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1. Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program

Author

Verma, Anurag, Huffman, Jennifer E, Rodriguez, Alex, Conery, Mitchell, Liu, Molei, Ho, Yuk-Lam, Kim, Youngdae, Heise, David A, Guare, Lindsay, Panickan, Vidul Ayakulangara, Garcon, Helene, Linares, Franciel, Costa, Lauren, Goethert, Ian, Tipton, Ryan, Honerlaw, Jacqueline, Davies, Laura, Whitbourne, Stacey, Cohen, Jeremy, Posner, Daniel C, Sangar, Rahul, Murray, Michael, Wang, Xuan, Dochtermann, Daniel R, Devineni, Poornima, Shi, Yunling, Nandi, Tarak Nath, Assimes, Themistocles L, Brunette, Charles A, Carroll, Robert J, Clifford, Royce, Duvall, Scott, Gelernter, Joel, Hung, Adriana, Iyengar, Sudha K, Joseph, Jacob, Kember, Rachel, Kranzler, Henry, Kripke, Colleen M, Levey, Daniel, Luoh, Shiuh-Wen, Merritt, Victoria C, Overstreet, Cassie, Deak, Joseph D, Grant, Struan FA, Polimanti, Renato, Roussos, Panos, Shakt, Gabrielle, Sun, Yan V, Tsao, Noah, Venkatesh, Sanan, Voloudakis, Georgios, Justice, Amy, Begoli, Edmon, Ramoni, Rachel, Tourassi, Georgia, Pyarajan, Saiju, Tsao, Philip, O'Donnell, Christopher J, Muralidhar, Sumitra, Moser, Jennifer, Casas, Juan P, Bick, Alexander G, Zhou, Wei, Cai, Tianxi, Voight, Benjamin F, Cho, Kelly, Gaziano, J Michael, Madduri, Ravi K, Damrauer, Scott, and Liao, Katherine P

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, 2.1 Biological and endogenous factors, Mental health, Humans, Male, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Longitudinal Studies, Polymorphism, Single Nucleotide, Quantitative Trait Loci, United States, United States Department of Veterans Affairs, Veterans, Female, General Science & Technology
Abstract

One of the justifiable criticisms of human genetic studies is the underrepresentation of participants from diverse populations. Lack of inclusion must be addressed at-scale to identify causal disease factors and understand the genetic causes of health disparities. We present genome-wide associations for 2068 traits from 635,969 participants in the Department of Veterans Affairs Million Veteran Program, a longitudinal study of diverse United States Veterans. Systematic analysis revealed 13,672 genomic risk loci; 1608 were only significant after including non-European populations. Fine-mapping identified causal variants at 6318 signals across 613 traits. One-third (n = 2069) were identified in participants from non-European populations. This reveals a broadly similar genetic architecture across populations, highlights genetic insights gained from underrepresented groups, and presents an extensive atlas of genetic associations.

Published
2024

2. Agent orange exposure and prostate cancer risk in the million veteran program

Author

Pagadala, Meghana S, Lui, Asona J, Zhong, Allison Y, Lynch, Julie A, Karunamuni, Roshan, Lee, Kyung Min, Plym, Anna, Rose, Brent S, Carter, Hannah K, Kibel, Adam S, DuVall, Scott L, Gaziano, J Michael, Panizzon, Matthew S, Hauger, Richard L, and Seibert, Tyler M

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Prostate Cancer, Cancer, Urologic Diseases, Humans, Male, Agent Orange, Prostatic Neoplasms, Veterans, Middle Aged, Aged, Vietnam Conflict, United States, Defoliants, Chemical, Risk Factors, 2, 4, 5-Trichlorophenoxyacetic Acid, 2, 4-Dichlorophenoxyacetic Acid, Polychlorinated Dibenzodioxins, prostate cancer, MVP, race/ ethnicity, health disparities, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundThe US government considers veterans to have been exposed to Agent Orange if they served in Vietnam while the carcinogen was in use, and these veterans are often deemed at high risk of prostate cancer (PCa). Here, we assess whether presumed Agent Orange exposure is independently associated with increased risk of any metastatic or fatal PCa in a diverse Veteran cohort still alive in the modern era (at least 2011), when accounting for race/ethnicity, family history, and genetic risk.Patients and methodsParticipants in the Million Veteran Program (MVP; enrollment began in 2011) who were on active duty during the Vietnam War era (August 1964-April 1975) were included (n = 301,470). Agent Orange exposure was determined using the US government definition. Genetic risk was assessed via a validated polygenic hazard score. Associations with age at diagnosis of any PCa, metastatic PCa, and death from PCa were assessed via Cox proportional hazards models.Results and interpretationOn univariable analysis, exposure to Agent Orange was not associated with increased PCa (hazard ratio [HR]: 1.02, 95% confidence interval [CI]: 1.00-1.04, p = 0.06), metastatic PCa (HR: 0.98, 95% CI: 0.91-1.05, p = 0.55), or fatal PCa (HR: 0.94, 95% CI: 0.79-1.09, p = 0.41). When accounting for race/ethnicity and family history, Agent Orange exposure was independently associated with slightly increased risk of PCa (HR: 1.06, 95% CI: 1.04-1.09,

Published
2024

3. Polygenic risk of any, metastatic, and fatal prostate cancer in the Million Veteran Program

Author

Pagadala, Meghana S, Lynch, Julie, Karunamuni, Roshan, Alba, Patrick R, Lee, Kyung Min, Agiri, Fatai Y, Anglin, Tori, Carter, Hannah, Gaziano, J Michael, Jasuja, Guneet Kaur, Deka, Rishi, Rose, Brent S, Panizzon, Matthew S, Hauger, Richard L, and Seibert, Tyler M

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Prevention, Prostate Cancer, Cancer, Urologic Diseases, Clinical Research, Genetics, Aging, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Good Health and Well Being, Humans, Male, Aged, Prostatic Neoplasms, Veterans, Retrospective Studies, Prostate-Specific Antigen, Cohort Studies, Early Detection of Cancer, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundGenetic scores may provide an objective measure of prostate cancer risk and thus inform screening decisions. We evaluated whether a polygenic hazard score based on 290 genetic variants (PHS290) is associated with prostate cancer risk in a diverse population, including Black men, who have higher average risk of prostate cancer death but are often treated as a homogeneously high-risk group.MethodsThis was a retrospective analysis of the Million Veteran Program, a national, population-based cohort study of US military veterans conducted 2011-2021. Cox proportional hazards analyses tested for association of genetic and other risk factors (including self-reported race and ethnicity and family history) with age at death from prostate cancer, age at diagnosis of metastatic (nodal or distant) prostate cancer, and age at diagnosis of any prostate cancer.ResultsA total of 590 750 male participants were included. Median age at last follow-up was 69 years. PHS290 was associated with fatal prostate cancer in the full cohort and for each racial and ethnic group (P

Published
2023

4. A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation

Author

Vujkovic, Marijana, Ramdas, Shweta, Lorenz, Kim M, Guo, Xiuqing, Darlay, Rebecca, Cordell, Heather J, He, Jing, Gindin, Yevgeniy, Chung, Chuhan, Myers, Robert P, Schneider, Carolin V, Park, Joseph, Lee, Kyung Min, Serper, Marina, Carr, Rotonya M, Kaplan, David E, Haas, Mary E, MacLean, Matthew T, Witschey, Walter R, Zhu, Xiang, Tcheandjieu, Catherine, Kember, Rachel L, Kranzler, Henry R, Verma, Anurag, Giri, Ayush, Klarin, Derek M, Sun, Yan V, Huang, Jie, Huffman, Jennifer E, Creasy, Kate Townsend, Hand, Nicholas J, Liu, Ching-Ti, Long, Michelle T, Yao, Jie, Budoff, Matthew, Tan, Jingyi, Li, Xiaohui, Lin, Henry J, Chen, Yii-Der Ida, Taylor, Kent D, Chang, Ruey-Kang, Krauss, Ronald M, Vilarinho, Silvia, Brancale, Joseph, Nielsen, Jonas B, Locke, Adam E, Jones, Marcus B, Verweij, Niek, Baras, Aris, Reddy, K Rajender, Neuschwander-Tetri, Brent A, Schwimmer, Jeffrey B, Sanyal, Arun J, Chalasani, Naga, Ryan, Kathleen A, Mitchell, Braxton D, Gill, Dipender, Wells, Andrew D, Manduchi, Elisabetta, Saiman, Yedidya, Mahmud, Nadim, Miller, Donald R, Reaven, Peter D, Phillips, Lawrence S, Muralidhar, Sumitra, DuVall, Scott L, Lee, Jennifer S, Assimes, Themistocles L, Pyarajan, Saiju, Cho, Kelly, Edwards, Todd L, Damrauer, Scott M, Wilson, Peter W, Gaziano, J Michael, O’Donnell, Christopher J, Khera, Amit V, Grant, Struan FA, Brown, Christopher D, Tsao, Philip S, Saleheen, Danish, Lotta, Luca A, Bastarache, Lisa, Anstee, Quentin M, Daly, Ann K, Meigs, James B, Rotter, Jerome I, Lynch, Julie A, Rader, Daniel J, Voight, Benjamin F, and Chang, Kyong-Mi

Subjects
Genetics, Liver Disease, Human Genome, Digestive Diseases, Chronic Liver Disease and Cirrhosis, Aetiology, 2.1 Biological and endogenous factors, Alanine Transaminase, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Genome-Wide Association Study, Humans, Intracellular Signaling Peptides and Proteins, Lipase, Membrane Proteins, Non-alcoholic Fatty Liver Disease, Polymorphism, Single Nucleotide, Protein Serine-Threonine Kinases, Regeneron Genetics Center, Geisinger-Regeneron DiscovEHR Collaboration, EPoS Consortium, VA Million Veteran Program, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Nonalcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease. Using a proxy NAFLD definition of chronic elevation of alanine aminotransferase (cALT) levels without other liver diseases, we performed a multiancestry genome-wide association study (GWAS) in the Million Veteran Program (MVP) including 90,408 cALT cases and 128,187 controls. Seventy-seven loci exceeded genome-wide significance, including 25 without prior NAFLD or alanine aminotransferase associations, with one additional locus identified in European American-only and two in African American-only analyses (P

Published
2022

5. Genetically regulated multi-omics study for symptom clusters of posttraumatic stress disorder highlights pleiotropy with hematologic and cardio-metabolic traits

Author

Pathak, Gita A, Singh, Kritika, Wendt, Frank R, Fleming, Tyne W, Overstreet, Cassie, Koller, Dora, Tylee, Daniel S, De Angelis, Flavio, Cabrera Mendoza, Brenda, Levey, Daniel F, Koenen, Karestan C, Krystal, John H, Pietrzak, Robert H, O’ Donell, Christopher, Gaziano, J Michael, Falcone, Guido, Stein, Murray B, Gelernter, Joel, Pasaniuc, Bogdan, Mancuso, Nicholas, Davis, Lea K, and Polimanti, Renato

Subjects
Biotechnology, Human Genome, Mental Health, Post-Traumatic Stress Disorder (PTSD), Brain Disorders, Anxiety Disorders, Clinical Research, Genetics, Aetiology, 2.1 Biological and endogenous factors, Mental health, Metabolic and endocrine, Good Health and Well Being, Diagnostic and Statistical Manual of Mental Disorders, Humans, Phenotype, Stress Disorders, Post-Traumatic, Syndrome, Veterans, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

Posttraumatic stress disorder (PTSD) is a psychiatric disorder that may arise in response to severe traumatic event and is diagnosed based on three main symptom clusters (reexperiencing, avoidance, and hyperarousal) per the Diagnostic Manual of Mental Disorders (version DSM-IV-TR). In this study, we characterized the biological heterogeneity of PTSD symptom clusters by performing a multi-omics investigation integrating genetically regulated gene, splicing, and protein expression in dorsolateral prefrontal cortex tissue within a sample of US veterans enrolled in the Million Veteran Program (N total = 186,689). We identified 30 genes in 19 regions across the three PTSD symptom clusters. We found nine genes to have cell-type specific expression, and over-representation of miRNA-families - miR-148, 30, and 8. Gene-drug target prioritization approach highlighted cyclooxygenase and acetylcholine compounds. Next, we tested molecular-profile based phenome-wide impact of identified genes with respect to 1678 phenotypes derived from the Electronic Health Records of the Vanderbilt University biorepository (N = 70,439). Lastly, we tested for local genetic correlation across PTSD symptom clusters which highlighted metabolic (e.g., obesity, diabetes, vascular health) and laboratory traits (e.g., neutrophil, eosinophil, tau protein, creatinine kinase). Overall, this study finds comprehensive genomic evidence including clinical and regulatory profiles between PTSD, hematologic and cardiometabolic traits, that support comorbidities observed in epidemiologic studies of PTSD.

Published
2022

6. Exogenous hormone use, reproductive factors and risk of intrahepatic cholangiocarcinoma among women: results from cohort studies in the Liver Cancer Pooling Project and the UK Biobank

Author

Petrick, Jessica L, McMenamin, Úna C, Zhang, Xuehong, Zeleniuch-Jacquotte, Anne, Wactawski-Wende, Jean, Simon, Tracey G, Sinha, Rashmi, Sesso, Howard D, Schairer, Catherine, Rosenberg, Lynn, Rohan, Thomas E, Robien, Kim, Purdue, Mark P, Poynter, Jenny N, Palmer, Julie R, Lu, Yunxia, Linet, Martha S, Liao, Linda M, Lee, I-Min, Koshiol, Jill, Kitahara, Cari M, Kirsh, Victoria A, Hofmann, Jonathan N, Graubard, Barry I, Giovannucci, Edward, Gaziano, J Michael, Gapstur, Susan M, Freedman, Neal D, Florio, Andrea A, Chong, Dawn Q, Chen, Yu, Chan, Andrew T, Buring, Julie E, Freeman, Laura E Beane, Bea, Jennifer W, Cardwell, Christopher R, Campbell, Peter T, and McGlynn, Katherine A

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Liver Disease, Cancer, Digestive Diseases, Contraception/Reproduction, Clinical Research, Digestive Diseases - (Gallbladder), Liver Cancer, Prevention, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Reproductive health and childbirth, Good Health and Well Being, Aged, Bile Ducts, Bile Ducts, Intrahepatic, Biological Specimen Banks, Cholangiocarcinoma, Cohort Studies, Contraceptives, Oral, Hormonal, Estrogen Receptor alpha, Estrogen Receptor beta, Female, Gene Expression Regulation, Neoplastic, Hormones, Humans, Hysterectomy, Liver Neoplasms, Menopause, Middle Aged, Proportional Hazards Models, Risk Factors, United Kingdom, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundIntrahepatic cholangiocarcinoma (ICC) arises from cholangiocytes in the intrahepatic bile duct and is the second most common type of liver cancer. Cholangiocytes express both oestrogen receptor-α and -β, and oestrogens positively modulate cholangiocyte proliferation. Studies in women and men have reported higher circulating oestradiol is associated with increased ICC risk, further supporting a hormonal aetiology. However, no observational studies have examined the associations between exogenous hormone use and reproductive factors, as proxies of endogenous hormone levels, and risk of ICC.MethodsWe harmonised data from 1,107,498 women who enroled in 12 North American-based cohort studies (in the Liver Cancer Pooling Project, LCPP) and the UK Biobank between 1980-1998 and 2006-2010, respectively. Cox proportional hazards regression models were used to generate hazard ratios (HR) and 95% confidence internals (CI). Then, meta-analytic techniques were used to combine the estimates from the LCPP (n = 180 cases) and the UK Biobank (n = 57 cases).ResultsHysterectomy was associated with a doubling of ICC risk (HR = 1.98, 95% CI: 1.27-3.09), compared to women aged 50-54 at natural menopause. Long-term oral contraceptive use (9+ years) was associated with a 62% increased ICC risk (HR = 1.62, 95% CI: 1.03-2.55). There was no association between ICC risk and other exogenous hormone use or reproductive factors.ConclusionsThis study suggests that hysterectomy and long-term oral contraceptive use may be associated with an increased ICC risk.

