromosomes, Human, Pair 1, Neural Crest, 030220 oncology & carcinogenesis, Cancer research, Female, Carcinogenesis, Genome-Wide Association Study
Abstract

Neuroblastoma (NB) and malignant cutaneous melanoma (CMM) are neural crest cells (NCC)-derived tumors and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association studies (GWAS). We took a three-staged approach to conduct cross-disease meta-analysis of GWAS for NB and CMM (2101 NB cases and 4202 controls; 12 874 CMM cases and 23 203 controls) to identify shared loci. Findings were replicated in 1403 NB cases and 1403 controls of European ancestry and in 636 NB, 508 CMM cases and 2066 controls of Italian origin. We found a cross-association at locus 1p13.2 (rs2153977, odds ratio = 0.91, P = 5.36 × 10−8). We also detected a suggestive (P < 10−7) NB-CMM cross-association at 2q37.1 with opposite effect on cancer risk. Pathway analysis of 110 NB-CMM risk loci with P < 10−4 demonstrated enrichment of biological processes such as cell migration, cell cycle, metabolism and immune response, which are essential of human NCC development, underlying both tumors. In vitro and in silico analyses indicated that the rs2153977-T protective allele, located in an NB and CMM enhancer, decreased expression of SLC16A1 via long-range loop formation and altered a T-box protein binding site. Upon depletion of SLC16A1, we observed a decrease of cellular proliferation and invasion in both NB and CMM cell lines, suggesting its role as oncogene. This is the largest study to date examining pleiotropy across two NC cell-derived tumors identifying 1p13.2 as common susceptibility locus for NB and CMM risk. We demonstrate that combining genome-wide association studies results across cancers with same origins can identify new loci common to neuroblastoma and melanoma arising from tissues which originate from neural crest cells. Our results also show 1p13.2 confer risk to neuroblastoma and melanoma by regulating SLC16A1.

Published
2020

37. Aging of the HIV Population in Australia: A Modeling Study

Author

Matthew Law, Richard Gray, Rebecca Guy, Neil Arvin Bretaña, Bretaña, Neil Arvin, Gray, Richard, Law, Matthew, and Guy, Rebecca

Subjects
Male, Aging, Population, MEDLINE, Human immunodeficiency virus (HIV), HIV Infections, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Age Distribution, Environmental health, Medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, education, Aged, Aged, 80 and over, education.field_of_study, 030505 public health, Models, Statistical, business.industry, Australia, HIV, Middle Aged, Infectious Diseases, Epidemiological Monitoring, Age distribution, Female, 0305 other medical science, business
Abstract

usc Refereed/Peer-reviewed

Published
2018

38. Pregnancy outcomes among HIV-infected women who conceived on antiretroviral therapy

Author

Karin Nielsen-Saines, Xingye Wu, Michelle A. Kendall, Elizabeth M. Stringer, Judith S. Currier, Susan Cu-Uvin, Thomas B. Campbell, Fred Sawe, Shahin Lockman, and Law, Matthew

Subjects
0301 basic medicine, HPTN 052, RNA viruses, medicine.medical_treatment, Maternal Health, HIV Infections, Reproductive health and childbirth, Abortion, Low Birth Weight and Health of the Newborn, Miscarriage, Pathology and Laboratory Medicine, Assisted Reproductive Technology, 0302 clinical medicine, Immunodeficiency Viruses, Pregnancy, Antiretroviral Therapy, Highly Active, Infant Mortality, Medicine and Health Sciences, Public and Occupational Health, 030212 general & internal medicine, Termination of Pregnancy, Pregnancy Complications, Infectious, Pediatric, Multidisciplinary, Ectopic pregnancy, Obstetrics, Infectious, Pregnancy Outcome, Obstetrics and Gynecology, Stillbirth, Vaccination and Immunization, Infectious Diseases, Mental Health, Medical Microbiology, Viral Pathogens, Viruses, Gestation, Premature Birth, Medicine, Female, Pathogens, Live birth, Stillbirths, Research Article, Adult, medicine.medical_specialty, General Science & Technology, Anti-HIV Agents, Science, Immunology, Antiretroviral Therapy, Preterm Birth, Microbiology, 03 medical and health sciences, Antiviral Therapy, Clinical Research, Preterm, Retroviruses, medicine, Humans, Highly Active, Conditions Affecting the Embryonic and Fetal Periods, Microbial Pathogens, Proportional Hazards Models, Assisted reproductive technology, business.industry, Contraception/Reproduction, Lentivirus, Organisms, Biology and Life Sciences, HIV, Perinatal Period - Conditions Originating in Perinatal Period, medicine.disease, 030112 virology, United States, Pregnancy Complications, Birth, Women's Health, Preventive Medicine, business
Abstract

As antiretroviral therapy (ART) expands in resource-limited settings, understanding the impact of ART on pregnancy outcomes is critical. We analyzed women who became pregnant on ART while enrolled in a clinical trial (HPTN 052, ACTG A5208, and ACTG A5175); the majority of women were from Africa, with a median age of 29 years. Eligible women were on ART at conception and had a documented date of a last menstrual period and a pregnancy outcome. The primary outcome was non-live birth (stillbirth; spontaneous abortion; elective termination; or ectopic pregnancy) versus live birth. Preterm birth (