Published
2020

7. Rare Genetic Variants Associated With Sudden Cardiac Death in Adults

Author

Khera, Amit V, Mason-Suares, Heather, Brockman, Deanna, Wang, Minxian, VanDenburgh, Martin J, Senol-Cosar, Ozlem, Patterson, Candace, Newton-Cheh, Christopher, Zekavat, Seyedeh M, Pester, Julie, Chasman, Daniel I, Kabrhel, Christopher, Jensen, Majken K, Manson, JoAnn E, Gaziano, J Michael, Taylor, Kent D, Sotoodehnia, Nona, Post, Wendy S, Rich, Stephen S, Rotter, Jerome I, Lander, Eric S, Rehm, Heidi L, Ng, Kenney, Philippakis, Anthony, Lebo, Matthew, Albert, Christine M, and Kathiresan, Sekar

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Prevention, Genetics, Clinical Research, Heart Disease, Cardiovascular, 4.2 Evaluation of markers and technologies, Aetiology, Detection, screening and diagnosis, 2.4 Surveillance and distribution, 2.1 Biological and endogenous factors, Good Health and Well Being, Aged, Aged, 80 and over, Case-Control Studies, Death, Sudden, Cardiac, Female, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Exome Sequencing, gene sequencing, genomic medicine, sudden cardiac death, Cardiorespiratory Medicine and Haematology, Public Health and Health Services, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract

BackgroundSudden cardiac death occurs in ∼220,000 U.S. adults annually, the majority of whom have no prior symptoms or cardiovascular diagnosis. Rare pathogenic DNA variants in any of 49 genes can pre-dispose to 4 important causes of sudden cardiac death: cardiomyopathy, coronary artery disease, inherited arrhythmia syndrome, and aortopathy or aortic dissection.ObjectivesThis study assessed the prevalence of rare pathogenic variants in sudden cardiac death cases versus controls, and the prevalence and clinical importance of such mutations in an asymptomatic adult population.MethodsThe authors performed whole-exome sequencing in a case-control cohort of 600 adult-onset sudden cardiac death cases and 600 matched controls from 106,098 participants of 6 prospective cohort studies. Observed DNA sequence variants in any of 49 genes with known association to cardiovascular disease were classified as pathogenic or likely pathogenic by a clinical laboratory geneticist blinded to case status. In an independent population of 4,525 asymptomatic adult participants of a prospective cohort study, the authors performed whole-genome sequencing and determined the prevalence of pathogenic or likely pathogenic variants and prospective association with cardiovascular death.ResultsAmong the 1,200 sudden cardiac death cases and controls, the authors identified 5,178 genetic variants and classified 14 as pathogenic or likely pathogenic. These 14 variants were present in 15 individuals, all of whom had experienced sudden cardiac death-corresponding to a pathogenic variant prevalence of 2.5% in cases and 0% in controls (p

Published
2019

8. Harmonizing Genetic Ancestry and Self-identified Race/Ethnicity in Genome-wide Association Studies

Author

Fang, Huaying, Hui, Qin, Lynch, Julie, Honerlaw, Jacqueline, Assimes, Themistocles L, Huang, Jie, Vujkovic, Marijana, Damrauer, Scott M, Pyarajan, Saiju, Gaziano, J Michael, DuVall, Scott L, O’Donnell, Christopher J, Cho, Kelly, Chang, Kyong-Mi, Wilson, Peter WF, Tsao, Philip S, Sun, Yan, Tang, Hua, Ramoni, Rachel, Breeling, Jim, Huang, Grant, Muralidhar, Sumitra, Moser, Jennifer, Whitbourne, Stacey B, Brewer, Jessica V, Concato, John, Warren, Stuart, Argyres, Dean P, Stephens, Brady, Brophy, Mary T, Humphries, Donald E, Do, Nhan, Shayan, Shahpoor, Nguyen, Xuan-Mai T, Hauser, Elizabeth, Sun, Yan V, Zhao, Hongyu, Wilson, Peter, McArdle, Rachel, Dellitalia, Louis, Harley, John, Whittle, Jeffrey, Beckham, Jean, Wells, John, Gutierrez, Salvador, Gibson, Gretchen, Kaminsky, Laurence, Villareal, Gerardo, Kinlay, Scott, Xu, Junzhe, Hamner, Mark, Haddock, Kathlyn Sue, Bhushan, Sujata, Iruvanti, Pran, Godschalk, Michael, Ballas, Zuhair, Buford, Malcolm, Mastorides, Stephen, Klein, Jon, Ratcliffe, Nora, Florez, Hermes, Swann, Alan, Murdoch, Maureen, Sriram, Peruvemba, Yeh, Shing Shing, Washburn, Ronald, Jhala, Darshana, Aguayo, Samuel, Cohen, David, Sharma, Satish, Callaghan, John, Oursler, Kris Ann, Whooley, Mary, Ahuja, Sunil, Gutierrez, Amparo, Schifman, Ronald, Greco, Jennifer, Rauchman, Michael, Servatius, Richard, Oehlert, Mary, Wallbom, Agnes, Fernando, Ronald, Morgan, Timothy, Stapley, Todd, Sherman, Scott, Anderson, Gwenevere, Sonel, Elif, Boyko, Edward, Meyer, Laurence, Gupta, Samir, Fayad, Joseph, Hung, Adriana, and Lichy, Jack

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Generic health relevance, Algorithms, Ethnicity, Genome-Wide Association Study, Humans, Machine Learning, Racial Groups, Support Vector Machine, VA Million Veteran Program, biobank, ethnicity-specific trait loci, genetic ancestry, multi-ethnic cohort, self-reported race/ethnicity, stratified analysis, trans-ethnic GWAS, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Large-scale multi-ethnic cohorts offer unprecedented opportunities to elucidate the genetic factors influencing complex traits related to health and disease among minority populations. At the same time, the genetic diversity in these cohorts presents new challenges for analysis and interpretation. We consider the utility of race and/or ethnicity categories in genome-wide association studies (GWASs) of multi-ethnic cohorts. We demonstrate that race/ethnicity information enhances the ability to understand population-specific genetic architecture. To address the practical issue that self-identified racial/ethnic information may be incomplete, we propose a machine learning algorithm that produces a surrogate variable, termed HARE. We use height as a model trait to demonstrate the utility of HARE and ethnicity-specific GWASs.

Published
2019

9. Genome-wide Association Study of Maximum Habitual Alcohol Intake in >140,000 U.S. European and African American Veterans Yields Novel Risk Loci

Author

Gelernter, Joel, Sun, Ning, Polimanti, Renato, Pietrzak, Robert H, Levey, Daniel F, Lu, Qiongshi, Hu, Yiming, Li, Boyang, Radhakrishnan, Krishnan, Aslan, Mihaela, Cheung, Kei-Hoi, Li, Yuli, Rajeevan, Nallakkandi, Sayward, Fred, Harrington, Kelly, Chen, Quan, Cho, Kelly, Honerlaw, Jacqueline, Pyarajan, Saiju, Lencz, Todd, Quaden, Rachel, Shi, Yunling, Hunter-Zinck, Haley, Gaziano, J Michael, Kranzler, Henry R, Concato, John, Zhao, Hongyu, Stein, Murray B, Program, Department of Veterans Affairs Cooperative Studies, and Program, Million Veteran

Subjects
Brain Disorders, Genetics, Human Genome, Substance Misuse, Alcoholism, Alcohol Use and Health, Prevention, Good Health and Well Being, Adolescent, Adult, Black or African American, Aged, Aged, 80 and over, Alcohol Drinking, Alcoholism, Female, Genome-Wide Association Study, Humans, Linear Models, Male, Middle Aged, Receptors, Corticotropin-Releasing Hormone, United States, Veterans, White People, Young Adult, ADH1B, CRHR1, Genome-wide association study, Habitual alcohol use, Million Veteran Program, Department of Veterans Affairs Cooperative Studies Program, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

BackgroundHabitual alcohol use can be an indicator of alcohol dependence, which is associated with a wide range of serious health problems.MethodsWe completed a genome-wide association study in 126,936 European American and 17,029 African American subjects in the Veterans Affairs Million Veteran Program for a quantitative phenotype based on maximum habitual alcohol consumption.ResultsADH1B, on chromosome 4, was the lead locus for both populations: for the European American sample, rs1229984 (p = 4.9 × 10-47); for African American, rs2066702 (p = 2.3 × 10-12). In the European American sample, we identified three additional genome-wide-significant maximum habitual alcohol consumption loci: on chromosome 17, rs77804065 (p = 1.5 × 10-12), at CRHR1 (corticotropin-releasing hormone receptor 1); the protein product of this gene is involved in stress and immune responses; and on chromosomes 8 and 10. European American and African American samples were then meta-analyzed; the associated region at CRHR1 increased in significance to 1.02 × 10-13, and we identified two additional genome-wide significant loci, FGF14 (p = 9.86 × 10-9) (chromosome 13) and a locus on chromosome 11. Besides ADH1B, none of the five loci have prior genome-wide significant support. Post-genome-wide association study analysis identified genetic correlation to other alcohol-related traits, smoking-related traits, and many others. Replications were observed in UK Biobank data. Genetic correlation between maximum habitual alcohol consumption and alcohol dependence was 0.87 (p = 4.78 × 10-9). Enrichment for cell types included dopaminergic and gamma-aminobutyric acidergic neurons in midbrain, and pancreatic delta cells.ConclusionsThe present study supports five novel alcohol-use risk loci, with particularly strong statistical support for CRHR1. Additionally, we provide novel insight regarding the biology of harmful alcohol use.

Published
2019

10. Gender Differences in Demographic and Health Characteristics of the Million Veteran Program Cohort

Author

Harrington, Kelly M, Nguyen, Xuan-Mai T, Song, Rebecca J, Hannagan, Keri, Quaden, Rachel, Gagnon, David R, Cho, Kelly, Deen, Jennifer E, Muralidhar, Sumitra, O’Leary, Timothy J, Gaziano, John Michael, Whitbourne, Stacey B, Gaziano, J Michael, Ramoni, Rachel, Breeling, Jim, Chang, Kyong-Mi, Huang, Grant, O’Donnell, Christopher J, Tsao, Philip S, Moser, Jennifer, Brewer, Jessica V, Concato, John, Warren, Stuart, Pharm, D, Argyres, Dean P, Tsao, Philip, Stephens, Brady, Brophy, Mary T, Humphries, Donald E, Do, Nhan, Shayan, Shahpoor, Pyarajan, Saiju, Hauser, Elizabeth, Sun, Yan, Zhao, Hongyu, Wilson, Peter, McArdle, Rachel, Dellitalia, Louis, Harley, John, Whittle, Jeffrey, Beckham, Jean, Wells, John, Gutierrez, Salvador, Gibson, Gretchen, Kaminsky, Laurence, Villareal, Gerardo, Kinlay, Scott, Xu, Junzhe, Hamner, Mark, Haddock, Kathlyn Sue, Bhushan, Sujata, Iruvanti, Pran, Godschalk, Michael, Ballas, Zuhair, Buford, Malcolm, Mastorides, Stephen, Klein, Jon, Ratcliffe, Nora, Florez, Hermes, Swann, Alan, Murdoch, Maureen, Sriram, Peruvemba, Yeh, Shing Shing, Washburn, Ronald, Jhala, Darshana, Aguayo, Samuel, Cohen, David, Sharma, Satish, Callaghan, John, Oursler, Kris Ann, Whooley, Mary, Ahuja, Sunil, Gutierrez, Amparo, Schifman, Ronald, Greco, Jennifer, Rauchman, Michael, Servatius, Richard, Oehlert, Mary, Wallbom, Agnes, Fernando, Ronald, Morgan, Timothy, Stapley, Todd, Sherman, Scott, Anderson, Gwenevere, Sonel, Elif, Boyko, Edward, Meyer, Laurence, Gupta, Samir, Fayad, Joseph, and Hung, Adriana

Subjects
Health Services and Systems, Health Sciences, Cardiovascular, Clinical Research, Prevention, 2.4 Surveillance and distribution, Aetiology, Good Health and Well Being, Adult, Aged, Cardiovascular Diseases, Cohort Studies, Female, Health Status, Humans, Male, Mental Disorders, Middle Aged, Migraine Disorders, Musculoskeletal Diseases, Physical Fitness, Prevalence, Sex Distribution, Sex Factors, Smoking, Surveys and Questionnaires, United States, United States Department of Veterans Affairs, Veterans, Veterans Health, Young Adult, VA Million Veteran Program, Paediatrics and Reproductive Medicine, Public Health and Health Services, Public Health, Midwifery, Public health, Policy and administration
Abstract

BackgroundThe Department of Veterans Affairs Million Veteran Program (MVP) is the largest ongoing cohort program of its kind, with 654,903 enrollees as of June 2018. The objectives of this study were to examine gender differences in the MVP cohort with respect to response and enrollment rates; demographic, health, and health care characteristics; and prevalence of self-reported health conditions.MethodsThe MVP Baseline Survey was completed by 415,694 veterans (8% women), providing self-report measures of demographic characteristics, health status, and medical history.ResultsRelative to men, women demonstrated a higher positive responder rate (23.0% vs. 16.0%), slightly higher enrollment rate (13.5% vs. 12.9%), and, among enrollees, a lower survey completion rate (59.7% vs. 63.8%). Women were younger, more racially diverse, had higher educational attainment, and were less likely to be married or cohabitating with a partner than men. Women were more likely to report good to excellent health status but poorer physical fitness, and less likely to report lifetime smoking and drinking than men. Compared with men, women veterans showed an increased prevalence of musculoskeletal conditions, thyroid problems, gastrointestinal conditions, migraine headaches, and mental health disorders, as well as a decreased prevalence of gout, cardiovascular diseases, high cholesterol, diabetes, and hearing problems.ConclusionsThese results revealed some substantial gender differences in the research participation rates, demographic profile, health characteristics, and prevalence of health conditions for veterans in the MVP cohort. Findings highlight the need for tailoring recruitment efforts to ensure representation of the increasing women veteran population receiving care through the Veterans Health Administration.

Published
2019

11. Alcohol Consumption and Risk of Coronary Artery Disease (from the Million Veteran Program)

Author

Song, Rebecca J, Nguyen, Xuan-Mai T, Quaden, Rachel, Ho, Yuk-Lam, Justice, Amy C, Gagnon, David R, Cho, Kelly, O'Donnell, Christopher J, Concato, John, Gaziano, J Michael, Djoussé, Luc, Program, VA Million Veteran, Halasz, Ildiko, Federman, Daniel, Beckham, Jean, Sherman, Scott E, Sriram, Peruvemba, Tsao, Philip S, Boyko, Edward J, Xu, Junzhe, Lederle, Frank, Dellitalia, Louis J, McArdle, Rachel, Kaminsky, Laurence, Swann, Alan C, Hamner, Mark B, Florez, Hermes J, Pandya, Prashant, Villarreal, Gerardo, Wilson, Peter, Morgan, Timothy R, Davis, Lori, Hurley, Robin A, Meyer, Laurence, Ahuja, Sunil K, Konicki, Eric P, Cohen, David, Lichy, Jack, Whittle, Jeffrey, Haddock, Kathlyn Sue, Straub, Karl D, Callaghan, John T, Aguayo, Samuel M, Gupta, Samir, Washburn, Ronald G, Oehlert, Mary E, Hung, Adriana M, Wallbom, Agnes, Keith, Robert, Sonel, Elif, Schifman, Ronald B, Childress, Richard D, Godschalk, Michael F, Shuldiner, Alan R, Rastogi, Padmashri, Gutierrez, Salvador, Fernando, Ronald, Iruvanti, Pran R, Jhala, Darshana, Rosado-Rodriguez, Carlos, Mastorides, Stephen M, Harley, John B, Mattocks, Kristin, Robey, Brooks, Striker, Robert T, Rauchman, Michael, Wells, John, Ballas, Zuhair K, Woods, Susan S, Yeh, Shing Shing, Ratcliffe, Nora R, Klein, Jon B, Golden, Adam G, Ginzburg, Harold M, Sharma, Satish, Oursler, Kris Ann K, Whooley, Mary A, Gibson, Gretchen, and Heinz

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Substance Misuse, Brain Disorders, Heart Disease - Coronary Heart Disease, Alcoholism, Alcohol Use and Health, Heart Disease, Cardiovascular, Clinical Research, Atherosclerosis, Stroke, Oral and gastrointestinal, Good Health and Well Being, Aged, Alcohol Drinking, Alcoholic Beverages, Alcoholism, Coronary Artery Disease, Female, Humans, Male, Middle Aged, Proportional Hazards Models, Protective Factors, Risk Factors, Self Report, United States, Veterans, VA Million Veteran Program, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract

Moderate alcohol consumption has been associated with a lower risk of coronary artery disease (CAD) in the general population but has not been well studied in US veterans. We obtained self-reported alcohol consumption from Million Veteran Program participants. Using electronic health records, CAD events were defined as 1 inpatient or 2 outpatient diagnosis codes for CAD, or 1 code for a coronary procedure. We excluded participants with prevalent CAD (n = 69,995) or incomplete alcohol information (n = 8,449). We used a Cox proportional hazards model to estimate hazard ratios and 95% confidence intervals for CAD, adjusting for age, gender, body mass index, race, smoking, education, and exercise. Among 156,728 participants, the mean age was 65.3 years (standard deviation = 12.1) and 91% were men. There were 6,153 CAD events during a mean follow-up of 2.9 years. Adjusted hazard ratios (95% confidence intervals) for CAD were 1.00 (reference), 1.02 (0.92 to 1.13), 0.83 (0.74 to 0.93), 0.77 (0.67 to 0.87), 0.71 (0.62 to 0.81), 0.62 (0.51 to 0.76), 0.58 (0.46 to 0.74), and 0.95 (0.85 to 1.06) for categories of never drinker; former drinker; current drinkers of ≤0.5 drink/day, >0.5 to 1 drink/day, >1 to 2 drinks/day, >2 to 3 drinks/day, and >3 to 4 drinks/day; and heavy drinkers (>4 drinks/day) or alcohol use disorder, respectively. For a fixed amount of ethanol, intake at ≥3 days/week was associated with lower CAD risk compared with ≤1 day/week. Beverage preference (beer, wine, or liquor) did not influence the alcohol-CAD relation. Our data show a lower risk of CAD with light-to-moderate alcohol consumption among US veterans, and drinking frequency may provide a further reduction in risk.

Published
2018

12. DASH Score and Subsequent Risk of Coronary Artery Disease: The Findings From Million Veteran Program

Author

Djoussé, Luc, Ho, Yuk‐Lam, Nguyen, Xuan‐Mai T, Gagnon, David R, Wilson, Peter WF, Cho, Kelly, Gaziano, J Michael, Program, the VA Million Veteran, Halasz, Ildiko, Federman, Daniel, Beckham, Jean, Sherman, Scott E, Sriram, Peruvemba, Tsao, Philip S, Boyko, Edward J, Xu, Junzhe, Lederle, Frank, Dellitalia, Louis J, McArdle, Rachel, Kaminsky, Laurence, Swann, Alan C, Hamner, Mark B, Florez, Hermes J, Pandya, Prashant, Villarreal, Gerardo, Wilson, Peter, Morgan, Timothy R, Davis, Lori, Hurley, Robin A, Meyer, Laurence, Ahuja, Sunil K, Konicki, Eric P, Cohen, David, Lichy, Jack, Whittle, Jeffrey, Haddock, Kathlyn Sue, Straub, Karl D, Callaghan, John T, Aguayo, Samuel M, Gupta, Samir, Washburn, Ronald G, Oehlert, Mary E, Hung, Adriana M, Wallbom, Agnes, Keith, Robert, Sonel, Elif, Schifman, Ronald B, Childress, Richard D, Godschalk, Michael F, Shuldiner, Alan R, Rastogi, Padmashri, Gutierrez, Salvador, Fernando, Ronald, Iruvanti, Pran R, Jhala, Darshana, Rosado‐Rodriguez, Carlos, Mastorides, Stephen M, Harley, John B, Mattocks, Kristin, Striker, Robert T, Rauchman, Michael, Wells, John, Ballas, Zuhair K, Woods, Susan S, Yeh, Shing, Ratcliffe, Nora R, Klein, Jon B, Golden, Adam G, Ginzburg, Harold M, Sharma, Satish, Oursler, Kris Ann K, Whooley, Mary A, and Gibson, Gretchen

Subjects
Biomedical and Clinical Sciences, Nutrition and Dietetics, Nutrition, Hypertension, Atherosclerosis, Clinical Research, Cardiovascular, Prevention, Good Health and Well Being, Aged, Coronary Artery Disease, Diet, Healthy, Dietary Approaches To Stop Hypertension, Female, Humans, Incidence, Male, Middle Aged, Patient Compliance, Prognosis, Prospective Studies, Protective Factors, Risk Assessment, Risk Factors, Risk Reduction Behavior, Time Factors, United States, Veterans Health, VA Million Veteran Program, coronary artery disease, epidemiology, nutrition, Cardiorespiratory Medicine and Haematology, Cardiovascular medicine and haematology
Abstract

While adherence to healthful dietary patterns has been associated with a lower risk of coronary artery disease (CAD) in the general population, limited data are available among US veterans. We tested the hypothesis that adherence to Dietary Approach to Stop Hypertension (DASH) food pattern is associated with a lower risk of developing CAD among veterans. We analyzed data on 153 802 participants of the Million Veteran Program enrolled between 2011 and 2016. Information on dietary habits was obtained using a food frequency questionnaire at enrollment. We used electronic health records to assess the development of CAD during follow-up. Of the 153 802 veterans who provided information on diet and were free of CAD at baseline, the mean age was 64.0 (SD=11.8) years and 90.4% were men. During a mean follow-up of 2.8 years, 5451 CAD cases occurred. The crude incidence rate of CAD was 14.0, 13.1, 12.6, 12.3, and 11.1 cases per 1000 person-years across consecutive quintiles of Dietary Approach to Stop Hypertension score. Hazard ratios (95% confidence interval) for CAD were 1.0 (ref), 0.91 (0.84-0.99), 0.87 (0.80-0.95), 0.86 (0.79-0.94), and 0.80 (0.73-0.87) from the lowest to highest quintile of Dietary Approach to Stop Hypertension score controlling for age, sex, body mass index, race, smoking, exercise, alcohol intake, and statin use (P linear trend,

Published
2018

13. Transforming Evidence Generation to Support Health and Health Care Decisions

Author

Califf, Robert M, Robb, Melissa A, Bindman, Andrew B, Briggs, Josephine P, Collins, Francis S, Conway, Patrick H, Coster, Trinka S, Cunningham, Francesca E, De Lew, Nancy, DeSalvo, Karen B, Dymek, Christine, Dzau, Victor J, Fleurence, Rachael L, Frank, Richard G, Gaziano, J Michael, Kaufmann, Petra, Lauer, Michael, Marks, Peter W, McGinnis, J Michael, Richards, Chesley, Selby, Joe V, Shulkin, David J, Shuren, Jeffrey, Slavitt, Andrew M, Smith, Scott R, Washington, B Vindell, White, P Jon, Woodcock, Janet, Woodson, Jonathan, and Sherman, Rachel E

Subjects
Clinical Research, Health Services, 8.1 Organisation and delivery of services, 7.3 Management and decision making, Health and social care services research, Management of diseases and conditions, Generic health relevance, Good Health and Well Being, Biomedical Research, Decision Making, Delivery of Health Care, Evidence-Based Medicine, Health Policy, Humans, Translational Research, Biomedical, United States, Medical and Health Sciences, General & Internal Medicine
Published
2016

14. Association of Fruit and Vegetable Consumption During Early Adulthood With the Prevalence of Coronary Artery Calcium After 20 Years of Follow-Up

Author

Miedema, Michael D, Petrone, Andrew, Shikany, James M, Greenland, Philip, Lewis, Cora E, Pletcher, Mark J, Gaziano, J Michael, and Djousse, Luc

Subjects
Heart Disease - Coronary Heart Disease, Prevention, Heart Disease, Clinical Research, Nutrition, Atherosclerosis, Cardiovascular, Adult, Calcium, Coronary Artery Disease, Diet, Female, Follow-Up Studies, Fruit, Humans, Life Style, Male, Prevalence, Prospective Studies, Risk, United States, Vascular Calcification, Vegetables, Young Adult, atherosclerosis, coronary disease, diet, epidemiology, imaging, diagnostic, nutrition, imaging, diagnostic, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Public Health and Health Services, Cardiovascular System & Hematology
Abstract

BackgroundThe relationship between intake of fruits and vegetables (F/V) during young adulthood and coronary atherosclerosis later in life is unclear.Methods and resultsWe studied participants of the Coronary Artery Risk Development in Young Adults (CARDIA) study, a cohort of young, healthy black and white individuals at baseline (1985-1986). Intake of F/V at baseline was assessed using a semiquantitative interview administered diet history, and coronary artery calcium was measured at year 20 (2005-2006) using computed tomography. We used logistic regression to adjust for relevant variables and estimate the adjusted odds ratios and 95% confidence intervals across energy-adjusted, sex-specific tertiles of total servings of F/V per day. Among our sample (n=2506), the mean (SD) age at baseline was 25.3 (3.5) years, and 62.7% were female. After adjustment for demographics and lifestyle variables, higher intake of F/V was associated with a lower prevalence of coronary artery calcium: odds ratio (95% confidence interval) =1.00 (reference), 0.78 (0.59-1.02), and 0.74 (0.56-0.99), from the lowest to the highest tertile of F/V, P value for trend

Published
2015

15. Characterization of Large Structural Genetic Mosaicism in Human Autosomes

Author

Machiela, Mitchell J, Zhou, Weiyin, Sampson, Joshua N, Dean, Michael C, Jacobs, Kevin B, Black, Amanda, Brinton, Louise A, Chang, I-Shou, Chen, Chu, Chen, Constance, Chen, Kexin, Cook, Linda S, Bou, Marta Crous, De Vivo, Immaculata, Doherty, Jennifer, Friedenreich, Christine M, Gaudet, Mia M, Haiman, Christopher A, Hankinson, Susan E, Hartge, Patricia, Henderson, Brian E, Hong, Yun-Chul, Hosgood, H Dean, Hsiung, Chao A, Hu, Wei, Hunter, David J, Jessop, Lea, Kim, Hee Nam, Kim, Yeul Hong, Kim, Young Tae, Klein, Robert, Kraft, Peter, Lan, Qing, Lin, Dongxin, Liu, Jianjun, Le Marchand, Loic, Liang, Xiaolin, Lissowska, Jolanta, Lu, Lingeng, Magliocco, Anthony M, Matsuo, Keitaro, Olson, Sara H, Orlow, Irene, Park, Jae Yong, Pooler, Loreall, Prescott, Jennifer, Rastogi, Radhai, Risch, Harvey A, Schumacher, Fredrick, Seow, Adeline, Setiawan, Veronica Wendy, Shen, Hongbing, Sheng, Xin, Shin, Min-Ho, Shu, Xiao-Ou, Berg, David VanDen, Wang, Jiu-Cun, Wentzensen, Nicolas, Wong, Maria Pik, Wu, Chen, Wu, Tangchun, Wu, Yi-Long, Xia, Lucy, Yang, Hannah P, Yang, Pan-Chyr, Zheng, Wei, Zhou, Baosen, Abnet, Christian C, Albanes, Demetrius, Aldrich, Melinda C, Amos, Christopher, Amundadottir, Laufey T, Berndt, Sonja I, Blot, William J, Bock, Cathryn H, Bracci, Paige M, Burdett, Laurie, Buring, Julie E, Butler, Mary A, Carreón, Tania, Chatterjee, Nilanjan, Chung, Charles C, Cook, Michael B, Cullen, Michael, Davis, Faith G, Ding, Ti, Duell, Eric J, Epstein, Caroline G, Fan, Jin-Hu, Figueroa, Jonine D, Fraumeni, Joseph F, Freedman, Neal D, Fuchs, Charles S, Gao, Yu-Tang, Gapstur, Susan M, Patiño-Garcia, Ana, Garcia-Closas, Montserrat, Gaziano, J Michael, Giles, Graham G, and Gillanders, Elizabeth M

Subjects
Biological Sciences, Genetics, Human Genome, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Aged, Chromosome Aberrations, Female, Genome, Human, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Mosaicism, Neoplasms, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.

Published
2015

16. Age-Related Cataract in Men in the Selenium and Vitamin E Cancer Prevention Trial Eye Endpoints Study: A Randomized Clinical Trial

Author

Christen, William G, Glynn, Robert J, Gaziano, J Michael, Darke, Amy K, Crowley, John J, Goodman, Phyllis J, Lippman, Scott M, Lad, Thomas E, Bearden, James D, Goodman, Gary E, Minasian, Lori M, Thompson, Ian M, Blanke, Charles D, and Klein, Eric A

Subjects
Clinical Research, Complementary and Integrative Health, Aging, Nutrition, Cancer, Prevention, Clinical Trials and Supportive Activities, Eye Disease and Disorders of Vision, 3.3 Nutrition and chemoprevention, Evaluation of treatments and therapeutic interventions, Prevention of disease and conditions, and promotion of well-being, 6.1 Pharmaceuticals, Aged, Antioxidants, Cataract, Cataract Extraction, Double-Blind Method, Drug Combinations, Endpoint Determination, Humans, Incidence, Male, Middle Aged, Proportional Hazards Models, Prostatic Neoplasms, Risk Factors, Selenomethionine, Surveys and Questionnaires, Vitamin E, Opthalmology and Optometry, Ophthalmology & Optometry
Abstract

ImportanceObservational studies suggest a role for dietary nutrients such as vitamin E and selenium in cataract prevention. However, the results of randomized clinical trials of vitamin E supplements and cataract have been disappointing and are not yet available for selenium.ObjectiveTo test whether long-term supplementation with selenium and vitamin E affects the incidence of cataract in a large cohort of men.Design, setting, and participantsThe Selenium and Vitamin E Cancer Prevention Trial (SELECT) Eye Endpoints Study was an ancillary study of the Southwest Oncology Group-coordinated SELECT, a randomized placebo-controlled 4-arm trial of selenium and vitamin E conducted among 35,533 men, 50 years and older for African American participants and 55 years and older for all other men, at 427 participating sites in the United States, Canada, and Puerto Rico. A total of 11,267 SELECT participants from 128 SELECT sites participated in the SELECT Eye Endpoints ancillary study.InterventionsIndividual supplements of selenium (200 μg per day from L-selenomethionine) and vitamin E (400 IU per day of all rac-α-tocopheryl acetate).Main outcomes and measuresIncident cataract was defined as a lens opacity, age related in origin, and responsible for a reduction in best-corrected visual acuity to 20/30 or worse based on self-reports confirmed by medical record review. Cataract extraction was defined as the surgical removal of an incident cataract.ResultsDuring a mean (SD) of 5.6 (1.2) years of treatment and follow-up, 389 cases of cataract were documented. There were 185 cataracts in the selenium group and 204 in the no selenium group (hazard ratio, 0.91; 95 % CI, 0.75-1.11; P = .37). For vitamin E, there were 197 cases in the treated group and 192 in the placebo group (hazard ratio, 1.02; 95 % CI, 0.84-1.25; P = .81). Similar results were observed for cataract extraction.Conclusions and relevanceThese data from a large cohort of apparently healthy men indicate that long-term daily supplementation with selenium and/or vitamin E is unlikely to have a large beneficial effect on age-related cataract.Trial registrationClinicalTrials.gov Identifier: NCT00784225.