Published
2018

39. Gender differences in the use of cardiovascular interventions in HIV-positive persons; the D:A:D study

Author

Hatleberg, Ci, Ryom, L, El-Sadr, W, Mocroft, A, Reiss, P, De Wit, S, Dabis, F, Pradier, C, d'Arminio Monforte, A, Kovari, H, Law, M, Lundgren, Jd, Sabin, Ca, Data Collection of Adverse Events of Anti-HIV drugs (D:A:D) Study group, Calvo, G, Bonnet, F, Kirk, O, Morfeldt, L, Weber, R, Lind-Thomsen, A, Salbøl Brandt, R, Hillebreght, M, Zaheri, S, Wit, F, Scherrer, A, Schöni-Affolter, F, Rickenbach, M, Tavelli, A, Fanti, I, Leleux, O, Mourali, J, Le Marec, F, Boerg, E, Thulin, E, Sundström, A, Bartsch, G, Thompsen, G, Necsoi, C, Delforge, M, Fontas, E, Caissotti, C, Mateu, S, Torres, F, Petoumenos, K, Blance, A, Huang, R, Puhr, R, Laut, K, Kristensen, D, Phillips, An, Kamara, Da, Smith, Cj, Brandt, Rs, Raben, D, Matthews, C, Bojesen, A, Grevsen, Al, Powderly, B, Shortman, N, Moecklinghoff, C, Reilly, G, Franquet, X, Smit, C, Ross, M, Fux, Ca, Morlat, P, Friis-Møller, N, Kowalska, J, Bohlius, J, Bower, M, Fätkenheuer, G, Grulich, A, Sjøl, A, Meidahl, P, Iversen, Js, Hillebregt, M, Prins, Jm, Kuijpers, Tw, Scherpbier, Hj, van der Meer, J, Godfried, Mh, van der Poll, T, Nellen, F, Geerlings, Se, van Vugt, M, Pajkrt, D, Bos, Jc, Wiersinga, Wj, van der Valk, M, Goorhuis, A, Hovius, Jw, van Eden, J, Henderiks, A, van Hes, A, Mutschelknauss, M, Nobel, He, Pijnappel, F, Jurriaans, S, Back, N, Zaaijer, Hl, Berkhout, B, Cornelissen, M, Schinkel, Cj, Thomas, Xv, De Ruyter Ziekenhuis, A, van den Berge, M, Stegeman, A, Baas, S, Hage de Looff, L, Ziekenhuis, C, Pronk, M, Ammerlaan, H, de Munnik, E, Tjhie, J, Wegdam, M, Deiman, B, Scharnhorst, V, Weijsenfeld, Am, van der Ende ME, van Gorp, E, Schurink, C, Nouwen, Jl, Verbon, A, Rijnders, B, Bax, Hi, van der Feltz, M, van der Bassant, N, van Beek, J, Vriesde, M, van Zonneveld LM, de Oude-Lubbers, A, van den Berg-Cameron HJ, Bruinsma-Broekman, Fb, de Groot, J, de Zeeuw-de Man, M, Boucher, C, Koopmans, M, van Kampen, J, Pas, Sd, Driessen, G, van Rossum, A, van der Knaap LC, Flevoziekenhuis, E, Branger, J, Rijkeboer-Mes, A, Schippers, Ef, van IJperen JM, Geilings, J, van der Hut, G, Franck, P, van Eeden, A, Brokking, W, Groot, M, Elsenburg, L, Damen, M, Isala, Is, Groeneveld, P, Bouwhuis, Jw, den Berg JF, van Hulzen, A, van der Bliek GL, Bor, P, Bloembergen, P, Wolfhagen, M, Ruijs, G, Kroon, Fp, de Boer, M, Bauer, Mp, Jolink, H, Vollaard, Am, Dorama, W, van Holten, N, Claas, E, Wessels, E, den Hollander JG, Pogany, K, Roukens, A, Kastelijns, M, Smit, Jv, Smit, E, Struik-Kalkman, D, Tearno, C, Bezemer, M, van Niekerk, T, Pontesilli, O, Lowe, Sh, Oude Lashof, A, Posthouwer, D, Ackens, Rp, Schippers, J, Vergoossen, R, Weijenberg-Maes, B, van Loo, I, Havenith, T, Leyten, E, Gelinck, L, van Hartingsveld, A, Meerkerk, C, Wildenbeest, Gs, Mutsaers, J, Jansen, Cl, Mulder, Jw, Vrouenraets, S, Lauw, Fn, van Broekhuizen MC, Paap, H, Vlasblom, Dj, Smits, P, Weijer, S, El Moussaoui, R, Bosma, As, van Vonderen, M, van Houte, D, Kampschreur, Lm, Dijkstra, K, Faber, S, Weel, J, Kootstra, Gj, Delsing, Ce, van der Burg-van de Plas, M, Heins, H, Lucas, E, Kortmann, W, van Twillert, G, Cohen Stuart, J, Diederen, B, Pronk, D, van Truijen-Oud FA, van der Reijden WA, Jansen, R, Brinkman, K, den Berk, G, Blok, Wl, Frissen, P, Lettinga, Kd, Schouten, W, Veenstra, J, Brouwer, Cj, Geerders, Gf, Hoeksema, K, Kleene, Mj, van der Meché IB, Spelbrink, M, Sulman, H, Toonen, A, Wijnands, S, Kwa, D, Witte, E, Koopmans, Pp, Keuter, M, van der Ven, A, Ter Hofstede, H, Dofferhoff, A, van Crevel, R, Albers, M, Bosch, M, Grintjes-Huisman, K, Zomer, Bj, Stelma, Ff, Rahamat-Langendoen, J, Burger, D, Richter, C, Gisolf, Eh, Hassing, Rj, Ter Beest, G, van Bentum, P, Langebeek, N, Tiemessen, R, Swanink, C, van Lelyveld, S, Soetekouw, R, Hulshoff, N, van der Prijt, L, van der Swaluw, J, Bermon, N, Herpers, Bl, Veenendaal, D, Verhagen, D, van Wijk, M, Brouwer, Ae, Kuipers, M, Santegoets, R, van der Ven, B, Marcelis, Jh, Buiting, A, Kabel, Pj, Bierman, W, Scholvinck, H, Wilting, Kr, Stienstra, Y, van der Meulen PA, de Weerd DA, Ludwig-Roukema, J, Niesters, H, Riezebos-Brilman, A, van Leer-Buter CC, Knoester, M, Hoepelman, A, Mudrikova, T, Ellerbroek, Pm, Oosterheert, Jj, Arends, Je, Barth, Re, Wassenberg, M, Schadd, Em, van Elst-Laurijssen, D, van Oers-Hazelzet, E, Vervoort, S, van Berkel, M, Schuurman, R, Verduyn-Lunel, F, Wensing, A, Peters, E, van Agtmael MA, Bomers, M, de Vocht, J, Heitmuller, M, Laan, Lm, Pettersson, Am, Ang, Cw, Geelen, S, Wolfs, T, Bont, Lj, Bezemer, Do, van Sighem AI, Boender, Ts, de Jong, A, Bergsma, D, Hoekstra, P, de Lang, A, Grivell, S, Jansen, A, Rademaker, Mj, Raethke, M, Meijering, R, Schnörr, S, de Groot, L, van den Akker, M, Bakker, Y, Claessen, E, El Berkaoui, A, Koops, J, Kruijne, E, Lodewijk, C, Munjishvili, L, Peeck, B, Ree, C, Regtop, R, Ruijs, Y, Rutkens, T, van de Sande, L, Schoorl, M, Timmerman, A, Tuijn, E, Veenenberg, L, van der Vliet, S, Wisse, A, Woudstra, T, Tuk, B, Dupon, M, Gaborieau, V, Lacoste, D, Malvy, D, Mercié, P, Neau, D, Pellegrin, Jl, Tchamgoué, S, Lazaro, E, Cazanave, C, Vandenhende, M, Vareil, Mo, Gérard, Y, Blanco, P, Bouchet, S, Breilh, D, Fleury, H, Pellegrin, I, Chêne, G, Thiébaut, R, Wittkop, L, Lawson-Ayayi, S, Gimbert, A, Desjardin, S, Lacaze-Buzy, L, Petrov-Sanchez, V, André, K, Bernard, N, Caubet, O, Caunegre, L, Chossat, I, Courtault, C, Dauchy, Fa, Dondia, D, Duffau, P, Dutronc, H, Farbos, S, Faure, I, Ferrand, H, Gerard, Y, Greib, C, Hessamfar, M, Imbert, Y, Lataste, P, Marie, J, Mechain, M, Monlun, E, Ochoa, A, Pistone, T, Raymond, I, Receveur, Mc, Rispal, P, Sorin, L, Valette, C, Vandenhende, Ma, Viallard, Jf, Wille, H, Wirth, G, Lafon, Me, Trimoulet, P, Bellecave, P, Tumiotto, C, Haramburu, F, Miremeont-Salamé, G, Blaizeau, Mj, Decoin, M, Hannapier, C, Pougetoux, Elea, Delveaux, S, D'Ivernois, C, Diarra, F, Uwamaliya-Nziyumvira, B, Palmer, G, Conte, V, Sapparrart, V, Moore, R, Edwards, S, Hoy, J, Watson, K, Roth, N, Lau, H, Bloch, M, Baker, D, Carr, A, Cooper, D, O'Sullivan, M, Nolan, D, Guelfi, G, Domingo, P, Sambeat, Ma, Gatell, J, Del Cacho, E, Cadafalch, J, Fuster, M, Codina, C, Sirera, G, Vaqué, A, Clumeck, N, Gennotte, Af, Gerard, M, Kabeya, K, Konopnicki, D, Libois, A, Martin, C, Payen, Mc, Semaille, P, Van Laethem, Y, Neaton, J, Krum, E, Thompson, G, Luskin-Hawk, R, Telzak, E, Abrams, Di, Cohn, D, Markowitz, N, Arduino, R, Mushatt, D, Friedland, G, Perez, G, Tedaldi, E, Fisher, E, Gordin, F, Crane, Lr, Sampson, J, Baxter, J, Gazzard, B, Horban, A, Karpov, I, Losso, M, Pedersen, C, Ristola, M, Phillips, A, Rockstroh, J, Peters, L, Fischer, Ah, Grønborg Laut, K, Larsen, Jf, Podlekareva, D, Cozzi-Lepri, A, Shepherd, L, Schultze, A, Amele, S, Kundro, M, Schmied, B, Vassilenko, A, Mitsura, Vm, Paduto, D, Florence, E, Vandekerckhove, L, Hadziosmanovic, V, Begovac, J, Machala, L, Jilich, D, Kronborg, G, Benfield, T, Gerstoft, J, Katzenstein, T, Møller, Nf, Ostergaard, L, Wiese, L, Nielsen, Ln, Zilmer, K, Aho, I, Viard, Jp, Girard, Pm, Duvivier, C, Degen, O, Stellbrink, Hj, Stefan, C, Bogner, J, Chkhartishvili, N, Gargalianos, P, Szlávik, J, Gottfredsson, M, Mulcahy, F, Yust, I, Turner, D, Burke, M, Shahar, E, Hassoun, G, Elinav, H, Haouzi, M, Elbirt, D, Sthoeger, Zm, Esposito, R, Mazeu, I, Mussini, C, Mazzotta, F, Gabbuti, A, Vullo, V, Lichtner, M, Zaccarelli, M, Antinori, A, Acinapura, R, Plazzi, M, Lazzarin, A, Castagna, A, Gianotti, N, Galli, M, Ridolfo, A, Rozentale, B, Uzdaviniene, V, Staub, T, Ormaasen, V, Maeland, A, Bruun, J, Knysz, B, Gasiorowski, J, Inglot, M, Bakowska, E, Flisiak, R, Grzeszczuk, A, Parczewski, M, Maciejewska, K, Aksak-Was, B, Beniowski, M, Mularska, E, Smiatacz, T, Gensing, M, Jablonowska, E, Malolepsza, E, Wojcik, K, Mozer-Lisewska, I, Caldeira, L, Radoi, R, Panteleev, A, Yakovlev, A, Trofimora, T, Khromova, I, Kuzovatova, E, Borodulina, E, Vdoushkina, E, Jevtovic, D, Tomazic, J, Gatell, Jm, Miró, Jm, Moreno, S, Rodriguez, Jm, Clotet, B, Jou, A, Paredes, R, Tural, C, Puig, J, Bravo, I, Gutierrez, M, Mateo, G, Laporte, Jm, Falconer, K, Thalme, A, Sonnerborg, A, Blaxhult, A, Flamholc, L, Cavassini, M, Calmy, A, Furrer, H, Schmid, P, Kuznetsova, A, Kyselyova, G, Sluzhynska, M, Johnson, Am, Simons, E, Johnson, Ma, Orkin, C, Weber, J, Scullard, G, Clarke, A, Leen, C, Thulin, G, Åkerlund, B, Koppel, K, Karlsson, A, Håkangård, C, Castelli, F, Cauda, R, Di Perri, G, Iardino, R, Ippolito, G, Marchetti, Gc, Perno, Cf, von Schloesser, F, Viale, P, Ceccherini-Silberstein, F, Girardi, E, Lo Caputo, S, Puoti, M, Andreoni, M, Ammassari, A, Balotta, C, Bandera, A, Bonfanti, P, Bonora, S, Borderi, M, Calcagno, A, Calza, L, Capobianchi, Mr, Cingolani, A, Cinque, P, De Luca, A, Di Biagio, A, Gori, A, Guaraldi, G, Lapadula, G, Madeddu, G, Maggiolo, F, Marchetti, G, Marcotullio, S, Monno, L, Nozza, S, Quiros Roldan, E, Rossotti, R, Rusconi, S, Santoro, Mm, Saracino, A, Galli, L, Lorenzini, P, Rodano, A, Shanyinde, M, Carletti, F, Carrara, S, Di Caro, A, Graziano, S, Petrone, F, Prota, G, Quartu, S, Truffa, S, Giacometti, A, Costantini, A, Barocci, V, Angarano, G, Santoro, C, Suardi, C, Donati, V, Verucchi, G, Minardi, C, Quirino, T, Abeli, C, Manconi, Pe, Piano, P, Cacopardo, B, Celesia, B, Vecchiet, J, Falasca, K, Pan, A, Lorenzotti, S, Sighinolfi, L, Segala, D, Vichi, F, Cassola, G, Viscoli, C, Alessandrini, A, Bobbio, N, Mazzarello, G, Mastroianni, C, Belvisi, V, Caramma, I, Chiodera, A, Milini, P, Rizzardini, G, Moioli, Mc, Piolini, R, Ridolfo, Al, Salpietro, S, Tincati, C, Puzzolante, C, Abrescia, N, Chirianni, A, Borgia, G, Orlando, R, Bonadies, G, Di Martino, F, Gentile, I, Maddaloni, L, Cattelan, Am, Marinello, S, Cascio, A, Colomba, C, Baldelli, F, Schiaroli, E, Parruti, G, Sozio, F, Magnani, G, Ursitti, Ma, Cristaudo, A, Baldin, G, Capozzi, M, Cicalini, S, Fontanelli Sulekova, L, Iaiani, G, Latini, A, Mastrorosa, I, Plazzi, Mm, Savinelli, S, Vergori, A, Cecchetto, M, Viviani, F, Bagella, P, Rossetti, B, Franco, A, Fontana Del Vecchio, R, Francisci, D, Di Giuli, C, Caramello, P, Orofino, Gc, Sciandra, M, Bassetti, M, Londero, A, Pellizzer, G, Manfrin, V, Starnini, G, Ialungo, A, Dollet, K, Dellamonica, P, Bernard, E, Courjon, J, Cua, E, De Salvador-Guillouet, F, Durant, J, Etienne, C, Ferrando, S, Mondain-Miton, V, Naqvi, A, Perbost, I, Pillet, S, Prouvost-Keller, B, Pugliese, P, Rio, V, Risso, K, Roger, Pm, Aubert, V, Battegay, M, Bernasconi, E, Böni, J, Braun, Dl, Bucher, H, Ciuffi, A, Dollenmaier, G, Egger, M, Elzi, L, Fehr, J, Fellay, J, Günthard, Hf, Haerry, D, Hasse, B, Hirsch, Hh, Hoffmann, M, Hösli, I, Kahlert, C, Kaiser, L, Keiser, O, Klimkait, T, Kouyos, Rd, Ledergerber, B, Martinetti, G, Martinez de Tejada, B, Marzolini, C, Metzner, Kj, Müller, N, Nicca, D, Pantaleo, G, Paioni, P, Rauch, A, Rudin, C, Scherrer, Au, Speck, R, Stöckle, M, Tarr, P, Trkola, A, Vernazza, P, Wandeler, G, Yerly, S., Infectious diseases, AII - Infectious diseases, APH - Aging & Later Life, Global Health, Paediatric Infectious Diseases / Rheumatology / Immunology, AII - Inflammatory diseases, AII - Amsterdam institute for Infection and Immunity, General Internal Medicine, APH - Quality of Care, Graduate School, Center of Experimental and Molecular Medicine, Medical Microbiology and Infection Prevention, Gastroenterology and Hepatology, ARD - Amsterdam Reproduction and Development, Hatleberg, Camilla I, Ryom, Lene, El-Sadr, Wafaa, Mocroft, Amanda, Reiss, Peter, De Wit, Stephane, Dabis, Francoi, Pradier, Christian, d'Arminio Monforte, Antonella, Kovari, Helen, Law, Matthew, Lundgren, Jens D, Sabin, Caroline A, Dad, Study, Castagna, A, Infektiosairauksien yksikkö, Department of Medicine, Clinicum, HUS Inflammation Center, HUS Internal Medicine and Rehabilitation, MUMC+: DA MMI AIOS (9), MUMC+: DA MMI Infectieserologie (9), Med Microbiol, Infect Dis & Infect Prev, MUMC+: DA MMI Staf (9), RS: FHML non-thematic output, and University of Zurich