Published
2015

17. Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer

Author

Wolpin, Brian M, Rizzato, Cosmeri, Kraft, Peter, Kooperberg, Charles, Petersen, Gloria M, Wang, Zhaoming, Arslan, Alan A, Beane-Freeman, Laura, Bracci, Paige M, Buring, Julie, Canzian, Federico, Duell, Eric J, Gallinger, Steven, Giles, Graham G, Goodman, Gary E, Goodman, Phyllis J, Jacobs, Eric J, Kamineni, Aruna, Klein, Alison P, Kolonel, Laurence N, Kulke, Matthew H, Li, Donghui, Malats, Núria, Olson, Sara H, Risch, Harvey A, Sesso, Howard D, Visvanathan, Kala, White, Emily, Zheng, Wei, Abnet, Christian C, Albanes, Demetrius, Andreotti, Gabriella, Austin, Melissa A, Barfield, Richard, Basso, Daniela, Berndt, Sonja I, Boutron-Ruault, Marie-Christine, Brotzman, Michelle, Büchler, Markus W, Bueno-de-Mesquita, H Bas, Bugert, Peter, Burdette, Laurie, Campa, Daniele, Caporaso, Neil E, Capurso, Gabriele, Chung, Charles, Cotterchio, Michelle, Costello, Eithne, Elena, Joanne, Funel, Niccola, Gaziano, J Michael, Giese, Nathalia A, Giovannucci, Edward L, Goggins, Michael, Gorman, Megan J, Gross, Myron, Haiman, Christopher A, Hassan, Manal, Helzlsouer, Kathy J, Henderson, Brian E, Holly, Elizabeth A, Hu, Nan, Hunter, David J, Innocenti, Federico, Jenab, Mazda, Kaaks, Rudolf, Key, Timothy J, Khaw, Kay-Tee, Klein, Eric A, Kogevinas, Manolis, Krogh, Vittorio, Kupcinskas, Juozas, Kurtz, Robert C, LaCroix, Andrea, Landi, Maria T, Landi, Stefano, Le Marchand, Loic, Mambrini, Andrea, Mannisto, Satu, Milne, Roger L, Nakamura, Yusuke, Oberg, Ann L, Owzar, Kouros, Patel, Alpa V, Peeters, Petra HM, Peters, Ulrike, Pezzilli, Raffaele, Piepoli, Ada, Porta, Miquel, Real, Francisco X, Riboli, Elio, Rothman, Nathaniel, Scarpa, Aldo, Shu, Xiao-Ou, Silverman, Debra T, Soucek, Pavel, Sund, Malin, Talar-Wojnarowska, Renata, Taylor, Philip R, and Theodoropoulos, George E

Subjects
Cancer, Aged, Case-Control Studies, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Pancreatic Neoplasms, Polymorphism, Single Nucleotide, White People, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

We performed a multistage genome-wide association study including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT, per-allele odds ratio (OR) = 0.79, 95% confidence interval (CI) 0.74-0.84, P = 3.0 × 10(-12)), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2, OR = 1.46, 95% CI 1.30-1.65, P = 1.1 × 10(-10)), rs9581943 at 13q12.2 (PDX1, OR = 1.15, 95% CI 1.10-1.20, P = 2.4 × 10(-9)) and rs16986825 at 22q12.1 (ZNRF3, OR = 1.18, 95% CI 1.12-1.25, P = 1.2 × 10(-8)). We identified an independent signal in exon 2 of TERT at the established region 5p15.33 (rs2736098, OR = 0.80, 95% CI 0.76-0.85, P = 9.8 × 10(-14)). We also identified a locus at 8q24.21 (rs1561927, P = 1.3 × 10(-7)) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study identified multiple new susceptibility alleles for pancreatic cancer that are worthy of follow-up studies.

Published
2014

18. Genome-wide association study of survival in patients with pancreatic adenocarcinoma

Author

Wu, Chen, Kraft, Peter, Stolzenberg-Solomon, Rachael, Steplowski, Emily, Brotzman, Michelle, Xu, Mousheng, Mudgal, Poorva, Amundadottir, Laufey, Arslan, Alan A, Bueno-de-Mesquita, H Bas, Gross, Myron, Helzlsouer, Kathy, Jacobs, Eric J, Kooperberg, Charles, Petersen, Gloria M, Zheng, Wei, Albanes, Demetrius, Boutron-Ruault, Marie-Christine, Buring, Julie E, Canzian, Federico, Cao, Guangwen, Duell, Eric J, Elena, Joanne W, Gaziano, J Michael, Giovannucci, Edward L, Hallmans, Goran, Hutchinson, Amy, Hunter, David J, Jenab, Mazda, Jiang, Guoliang, Khaw, Kay-Tee, LaCroix, Andrea, Li, Zhaoshen, Mendelsohn, Julie B, Panico, Salvatore, Patel, Alpa V, Qian, Zhi Rong, Riboli, Elio, Sesso, Howard, Shen, Hongbing, Shu, Xiao-Ou, Tjonneland, Anne, Tobias, Geoffrey S, Trichopoulos, Dimitrios, Virtamo, Jarmo, Visvanathan, Kala, Wactawski-Wende, Jean, Wang, Chengfeng, Yu, Kai, Zeleniuch-Jacquotte, Anne, Chanock, Stephen, Hoover, Robert, Hartge, Patricia, Fuchs, Charles S, Lin, Dongxin, and Wolpin, Brian M

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Digestive Diseases, Prevention, Rare Diseases, Pancreatic Cancer, Genetics, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Adenocarcinoma, Adult, Aged, Aged, 80 and over, Asian People, Biomarkers, Tumor, China, Europe, Female, Follow-Up Studies, Genome-Wide Association Study, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Models, Genetic, Pancreatic Neoplasms, Polymorphism, Single Nucleotide, Principal Component Analysis, Proportional Hazards Models, Protein Tyrosine Phosphatases, Non-Receptor, Survival Rate, White People, Cancer Genetics, Molecular Epidemiology, Clinical Sciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology, Clinical sciences, Nutrition and dietetics
Abstract

Background and objectiveSurvival of patients with pancreatic adenocarcinoma is limited and few prognostic factors are known. We conducted a two-stage genome-wide association study (GWAS) to identify germline variants associated with survival in patients with pancreatic adenocarcinoma.MethodsWe analysed overall survival in relation to single nucleotide polymorphisms (SNPs) among 1005 patients from two large GWAS datasets, PanScan I and ChinaPC. Cox proportional hazards regression was used in an additive genetic model with adjustment for age, sex, clinical stage and the top four principal components of population stratification. The first stage included 642 cases of European ancestry (PanScan), from which the top SNPs (p≤10(-5)) were advanced to a joint analysis with 363 additional patients from China (ChinaPC).ResultsIn the first stage of cases of European descent, the top-ranked loci were at chromosomes 11p15.4, 18p11.21 and 1p36.13, tagged by rs12362504 (p=1.63×10(-7)), rs981621 (p=1.65×10(-7)) and rs16861827 (p=3.75×10(-7)), respectively. 131 SNPs with p≤10(-5) were advanced to a joint analysis with cases from the ChinaPC study. In the joint analysis, the top-ranked SNP was rs10500715 (minor allele frequency, 0.37; p=1.72×10(-7)) on chromosome 11p15.4, which is intronic to the SET binding factor 2 (SBF2) gene. The HR (95% CI) for death was 0.74 (0.66 to 0.84) in PanScan I, 0.79 (0.65 to 0.97) in ChinaPC and 0.76 (0.68 to 0.84) in the joint analysis.ConclusionsGermline genetic variation in the SBF2 locus was associated with overall survival in patients with pancreatic adenocarcinoma of European and Asian ancestry. This association should be investigated in additional large patient cohorts.

Published
2014

19. Polymorphisms in genes related to one-carbon metabolism are not related to pancreatic cancer in PanScan and PanC4

Author

Leenders, Max, Bhattacharjee, Samsiddhi, Vineis, Paolo, Stevens, Victoria, Bueno-de-Mesquita, H Bas, Shu, Xiao-Ou, Amundadottir, Laufey, Gross, Myron, Tobias, Geoffrey S, Wactawski-Wende, Jean, Arslan, Alan A, Duell, Eric J, Fuchs, Charles S, Gallinger, Steven, Hartge, Patricia, Hoover, Robert N, Holly, Elizabeth A, Jacobs, Eric J, Klein, Alison P, Kooperberg, Charles, LaCroix, Andrea, Li, Donghui, Mandelson, Margaret T, Olson, Sara H, Petersen, Gloria, Risch, Harvey A, Yu, Kai, Wolpin, Brian M, Zheng, Wei, Agalliu, Ilir, Albanes, Demetrius, Boutron-Ruault, Marie-Christine, Bracci, Paige M, Buring, Julie E, Canzian, Federico, Chang, Kenneth, Chanock, Stephen J, Cotterchio, Michelle, Gaziano, J Michael, Giovanucci, Edward L, Goggins, Michael, Hallmans, Göran, Hankinson, Susan E, Hoffman-Bolton, Judith A, Hunter, David J, Hutchinson, Amy, Jacobs, Kevin B, Jenab, Mazda, Khaw, Kay-Tee, Kraft, Peter, Krogh, Vittorio, Kurtz, Robert C, McWilliams, Robert R, Mendelsohn, Julie B, Patel, Alpa V, Rabe, Kari G, Riboli, Elio, Tjønneland, Anne, Trichopoulos, Dimitrios, Virtamo, Jarmo, Visvanathan, Kala, Elena, Joanne W, Yu, Herbert, Zeleniuch-Jacquotte, Anne, and Stolzenberg-Solomon, Rachael Z

Subjects
Epidemiology, Biomedical and Clinical Sciences, Health Sciences, Oncology and Carcinogenesis, Cancer, Digestive Diseases, Genetics, Pancreatic Cancer, Prevention, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Carbon, Case-Control Studies, Cohort Studies, Germ-Line Mutation, Humans, Pancreatic Neoplasms, Polymorphism, Single Nucleotide, United States, Pancreatic cancer, One-carbon metabolism, Polymorphisms, Biomarkers, Public Health and Health Services, Oncology and carcinogenesis
Abstract

PurposeThe evidence of a relation between folate intake and one-carbon metabolism (OCM) with pancreatic cancer (PanCa) is inconsistent. In this study, the association between genes and single-nucleotide polymorphisms (SNPs) related to OCM and PanCa was assessed.MethodsUsing biochemical knowledge of the OCM pathway, we identified thirty-seven genes and 834 SNPs to examine in association with PanCa. Our study included 1,408 cases and 1,463 controls nested within twelve cohorts (PanScan). The ten SNPs and five genes with lowest p values (

Published
2013

20. Diabetes and risk of pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium

Author

Elena, Joanne W, Steplowski, Emily, Yu, Kai, Hartge, Patricia, Tobias, Geoffrey S, Brotzman, Michelle J, Chanock, Stephen J, Stolzenberg-Solomon, Rachael Z, Arslan, Alan A, Bueno-de-Mesquita, H Bas, Helzlsouer, Kathy, Jacobs, Eric J, LaCroix, Andrea, Petersen, Gloria, Zheng, Wei, Albanes, Demetrius, Allen, Naomi E, Amundadottir, Laufey, Bao, Ying, Boeing, Heiner, Boutron-Ruault, Marie-Christine, Buring, Julie E, Gaziano, J Michael, Giovannucci, Edward L, Duell, Eric J, Hallmans, Göran, Howard, Barbara V, Hunter, David J, Hutchinson, Amy, Jacobs, Kevin B, Kooperberg, Charles, Kraft, Peter, Mendelsohn, Julie B, Michaud, Dominique S, Palli, Domenico, Phillips, Lawrence S, Overvad, Kim, Patel, Alpa V, Sansbury, Leah, Shu, Xiao-Ou, Simon, Michael S, Slimani, Nadia, Trichopoulos, Dimitrios, Visvanathan, Kala, Virtamo, Jarmo, Wolpin, Brian M, Zeleniuch-Jacquotte, Anne, Fuchs, Charles S, Hoover, Robert N, and Gross, Myron

Subjects
Biomedical and Clinical Sciences, Epidemiology, Health Services and Systems, Health Sciences, Oncology and Carcinogenesis, Rare Diseases, Cancer, Pancreatic Cancer, Prevention, Digestive Diseases, Clinical Research, Diabetes, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Good Health and Well Being, Adenocarcinoma, Adult, Aged, Aged, 80 and over, Case-Control Studies, Cohort Studies, Diabetes Complications, Diabetes Mellitus, Female, Humans, Male, Middle Aged, Pancreatic Neoplasms, Risk Factors, Public Health and Health Services, Oncology and carcinogenesis
Abstract

PurposeDiabetes is a suspected risk factor for pancreatic cancer, but questions remain about whether it is a risk factor or a result of the disease. This study prospectively examined the association between diabetes and the risk of pancreatic adenocarcinoma in pooled data from the NCI pancreatic cancer cohort consortium (PanScan).MethodsThe pooled data included 1,621 pancreatic adenocarcinoma cases and 1,719 matched controls from twelve cohorts using a nested case-control study design. Subjects who were diagnosed with diabetes near the time (

Published
2013

21. Genome-wide association study of glioma and meta-analysis

Author

Rajaraman, Preetha, Melin, Beatrice S, Wang, Zhaoming, McKean-Cowdin, Roberta, Michaud, Dominique S, Wang, Sophia S, Bondy, Melissa, Houlston, Richard, Jenkins, Robert B, Wrensch, Margaret, Yeager, Meredith, Ahlbom, Anders, Albanes, Demetrius, Andersson, Ulrika, Freeman, Laura E Beane, Buring, Julie E, Butler, Mary Ann, Braganza, Melissa, Carreon, Tania, Feychting, Maria, Fleming, Sarah J, Gapstur, Susan M, Gaziano, J Michael, Giles, Graham G, Hallmans, Goran, Henriksson, Roger, Hoffman-Bolton, Judith, Inskip, Peter D, Johansen, Christoffer, Kitahara, Cari M, Lathrop, Mark, Liu, Chenwei, Le Marchand, Loic, Linet, Martha S, Lonn, Stefan, Peters, Ulrike, Purdue, Mark P, Rothman, Nathaniel, Ruder, Avima M, Sanson, Marc, Sesso, Howard D, Severi, Gianluca, Shu, Xiao-Ou, Simon, Matthias, Stampfer, Meir, Stevens, Victoria L, Visvanathan, Kala, White, Emily, Wolk, Alicja, Zeleniuch-Jacquotte, Anne, Zheng, Wei, Decker, Paul, Enciso-Mora, Victor, Fridley, Brooke, Gao, Yu-Tang, Kosel, Matthew, Lachance, Daniel H, Lau, Ching, Rice, Terri, Swerdlow, Anthony, Wiemels, Joseph L, Wiencke, John K, Shete, Sanjay, Xiang, Yong-Bing, Xiao, Yuanyuan, Hoover, Robert N, Fraumeni, Joseph F, Chatterjee, Nilanjan, Hartge, Patricia, and Chanock, Stephen J

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Clinical Research, Brain Disorders, Prevention, Brain Cancer, Neurosciences, Cancer, Human Genome, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Aged, Brain Neoplasms, Case-Control Studies, Cohort Studies, Cyclin-Dependent Kinase Inhibitor p15, DNA Helicases, Female, Genome-Wide Association Study, Glioblastoma, Glioma, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Telomerase, Complementary and Alternative Medicine, Paediatrics and Reproductive Medicine, Genetics & Heredity, Reproductive medicine
Abstract

Gliomas account for approximately 80 % of all primary malignant brain tumors and, despite improvements in clinical care over the last 20 years, remain among the most lethal tumors, underscoring the need for gaining new insights that could translate into clinical advances. Recent genome-wide association studies (GWAS) have identified seven new susceptibility regions. We conducted a new independent GWAS of glioma using 1,856 cases and 4,955 controls (from 14 cohort studies, 3 case-control studies, and 1 population-based case-only study) and found evidence of strong replication for three of the seven previously reported associations at 20q13.33 (RTEL), 5p15.33 (TERT), and 9p21.3 (CDKN2BAS), and consistent association signals for the remaining four at 7p11.2 (EGFR both loci), 8q24.21 (CCDC26) and 11q23.3 (PHLDB1). The direction and magnitude of the signal were consistent for samples from cohort and case-control studies, but the strength of the association was more pronounced for loci rs6010620 (20q,13.33; RTEL) and rs2736100 (5p15.33, TERT) in cohort studies despite the smaller number of cases in this group, likely due to relatively more higher grade tumors being captured in the cohort studies. We further examined the 85 most promising single nucleotide polymorphism (SNP) markers identified in our study in three replication sets (5,015 cases and 11,601 controls), but no new markers reached genome-wide significance. Our findings suggest that larger studies focusing on novel approaches as well as specific tumor subtypes or subgroups will be required to identify additional common susceptibility loci for glioma risk.

Published
2012

22. Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer.

Author

Li, Donghui, Duell, Eric J, Yu, Kai, Risch, Harvey A, Olson, Sara H, Kooperberg, Charles, Wolpin, Brian M, Jiao, Li, Dong, Xiaoqun, Wheeler, Bill, Arslan, Alan A, Bueno-de-Mesquita, H Bas, Fuchs, Charles S, Gallinger, Steven, Gross, Myron, Hartge, Patricia, Hoover, Robert N, Holly, Elizabeth A, Jacobs, Eric J, Klein, Alison P, LaCroix, Andrea, Mandelson, Margaret T, Petersen, Gloria, Zheng, Wei, Agalliu, Ilir, Albanes, Demetrius, Boutron-Ruault, Marie-Christine, Bracci, Paige M, Buring, Julie E, Canzian, Federico, Chang, Kenneth, Chanock, Stephen J, Cotterchio, Michelle, Gaziano, J Michael, Giovannucci, Edward L, Goggins, Michael, Hallmans, Göran, Hankinson, Susan E, Hoffman Bolton, Judith A, Hunter, David J, Hutchinson, Amy, Jacobs, Kevin B, Jenab, Mazda, Khaw, Kay-Tee, Kraft, Peter, Krogh, Vittorio, Kurtz, Robert C, McWilliams, Robert R, Mendelsohn, Julie B, Patel, Alpa V, Rabe, Kari G, Riboli, Elio, Shu, Xiao-Ou, Tjønneland, Anne, Tobias, Geoffrey S, Trichopoulos, Dimitrios, Virtamo, Jarmo, Visvanathan, Kala, Watters, Joanne, Yu, Herbert, Zeleniuch-Jacquotte, Anne, Amundadottir, Laufey, and Stolzenberg-Solomon, Rachael Z

Subjects
Humans, Pancreatic Neoplasms, Genetic Predisposition to Disease, Case-Control Studies, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Oncology & Carcinogenesis, Oncology and Carcinogenesis
Abstract

Four loci have been associated with pancreatic cancer through genome-wide association studies (GWAS). Pathway-based analysis of GWAS data is a complementary approach to identify groups of genes or biological pathways enriched with disease-associated single-nucleotide polymorphisms (SNPs) whose individual effect sizes may be too small to be detected by standard single-locus methods. We used the adaptive rank truncated product method in a pathway-based analysis of GWAS data from 3851 pancreatic cancer cases and 3934 control participants pooled from 12 cohort studies and 8 case-control studies (PanScan). We compiled 23 biological pathways hypothesized to be relevant to pancreatic cancer and observed a nominal association between pancreatic cancer and five pathways (P < 0.05), i.e. pancreatic development, Helicobacter pylori lacto/neolacto, hedgehog, Th1/Th2 immune response and apoptosis (P = 2.0 × 10(-6), 1.6 × 10(-5), 0.0019, 0.019 and 0.023, respectively). After excluding previously identified genes from the original GWAS in three pathways (NR5A2, ABO and SHH), the pancreatic development pathway remained significant (P = 8.3 × 10(-5)), whereas the others did not. The most significant genes (P < 0.01) in the five pathways were NR5A2, HNF1A, HNF4G and PDX1 for pancreatic development; ABO for H.pylori lacto/neolacto; SHH for hedgehog; TGFBR2 and CCL18 for Th1/Th2 immune response and MAPK8 and BCL2L11 for apoptosis. Our results provide a link between inherited variation in genes important for pancreatic development and cancer and show that pathway-based approaches to analysis of GWAS data can yield important insights into the collective role of genetic risk variants in cancer.

Published
2012

23. Vitamin E and the Risk of Prostate Cancer: The Selenium and Vitamin E Cancer Prevention Trial (SELECT)

Author

Klein, Eric A, Thompson, Ian M, Tangen, Catherine M, Crowley, John J, Lucia, M Scott, Goodman, Phyllis J, Minasian, Lori M, Ford, Leslie G, Parnes, Howard L, Gaziano, J Michael, Karp, Daniel D, Lieber, Michael M, Walther, Philip J, Klotz, Laurence, Parsons, J Kellogg, Chin, Joseph L, Darke, Amy K, Lippman, Scott M, Goodman, Gary E, Meyskens, Frank L, and Baker, Laurence H

Subjects
Clinical Research, Aging, Nutrition, Complementary and Integrative Health, Cancer, Clinical Trials and Supportive Activities, Urologic Diseases, Prostate Cancer, Prevention, 3.3 Nutrition and chemoprevention, Evaluation of treatments and therapeutic interventions, Prevention of disease and conditions, and promotion of well-being, 6.1 Pharmaceuticals, Aged, Antioxidants, Dietary Supplements, Follow-Up Studies, Humans, Incidence, Male, Middle Aged, Prostatic Neoplasms, Risk, Selenium, Vitamin E, Medical and Health Sciences, General & Internal Medicine
Abstract

ContextThe initial report of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) found no reduction in risk of prostate cancer with either selenium or vitamin E supplements but a statistically nonsignificant increase in prostate cancer risk with vitamin E. Longer follow-up and more prostate cancer events provide further insight into the relationship of vitamin E and prostate cancer.ObjectiveTo determine the long-term effect of vitamin E and selenium on risk of prostate cancer in relatively healthy men.Design, setting, and participantsA total of 35,533 men from 427 study sites in the United States, Canada, and Puerto Rico were randomized between August 22, 2001, and June 24, 2004. Eligibility criteria included a prostate-specific antigen (PSA) of 4.0 ng/mL or less, a digital rectal examination not suspicious for prostate cancer, and age 50 years or older for black men and 55 years or older for all others. The primary analysis included 34,887 men who were randomly assigned to 1 of 4 treatment groups: 8752 to receive selenium; 8737, vitamin E; 8702, both agents, and 8696, placebo. Analysis reflect the final data collected by the study sites on their participants through July 5, 2011.InterventionsOral selenium (200 μg/d from L-selenomethionine) with matched vitamin E placebo, vitamin E (400 IU/d of all rac-α-tocopheryl acetate) with matched selenium placebo, both agents, or both matched placebos for a planned follow-up of a minimum of 7 and maximum of 12 years.Main outcome measuresProstate cancer incidence.ResultsThis report includes 54,464 additional person-years of follow-up and 521 additional cases of prostate cancer since the primary report. Compared with the placebo (referent group) in which 529 men developed prostate cancer, 620 men in the vitamin E group developed prostate cancer (hazard ratio [HR], 1.17; 99% CI, 1.004-1.36, P = .008); as did 575 in the selenium group (HR, 1.09; 99% CI, 0.93-1.27; P = .18), and 555 in the selenium plus vitamin E group (HR, 1.05; 99% CI, 0.89-1.22, P = .46). Compared with placebo, the absolute increase in risk of prostate cancer per 1000 person-years was 1.6 for vitamin E, 0.8 for selenium, and 0.4 for the combination.ConclusionDietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men.Trial registrationClinicaltrials.gov Identifier: NCT00006392.

Published
2011

24. Variant ABO Blood Group Alleles, Secretor Status, and Risk of Pancreatic Cancer: Results from the Pancreatic Cancer Cohort Consortium

Author

Wolpin, Brian M, Kraft, Peter, Xu, Mousheng, Steplowski, Emily, Olsson, Martin L, Arslan, Alan A, Bueno-de-Mesquita, H Bas, Gross, Myron, Helzlsouer, Kathy, Jacobs, Eric J, LaCroix, Andrea, Petersen, Gloria, Stolzenberg-Solomon, Rachael Z, Zheng, Wei, Albanes, Demetrius, Allen, Naomi E, Amundadottir, Laufey, Austin, Melissa A, Boutron-Ruault, Marie-Christine, Buring, Julie E, Canzian, Federico, Chanock, Stephen J, Gaziano, J Michael, Giovannucci, Edward L, Hallmans, Göran, Hankinson, Susan E, Hoover, Robert N, Hunter, David J, Hutchinson, Amy, Jacobs, Kevin B, Kooperberg, Charles, Mendelsohn, Julie B, Michaud, Dominique S, Overvad, Kim, Patel, Alpa V, Sanchéz, Maria-José, Sansbury, Leah, Shu, Xiao-Ou, Slimani, Nadia, Tobias, Geoffrey S, Trichopoulos, Dimitrios, Vineis, Paolo, Visvanathan, Kala, Virtamo, Jarmo, Wactawski-Wende, Jean, Watters, Joanne, Yu, Kai, Zeleniuch-Jacquotte, Anne, Hartge, Patricia, and Fuchs, Charles S

Subjects
Digestive Diseases, Cancer, Clinical Research, Genetics, Rare Diseases, Pancreatic Cancer, Prevention, Human Genome, Aetiology, 2.1 Biological and endogenous factors, ABO Blood-Group System, Alleles, Cohort Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Glycosyltransferases, Humans, Odds Ratio, Pancreatic Neoplasms, Phenotype, Polymorphism, Single Nucleotide, Medical and Health Sciences, Epidemiology
Abstract

BackgroundSubjects with non-O ABO blood group alleles have increased risk of pancreatic cancer. Glycosyltransferase activity is greater for the A(1) versus A(2) variant, whereas O01 and O02 variants are nonfunctioning. We hypothesized: 1) A(1) allele would confer greater risk than A(2) allele, 2) protective effect of the O allele would be equivalent for O01 and O02 variants, 3) secretor phenotype would modify the association with risk.MethodsWe determined ABO variants and secretor phenotype from single nucleotide polymorphisms in ABO and FUT2 genes in 1,533 cases and 1,582 controls from 12 prospective cohort studies. Adjusted odds ratios (OR) for pancreatic cancer were calculated using logistic regression.ResultsAn increased risk was observed in participants with A(1) but not A(2) alleles. Compared with subjects with genotype O/O, genotypes A(2)/O, A(2)/A(1), A(1)/O, and A(1)/A(1) had ORs of 0.96 (95% CI, 0.72-1.26), 1.46 (95% CI, 0.98-2.17), 1.48 (95% CI, 1.23-1.78), and 1.71 (95% CI, 1.18-2.47). Risk was similar for O01 and O02 variant O alleles. Compared with O01/O01, the ORs for each additional allele of O02, A(1), and A(2) were 1.00 (95% CI, 0.87-1.14), 1.38 (95% CI, 1.20-1.58), and 0.96 (95% CI, 0.77-1.20); P, O01 versus O02 = 0.94, A(1) versus A(2) = 0.004. Secretor phenotype was not an effect modifier (P-interaction = 0.63).ConclusionsAmong participants in a large prospective cohort consortium, ABO allele subtypes corresponding to increased glycosyltransferase activity were associated with increased pancreatic cancer risk.ImpactThese data support the hypothesis that ABO glycosyltransferase activity influences pancreatic cancer risk rather than actions of other nearby genes on chromosome 9q34.

Published
2010

25. Family history of cancer and risk of pancreatic cancer: a pooled analysis from the Pancreatic Cancer Cohort Consortium (PanScan).

Author

Jacobs, Eric J, Chanock, Stephen J, Fuchs, Charles S, Lacroix, Andrea, McWilliams, Robert R, Steplowski, Emily, Stolzenberg-Solomon, Rachael Z, Arslan, Alan A, Bueno-de-Mesquita, H Bas, Gross, Myron, Helzlsouer, Kathy, Petersen, Gloria, Zheng, Wei, Agalliu, Ilir, Allen, Naomi E, Amundadottir, Laufey, Boutron-Ruault, Marie-Christine, Buring, Julie E, Canzian, Federico, Clipp, Sandra, Dorronsoro, Miren, Gaziano, J Michael, Giovannucci, Edward L, Hankinson, Susan E, Hartge, Patricia, Hoover, Robert N, Hunter, David J, Jacobs, Kevin B, Jenab, Mazda, Kraft, Peter, Kooperberg, Charles, Lynch, Shannon M, Sund, Malin, Mendelsohn, Julie B, Mouw, Tracy, Newton, Christina C, Overvad, Kim, Palli, Domenico, Peeters, Petra HM, Rajkovic, Aleksandar, Shu, Xiao-Ou, Thomas, Gilles, Tobias, Geoffrey S, Trichopoulos, Dimitrios, Virtamo, Jarmo, Wactawski-Wende, Jean, Wolpin, Brian M, Yu, Kai, and Zeleniuch-Jacquotte, Anne

Subjects
Humans, Pancreatic Neoplasms, Genetic Predisposition to Disease, Case-Control Studies, Cohort Studies, Genome-Wide Association Study, Colo-Rectal Cancer, Clinical Research, Rare Diseases, Aging, Cancer, Digestive Diseases, Prostate Cancer, Ovarian Cancer, Pancreatic Cancer, Breast Cancer, Prevention, Urologic Diseases, 2.1 Biological and endogenous factors, Oncology & Carcinogenesis, Oncology and Carcinogenesis
Abstract

A family history of pancreatic cancer has consistently been associated with increased risk of pancreatic cancer. However, uncertainty remains about the strength of this association. Results from previous studies suggest a family history of select cancers (i.e., ovarian, breast and colorectal) could also be associated, although not as strongly, with increased risk of pancreatic cancer. We examined the association between a family history of 5 types of cancer (pancreas, prostate, ovarian, breast and colorectal) and risk of pancreatic cancer using data from a collaborative nested case-control study conducted by the Pancreatic Cancer Cohort Consortium. Cases and controls were from cohort studies from the United States, Europe and China, and a case-control study from the Mayo Clinic. Analyses of family history of pancreatic cancer included 1,183 cases and 1,205 controls. A family history of pancreatic cancer in a parent, sibling or child was associated with increased risk of pancreatic cancer [multivariate-adjusted odds ratios (ORs) = 1.76, 95% confidence interval (CI) = 1.19-2.61]. A family history of prostate cancer was also associated with increased risk (OR = 1.45, 95% CI = 1.12-1.89). There were no statistically significant associations with a family history of ovarian cancer (OR = 0.82, 95% CI = 0.52-1.31), breast cancer (OR = 1.21, 95% CI = 0.97-1.51) or colorectal cancer (OR = 1.17, 95% CI = 0.93-1.47). Our results confirm a moderate sized association between a family history of pancreatic cancer and risk of pancreatic cancer and also provide evidence for an association with a family history of prostate cancer worth further study.