Subjects
Male, Cardiovascular disease, gender, cardiovascular disease interventions, cohort studies, HIV, women, myocardial infarction, stroke, Heart disease, Psychological intervention, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], 030204 cardiovascular system & hematology, Santé publique, ACUTE CORONARY SYNDROME, 10234 Clinic for Infectious Diseases, Cohort Studies, 0302 clinical medicine, Risk Factors, HIV Seropositivity, Medicine and Health Sciences, IN-HOSPITAL MORTALITY, 030212 general & internal medicine, Pathologie maladies infectieuses, Stroke, Research Articles, PRESENTATION, GENERAL-POPULATION, INFECTED PATIENTS, Sex Characteristics, Confounding, Middle Aged, 3. Good health, Infectious Diseases, Cardiovascular Diseases, Cardiovascular disease interventions, Cohort studies, Gender, Hiv, Myocardial infarction, Women, symbols, Female, Cohort study, Research Article, Adult, medicine.medical_specialty, Acute coronary syndrome, ACUTE MYOCARDIAL-INFARCTION, SEX-DIFFERENCES, SYMPTOM PRESENTATION, education, 610 Medicine & health, HEART-DISEASE, NO, INFECTED, 03 medical and health sciences, symbols.namesake, Internal medicine, cardiovascular disease intervention, PATIENTS, medicine, Humans, SYMPTOM, Poisson regression, IN-HOSPITAL, business.industry, MORTALITY, CLINICAL PRESENTATION, Public Health, Environmental and Occupational Health, 2739 Public Health, Environmental and Occupational Health, 2725 Infectious Diseases, medicine.disease, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], 10036 Medical Clinic, 3121 General medicine, internal medicine and other clinical medicine, RISK-FACTORS, Observational study, business, cohort studie
Abstract

There is paucity of data related to potential gender differences in the use of interventions to prevent and treat cardiovascular disease (CVD) among HIV-positive individuals. We investigated whether such differences exist in the observational D:A:D cohort study. Methods: Participants were followed from study enrolment until the earliest of death, six months after last visit or February 1, 2015. Initiation of CVD interventions [lipid-lowering drugs (LLDs), angiotensin-converting enzyme inhibitors (ACEIs), anti-hypertensives, invasive cardiovascular procedures (ICPs) were investigated and Poisson regression models calculated whether rates were lower among women than men, adjusting for potential confounders. Results: Women (n = 12,955) were generally at lower CVD risk than men (n = 36,094). Overall, initiation rates of CVD interventions were lower in women than men; LLDs: incidence rate 1.28 [1.21, 1.35] vs. 2.40 [2.34, 2.46]; ACEIs: 0.88 [0.82, 0.93] vs. 1.43 [1.39, 1.48]; anti-hypertensives: 1.40 [1.33, 1.47] vs. 1.72 [1.68, 1.77] and ICPs: 0.08 [0.06, 0.10] vs. 0.30 [0.28, 0.32], and this was also true for most CVD interventions when exclusively considering periods of follow-up for which individuals were at high CVD risk. In fully adjusted models, women were less likely to receive CVD interventions than men (LLDs: relative rate 0.83 [0.78, 0.88]; ACEIs: 0.93 [0.86, 1.01]; ICPs: 0.54 [0.43, 0.68]), except for the receipt of anti-hypertensives (1.17 [1.10, 1.25]). Conclusion: The use of most CVD interventions was lower among women than men. Interventions are needed to ensure that all HIV-positive persons, particularly women, are appropriately monitored for CVD and, if required, receive appropriate CVD interventions., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2018

40. Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration

Author

Ferran Torres, Roberto CAUDA, Hamish McManus, Jens Lundgren, Clifford Leen, Giuseppe Ippolito, CARLO FEDERICO PERNO, Vicente Soriano, Sergio Lo Caputo, Matthew Law, Linos Vandekerckhove, Colette Smith, Matti Ristola, Antonella D'Arminio Monforte, Lars Østergaard, Justyna Kowalska, Caroline Sabin, Terese L Katzenstein, GUIDO CAMANNI, Bart Rijnders, Agnes LIBOIS, ANDREA COSTANTINI, Robert Colebunders, University of Zurich, Smith, Colette J, AII - Amsterdam institute for Infection and Immunity, APH - Amsterdam Public Health, Global Health, Other departments, Infectious diseases, Paediatric Infectious Diseases / Rheumatology / Immunology, Other Research, Obstetrics and Gynaecology, General Internal Medicine, Center of Experimental and Molecular Medicine, Medical Microbiology and Infection Prevention, Smith, Colette J., Ryom, Lene, Weber, Rainer, Morlat, Philippe, Pradier, Christian, Reiss, Peter, Kowalska, Justyna D., De Wit, Stephane, Law, Matthew, Sadr, Wafaael, Kirk, Ole, Friis moller, Nina, D'arminio Monforte, Antonella, Phillips, Andrew N., Sabin, Caroline A., Lundgren, Jens D., D:a:d Study, Group, Castagna, Antonella, Med Microbiol, Infect Dis & Infect Prev, RS: CAPHRI School for Public Health and Primary Care, Interne Geneeskunde, and RS: CAPHRI - Public Health: Infectious diseases and antibiotic resistance

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Population, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], 610 Medicine & health, HIV Infections, 2700 General Medicine, 10234 Clinic for Infectious Diseases, symbols.namesake, Liver disease, Risk Factors, Cause of Death, Medicine, Humans, Poisson regression, Poisson Distribution, education, Adverse effect, Cause of death, education.field_of_study, Acquired Immunodeficiency Syndrome, business.industry, Mortality rate, Medicine (all), Australia, General Medicine, Hepatitis C, Middle Aged, medicine.disease, United States, Europe, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], symbols, Female, business, Cause of Death/ trends, Europe/epidemiology, HIV Infections/ mortality, Cohort study
Abstract

Contains fulltext : 137128.pdf (Publisher’s version ) (Closed access) BACKGROUND: With the advent of effective antiretroviral treatment, the life expectancy for people with HIV is now approaching that seen in the general population. Consequently, the relative importance of other traditionally non-AIDS-related morbidities has increased. We investigated trends over time in all-cause mortality and for specific causes of death in people with HIV from 1999 to 2011. METHODS: Individuals from the Data collection on Adverse events of anti-HIV Drugs (D:A:D) study were followed up from March, 1999, until death, loss to follow-up, or Feb 1, 2011, whichever occurred first. The D:A:D study is a collaboration of 11 cohort studies following HIV-1-positive individuals receiving care at 212 clinics in Europe, USA, and Australia. All fatal events were centrally validated at the D:A:D coordinating centre using coding causes of death in HIV (CoDe) methodology. We calculated relative rates using Poisson regression. FINDINGS: 3909 of the 49,731 D:A:D study participants died during the 308,719 person-years of follow-up (crude incidence mortality rate, 12.7 per 1000 person-years [95% CI 12.3-13.1]). Leading underlying causes were: AIDS-related (1123 [29%] deaths), non-AIDS-defining cancers (590 [15%] deaths), liver disease (515 [13%] deaths), and cardiovascular disease (436 [11%] deaths). Rates of all-cause death per 1000 person-years decreased from 17.5 in 1999-2000 to 9.1 in 2009-11; we saw similar decreases in death rates per 1000 person-years over the same period for AIDS-related deaths (5.9 to 2.0), deaths from liver disease (2.7 to 0.9), and cardiovascular disease deaths (1.8 to 0.9). However, non-AIDS cancers increased slightly from 1.6 per 1000 person-years in 1999-2000 to 2.1 in 2009-11 (p=0.58). After adjustment for factors that changed over time, including CD4 cell count, we detected no decreases in AIDS-related death rates (relative rate for 2009-11 vs 1999-2000: 0.92 [0.70-1.22]). However, all-cause (0.72 [0.61-0.83]), liver disease (0.48 [0.32-0.74]), and cardiovascular disease (0.33 [0.20-0.53) death rates still decreased over time. The percentage of all deaths that were AIDS-related (87/256 [34%] in 1999-2000 and 141/627 [22%] in 2009-11) and liver-related (40/256 [16%] in 1999-2000 and 64/627 [10%] in 2009-11) decreased over time, whereas non-AIDS cancers increased (24/256 [9%] in 1999-2000 to 142/627 [23%] in 2009-11). INTERPRETATION: Recent reductions in rates of AIDS-related deaths are linked with continued improvement in CD4 cell count. We hypothesise that the substantially reduced rates of liver disease and cardiovascular disease deaths over time could be explained by improved use of non-HIV-specific preventive interventions. Non-AIDS cancer is now the leading non-AIDS cause and without any evidence of improvement. FUNDING: Oversight Committee for the Evaluation of Metabolic Complications of HAART, with representatives from academia, patient community, US Food and Drug Administration, European Medicines Agency and consortium of AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, ViiV Healthcare, Merck, Pfizer, F Hoffmann-La Roche, and Janssen Pharmaceuticals.

Published
2014

41. Non-AIDS defining cancers in the D:A:D Study--time trends and predictors of survival: a cohort study

Author

Worm, S, Bower, M, Reiss, P, Bonnet, F, Law, M, Fätkenheuer, G, d'Arminio Monforte, A, Abrams, D, Grulich, A, Fontas, E, Kirk, O, Furrer, H, Wit, S, Phillips, A, Lundgren, J, Sabin, C, Butcher, D, Delforge, M, Fanti, I, Franquet, X, Geffard, S, Gras, L, Helweg Larsen, J, Hillebregt, M, Kamara, D, Kjær, J, Krum, E, McManus, H, Meidahl, P, Mocroft, A, Nielsen, J, Powderl, W, Rickenbach, M, Rode, R, Ryom, L, Salbøl Brandt, R, Schmidt Iversen, J, Shortman, N, Sjøl, A, Smith, C, Torres, F, Tverland, J, Wright, S, Zaheri, S, de Wolf, F, Smidt, J, Ristola, M, Katlama, C, Viard, J, Girard, P, Livrozet, J, Vanhems, P, Pradier, C, Dabis, F, Neau, D, Rockstroh, J, Schmidt, R, Degen, O, van Lunzen, J, Stellbrink, H, Staszewski, S, Bogner, J, Gargalianos, P, Kosmidis, J, Perdios, J, Xylomenos, G, Filandras, A, Karabatsaki, E, Panos, G, Sambatakou, H, Banhegyi, D, Mulcahy, F, Burke, M, Turner, D, Yust, I, Hassoun, G, Pollack, S, Maayan, S, Vella, S, Esposito, R, Mazeu, I, Mussini, C, Arici, C, Pristera, R, Gabbuti, A, Mazzotta, F, Lichtner, M, Vullo, V, Boer, K, Geerlings, S, Godfried, M, Kuijpers, T, Lange, J, Nellen, F, Pajkrt, D, Prins, J, Scherpbier, H, Vrouenraets, S, Wit, F, van Vugt, M, van der Meer, J, van der Poll, T, van der Valk, M, Chirianni, A, Gargiulo, M, Montesarchio, E, Antonucci, G, Narciso, P, Testa, A, Vlassi, C, Zaccarelli, M, Castagna, A, Gianotti, N, Lazzarin, A, Galli, M, Ridolfo, A, Rozentale, B, Zeltina, I, Chaplinskas, S, Hemmer, R, Staub, T, Bruun, J, Maeland, A, Ormaasen, V, Lowe, S, Oude Lashof, A, Schreij, G, Gasiorowski, J, Knysz, B, Bakowska, E, Horban, A, Flisiak, R, Grzeszczuk, A, Boron Kaczmarska, A, Parczewski, M, Pynka, M, Beniowski, M, Mularska, E, Trocha, H, Jablonowska, E, Malolepsza, E, Wojcik, K, Antunes, F, Caldeira, L, Doroana, M, Mansinho, K, Maltez, F, Bravenboer, B, Pronk, M, Duiculescu, D, Rakhmanova, A, Zakharova, N, Buzunova, S, Jevtovic, D, Mokráš, M, Staneková, D, Tomazic, J, González Lahoz, J, Labarga, P, Medrano, J, Soriano, V, Moreno, S, Rodriguez, J, Bravo, I, Clotet, B, Jou, A, Paredes, R, Puig, J, Tural, C, Gelinck, L, Nouwen, J, Rijnders, B, Schurink, C, Slobbe, L, Verbon, A, de Vries Sluijs, T, van der Ende, M, van der Feltz, M, Gatell, J, Miró, J, Domingo, P, Gutierrez, M, Mateo, G, Sambeat, M, Karlsson, A, Flamholc, L, Ledergerber, B, Weber, R, Cavassini, M, Francioli, P, Boffi, E, Hirschel, B, Battegay, M, Elzi, L, Chentsova, N, Kravchenko, E, Driessen, G, Hartwig, N, Frolov, V, Kutsyna, G, Servitskiy, S, Krasnov, M, Barton, S, Johnson, A, Mercey, D, Johnson, M, Murphy, M, Scullard, G, Weber, J, Fisher, M, Leen, C, Branger, J, Åkerlund, B, Morfeldt, L, S.u.n.d.s.t.r.ö.m. , A, Thulin, G, Koppel, K, Ho̊kangård, C, Angarano, G, Antinori, A, Armignacco, O, Castelli, F, Cauda, R, Di Perri, G, Iardino, R, Ippolito, G, Moroni, M, Perno, C, Viale, P, Von Schlosser, F, Ammassari, A, Andreoni, M, Balotta, C, Bonfanti, P, Bonora, S, Borderi, M, Capobianchi, M, Ceccherini Silberstein, F, Cinque, P, Cozzi Lepri, A, De Luca, A, Gervasoni, C, Girardi, E, Guaraldi, G, Lo Caputo, S, Madeddu, G, Maggiolo, F, Marchetti, G, Marcotullio, S, Monno, L, Murri, R, Puoti, M, Torti, C, Cicconi, P, Formenti, T, Galli, L, Lorenzini, P, Costantini, A, Giacometti, A, Riva, A, Carrisa, C, Lazzari, G, Verucchi, G, Kauffmann, R, Schippers, E, Minardi, C, Abeli, C, Quirino, T, Manconi, P, Piano, P, Falasca, K, Vecchiet, J, Segala, D, Sighinolfi, L, Alessandrini, A, Cassola, G, Mazzarello, G, Piscopo, R, Viscoli, G, Belvisi, V, Mastroianni, C, Caramma, I, Castelli, P, Chiodera, A, Alleman, M, Bouwhuis, J, Groeneveld, P, Bigoloni, A, Carenzi, L, Galli, A, Moioli, M, Piolini, R, Rizzardini, G, Rossotti, R, Salpietro, S, Spagnuolo, V, Zucchi, P, Bisio, L, Gori, A, Lapadula, G, Abrescia, N, Guida, M, Baldelli, F, Belfiori, B, Parruti, G, Ursini, T, Magnani, G, Ursitti, M, Acinapura, R, Capozzi, M, Gallo, L, Libertone, R, Nicastro, E, Tebano, G, Tozzi, V, d'Avino, A, Mura, M, Caramello, P, Orofino, G, Sciandra, M, Soetekouw, R, ten Kate, R, Manfrin, V, Pellizzer, G, Bernard, E, Caissotti, C, Cua, E, De Salvador Guillouet, F, Dellamonica, P, Dollet, K, Durant, J, Ferrando, S, Mondain Miton, V, Naqvi, A, Perbost, I, Pillet, S, Prouvost Keller, B, Pugliese, P, Rahelinirina, V, Roger, P, Barth, J, Bernasconi, E, Böni, J, Bucher, H, Burton Jeangros, C, Calmy, A, Cellerai, C, Dubs, R, Egger, M, Fehr, J, Flepp, M, Fux, C, Gorgievski, M, Günthard, H, Hasse, B, Hirsch, H, Hösli, I, Kahlert, C, Kaiser, L, Keiser, O, Kind, C, Klimkait, T, Kovari, H, Martinetti, G, Martinez de Tejada, B, Müller, N, Nadal, D, Pantaleo, G, Rauch, A, Regenass, S, Rudin, C, Schmid, P, Schöni Affolter, F, Schüpbach, J, Schultze, D, Speck, R, Taffé, P, Telenti, A, Trkola, A, Vernazza, P, Yerly, S, von Wyl, V, Arend, S, Jolink, H, Kroon, F, de Boer, M, van Dissel, J, van Nieuwkoop, C, van den Broek, P, Pogany, K, den Hollander, J, Kortmann, W, van Twillert, G, Leyten, E, Vriesendorp, R, Kootstra, G, ten Napel, C, Blok, W, Brinkman, K, Frissen, P, Schouten, W, van den Berk, G, Brouwer, A, Juttmann, J, van Kasteren, M, Lettinga, K, Veenstra, J, Mulder, J, Smit, P, Weijer, S, van Gorp, E, Verhagen, D, van Eeden, A, Doedens, R, Scholvinck, E, Sprenger, H, Stek, C, van Assen, S, Dofferhoff, A, Keuter, M, Koopmans, P, de Groot, R, ter Hofstede, H, van der Flier, M, van der Ven, A, Arends, J, Ellerbroek, P, Hoepelman, A, Jaspers, C, Maarschalk Ellerbroek, L, Mudrikova, T, Oosterheert, J, Peters, E, Schneider, M, Wassenberg, M, van der Hilst, J, Bierman, W, Claessen, F, Danner, S, Perenboom, R, bij de Vaate, E, de Jong, E, de Vocht, J, van Agtmael, M, Geelen, S, Wolfs, T, Gisolf, E, Richter, J, van der Berg, C, Stegeman, A, van den Berge, M, Polée, M, van Houte, D, van Vonderen, M, Duits, A, Winkel, C, Chêne, G, Dupon, M, Fleury, H, Lacoste, D, Malvy, D, Mercié, P, Morlat, P, Pellegrin, I, Pellegrin, J, Thiébaut, R, Titier, K, Bruyand, M, Lawson Ayayi, S, Wittkop, L, Bernard, N, Bonnal, F, Caunègre, L, Cazanave, C, Ceccaldi, J, Chambon, D, Chossat, I, Courtaud, K, Dauchy, F, De Witte, S, Duffau, P, Dupont, A, Dutronc, H, Farbos, S, Gaboriau, V, Gemain, M, Gerard, Y, Greib, C, Hessamfar, M, Lafarie Castet, S, Lataste, P, Lazaro, E, Longy Boursier, M, Meraud, J, Monlun, E, Ochoa, A, Pistone, T, Ragnaud, J, Receveur, M, Roger Schmeltz, J, Tchamgoué, S, Thibaut, P, Vandenhende, M, Viallard, J, Moreau, J, P.e.l.l.e.g.r.i.n. , I, Lafon, M, Masquelier, B, Trimoulet, P, Breilh, D, Haramburu, F, Miremont Salamé, G, Blaizeau, M, D'Ivernois, C, Decoin, M, Delaune, J, Delveaux, S, Hanappier, C, Leleux, O, Sicard, X, Uwamaliya Nziyumvira, B, Leray, J, Palmer, G, Touchard, D, Baker, D, Bendall, C, Bloch, M, Carr, A, Cooper, D, Franic, T, Petoumenos, K, Vale, R, Edwards, S, Hoy, J, Moore, R, Nicholson, J, Roth, N, Watson, K, Chuah, J, Ngieng, M, Nolan, D, Skett, J, Cadafalch, J, Calvo, G, Codina, C, Del Cacho, E, Fuster, M, Mateu, S, Sirera, G, Vaqué, A, Clumeck, N, De Wit, S, Gennotte, A, Gerard, M, Kabeya, K, Konopnicki, D, Libois, A, Martin, C, Necsoi, C, Payen, M, Semaille, P, Van Laethem, Y, Bartsch, G, El Sadr, W, Neaton, J, Thompson, G, Wentworth, D, Luskin Hawk, R, Telzak, E, Cohn, D, Markowitz, N, Arduino, R, Mushatt, D, Friedland, G, Perez, G, Tedaldi, E, Fisher, E, Gordin, F, Crane, L, Sampson, J, Baxter, J, Fischer, A, Grint, D, Kjaer, J, Kowalska, J, Peters, L, Podlekareva, D, Reekie, J, Elias, C, Losso, M, Vetter, N, Zangerle, R, Karpov, I, Vassilenko, A, Mitsura, V, Suetnov, O, Colebunders, R, Vandekerckhove, L, Hadziosmanovic, V, Kostov, K, Begovac, J, Jilich, D, Machala, L, Sedlacek, D, Benfield, T, Kronborg, G, Larsen, M, Gerstoft, J, Hansen, A, Katzenstein, T, Skinhøj, P, Pedersen, C, Ostergaard, L, Zilmer, K, Gori, A., GORI, ANDREA, Groupement de Recherche et d'Etudes en Gestion à HEC (GREGH), Ecole des Hautes Etudes Commerciales (HEC Paris)-Centre National de la Recherche Scientifique (CNRS), Department of Pediatrics, Fairview-University Medical Center, Structures et propriétés d'architectures moléculaire (SPRAM - UMR 5819), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Institut Nanosciences et Cryogénie (INAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Observatoire des Micro et Nano Technologies (OMNT - UMS 2920), Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information (CEA-LETI), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Université Paris 1 Panthéon-Sorbonne - UFR d'Économie (UP1 UFR02), Université Paris 1 Panthéon-Sorbonne (UP1), Laboratory, Royal GD [Deventer], Economics, Umeå University, Research Department of Infection and Population Health [London], University College of London [London] (UCL), Clinicum, Department of Medicine, Infektiosairauksien yksikkö, Worm, S, Bower, M, Reiss, P, Bonnet, F, Law, M, Fätkenheuer, G, d'Arminio Monforte, A, Abrams, D, Grulich, A, Fontas, E, Kirk, O, Furrer, H, Wit, S, Phillips, A, Lundgren, J, Sabin, C, Butcher, D, Delforge, M, Fanti, I, Franquet, X, Geffard, S, Gras, L, Helweg Larsen, J, Hillebregt, M, Kamara, D, Kjær, J, Krum, E, Mcmanus, H, Meidahl, P, Mocroft, A, Nielsen, J, Powderl, W, Rickenbach, M, Rode, R, Ryom, L, Salbøl Brandt, R, Schmidt Iversen, J, Shortman, N, Sjøl, A, Smith, C, Torres, F, Tverland, J, Wright, S, Zaheri, S, de Wolf, F, Smidt, J, Ristola, M, Katlama, C, Viard, J, Girard, P, Livrozet, J, Vanhems, P, Pradier, C, Dabis, F, Neau, D, Rockstroh, J, Schmidt, R, Degen, O, van Lunzen, J, Stellbrink, H, Staszewski, S, Bogner, J, Gargalianos, P, Kosmidis, J, Perdios, J, Xylomenos, G, Filandras, A, Karabatsaki, E, Panos, G, Sambatakou, H, Banhegyi, D, Mulcahy, F, Burke, M, Turner, D, Yust, I, Hassoun, G, Pollack, S, Maayan, S, Vella, S, Esposito, R, Mazeu, I, Mussini, C, Arici, C, Pristera, R, Gabbuti, A, Mazzotta, F, Lichtner, M, Vullo, V, Boer, K, Geerlings, S, Godfried, M, Kuijpers, T, Lange, J, Nellen, F, Pajkrt, D, Prins, J, Scherpbier, H, Vrouenraets, S, Wit, F, van