Published
2010

26. Anthropometric Measures, Body Mass Index, and Pancreatic Cancer: A Pooled Analysis From the Pancreatic Cancer Cohort Consortium (PanScan)

Author

Arslan, Alan A, Helzlsouer, Kathy J, Kooperberg, Charles, Shu, Xiao-Ou, Steplowski, Emily, Bueno-de-Mesquita, H Bas, Fuchs, Charles S, Gross, Myron D, Jacobs, Eric J, Lacroix, Andrea Z, Petersen, Gloria M, Stolzenberg-Solomon, Rachael Z, Zheng, Wei, Albanes, Demetrius, Amundadottir, Laufey, Bamlet, William R, Barricarte, Aurelio, Bingham, Sheila A, Boeing, Heiner, Boutron-Ruault, Marie-Christine, Buring, Julie E, Chanock, Stephen J, Clipp, Sandra, Gaziano, J Michael, Giovannucci, Edward L, Hankinson, Susan E, Hartge, Patricia, Hoover, Robert N, Hunter, David J, Hutchinson, Amy, Jacobs, Kevin B, Kraft, Peter, Lynch, Shannon M, Manjer, Jonas, Manson, Joann E, McTiernan, Anne, McWilliams, Robert R, Mendelsohn, Julie B, Michaud, Dominique S, Palli, Domenico, Rohan, Thomas E, Slimani, Nadia, Thomas, Gilles, Tjønneland, Anne, Tobias, Geoffrey S, Trichopoulos, Dimitrios, Virtamo, Jarmo, Wolpin, Brian M, Yu, Kai, Zeleniuch-Jacquotte, Anne, and Patel, Alpa V

Subjects
Obesity, Cancer, Clinical Research, Nutrition, Prevention, Pancreatic Cancer, Rare Diseases, Digestive Diseases, Adult, Aged, Aged, 80 and over, Body Mass Index, Case-Control Studies, Female, Humans, Logistic Models, Male, Middle Aged, Overweight, Pancreatic Neoplasms, Risk Factors, Sex Distribution, United States, Waist Circumference, Pancreatic Cancer Cohort Consortium, Clinical Sciences, Opthalmology and Optometry, Public Health and Health Services
Abstract

BackgroundObesity has been proposed as a risk factor for pancreatic cancer.MethodsPooled data were analyzed from the National Cancer Institute Pancreatic Cancer Cohort Consortium (PanScan) to study the association between prediagnostic anthropometric measures and risk of pancreatic cancer. PanScan applied a nested case-control study design and included 2170 cases and 2209 control subjects. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression for cohort-specific quartiles of body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]), weight, height, waist circumference, and waist to hip ratio as well as conventional BMI categories (underweight, or = 35.0). Models were adjusted for potential confounders.ResultsIn all of the participants, a positive association between increasing BMI and risk of pancreatic cancer was observed (adjusted OR for the highest vs lowest BMI quartile, 1.33; 95% CI, 1.12-1.58; P(trend) < .001). In men, the adjusted OR for pancreatic cancer for the highest vs lowest quartile of BMI was 1.33 (95% CI, 1.04-1.69; P(trend) < .03), and in women it was 1.34 (95% CI, 1.05-1.70; P(trend) = .01). Increased waist to hip ratio was associated with increased risk of pancreatic cancer in women (adjusted OR for the highest vs lowest quartile, 1.87; 95% CI, 1.31-2.69; P(trend) = .003) but less so in men.ConclusionsThese findings provide strong support for a positive association between BMI and pancreatic cancer risk. In addition, centralized fat distribution may increase pancreatic cancer risk, especially in women.

Published
2010

27. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33.

Author

Petersen, Gloria M, Amundadottir, Laufey, Fuchs, Charles S, Kraft, Peter, Stolzenberg-Solomon, Rachael Z, Jacobs, Kevin B, Arslan, Alan A, Bueno-de-Mesquita, H Bas, Gallinger, Steven, Gross, Myron, Helzlsouer, Kathy, Holly, Elizabeth A, Jacobs, Eric J, Klein, Alison P, LaCroix, Andrea, Li, Donghui, Mandelson, Margaret T, Olson, Sara H, Risch, Harvey A, Zheng, Wei, Albanes, Demetrius, Bamlet, William R, Berg, Christine D, Boutron-Ruault, Marie-Christine, Buring, Julie E, Bracci, Paige M, Canzian, Federico, Clipp, Sandra, Cotterchio, Michelle, de Andrade, Mariza, Duell, Eric J, Gaziano, J Michael, Giovannucci, Edward L, Goggins, Michael, Hallmans, Göran, Hankinson, Susan E, Hassan, Manal, Howard, Barbara, Hunter, David J, Hutchinson, Amy, Jenab, Mazda, Kaaks, Rudolf, Kooperberg, Charles, Krogh, Vittorio, Kurtz, Robert C, Lynch, Shannon M, McWilliams, Robert R, Mendelsohn, Julie B, Michaud, Dominique S, Parikh, Hemang, Patel, Alpa V, Peeters, Petra HM, Rajkovic, Aleksandar, Riboli, Elio, Rodriguez, Laudina, Seminara, Daniela, Shu, Xiao-Ou, Thomas, Gilles, Tjønneland, Anne, Tobias, Geoffrey S, Trichopoulos, Dimitrios, Van Den Eeden, Stephen K, Virtamo, Jarmo, Wactawski-Wende, Jean, Wang, Zhaoming, Wolpin, Brian M, Yu, Herbert, Yu, Kai, Zeleniuch-Jacquotte, Anne, Fraumeni, Joseph F, Hoover, Robert N, Hartge, Patricia, and Chanock, Stephen J

Subjects
Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 5, Chromosomes, Human, Pair 13, Humans, Carcinoma, Pancreatic Neoplasms, Genetic Predisposition to Disease, Case-Control Studies, Cohort Studies, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Genetic Loci, Rare Diseases, Cancer, Genetics, Clinical Research, Pancreatic Cancer, Digestive Diseases, Human Genome, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

We conducted a genome-wide association study of pancreatic cancer in 3,851 affected individuals (cases) and 3,934 unaffected controls drawn from 12 prospective cohort studies and 8 case-control studies. Based on a logistic regression model for genotype trend effect that was adjusted for study, age, sex, self-described ancestry and five principal components, we identified eight SNPs that map to three loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Two correlated SNPs, rs9543325 (P = 3.27 x 10(-11), per-allele odds ratio (OR) 1.26, 95% CI 1.18-1.35) and rs9564966 (P = 5.86 x 10(-8), per-allele OR 1.21, 95% CI 1.13-1.30), map to a nongenic region on chromosome 13q22.1. Five SNPs on 1q32.1 map to NR5A2, and the strongest signal was at rs3790844 (P = 2.45 x 10(-10), per-allele OR 0.77, 95% CI 0.71-0.84). A single SNP, rs401681 (P = 3.66 x 10(-7), per-allele OR 1.19, 95% CI 1.11-1.27), maps to the CLPTM1L-TERT locus on 5p15.33, which is associated with multiple cancers. Our study has identified common susceptibility loci for pancreatic cancer that warrant follow-up studies.

Published
2010

28. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer.

Author

Amundadottir, Laufey, Kraft, Peter, Stolzenberg-Solomon, Rachael Z, Fuchs, Charles S, Petersen, Gloria M, Arslan, Alan A, Bueno-de-Mesquita, H Bas, Gross, Myron, Helzlsouer, Kathy, Jacobs, Eric J, LaCroix, Andrea, Zheng, Wei, Albanes, Demetrius, Bamlet, William, Berg, Christine D, Berrino, Franco, Bingham, Sheila, Buring, Julie E, Bracci, Paige M, Canzian, Federico, Clavel-Chapelon, Françoise, Clipp, Sandra, Cotterchio, Michelle, de Andrade, Mariza, Duell, Eric J, Fox, John W, Gallinger, Steven, Gaziano, J Michael, Giovannucci, Edward L, Goggins, Michael, González, Carlos A, Hallmans, Göran, Hankinson, Susan E, Hassan, Manal, Holly, Elizabeth A, Hunter, David J, Hutchinson, Amy, Jackson, Rebecca, Jacobs, Kevin B, Jenab, Mazda, Kaaks, Rudolf, Klein, Alison P, Kooperberg, Charles, Kurtz, Robert C, Li, Donghui, Lynch, Shannon M, Mandelson, Margaret, McWilliams, Robert R, Mendelsohn, Julie B, Michaud, Dominique S, Olson, Sara H, Overvad, Kim, Patel, Alpa V, Peeters, Petra HM, Rajkovic, Aleksandar, Riboli, Elio, Risch, Harvey A, Shu, Xiao-Ou, Thomas, Gilles, Tobias, Geoffrey S, Trichopoulos, Dimitrios, Van Den Eeden, Stephen K, Virtamo, Jarmo, Wactawski-Wende, Jean, Wolpin, Brian M, Yu, Herbert, Yu, Kai, Zeleniuch-Jacquotte, Anne, Chanock, Stephen J, Hartge, Patricia, and Hoover, Robert N

Subjects
Chromosomes, Human, Pair 9, Humans, Pancreatic Neoplasms, Genetic Predisposition to Disease, ABO Blood-Group System, Logistic Models, Odds Ratio, Risk Factors, Case-Control Studies, Cohort Studies, Prospective Studies, Gene Frequency, Genotype, Haplotypes, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Alleles, Introns, United States, Female, Male, Genetic Variation, Genome-Wide Association Study, Prevention, Rare Diseases, Cancer, Genetics, Clinical Research, Pancreatic Cancer, Digestive Diseases, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

We conducted a two-stage genome-wide association study of pancreatic cancer, a cancer with one of the lowest survival rates worldwide. We genotyped 558,542 SNPs in 1,896 individuals with pancreatic cancer and 1,939 controls drawn from 12 prospective cohorts plus one hospital-based case-control study. We conducted a combined analysis of these groups plus an additional 2,457 affected individuals and 2,654 controls from eight case-control studies, adjusting for study, sex, ancestry and five principal components. We identified an association between a locus on 9q34 and pancreatic cancer marked by the SNP rs505922 (combined P = 5.37 x 10(-8); multiplicative per-allele odds ratio 1.20; 95% confidence interval 1.12-1.28). This SNP maps to the first intron of the ABO blood group gene. Our results are consistent with earlier epidemiologic evidence suggesting that people with blood group O may have a lower risk of pancreatic cancer than those with groups A or B.

Published
2009

29. Effect of Selenium and Vitamin E on Risk of Prostate Cancer and Other Cancers: The Selenium and Vitamin E Cancer Prevention Trial (SELECT)

Author

Lippman, Scott M, Klein, Eric A, Goodman, Phyllis J, Lucia, M Scott, Thompson, Ian M, Ford, Leslie G, Parnes, Howard L, Minasian, Lori M, Gaziano, J Michael, Hartline, Jo Ann, Parsons, J Kellogg, Bearden, James D, Crawford, E David, Goodman, Gary E, Claudio, Jaime, Winquist, Eric, Cook, Elise D, Karp, Daniel D, Walther, Philip, Lieber, Michael M, Kristal, Alan R, Darke, Amy K, Arnold, Kathryn B, Ganz, Patricia A, Santella, Regina M, Albanes, Demetrius, Taylor, Philip R, Probstfield, Jeffrey L, Jagpal, TJ, Crowley, John J, Meyskens, Frank L, Baker, Laurence H, and Coltman, Charles A

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Aging, Complementary and Integrative Health, Clinical Research, Cancer, Clinical Trials and Supportive Activities, Nutrition, Prevention, Prostate Cancer, Urologic Diseases, 3.3 Nutrition and chemoprevention, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Prevention of disease and conditions, and promotion of well-being, Aged, Antioxidants, Dietary Supplements, Double-Blind Method, Humans, Male, Middle Aged, Neoplasms, Prostatic Neoplasms, Selenium, Selenomethionine, Treatment Outcome, Vitamin E, alpha-Tocopherol, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

ContextSecondary analyses of 2 randomized controlled trials and supportive epidemiologic and preclinical data indicated the potential of selenium and vitamin E for preventing prostate cancer.ObjectiveTo determine whether selenium, vitamin E, or both could prevent prostate cancer and other diseases with little or no toxicity in relatively healthy men.Design, setting, and participantsA randomized, placebo-controlled trial (Selenium and Vitamin E Cancer Prevention Trial [SELECT]) of 35,533 men from 427 participating sites in the United States, Canada, and Puerto Rico randomly assigned to 4 groups (selenium, vitamin E, selenium + vitamin E, and placebo) in a double-blind fashion between August 22, 2001, and June 24, 2004. Baseline eligibility included age 50 years or older (African American men) or 55 years or older (all other men), a serum prostate-specific antigen level of 4 ng/mL or less, and a digital rectal examination not suspicious for prostate cancer.InterventionsOral selenium (200 microg/d from L-selenomethionine) and matched vitamin E placebo, vitamin E (400 IU/d of all rac-alpha-tocopheryl acetate) and matched selenium placebo, selenium + vitamin E, or placebo + placebo for a planned follow-up of minimum of 7 years and a maximum of 12 years.Main outcome measuresProstate cancer and prespecified secondary outcomes, including lung, colorectal, and overall primary cancer.ResultsAs of October 23, 2008, median overall follow-up was 5.46 years (range, 4.17-7.33 years). Hazard ratios (99% confidence intervals [CIs]) for prostate cancer were 1.13 (99% CI, 0.95-1.35; n = 473) for vitamin E, 1.04 (99% CI, 0.87-1.24; n = 432) for selenium, and 1.05 (99% CI, 0.88-1.25; n = 437) for selenium + vitamin E vs 1.00 (n = 416) for placebo. There were no significant differences (all P>.15) in any other prespecified cancer end points. There were statistically nonsignificant increased risks of prostate cancer in the vitamin E group (P = .06) and type 2 diabetes mellitus in the selenium group (relative risk, 1.07; 99% CI, 0.94-1.22; P = .16) but not in the selenium + vitamin E group.ConclusionSelenium or vitamin E, alone or in combination at the doses and formulations used, did not prevent prostate cancer in this population of relatively healthy men.Trial registrationclinicaltrials.gov identifier: NCT00006392.

Published
2009

30. Genomics and phenomics of body mass index reveals a complex disease network

Author

Huang, Jie, Huffman, Jennifer E, Huang, Yunfeng, Do Valle, Ítalo, Assimes, Themistocles L, Raghavan, Sridharan, Voight, Benjamin F, Liu, Chang-Mei, Barabási, Albert-László, Huang, Rose D. L., Hui, Qin, Nguyen, Xuan-Mai T., Ho, Yuk-Lam, Djoussé, Luc, Lynch, Julie, Vujkovic, Marijana, Tcheandjieu, Catherine, Tang, Hua, Damrauer, Scott M, Reaven, Peter D., Miller, Donald, Phillips, Lawrence S, Ng, Maggie C.Y., Graff, Mariaelisa, Haiman, Christopher A., Loos, Ruth Jf, North, Kari E, Yengo, Loic, Davey Smith, George, Saleheen, Danish, Gaziano, J. Michael, Rader, Daniel J, Tsao, Philip S, Cho, Kelly, Chang, Kyong-Mi, Wilson, Peter, Sun, Yan V, and O'Donnell, Christopher J

Subjects
Multidisciplinary, General Physics and Astronomy, Genomics, General Chemistry, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Body Mass Index, Humans, Obesity, Phenomics, Genome-Wide Association Study, Bristol Population Health Science Institute
Abstract

Elevated body mass index (BMI) is heritable and associated with many health conditions that impact morbidity and mortality. The study of the genetic association of BMI across a broad range of common disease conditions offers the opportunity to extend current knowledge regarding the breadth and depth of adiposity-related diseases. We identify 906 (364 novel) and 41 (6 novel) genome-wide significant loci for BMI among participants of European (N~1.1 million) and African (N~100,000) ancestry, respectively. Using a BMI genetic risk score including 2446 variants, 316 diagnoses are associated in the Million Veteran Program, with 96.5% showing increased risk. A co-morbidity network analysis reveals seven disease communities containing multiple interconnected diseases associated with BMI as well as extensive connections across communities. Mendelian randomization analysis confirms numerous phenotypes across a breadth of organ systems, including conditions of the circulatory (heart failure, ischemic heart disease, atrial fibrillation), genitourinary (chronic renal failure), respiratory (respiratory failure, asthma), musculoskeletal and dermatologic systems that are deeply interconnected within and across the disease communities. This work shows that the complex genetic architecture of BMI associates with a broad range of major health conditions, supporting the need for comprehensive approaches to prevent and treat obesity.