Vugt, M, van der Meer, J, van der Poll, T, van der Valk, M, Chirianni, A, Gargiulo, M, Montesarchio, E, Antonucci, G, Narciso, P, Testa, A, Vlassi, C, Zaccarelli, M, Castagna, A, Gianotti, N, Lazzarin, A, Galli, M, Ridolfo, A, Rozentale, B, Zeltina, I, Chaplinskas, S, Hemmer, R, Staub, T, Bruun, J, Maeland, A, Ormaasen, V, Lowe, S, Oude Lashof, A, Schreij, G, Gasiorowski, J, Knysz, B, Bakowska, E, Horban, A, Flisiak, R, Grzeszczuk, A, Boron Kaczmarska, A, Parczewski, M, Pynka, M, Beniowski, M, Mularska, E, Trocha, H, Jablonowska, E, Malolepsza, E, Wojcik, K, Antunes, F, Caldeira, L, Doroana, M, Mansinho, K, Maltez, F, Bravenboer, B, Pronk, M, Duiculescu, D, Rakhmanova, A, Zakharova, N, Buzunova, S, Jevtovic, D, Mokráš, M, Staneková, D, Tomazic, J, González Lahoz, J, Labarga, P, Medrano, J, Soriano, V, Moreno, S, Rodriguez, J, Bravo, I, Clotet, B, Jou, A, Paredes, R, Puig, J, Tural, C, Gelinck, L, Nouwen, J, Rijnders, B, Schurink, C, Slobbe, L, Verbon, A, de Vries Sluijs, T, van der Ende, M, van der Feltz, M, Gatell, J, Miró, J, Domingo, P, Gutierrez, M, Mateo, G, Sambeat, M, Karlsson, A, Flamholc, L, Ledergerber, B, Weber, R, Cavassini, M, Francioli, P, Boffi, E, Hirschel, B, Battegay, M, Elzi, L, Chentsova, N, Kravchenko, E, Driessen, G, Hartwig, N, Frolov, V, Kutsyna, G, Servitskiy, S, Krasnov, M, Barton, S, Johnson, A, Mercey, D, Johnson, M, Murphy, M, Scullard, G, Weber, J, Fisher, M, Leen, C, Branger, J, Åkerlund, B, Morfeldt, L, S. u. n. d. s. t. r. ö. m., A, Thulin, G, Koppel, K, Ho̊kangård, C, Angarano, G, Antinori, A, Armignacco, O, Castelli, F, Cauda, R, Di Perri, G, Iardino, R, Ippolito, G, Moroni, M, Perno, C, Viale, P, Von Schlosser, F, Ammassari, A, Andreoni, M, Balotta, C, Bonfanti, P, Bonora, S, Borderi, M, Capobianchi, M, Ceccherini Silberstein, F, Cinque, P, Cozzi Lepri, A, De Luca, A, Gervasoni, C, Girardi, E, Gori, A, Guaraldi, G, Lo Caputo, S, Madeddu, G, Maggiolo, F, Marchetti, G, Marcotullio, S, Monno, L, Murri, R, Puoti, M, Torti, C, Cicconi, P, Formenti, T, Galli, L, Lorenzini, P, Costantini, A, Giacometti, A, Riva, A, Carrisa, C, Lazzari, G, Verucchi, G, Kauffmann, R, Schippers, E, Minardi, C, Abeli, C, Quirino, T, Manconi, P, Piano, P, Falasca, K, Vecchiet, J, Segala, D, Sighinolfi, L, Alessandrini, A, Cassola, G, Mazzarello, G, Piscopo, R, Viscoli, G, Belvisi, V, Mastroianni, C, Caramma, I, Castelli, P, Chiodera, A, Alleman, M, Bouwhuis, J, Groeneveld, P, Bigoloni, A, Carenzi, L, Galli, A, Moioli, M, Piolini, R, Rizzardini, G, Rossotti, R, Salpietro, S, Spagnuolo, V, Zucchi, P, Bisio, L, Lapadula, G, Abrescia, N, Guida, M, Baldelli, F, Belfiori, B, Parruti, G, Ursini, T, Magnani, G, Ursitti, M, Acinapura, R, Capozzi, M, Gallo, L, Libertone, R, Nicastro, E, Tebano, G, Tozzi, V, D'Avino, A, Mura, M, Caramello, P, Orofino, G, Sciandra, M, Soetekouw, R, ten Kate, R, Manfrin, V, Pellizzer, G, Bernard, E, Caissotti, C, Cua, E, De Salvador Guillouet, F, Dellamonica, P, Dollet, K, Durant, J, Ferrando, S, Mondain Miton, V, Naqvi, A, Perbost, I, Pillet, S, Prouvost Keller, B, Pugliese, P, Rahelinirina, V, Roger, P, Barth, J, Bernasconi, E, Böni, J, Bucher, H, Burton Jeangros, C, Calmy, A, Cellerai, C, Dubs, R, Egger, M, Fehr, J, Flepp, M, Fux, C, Gorgievski, M, Günthard, H, Hasse, B, Hirsch, H, Hösli, I, Kahlert, C, Kaiser, L, Keiser, O, Kind, C, Klimkait, T, Kovari, H, Martinetti, G, Martinez de Tejada, B, Müller, N, Nadal, D, Pantaleo, G, Rauch, A, Regenass, S, Rudin, C, Schmid, P, Schöni Affolter, F, Schüpbach, J, Schultze, D, Speck, R, Taffé, P, Telenti, A, Trkola, A, Vernazza, P, Yerly, S, von Wyl, V, Arend, S, Jolink, H, Kroon, F, de Boer, M, van Dissel, J, van Nieuwkoop, C, van den Broek, P, Pogany, K, den Hollander, J, Kortmann, W, van Twillert, G, Leyten, E, Vriesendorp, R, Kootstra, G, ten Napel, C, Blok, W, Brinkman, K, Frissen, P, Schouten, W, van den Berk, G, Brouwer, A, Juttmann, J, van Kasteren, M, Lettinga, K, Veenstra, J, Mulder, J, Smit, P, Weijer, S, van Gorp, E, Verhagen, D, van Eeden, A, Doedens, R, Scholvinck, E, Sprenger, H, Stek, C, van Assen, S, Dofferhoff, A, Keuter, M, Koopmans, P, de Groot, R, ter Hofstede, H, van der Flier, M, van der Ven, A, Arends, J, Ellerbroek, P, Hoepelman, A, Jaspers, C, Maarschalk Ellerbroek, L, Mudrikova, T, Oosterheert, J, Peters, E, Schneider, M, Wassenberg, M, van der Hilst, J, Bierman, W, Claessen, F, Danner, S, Perenboom, R, bij de Vaate, E, de Jong, E, de Vocht, J, van Agtmael, M, Geelen, S, Wolfs, T, Gisolf, E, Richter, J, van der Berg, C, Stegeman, A, van den Berge, M, Polée, M, van Houte, D, van Vonderen, M, Duits, A, Winkel, C, Chêne, G, Dupon, M, Fleury, H, Lacoste, D, Malvy, D, Mercié, P, Morlat, P, Pellegrin, I, Pellegrin, J, Thiébaut, R, Titier, K, Bruyand, M, Lawson Ayayi, S, Wittkop, L, Bernard, N, Bonnal, F, Caunègre, L, Cazanave, C, Ceccaldi, J, Chambon, D, Chossat, I, Courtaud, K, Dauchy, F, De Witte, S, Duffau, P, Dupont, A, Dutronc, H, Farbos, S, Gaboriau, V, Gemain, M, Gerard, Y, Greib, C, Hessamfar, M, Lafarie Castet, S, Lataste, P, Lazaro, E, Longy Boursier, M, Meraud, J, Monlun, E, Ochoa, A, Pistone, T, Ragnaud, J, Receveur, M, Roger Schmeltz, J, Tchamgoué, S, Thibaut, P, Vandenhende, M, Viallard, J, Moreau, J, P. e. l. l. e. g. r. i. n., I, Lafon, M, Masquelier, B, Trimoulet, P, Breilh, D, Haramburu, F, Miremont Salamé, G, Blaizeau, M, D'Ivernois, C, Decoin, M, Delaune, J, Delveaux, S, Hanappier, C, Leleux, O, Sicard, X, Uwamaliya Nziyumvira, B, Leray, J, Palmer, G, Touchard, D, Baker, D, Bendall, C, Bloch, M, Carr, A, Cooper, D, Franic, T, Petoumenos, K, Vale, R, Edwards, S, Hoy, J, Moore, R, Nicholson, J, Roth, N, Watson, K, Chuah, J, Ngieng, M, Nolan, D, Skett, J, Cadafalch, J, Calvo, G, Codina, C, Del Cacho, E, Fuster, M, Mateu, S, Sirera, G, Vaqué, A, Clumeck, N, De Wit, S, Gennotte, A, Gerard, M, Kabeya, K, Konopnicki, D, Libois, A, Martin, C, Necsoi, C, Payen, M, Semaille, P, Van Laethem, Y, Bartsch, G, El Sadr, W, Neaton, J, Thompson, G, Wentworth, D, Luskin Hawk, R, Telzak, E, Cohn, D, Markowitz, N, Arduino, R, Mushatt, D, Friedland, G, Perez, G, Tedaldi, E, Fisher, E, Gordin, F, Crane, L, Sampson, J, Baxter, J, Fischer, A, Grint, D, Kjaer, J, Kowalska, J, Peters, L, Podlekareva, D, Reekie, J, Elias, C, Losso, M, Vetter, N, Zangerle, R, Karpov, I, Vassilenko, A, Mitsura, V, Suetnov, O, Colebunders, R, Vandekerckhove, L, Hadziosmanovic, V, Kostov, K, Begovac, J, Jilich, D, Machala, L, Sedlacek, D, Benfield, T, Kronborg, G, Larsen, M, Gerstoft, J, Hansen, A, Katzenstein, T, Skinhøj, P, Pedersen, C, Ostergaard, L, Zilmer, K, Internal medicine, Pediatric surgery, Plastic, Reconstructive and Hand Surgery, CCA - Innovative therapy, IOO, Worm, Signe W., Bower, Mark, Reiss, Peter, Bonnet, Fabrice, Law, Matthew, Fã¤tkenheuer, Gerd, D'arminio Monforte, Antonella, Abrams, Donald I., Grulich, Andrew, Fontas, Eric, Kirk, Ole, Furrer, Hansjakob, Wit, Stephane D., Phillips, Andrew, Lundgren, Jens D., Sabin, Caroline A., D:A:D Study, Group, Experimental Psychology, Groningen Research Institute for Asthma and COPD (GRIAC), Amsterdam institute for Infection and Immunity, Amsterdam Public Health, Global Health, Other departments, Infectious diseases, Paediatric Infectious Diseases / Rheumatology / Immunology, Other Research, Obstetrics and Gynaecology, General Internal Medicine, Center of Experimental and Molecular Medicine, Medical Microbiology and Infection Prevention, Institut Nanosciences et Cryogénie (INAC), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Kaplan Meier method, proportional hazards model, SWISS HIV COHORT, HIV Infections, 0302 clinical medicine, 1108 Medical Microbiology, cancer diagnosis, Prospective Studies, Pathologie maladies infectieuses, cancer survival, ComputingMilieux_MISCELLANEOUS, IMMUNODEFICIENCY, Incidence, Sciences bio-médicales et agricoles, cohort analysis, Prognosis, 3. Good health, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, D:A:D Study Group, risk factor, 030220 oncology & carcinogenesis, Cohort, Cohort study, prospective study, Human, medicine.medical_specialty, Prognosi, HIV, Non-AIDS defining cancers, Trends, Adult, Anti-HIV Agents, Antiretroviral Therapy, Highly Active, CD4 Lymphocyte Count, Female, Humans, Kaplan-Meier Estimate, Middle Aged, Neoplasms, Infectious Diseases, non AIDS defining cancer, Microbiology, cancer prognosis, 03 medical and health sciences, death, Anal cancer, Risk factor, Proportional hazards model, HIV Infections -- drug therapy -- mortality, Anti-HIV Agent, Anti-HIV Agents/therapeutic use, Antiretroviral Therapy, HIV Infections/drug therapy/ mortality, medicine.disease, major clinical study, mortality, Prospective Studie, age, Neoplasms -- mortality, observational study, cancer incidence, anus cancer, gender, Trend, Medicine and Health Sciences, HIV Infection, 030212 general & internal medicine, Prospective cohort study, survival prediction, RISK, INFECTED PATIENTS, ACTIVE ANTIRETROVIRAL THERAPY, Incidence (epidemiology), article, Human immunodeficiency virus infected patient, ANAL CANCER, Non-AIDS defining cancer, Anti-HIV Agents -- therapeutic use, ethnicity, 0605 Microbiology, Research Article, Hodgkin disease, UNITED-STATES, 610 Medicine & health, smoking, NO, MALIGNANCIES, Internal medicine, mental disorders, medicine, follow up, Highly Active, controlled study, Lung cancer, HODGKINS-DISEASE, disseminated cancer, business.industry, 1103 Clinical Sciences, BONE-MARROW-TRANSPLANTATION, Surgery, lung cancer, 3121 General medicine, internal medicine and other clinical medicine, Neoplasm, business
Abstract