Published
2022

31. Large-scale genome-wide association study of coronary artery disease in genetically diverse populations

Author

Tcheandjieu, Catherine, Zhu, Xiang, Hilliard, Austin T, Clarke, Shoa L., Napolioni, Valerio, Ma, Shining, Lee, Kyung Min, Fang, Huaying, Chen, Fei, Lu, Yingchang, Tsao, Noah L., Raghavan, Sridharan, Koyama, Satoshi, Gorman, Bryan R., Vujkovic, Marijana, Klarin, Derek, Levin, Michael G., Sinnott-Armstrong, Nasa, Wojcik, Genevieve L., Plomondon, Mary E., Maddox, Thomas M., Waldo, Stephen W., Bick, Alexander G., Pyarajan, Saiju, Huang, Jie, Song, Rebecca, Ho, Yuk-Lam, Buyske, Steven, Kooperberg, Charles, Haessler, Jeffrey, Loos, Ruth J.F., Do, Ron, Verbanck, Marie, Chaudhary, Kumardeep, North, Kari E., Avery, Christy L., Graff, Mariaelisa, Haiman, Christopher A., Le Marchand, Loïc, Wilkens, Lynne R., Bis, Joshua C., Leonard, Hampton, Shen, Botong, Lange, Leslie A., Giri, Ayush, Dikilitas, Ozan, Kullo, Iftikhar J., Stanaway, Ian B., Jarvik, Gail P., Gordon, Adam S., Hebbring, Scott, Namjou, Bahram, Kaufman, Kenneth M., Ito, Kaoru, Ishigaki, Kazuyoshi, Kamatani, Yoichiro, Verma, Shefali S., Ritchie, Marylyn D., Kember, Rachel L., Baras, Aris, Lotta, Luca A., Japan, Biobank, Kathiresan, Sekar, Hauser, Elizabeth R., Miller, Donald R., Lee, Jennifer S, Saleheen, Danish, Reaven, Peter D., Cho, Kelly, Gaziano, J. Michael, Natarajan, Pradeep, Huffman, Jennifer E., Voight, Benjamin F., Rader, Daniel J, Chang, Kyong-Mi, Lynch, Julie A., Damrauer, Scott M., Wilson, Peter W. F., Tang, Hua, Sun, Yan V., Tsao, Philip S., O’Donnell, Christopher J., and Assimes, Themistocles L.

Subjects
Risk Factors, Humans, Genetic Predisposition to Disease, General Medicine, Coronary Artery Disease, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, Genome-Wide Association Study
Abstract

We report a genome-wide association study (GWAS) of coronary artery disease (CAD) incorporating nearly a quarter million cases, in which existing studies are integrated with data from cohorts of White, Black, and Hispanic individuals from the Million Veteran Program. We document near equivalent heritability of CAD across multiple ancestral groups, identify 95 novel loci, including the first nine to be identified on the X-chromosome, detect the first eight genome-wide significant loci among Blacks and Hispanics, and demonstrate that two common haplotypes at the 9p21 locus are responsible for risk stratification in all populations except those of African origin, where these haplotypes are virtually absent. Moreover, in the largest GWAS for angiographically derived coronary atherosclerosis performed to date, we find 15 genome-wide significant loci that robustly overlap with established loci for clinical CAD. Phenome-wide association analyses of novel loci and polygenic risk scores (PRS) augment signals related to insulin resistance, extend pleiotropic associations of these loci to include smoking and family history, and precisely document the markedly reduced transferability of existing PRS to Black individuals. Downstream integrative analyses reinforce the critical roles of vascular endothelial, fibroblast, and smooth muscle cells in CAD susceptibility, but also point to a shared biology between atherosclerosis and oncogenesis. Our study highlights the value of diverse populations in further characterizing the genetic architecture of CAD.

Published
2022

32. Association of Kidney Comorbidities and Acute Kidney Failure With Unfavorable Outcomes After COVID-19 in Individuals With the Sickle Cell Trait

Author

Verma, Anurag, Huffman, Jennifer E., Gao, Lina, Minnier, Jessica, Wu, Wen-Chih, Cho, Kelly, Ho, Yuk-Lam, Gorman, Bryan R., Pyarajan, Saiju, Rajeevan, Nallakkandi, Garcon, Helene, Joseph, Jacob, McGeary, John E., Suzuki, Ayako, Reaven, Peter D., Wan, Emily S., Lynch, Julie A., Petersen, Jeffrey M., Meigs, James B., Freiberg, Matthew S., Gatsby, Elise, Lynch, Kristine E., Zekavat, Seyedeh Maryam, Natarajan, Pradeep, Dalal, Sharvari, Jhala, Darshana N., Arjomandi, Mehrdad, Bonomo, Robert A., Thompson, Trevor K., Pathak, Gita A., Zhou, Jin J., Donskey, Curtis J., Madduri, Ravi K., Wells, Quinn S., Gelernter, Joel, Huang, Rose D. L., Polimanti, Renato, Chang, Kyong-Mi, Liao, Katherine P., Tsao, Philip S., Sun, Yan V., Wilson, Peter W. F., O’Donnell, Christopher J., Hung, Adriana M., Gaziano, J. Michael, Hauger, Richard L., Iyengar, Sudha K., and Luoh, Shiuh-Wen

Subjects
Black or African American, Hemoglobins, Internal Medicine, COVID-19, Humans, Acute Kidney Injury, Kidney, Original Investigation, Sickle Cell Trait
Abstract

IMPORTANCE: Sickle cell trait (SCT), defined as the presence of 1 hemoglobin beta sickle allele (rs334-T) and 1 normal beta allele, is prevalent in millions of people in the US, particularly in individuals of African and Hispanic ancestry. However, the association of SCT with COVID-19 is unclear. OBJECTIVE: To assess the association of SCT with the prepandemic health conditions in participants of the Million Veteran Program (MVP) and to assess the severity and sequelae of COVID-19. DESIGN, SETTING, AND PARTICIPANTS: COVID-19 clinical data include 2729 persons with SCT, of whom 353 had COVID-19, and 129 848 SCT-negative individuals, of whom 13 488 had COVID-19. Associations between SCT and COVID-19 outcomes were examined using firth regression. Analyses were performed by ancestry and adjusted for sex, age, age squared, and ancestral principal components to account for population stratification. Data for the study were collected between March 2020 and February 2021. EXPOSURES: The hemoglobin beta S (HbS) allele (rs334-T). MAIN OUTCOMES AND MEASURES: This study evaluated 4 COVID-19 outcomes derived from the World Health Organization severity scale and phenotypes derived from International Classification of Diseases codes in the electronic health records. RESULTS: Of the 132 577 MVP participants with COVID-19 data, mean (SD) age at the index date was 64.8 (13.1) years. Sickle cell trait was present in 7.8% of individuals of African ancestry and associated with a history of chronic kidney disease, diabetic kidney disease, hypertensive kidney disease, pulmonary embolism, and cerebrovascular disease. Among the 4 clinical outcomes of COVID-19, SCT was associated with an increased COVID-19 mortality in individuals of African ancestry (n = 3749; odds ratio, 1.77; 95% CI, 1.13 to 2.77; P = .01). In the 60 days following COVID-19, SCT was associated with an increased incidence of acute kidney failure. A counterfactual mediation framework estimated that on average, 20.7% (95% CI, −3.8% to 56.0%) of the total effect of SCT on COVID-19 fatalities was due to acute kidney failure. CONCLUSIONS AND RELEVANCE: In this genetic association study, SCT was associated with preexisting kidney comorbidities, increased COVID-19 mortality, and kidney morbidity.

Published
2022

33. Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19

Author

Gaziano, Liam, Giambartolomei, Claudia, Pereira, Alexandre C, Gaulton, Anna, Posner, Daniel C, Swanson, Sonja A, Ho, Yuk-Lam, Iyengar, Sudha K, Kosik, Nicole M, Vujkovic, Marijana, Gagnon, David R, Bento, A Patrícia, Barrio-Hernandez, Inigo, Rönnblom, Lars, Hagberg, Niklas, Lundtoft, Christian, Langenberg, Claudia, Pietzner, Maik, Valentine, Dennis, Gustincich, Stefano, Tartaglia, Gian Gaetano, Allara, Elias, Surendran, Praveen, Burgess, Stephen, Zhao, Jing Hua, Peters, James E, Prins, Bram P, Angelantonio, Emanuele Di, Devineni, Poornima, Shi, Yunling, Lynch, Kristine E, DuVall, Scott L, Garcon, Helene, Thomann, Lauren O, Zhou, Jin J, Gorman, Bryan R, Huffman, Jennifer E, O'Donnell, Christopher J, Tsao, Philip S, Beckham, Jean C, Pyarajan, Saiju, Muralidhar, Sumitra, Huang, Grant D, Ramoni, Rachel, Beltrao, Pedro, Danesh, John, Hung, Adriana M, Chang, Kyong-Mi, Sun, Yan V, Joseph, Jacob, Leach, Andrew R, Edwards, Todd L, Cho, Kelly, Gaziano, J Michael, Butterworth, Adam S, Casas, Juan P, VA Million Veteran Program COVID-19 Science Initiative, Epidemiology, Medical Research Council (MRC), Giambartolomei, Claudia [0000-0003-2786-1225], Gaulton, Anna [0000-0003-2634-7400], Posner, Daniel C [0000-0002-3056-6924], Kosik, Nicole M [0000-0003-1384-7035], Vujkovic, Marijana [0000-0003-4924-5714], Gagnon, David R [0000-0002-6367-3179], Bento, A Patrícia [0000-0003-1424-480X], Rönnblom, Lars [0000-0001-9403-6503], Hagberg, Niklas [0000-0003-2064-2716], Lundtoft, Christian [0000-0001-5872-4253], Langenberg, Claudia [0000-0002-5017-7344], Pietzner, Maik [0000-0003-3437-9963], Gustincich, Stefano [0000-0002-2749-2514], Tartaglia, Gian Gaetano [0000-0001-7524-6310], Allara, Elias [0000-0002-1634-8330], Burgess, Stephen [0000-0001-5365-8760], Peters, James E [0000-0002-9415-3440], Prins, Bram P [0000-0001-5774-034X], Huffman, Jennifer E [0000-0002-9672-2491], O'Donnell, Christopher J [0000-0002-2667-8624], Beltrao, Pedro [0000-0002-2724-7703], Chang, Kyong-Mi [0000-0001-6811-9364], Sun, Yan V [0000-0002-2838-1824], Butterworth, Adam S [0000-0002-6915-9015], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Biochemistry & Molecular Biology, Immunology, Quantitative Trait Loci, Druggability, Genome-wide association study, Receptor, Interferon alpha-beta, Computational biology, Research & Experimental Medicine, Quantitative trait locus, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Mendelian randomization, Humans, VA Million Veteran Program COVID-19 Science Initiative, health care economics and organizations, 11 Medical and Health Sciences, Repurposing, Science & Technology, RECEPTOR, SARS-CoV-2, Drug Repositioning, COVID-19, Cell Biology, IN-VITRO, General Medicine, Mendelian Randomization Analysis, Interleukin-10 Receptor beta Subunit, COVID-19 Drug Treatment, Drug repositioning, 030104 developmental biology, Medicine, Research & Experimental, Drug development, 030220 oncology & carcinogenesis, Expression quantitative trait loci, Angiotensin-Converting Enzyme 2, INTERFERON-ALPHA, Life Sciences & Biomedicine, Genome-Wide Association Study
Abstract

Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2, P = 1.6 × 10−6; IFNAR2, P = 9.8 × 10−11 and IL-10RB, P = 2.3 × 10−14) using cis-expression quantitative trait loci genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared expression quantitative trait loci signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19.

Published
2021

34. Comparative Safety of BNT162b2 and mRNA-1273 Vaccines in a Nationwide Cohort of US Veterans

Author

Dickerman, Barbra A., Madenci, Arin L., Gerlovin, Hanna, Kurgansky, Katherine E., Wise, Jessica K., Figueroa Muñiz, Michael J., Ferolito, Brian R., Gagnon, David R., Gaziano, J. Michael, Cho, Kelly, Casas, Juan P., and Hernán, Miguel A.

Subjects
Aged, 80 and over, Male, SARS-CoV-2, Myocardial Infarction, COVID-19, Cohort Studies, Internal Medicine, Humans, Female, mRNA Vaccines, BNT162 Vaccine, Original Investigation, 2019-nCoV Vaccine mRNA-1273, Aged, Ischemic Stroke, Veterans
Abstract

IMPORTANCE: The risk of adverse events has been found to be low for participants receiving the BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna Inc) vaccines in randomized trials. However, a head-to-head comparison of their safety for a broader range of potential adverse events over longer follow-up and in larger and more diverse populations is lacking, to our knowledge. OBJECTIVE: To compare the head-to-head safety in terms of risk of adverse events of the BNT162b2 and mRNA-1273 vaccines in the national health care databases of the US Department of Veterans Affairs, the largest integrated health care system in the US. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, the electronic health records of US veterans who received a first dose of the BNT162b2 or mRNA-1273 vaccine between January 4 and September 20, 2021, were used. Recipients of each vaccine were matched in a 1:1 ratio according to their risk factors. EXPOSURES: Vaccination with either the BNT162b2 vaccine, with a second dose scheduled 21 days later, or the mRNA-1273 vaccine, with a second dose scheduled 28 days later. MAIN OUTCOMES AND MEASURES: A large panel of potential adverse events was evaluated; the panel included neurologic events, hematologic events, hemorrhagic stroke, ischemic stroke, myocardial infarction, other thromboembolic events, myocarditis or pericarditis, arrhythmia, kidney injury, appendicitis, autoimmune events, herpes zoster or simplex, arthritis or arthropathy, and pneumonia. Risks over 38 weeks were estimated using the Kaplan-Meier estimator. RESULTS: Among 433 672 persons included in the matched vaccine groups, the median age was 69 years (IQR, 60-74 years), 93% of individuals were male, and 20% were Black. Estimated 38-week risks of adverse events were generally low after administration of either the BNT162b2 or the mRNA-1273 vaccine. Compared with the mRNA-1273 group, the BNT162b2 group had an excess per 10 000 persons of 10.9 events (95% CI, 1.9-17.4 events) of ischemic stroke, 14.8 events (95% CI, 7.9-21.8 events) of myocardial infarction, 11.3 events (95% CI, 3.4-17.7 events) of other thromboembolic events, and 17.1 events (95% CI, 8.8-30.2 events) of kidney injury. Estimates were largely similar among subgroups defined by age (

Published
2022

35. APOL1 Risk Variants, Acute Kidney Injury, and Death in Participants With African Ancestry Hospitalized With COVID-19 From the Million Veteran Program

Author

Hung, Adriana M., Shah, Shailja C., Bick, Alexander G., Yu, Zhihong, Chen, Hua-Chang, Hunt, Christine M., Wendt, Frank, Wilson, Otis, Greevy, Robert A., Chung, Cecilia P., Suzuki, Ayako, Ho, Yuk-Lam, Akwo, Elvis, Polimanti, Renato, Zhou, Jin, Reaven, Peter, Tsao, Philip S., Gaziano, J. Michael, Huffman, Jennifer E., Joseph, Jacob, Luoh, Shiuh-Wen, Iyengar, Sudha, Chang, Kyong-Mi, Casas, Juan P., Matheny, Michael E., O’Donnell, Christopher J., Cho, Kelly, Tao, Ran, Susztak, Katalin, Robinson-Cohen, Cassianne, Tuteja, Sony, and Siew, Edward D.