Non-AIDS defining cancers (NADC) are an important cause of morbidity and mortality in HIV-positive individuals. Using data from a large international cohort of HIV-positive individuals, we described the incidence of NADC from 2004-2010, and described subsequent mortality and predictors of these., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2013

42. Associations between immune depression and cardiovascular events in HIV infection

Author

Ferran Torres, Roberto CAUDA, Jens Lundgren, William Powderly, Clifford Leen, Giuseppe Ippolito, CARLO FEDERICO PERNO, Vicente Soriano, Matthew Law, Gianpiero Tebano, Linos Vandekerckhove, Daniela Segala, Matti Ristola, STEFANO VELLA, Antonella D'Arminio Monforte, Lars Østergaard, Caroline Sabin, Terese L Katzenstein, Bart Rijnders, ANDREA COSTANTINI, Sabin, C, Ryom, L, Wit, S, Mocroft, A, Phillips, A, Worm, S, Weber, R, Monforte, A, Reiss, P, Kamara, D, El Sadr, W, Pradier, C, Dabis, F, Law, M, Lundgren, J, Gori, A, University of Zurich, Sabin, Caroline A, Sabin, Caroline A., Ryom, Lene, Wit, Stephane De, Mocroft, Amanda, Phillips, Andrew N., Worm, Signe W., Weber, Rainer, Monforte, Antonella D'arminio, Reiss, Peter, Kamara, David, El sadr, Wafaa, Pradier, Christian, Dabis, Francoi, Law, Matthew, Lundgren, Jen, D:a:d Study, Group, Castagna, Antonella, Amsterdam institute for Infection and Immunity, Amsterdam Public Health, Global Health, Other departments, Infectious diseases, Paediatric Infectious Diseases / Rheumatology / Immunology, Other Research, Obstetrics and Gynaecology, General Internal Medicine, and Center of Experimental and Molecular Medicine

Subjects
Male, HIV Infections, Longitudinal Studie, Cohort Studies, 10234 Clinic for Infectious Diseases, 0302 clinical medicine, CD4+ lymphocyte count, 80 and over, Immunology and Allergy, HIV Infection, 030212 general & internal medicine, Myocardial infarction, Longitudinal Studies, Child, Stroke, Aged, 80 and over, Incidence (epidemiology), Incidence, CD4 Lymphocyte Count, Cardiovascular Diseases/ epidemiology, complications, immunology, Middle Aged, Cardiovascular disease, 3. Good health, Infectious Diseases, Cardiovascular Diseases, Child, Preschool, symbols, Cardiology, 2723 Immunology and Allergy, Female, Cohort study, Human, Adult, medicine.medical_specialty, Adolescent, Immunology, 610 Medicine & health, +, NO, 03 medical and health sciences, symbols.namesake, Young Adult, Bias, Diabetes mellitus, Internal medicine, Bia, medicine, Humans, Poisson regression, cardiovascular diseases, lymphocyte count, Preschool, Aged, 2403 Immunology, business.industry, 2725 Infectious Diseases, medicine.disease, CD4, Confidence interval, Metabolic syndrome, Cohort Studie, business, 030217 neurology & neurosurgery
Abstract

Objective: To consider associations between the latest/nadir CD4 + cell count, and time spent with CD4+ cell count less than 200 cells/ml (duration of immune depression), and myocardial infarction (MI), coronary heart disease (CHD), stroke, or cardiovascular disease (CVD) (CHD or stroke) in 33 301 HIV-positive individuals. Design: Longitudinal cohort study. Methods: Analyses were undertaken using Poisson regression. To investigate whether analyses of stroke were robust to the type of endpoint, we additionally included strokelike events and rejected strokes into the stroke endpoint. Results: Participants experienced 716 MI, 1056 CHD, 303 stroke, and 1284 CVD events. Whereas there was no evidence of a higher MI/CHD risk in those with lower latest/nadir CD4+ cell counts after adjustment [current CD4+

Published
2013

43. Contribution of genetic background, traditional risk factors, and HIV-related factors to coronary artery disease events in HIV-positive persons

Author

Rotger, M, Glass, Tr, Junier, T, Lundgren, J, Neaton, Jd, Poloni, Es, van 't Wout AB, Lubomirov, R, Colombo, S, Martinez, R, Rauch, A, Günthard, Hf, Neuhaus, J, Wentworth, D, van Manen, D, Gras, La, Schuitemaker, H, Albini, L, Torti, C, Jacobson, Lp, Li, X, Kingsley, La, Carli, F, Guaraldi, G, Ford, Es, Sereti, I, Hadigan, C, Martinez, E, Arnedo, M, Egaña-Gorroño, L, Gatell, Jm, Law, M, Bendall, C, Petoumenos, K, Rockstroh, J, Wasmuth, Jc, Kabamba, K, Delforge, M, De Wit, S, Berger, F, Mauss, S, de Paz Sierra, M, Losso, M, Belloso, Wh, Leyes, M, Campins, A, Mondi, A, De Luca, A, Bernardino, I, Barriuso-Iglesias, M, Torrecilla-Rodriguez, A, Gonzalez-Garcia, J, Arribas, Jr, Fanti, I, Gel, S, Puig, J, Negredo, E, Gutierrez, M, Domingo, P, Fischer, J, Fätkenheuer, G, Alonso-Villaverde, C, Macken, A, Woo, J, Mcginty, T, Mallon, P, Mangili, A, Skinner, S, Wanke, Ca, Reiss, P, Weber, R, Bucher, Hc, Fellay, J, Telenti, A, Tarr, Pe, Vullo, V, Magnificent, Consortium, Insight, Swiss HIV Cohort Study, Mastroianni, C, MAGNIFICENT Consortium, Swiss HIV Cohort Study, INSIGHT, Rotger, M., Glass, TR., Lubomirov, R., Bucher, HC., Telenti, A., Tarr, PE., Junier, T., Poloni, ES., Fellay, J., Colombo, S., Martinez, R., Rauch, A., Weber, R., Günthard, HF., Neuhaus, J., Wentworth, D., Lundgren, J., Neaton, JD., van Manen, D., Gras, AL., Schuitemaker, H., van Wout AB., Reiss, P., Albini, L., Torti, C., Jacobson, LP., Li, X., Kingsley, LA., Carli, F., Guaraldi, G., Ford, ES., Sereti, I., Hadigan, C., Martinez, E., Arnedo-Valero, M., Egaña-Gorroño, L., Gatell, JM., Law, M., Bendall, C., Petoumenos, K., Rockstroh, J., Wasmuth, JC., Kabamba, K., Delforge, M., De Wit, S., Berger, F., Mauss, S., Sierra Mde, P., Losso, M., Belloso, WH., Leyes, M., Campins, A., Mondi, A., De Luca, A., Bernardino, I., Barriuso-Iglesias£££Mónica£££ M., Rodriguez, AT., Garcia, JG., Arribas, JR., Fanti, I., Gel, S., Puig, J., Negredo, E., Gutierrez, M., Domingo, P., Fischer, J., Fätkenheuer, G., Alonso-Villaverde, C., Macken, A., Woo, J., McGinty, T., Mallon, P., Mangili, A., Skinner, S., Wanke, CA., Aubert, V., Barth, J., Battegay, M., Bernasconi, E., Böni, J., Burton-Jeangros, C., Calmy, A., Cavassini, M., Egger, M., Elzi, L., Fehr, J., Francioli, P., Furrer, H., Fux, CA., Gorgievski, M., Günthard, H., Haerry, D., Hasse, B., Hirsch, HH., Hirschel, B., Hösli, I., Kahlert, C., Kaiser, L., Keiser, O., Kind, C., Klimkait, T., Kovari, H., Ledergerber, B., Martinetti, G., Martinez de Tejada, B., Metzner, K., Müller, N., Nadal, D., Pantaleo, G., Regenass, S., Rickenbach, M., Rudin, C., Schmid, P., Schultze, D., Schöni-Affolter, F., Schüpbach, J., Speck, R., Taffé, P., Tarr, P., Trkola, A., Vernazza, P., Prins, YS., Kuijpers, TW., Scherpbier, HJ., Boer, K., van der Meer JT., Wit, FW., Godfried, MH., van der Poll, T., Nellen, FJ., Lange, JM., Geerlings, SE., van Vugt, M., Vrouenraets, SM., Pajkrt, D., Bos, JC., van der Valk, M., Schreij, G., Lowe, S., Lashof, AO., Pronk, MJ., Bravenboer, B., van der Ende ME., de Vries-Sluijs TE., Schurink, CA., van der Feltz, M., Nouwen, JL., Gelinck, LB., Verbon, A., Rijnders, BJ., van de Ven-de Ruiter ED., Slobbe, L., Haag, D., Kauffmann, RH., Schippers, EF., Groeneveld, PH., Alleman, MA., Bouwhuis, JW., ten Kate RW., Soetekouw, R., Kroon, FP., van den Broek PJ., van Dissel JT., Arend, SM., van Nieuwkoop, C., de Boer MJ., Jolink, H., den Hollander JG., Pogany, K., Bronsveld, W., Kortmann, W., van Twillert, G., van Houte DP., Polée, MB., van Vonderen MG., ten Napel CH., Kootstra, GJ., Brinkman, K., Blok, WL., Frissen, PH., Schouten, WE., van den Berk GE., Juttmann, JR., van Kasteren ME., Brouwer, AE., Mulder, JW., van Gorp EC., Smit, PM., Weijer, S., van Eeden, A., Verhagen, DW., Sprenger, HG., Doedens, R., Scholvinck, EH., van Assen, S., Stek, CJ., Hoepelman, IM., Mudrikova, T., Schneider, MM., Jaspers, CA., Ellerbroek, PM., Peters, EJ., Maarschalk-Ellerbroek, LJ., Oosterheert, JJ., Arends, JE., Wassenberg, MW., van der Hilst JC., Richter, C., van der Berg JP., Gisolf, EH., Margolick, JB., Plankey, M., Crain, B., Dobs, A., Farzadegan, H., Gallant, J., Johnson-Hill, L., Sacktor, N., Selnes, O., Shepard, J., Thio, C., Phair, JP., Wolinsky, SM., Badri, S., Conover, C., O'Gorman, M., Ostrow, D., Palella, F., Ragin, A., Detels, R., Martínez-Maza, O., Aronow, A., Bolan, R., Breen, E., Butch, A., Fahey, J., Jamieson, B., Miller, EN., Oishi, J., Vinters, H., Visscher, BR., Wiley, D., Witt, M., Yang, O., Young, S., Zhang, ZF., Rinaldo, CR., Becker, JT., Cranston, RD., Martinson, JJ., Mellors, JW., Silvestre, AJ., Stall, RD., Muñoz, A., Abraham, A., Althoff, K., Cox, C., D'Souza, G., Gange, SJ., Golub, E., Schollenberger, J., Seaberg, EC., Su, S., Huebner, RE., Dominguez, G., Moroni, M., Angarano, G., Antinori, A., Carosi, G., Cauda, R., Monforte£££A d'Arminio£££ A., Di Perri, G., Galli, M., Iardino, R., Ippolito, G., Lazzarin, A., Perno, CF., Sagnelli, E., Viale, PL., Von Schlosser, F., d'Arminio Monforte, A., Ammassari, A., Andreoni, M., Balotta, C., Bonfanti, P., Bonora, S., Borderi, M., Capobianchi, MR., Castagna, A., Ceccherini-Silberstein, F., Cozzi-Lepri, A., Gargiulo, M., Gervasoni, C., Girardi, E., Lichtner, M., Lo Caputo, S., Madeddu, G., Maggiolo, F., Marcotullio, S., Monno, L., Murri, R., Mussini, C., Puoti, M., Formenti, T., Galli, L., Lorenzini, P., Montroni, M., Giacometti, A., Costantini, A., Riva, A., Tirelli, U., Martellotta, F., Ladisa, N., Lazzari, G., Verucchi, G., Castelli, F., Scalzini, A., Minardi, C., Bertelli, D., Quirino, T., Abeli, C., Manconi, PE., Piano, P., Vecchiet, J., Falasca, K., Carnevale, G., Lorenzotti, S., Sighinolfi, L., Segala, D., Leoncini, F., Mazzotta, F., Pozzi, M., Cassola, G., Viscoli, G., Viscoli, A., Piscopo, R., Mazzarello, G., Mastroianni, C., Belvisi, V., Caramma, I., Chiodera, A., Castelli, P., Rizzardini, G., Ridolfo, AL., Foschi, A., Salpietro, S., Galli, A., Bigoloni, A., Spagnuolo, V., Merli, S., Carenzi, L., Moioli, MC., Cicconi, P., Bisio, L., Gori, A., Lapadula, G., Abrescia, N., Chirianni, A., De Marco, M., Ferrari, C., Borghi, R., Baldelli, F., Belfiori, B., Parruti, G., Ursini, T., Magnani, G., Ursitti, MA., Narciso, P., Tozzi, V., Vullo, V., d'Avino, A., Zaccarelli, M., Gallo, L., Acinapura, R., Capozzi, M., Libertone, R., Trotta, MP., Tebano, G., Cattelan, AM., Mura, MS., Caramello, P., Orofino, GC., Sciandra, M., Raise, Ebo, F., Pellizzer, G., Manfrin, V., McManus, H., Wright, S., Moore, R., Edwards, S., Medische Microbiologie, RS: CAPHRI School for Public Health and Primary Care, AII - Amsterdam institute for Infection and Immunity, Experimental Immunology, Other departments, Graduate School, APH - Amsterdam Public Health, Global Health, Medical Microbiology and Infection Prevention, Paediatric Infectious Diseases / Rheumatology / Immunology, Other Research, Obstetrics and Gynaecology, Infectious diseases, General Internal Medicine, Center of Experimental and Molecular Medicine, University of Zurich, Tarr, Philip E, Rotger, M, Glass, T, Junier, T, Lundgren, J, Neaton, J, Poloni, E, Van 'T Wout, A, Lubomirov, R, Colombo, S, Martinez, R, Rauch, A, Günthard, H, Neuhaus, J, Wentworth, D, Van Manen, D, Gras, L, Schuitemaker, H, Albini, L, Torti, C, Jacobson, L, Li, X, Kingsley, L, Carli, F, Guaraldi, G, Ford, E, Sereti, I, Hadigan, C, Martinez, E, Arnedo, M, Egaña Gorroño, L, Gatell, J, Law, M, Bendall, C, Petoumenos, K, Rockstroh, J, Wasmuth, J, Kabamba, K, Delforge, M, De Wit, S, Berger, F, Mauss, S, De Paz Sierra, M, Losso, M, Belloso, W, Leyes, M, Campins, A, Mondi, A, De Luca, A, Bernardino, I, Barriuso Iglesias, M, Torrecilla Rodriguez, A, Gonzalez Garcia, J, Arribas, J, Fanti, I, Gel, S, Puig, J, Negredo, E, Gutierrez, M, Domingo, P, Fischer, J, Fätkenheuer, G, Alonso Villaverde, C, Macken, A, Woo, J, Mcginty, T, Mallon, P, Mangili, A, Skinner, S, Wanke, C, Reiss, P, Weber, R, Bucher, H, Fellay, J, Telenti, A, Tarr, P, Gori, A, Junier, Thomas, Poloni, Estella S., Rotger, Margalida, Glass, Tracy R., Junier, Thoma, Lundgren, Jen, Neaton, James D., Van 't Wout, Angã©lique B., Lubomirov, Rubin, Colombo, Sara, Martinez, Raquel, Rauch, Andri, Gã¼nthard, Huldrych F., Neuhaus, Jacqueline, Wentworth, Deborah, Van Manen, Danielle, Gras, Luuk A., Schuitemaker, Hanneke, Albini, Laura, Torti, Carlo, Jacobson, Lisa P., Li, Xiuhong, Kingsley, Lawrence A., Carli, Federica, Guaraldi, Giovanni, Ford, Emily S., Sereti, Irini, Hadigan, Colleen, Martinez, Esteban, Arnedo, Mireia, Egaã±a gorroã±o, Lander, Gatell, Jose M., Law, Matthew, Bendall, Courtney, Petoumenos, Kathy, Rockstroh, Jã¼rgen, Wasmuth, Jan christian, Kabamba, Kabeya, Delforge, Marc, De Wit, Stephane, Berger, Florian, Mauss, Stefan, De Paz Sierra, Mariana, Losso, Marcelo, Belloso, Waldo H., Leyes, Maria, Campins, Antoni, Mondi, Annalisa, De Luca, Andrea, Bernardino, Ignacio, Barriuso iglesias, Mã³nica, Torrecilla rodriguez, Ana, Gonzalez garcia, Juan, Arribas, Josã© R., Fanti, Iuri, Gel, Silvia, Puig, Jordi, Negredo, Eugenia, Gutierrez, Mar, Domingo, Pere, Fischer, Julia, Fã¤tkenheuer, Gerd, Alonso villaverde, Carlo, Macken, Alan, Woo, Jame, Mcginty, Tara, Mallon, Patrick, Mangili, Alexandra, Skinner, Sally, Wanke, Christine A., Reiss, Peter, Weber, Rainer, Bucher, Heiner C., Fellay, Jacque, Telenti, Amalio, Tarr, Philip E. Swiss Hiv Cohort, and Castagna, Antonella

Subjects
Male, HIV Infections, Genome-wide association study, 030204 cardiovascular system & hematology, 2726 Microbiology (medical), 10234 Clinic for Infectious Diseases, Coronary artery disease, 0302 clinical medicine, ddc:590, Risk Factors, Abacavir, 80 and over, genetics, 030212 general & internal medicine, Family history, Articles and Commentaries, Aged, 80 and over, education.field_of_study, medicine.diagnostic_test, traditional risk factor, Single Nucleotide, Middle Aged, 3. Good health, Infectious Diseases, traditional risk factors, Cohort, Female, HIV infection, antiretroviral therapy, coronary artery disease, Human, medicine.drug, Adult, Microbiology (medical), medicine.medical_specialty, Adolescent, Population, Infectious Disease, 610 Medicine & health, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease, Aged, Coronary Artery Disease, Humans, Polymorphism, Young Adult, 03 medical and health sciences, Internal medicine, medicine, education, Genetic testing, business.industry, Risk Factor, 2725 Infectious Diseases, Odds ratio, medicine.disease, Immunology, genetic, business
Abstract

BACKGROUND: Persons infected with human immunodeficiency virus (HIV) have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the setting of HIV infection.METHODS: In the general population, 23 common single-nucleotide polymorphisms (SNPs) were shown to be associated with CAD through genome-wide association analysis. Using the Metabochip, we genotyped 1875 HIV-positive, white individuals enrolled in 24 HIV observational studies, including 571 participants with a first CAD event during the 9-year study period and 1304 controls matched on sex and cohort.RESULTS: A genetic risk score built from 23 CAD-associated SNPs contributed significantly to CAD (P = 2.9 × 10(-4)). In the final multivariable model, participants with an unfavorable genetic background (top genetic score quartile) had a CAD odds ratio (OR) of 1.47 (95% confidence interval [CI], 1.05-2.04). This effect was similar to hypertension (OR = 1.36; 95% CI, 1.06-1.73), hypercholesterolemia (OR = 1.51; 95% CI, 1.16-1.96), diabetes (OR = 1.66; 95% CI, 1.10-2.49), ≥ 1 year lopinavir exposure (OR = 1.36; 95% CI, 1.06-1.73), and current abacavir treatment (OR = 1.56; 95% CI, 1.17-2.07). The effect of the genetic risk score was additive to the effect of nongenetic CAD risk factors, and did not change after adjustment for family history of CAD.CONCLUSIONS: In the setting of HIV infection, the effect of an unfavorable genetic background was similar to traditional CAD risk factors and certain adverse antiretroviral exposures. Genetic testing may provide prognostic information complementary to family history of CAD.

Published
2013

44. Predicting the short-term risk of diabetes in HIV-positive patients: the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study

Author

Roberto CAUDA, Renato Alberto Finazzi, Jens Lundgren, William Powderly, Antonio Chiesi, Clifford Leen, Giuseppe Ippolito, CARLO FEDERICO PERNO, Vicente Soriano, Matthew Law, Linos Vandekerckhove, Matti Ristola, Antonella D'Arminio Monforte, Terese L Katzenstein, GUIDO CAMANNI, Bart Rijnders, ANDREA COSTANTINI, Petoumenos, Kathy, Worm, Signe W, Fontas, Eric, Weber, Rainer, De Wit, Stephane, Bruyand, Mathia, Reiss, Peter, El sadr, Wafaa, Monforte, Antonella D'arminio, Friis møller, Nina, Lundgren, Jens D, Law, Matthew G, D:a:d Study, Group, Castagna, Antonella, Petoumenos, K, Worm, S, Fontas, E, Weber, R, De Wit, S, Bruyand, M, Reiss, P, El Sadr, W, Monforte, A, Friis Møller, N, Lundgren, J, Law, M, Gori, A, Med Microbiol, Infect Dis & Infect Prev, RS: NUTRIM - R3 - Chronic inflammatory disease and wasting, Amsterdam institute for Infection and Immunity, Amsterdam Public Health, Global Health, Other departments, Infectious diseases, Paediatric Infectious Diseases / Rheumatology / Immunology, Other Research, Obstetrics and Gynaecology, General Internal Medicine, Center of Experimental and Molecular Medicine, Medical Microbiology and Infection Prevention, and University of Zurich

Subjects
Male, HIV Infections, 030204 cardiovascular system & hematology, Santé publique, risk equation, 10234 Clinic for Infectious Diseases, MELLITUS, 0302 clinical medicine, Diabetes mellitus, ANTIRETROVIRAL THERAPY, Antiretroviral Therapy, Highly Active, Combination antiretroviral treatment, Medicine and Health Sciences, MULTICENTER AIDS COHORT, HIV Infection, 030212 general & internal medicine, Prospective Studies, adult, anti-HIV agents/administration & dosage/ adverse effects, antiretroviral therapy, highly active/ adverse effects/methods, Decision Support Techniques, Diabetes Mellitus/ chemically induced, drug-related side effects and adverse reactions/ epidemiology, female, HIV Infections/ complications/ drug therapy, humans, male, middle aged, prognosis, prospective studies, risk assessment, Pathologie maladies infectieuses, combination antiretroviral treatment, 2. Zero hunger, LIPODYSTROPHY, education.field_of_study, INFECTED PATIENTS, Framingham Risk Score, virus diseases, Diabetes Mellitu, ASSOCIATION, Middle Aged, Prognosis, 3. Good health, Infectious Diseases, CARDIOVASCULAR-DISEASE, diabetes mellitus, Female, Public Health, Lipodystrophy, Human, Research Article, Adult, medicine.medical_specialty, Drug-Related Side Effects and Adverse Reactions, Prognosi, Anti-HIV Agents, Population, Antiretroviral Therapy, 610 Medicine & health, Risk Assessment, VALIDATION, Risk equation, 03 medical and health sciences, Insulin resistance, Internal medicine, mental disorders, medicine, Humans, Highly Active, Risk factor, education, business.industry, Environmental and Occupational Health, Public Health, Environmental and Occupational Health, Anti-HIV Agent, HIV, 2739 Public Health, Environmental and Occupational Health, 2725 Infectious Diseases, ADULTS, medicine.disease, PROGNOSTIC MODEL, Prospective Studie, Immunology, business, Drug-Related Side Effects and Adverse Reaction, Body mass index, Dyslipidemia
Abstract

Introduction: HIV-positive patients receiving combination antiretroviral therapy (cART) frequently experience metabolic complications such as dyslipidemia and insulin resistance, as well as lipodystrophy, increasing the risk of cardiovascular disease (CVD) and diabetes mellitus (DM). Rates of DM and other glucose-associated disorders among HIV-positive patients have been reported to range between 2 and 14%, and in an ageing HIV-positive population, the prevalence of DM is expected to continue to increase. This study aims to develop a model to predict the short-term (six-month) risk of DM in HIV-positive populations and to compare the existing models developed in the general population. Methods: All patients recruited to the Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) study with follow-up data, without prior DM, myocardial infarction or other CVD events and with a complete DM risk factor profile were included. Conventional risk factors identified in the general population as well as key HIV-related factors were assessed using Poissonregression methods. Expected probabilities of DM events were also determined based on the Framingham Offspring Study DM equation. The D:A:D and Framingham equations were then assessed using an internal-external validation process; area under the receiver operating characteristic (AUROC) curve and predicted DM events were determined. Results: Of 33,308 patients, 16,632 (50%) patients were included, with 376 cases of new onset DM during 89,469 person-years(PY). Factors predictive of DM included higher glucose, body mass index (BMI) and triglyceride levels, and older age. Among HIV-related factors, recent CD4 counts ofB200 cells/mL and lipodystrophy were predictive of new onset DM. The mean performance of the D:A:D and Framingham equations yielded AUROC of 0.894 (95% CI: 0.849, 0.940) and 0.877 (95% CI: 0.823, 0.932), respectively. The Framingham equation over-predicted DM events compared to D:A:D for lower glucose and lower triglycerides, and for BMI levels below 25 kg/m2. Conclusions: The D:A:D equation performed well in predicting the short-term onset of DM in the validation dataset and for specific subgroups provided better estimates of DM risk than the Framingham. Copyright: © 2012 Petoumenos K et al; licensee International AIDS Society., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2011

45. HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies

Author

Anne Johnson, Andrea Antinori, Ludmila Viksna, Ferran Torres, Adriano LAZZARIN, Roberto CAUDA, Jens Lundgren, LUZ MARTÍN CARBONERO, Frank Van Leth, Antonio Chiesi, Giuseppe Ippolito, CARLO FEDERICO PERNO, Vicente Soriano, Matthew Law, Paolo Bonfanti, Marc Van der Valk, Simon Collins, Patrizio Pezzotti, Kathleen Falster, STEFANO VELLA, Andrea De Luca, Adriana Ammassari, Đorđe Jevtović, Tatiana Katerina Galpérine, Simon Mallal, Raffaele Bruno, Adrian Streinu-Cercel, Thomas Benfield, Viktar M. Mitsura, Caroline Sabin, Terese L Katzenstein, Antonella Castagna, FRANCESCA CECCHERINI SILBERSTEIN, Bart Rijnders, Vassilenko Anna, Alicja Wiercińska-Drapało, Rita Murri, ANDREA COSTANTINI, Amsterdam institute for Infection and Immunity, Amsterdam Public Health, Infectious diseases, Other departments, General Internal Medicine, Global Health, Monforte, Antonella D'arminio, Abrams, Donald, Pradier, Christian, Weber, Rainer, Reiss, Peter, Bonnet, Fabrice, Kirk, Ole, Law, Matthew, De Wit, Stephane, Friis mã¸ller, Nina, Phillips, Andrew N., Sabin, Caroline A., Lundgren, Jens D., Collins, S., Loeliger, E., Tressler, R., Weiler, I., Friis mã¸ller, N., Worm, S. W., Sabin, C. A., Sjã¸l, A., Lundgren, J. D., Sawitz, A., Rickenbach, M., Pezzotti, P., Krum, E., Gras, L., Balestre, E., Sundstrã¶m, A., Poll, B., Fontas, E., Torres, F., Petoumenos, K., Kjã¦r, J. D:a:d Study Group, Castagna, Antonella, University of Zurich, D'Arminio Monforte, A, Internal medicine, and Medical psychology

Subjects
Male, d:a:d study, Lymphoma, HIV Infections, Sex Factor, 10234 Clinic for Infectious Diseases, non-aids-defining malignancies, Neoplasms, Immunology and Allergy, Age Factor, HIV Infection, Young adult, AIDS-Related, Immunodeficiency, Lymphoma, AIDS-Related, hiv infection, Mortality rate, Age Factors, Homosexuality, Middle Aged, AIDS-defining malignancie, Pathogenesis and modulation of inflammation [N4i 1], Infectious Diseases, Epidemiologic Method, 2723 Immunology and Allergy, symbols, Female, Human, Cohort study, Adult, medicine.medical_specialty, Anti-HIV Agents, Immunology, 610 Medicine & health, Article, Drug Administration Schedule, symbols.namesake, Immunocompromised Host, Young Adult, A:D study [D], Sex Factors, Acquired immunodeficiency syndrome (AIDS), Internal medicine, medicine, Humans, Poisson regression, Mortality, aids-defining malignancies, mortality, Homosexuality, Male, Aged, Hepatitis, 2403 Immunology, business.industry, Non-AIDS-defining malignancie, Anti-HIV Agent, 2725 Infectious Diseases, medicine.disease, Confidence interval, CD4 Lymphocyte Count, Neoplasm, Microbial pathogenesis and host defense [UMCN 4.1], business, Epidemiologic Methods
Abstract

Objective: To evaluate deaths from AIDS-defining malignancies (ADM) and non-AIDS-defining malignancies (nADM) in the D:A:D Study and to investigate the relationship between these deaths and immunodeficiency. Design: Observational cohort study. Methods: Patients (23 437) were followed prospectively for 104 921 person-years. We used Poisson regression models to identify factors independently associated with deaths from ADM and nADM. Analyses of factors associated with mortality due to nADM were repeated after excluding nADM known to be associated with a specific risk factor. Results: Three hundred five patients died due to a malignancy, 298 prior to the cutoff for this analysis (ADM: n = 110; nADM: n = 188). The mortality rate due to ADM decreased from 20.1/1000 person-years of follow-up [95% confidence interval (CI) 14.4, 25.9] when the most recent CD4 cell count was

Published
2008

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