Subjects
Male, COVID-19, Acute Kidney Injury, Middle Aged, Apolipoprotein L1, Black or African American, Cohort Studies, Hospitalization, Risk Factors, Internal Medicine, Humans, Female, Original Investigation, Aged, Retrospective Studies, Veterans
Abstract

IMPORTANCE: Coronavirus disease 2019 (COVID-19) confers significant risk of acute kidney injury (AKI). Patients with COVID-19 with AKI have high mortality rates. OBJECTIVE: Individuals with African ancestry with 2 copies of apolipoprotein L1 (APOL1) variants G1 or G2 (high-risk group) have significantly increased rates of kidney disease. We tested the hypothesis that the APOL1 high-risk group is associated with a higher-risk of COVID-19–associated AKI and death. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included 990 participants with African ancestry enrolled in the Million Veteran Program who were hospitalized with COVID-19 between March 2020 and January 2021 with available genetic information. EXPOSURES: The primary exposure was having 2 APOL1 risk variants (RV) (APOL1 high-risk group), compared with having 1 or 0 risk variants (APOL1 low-risk group). MAIN OUTCOMES AND MEASURES: The primary outcome was AKI. The secondary outcomes were stages of AKI severity and death. Multivariable logistic regression analyses adjusted for preexisting comorbidities, medications, and inpatient AKI risk factors; 10 principal components of ancestry were performed to study these associations. We performed a subgroup analysis in individuals with normal kidney function prior to hospitalization (estimated glomerular filtration rate ≥60 mL/min/1.73 m(2)). RESULTS: Of the 990 participants with African ancestry, 905 (91.4%) were male with a median (IQR) age of 68 (60-73) years. Overall, 392 (39.6%) patients developed AKI, 141 (14%) developed stages 2 or 3 AKI, 28 (3%) required dialysis, and 122 (12.3%) died. One hundred twenty-five (12.6%) of the participants were in the APOL1 high-risk group. Patients categorized as APOL1 high-risk group had significantly higher odds of AKI (adjusted odds ratio [OR], 1.95; 95% CI, 1.27-3.02; P = .002), higher AKI severity stages (OR, 2.03; 95% CI, 1.37-2.99; P

Published
2022

36. Circulating concentrations of biomarkers and metabolites related to vitamin status, one-carbon and the kynurenine pathways in US, Nordic, Asian, and Australian populations123

Author

Midttun, Øivind, Theofylaktopoulou, Despoina, McCann, Adrian, Fanidi, Anouar, Muller, David C, Meyer, Klaus, Ulvik, Arve, Zheng, Wei, Shu, Xiao-Ou, Xiang, Yong-Bing, Prentice, Ross, Thomson, Cynthia A, Pettinger, Mary, Giles, Graham G, Hodge, Allison, Cai, Qiuyin, Blot, William J, Wu, Jie, Johansson, Mikael, Hultdin, Johan, Grankvist, Kjell, Stevens, Victoria L, McCullough, Marjorie L, Weinstein, Stephanie J, Albanes, Demetrius, Langhammer, Arnulf, Hveem, Kristian, Næss, Marit, Sesso, Howard D, Gaziano, J Michael, Buring, Julie E, Lee, I-Min, Severi, Gianluca, Zhang, Xuehong, Han, Jiali, Stampfer, Meir J, Smith-Warner, Stephanie A, Zeleniuch-Jacquotte, Anne, le Marchand, Loic, Yuan, Jian-Min, Butler, Lesley M, Koh, Woon-Puay, Wang, Renwei, Gao, Yu-Tang, Ericson, Ulrika, Sonestedt, Emily, Ziegler, Regina G, Freedman, Neal D, Visvanathan, Kala, Jones, Miranda R, Relton, Caroline, Brennan, Paul, Johansson, Mattias, and Ueland, Per M

Subjects
Male, Asia, alpha-Tocopherol, Nutritional Status, Dietary Intake, and Body Composition, Scandinavian and Nordic Countries, Humans, Vitamin D, Vitamin A, tryptophan metabolism, Kynurenine, Aged, Lung Cancer Cohort Consortium, Australia, Tryptophan, Middle Aged, one-carbon metabolism, Carbon, United States, Cross-Sectional Studies, Dietary Supplements, Vitamin B Complex, vitamin status, biomarker, Female, Laboratories, Biomarkers
Abstract

Background: Circulating concentrations of biomarkers that are related to vitamin status vary by factors such as diet, fortification, and supplement use. Published biomarker concentrations have also been influenced by the variation across laboratories, which complicates a comparison of results from different studies. Objective: We robustly and comprehensively assessed differences in biomarkers that are related to vitamin status across geographic regions. Design: The trial was a cross-sectional study in which we investigated 38 biomarkers that are related to vitamin status and one-carbon and tryptophan metabolism in serum and plasma from 5314 healthy control subjects representing 20 cohorts recruited from the United States, Nordic countries, Asia, and Australia, participating in the Lung Cancer Cohort Consortium. All samples were analyzed in a centralized laboratory. Results: Circulating concentrations of riboflavin, pyridoxal 5′-phosphate, folate, vitamin B-12, all-trans retinol, 25-hydroxyvitamin D, and α-tocopherol as well as combined vitamin scores that were based on these nutrients showed that the general B-vitamin concentration was highest in the United States and that the B vitamins and lipid soluble vitamins were low in Asians. Conversely, circulating concentrations of metabolites that are inversely related to B vitamins involved in the one-carbon and kynurenine pathways were high in Asians. The high B-vitamin concentration in the United States appears to be driven mainly by multivitamin-supplement users. Conclusions: The observed differences likely reflect the variation in intake of vitamins and, in particular, the widespread multivitamin-supplement use in the United States. The results provide valuable information about the differences in biomarker concentrations in populations across continents.

Published
2017

37. Association of APOL1 Risk Alleles with Cardiovascular Disease in African Americans in the Million Veteran Program

Author

Bick, Alexander G, Akwo, Elvis, Robinson-Cohen, Cassianne, Lee, Kyung, Lynch, Julie, Assimes, Themistocles L, DuVall, Scott, Edwards, Todd, Fang, Huaying, Freiberg, S. Matthew, Giri, Ayush, Huffman, Jennifer E, Huang, Jie, Hull, Leland, Kember, Rachel L, Klarin, Derek, Lee, Jennifer S, Levin, Michael, Miller, Donald R, Natarajan, Pradeep, Saleheen, Danish, Shao, Qing, Sun, Yan V, Tang, Hua, Wilson, Otis, Chang, Kyong-Mi, Cho, Kelly, Concato, John, Gaziano, J. Michael, Kathiresan, Sekar, O’Donnell, Christopher J, Rader, Daniel J, Tsao, Philip S, Wilson, Peter W, Hung, Adriana M, and Damrauer, Scott M

Subjects
Adult, Male, Risk, Polymorphism, Genetic, Genotype, Incidence, Myocardial Infarction, Coronary Artery Disease, Middle Aged, Apolipoprotein L1, Article, United States, Black or African American, Peripheral Arterial Disease, Electronic Health Records, Humans, Female, Genetic Predisposition to Disease, Alleles, Retrospective Studies, Veterans
Abstract

BACKGROUND: Approximately 13% of African-American individuals carry two copies of the APOL1 risk alleles G1 or G2, which are associated with 1.5-2.5 fold increased risk of chronic kidney disease (CKD). There have been conflicting reports as to whether an association exists between APOL1 risk alleles and cardiovascular disease, independent of the effects of APOL1 on kidney disease. We sought to test the association of APOL1 G1/G2 alleles with coronary artery disease (CAD), peripheral artery disease (PAD), and stroke among African American individuals in the Million Veteran Program (MVP). METHODS: We performed a time-to-event analysis of retrospective electronic health record (EHR) data using Cox proportional hazard and competing risks Fine and Gray sub-distribution hazard models. The primary exposure was APOL1 risk allele status. The primary outcome was incident CAD amongst individuals without CKD during the 12.5 year follow up period. Separately we analyzed the cross-sectional association of APOL1 risk allele status with lipid traits and 115 cardiovascular diseases using phenome-wide association. RESULTS: Among 30,903 African American MVP participants, 3,941 (13%) carried the two APOL1 risk allele high-risk genotype. Individuals with normal kidney function at baseline with two risk alleles had slightly higher risk of developing CAD compared to those with no risk alleles (Hazard Ratio (HR): 1.11, 95% Confidence Interval (CI): 1.01-1.21, p=0.039). Similarly, modest associations were identified with incident stroke (HR: 1.20, 95% CI: 1.05-1.36, p=0.007) and PAD (HR: 1.15, 95% CI:1.01-1.29, p=0.031). When modeling both cardiovascular and renal outcomes, APOL1 was strongly associated with incident renal disease, while no significant association with the cardiovascular disease endpoints could be detected. Cardiovascular phenome-wide association analyses did not identify additional significant associations with cardiovascular disease subsets. CONCLUSIONS: APOL1 risk variants display a modest association with cardiovascular disease and this association is likely mediated by the known APOL1 association with CKD.

Published
2019

38. Circulating markers of cellular immune activation in pre-diagnostic human serum in relation to lung cancer risk in the Lung Cancer Cohort Consortium (LC3)

Author

Huang, Joyce Yongxu, Larose, Tricia L., Wang, Renwei, Fanidi, Anouar, Alcala, Karine, Stevens, Victoria L., Weinstein, Stephanie J., Albanes, Demetrius, Caporaso, Neil, Purdue, Mark, Zeigler, Regina, Freedman, Neal, Lan, Qin, Prentice, Ross, Pettinger, Mary, Thomsen, Cynthia A., Cai, Qiuyin, Wu, Jie, Blot, William J., Shu, Xiao-Ou, Zheng, Wei, Arslan, Alan A., Zeleniuch-Jacquotte, Anne, Le Marchand, Loïc, Wilkens, Lynn R., Haiman, Christopher A., Zhang, Xuehong, Stampfer, Meir, Smith-Warner, Stephanie, Han, Jiali, Giles, Graham G, Hodge, Allison M, Severi, Gianluca, Johansson, Mikael, Grankvist, Kjell, Langhammer, Arnulf, Hveem, Kristian, Xiang, Yong-Bing, Li, Hong-Lan, Gao, Yu-Tang, Visvanathan, Kala, Bolton, Judy Hoffman, Ueland, Per M, Midttun, Øivind, Ulvik, Arve, Buring, Julie E., Lee, I-Min, Sesso, Howard D., Gaziano, J. Michael, Manjer, Jonas, Relton, Caroline, Koh, Woon-Puay, Brennan, Paul, Johansson, Mattias, and Yuan, Jian-Min

Subjects
Adult, Inflammation, Male, Lung Neoplasms, Tryptophan, Adenocarcinoma of Lung, Middle Aged, Prognosis, Neopterin, Small Cell Lung Carcinoma, Article, Risk Factors, Case-Control Studies, Biomarkers, Tumor, Carcinoma, Squamous Cell, Carcinoma, Large Cell, Humans, Female, Prospective Studies, Kynurenine, Aged, Follow-Up Studies
Abstract

Cell-mediated immunity may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), kynurenine metabolite—quinolinic acid (QA), and neopterin as markers of interferon-gamma-induced cellular immune activation with lung cancer risk in 5,364 cases and 5,364 individually matched control subjects from 20 prospective cohorts included the international Lung Cancer Cohort Consortium (LC3). Tryptophan, kynurenine, QA, and neopterin were quantified by mass spectrometry-based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with different levels of these metabolites and KTR were calculated using conditional logistic regression with adjustment for matched smoking variables and circulating cotinine. Overall, the highest quintiles of circulating kynurenine, KTR, QA and neopterin were associated with a 20–30% higher risk of lung cancer, and tryptophan with a 15% lower risk compared with the lowest quintile (all P(trend)

Published
2019

39. A catalog of genetic loci associated with kidney function from analyses of a million individuals

Author

Wuttke, Matthias, Li, Yong, Li, Man, Sieber, Karsten B., Feitosa, Mary F., Gorski, Mathias, Tin, Adrienne, Wang, Lihua, Chu, Audrey Y., Hoppmann, Anselm, Kirsten, Holger, Giri, Ayush, Chai, Jin-Fang, Sveinbjornsson, Gardar, Tayo, Bamidele O., Nutile, Teresa, Fuchsberger, Christian, Marten, Jonathan, Cocca, Massimiliano, Ghasemi, Sahar, Xu, Yizhe, Horn, Katrin, Noce, Damia, van der Most, Peter J., Sedaghat, Sanaz, Yu, Zhi, Akiyama, Masato, Afaq, Saima, Ahluwalia, Tarunveer S., Almgren, Peter, Amin, Najaf, Ärnlöv, Johan, Bakker, Stephan J. L., Bansal, Nisha, Baptista, Daniela, Bergmann, Sven, Biggs, Mary L., Biino, Ginevra, Boehnke, Michael, Boerwinkle, Eric, Boissel, Mathilde, Bottinger, Erwin P., Boutin, Thibaud S., Brenner, Hermann, Brumat, Marco, Burkhardt, Ralph, Butterworth, Adam S., Campana, Eric, Campbell, Archie, Campbell, Harry, Canouil, Mickaël, Carroll, Robert J., Catamo, Eulalia, Chambers, John C., Chee, Miao-Ling, Chee, Miao-Li, Chen, Xu, Cheng, Ching-Yu, Cheng, Yurong, Christensen, Kaare, Cifkova, Renata, Ciullo, Marina, Pina Concas, Maria, Cook, James P., Coresh, Josef, Corre, Tanguy, Sala, Cinzia Felicita, Cusi, Daniele, Danesh, John, Daw, E. Warwick, de Borst, Martin H., De Grandi, Alessandro, de Mutsert, Renée, de Vries, Aiko P. J., Degenhardt, Frauke, Delgado, Graciela, Demirkan, Ayse, Di Angelantonio, Emanuele, Dittrich, Katalin, Divers, Jasmin, Dorajoo, Rajkumar, Eckardt, Kai-Uwe, Ehret, Georg, Elliott, Paul, Endlich, Karlhans, Evans, Michele K., Felix, Janine F., Foo, Valencia Hui Xian, Franco, Oscar H., Franke, Andre, Freedman, Barry I., Freitag-Wolf, Sandra, Friedlander, Yechiel, Froguel, Philippe, Gansevoort, Ron T., Gao, He, Gasparini, Paolo, Gaziano, J. Michael, Giedraitis, Vilmantas, Gieger, Christian, Girotto, Giorgia, Giulianini, Franco, Gögele, Martin, Gordon, Scott D., Gudbjartsson, Daniel F., Gudnason, Vilmundur, Haller, Toomas, Hamet, Pavel, Harris, Tamara B., Hartman, Catharina A., Hayward, Caroline, Hellwege, Jacklyn N., Heng, Chew-Kiat, Hickst, Andrew A., Hofer, Edith, Huang, Wei, Hutri-Kähönen, Nina, Hwang, Shih-Jen, ikram, M. Arfan, indridason, Olafur S., Ingelsson, Erik, ising, Marcus, Jaddoe, Vincent W. V., Jakobsdottir, Johanna, Jonas, Jost B, Joshi, Peter K., Shilpa Josyula, Navya, Jung, Bettina, Kähönen, Mika, Kamatani, Yoichiro, Kammerer, Candace M., Kanai, Masahiro, Kastarinen, Mika, Kerr, Shona M., Khor, Chiea-Chuen, Kiess, Wieland, Kleber, Marcus E., Koenig, Wolfgang, Kooner, Jaspal S., Körner, Antje, Kovacs, Peter, Kraja, Aldi T., Krajcoviechova, Alena, Kramer, Holly, Krämer, Bernhard K., Kronenberg, Florian, Kubo, Michiaki, Kühnel, Brigitte, Kuokkanen, Mikko, Kuusisto, Johanna, La Bianca, Martina, Laakso, Markku, Lange, Leslie A., Langefeld, Carl D., Jen-Mai Lee, Jeannette, Lehne, Benjamin, Lehtimäki, Terho, Lieb, Wolfgang, Cohort Study, Lifelines, Lim, Su-Chi, Lind, Lars, Lindgren, Cecilia M., Liu, Jun, Liu, Jianjun, Loeffler, Markus, Loos, Ruth J. F., Lucae, Susanne, Ann Lukas, Mary, Lyytikäinen, Leo-Pekka, Mägi, Reedik, Magnusson, Patrik K. E., Mahajan, Anubha, Martin, Nicholas G., Martins, Jade, März, Winfried, Mascalzoni, Deborah, Matsuda, Koichi, Christa Meisinger, Meitinger, Thomas, Melander, Olle, Metspalu, Andres, Mikaelsdottir, Evgenia K., Milaneschi, Yuri, Miliku, Kozeta, Mishra, Pashupati P., Veteran Program, V. A. Million, Mohlke, Karen L., Mononen, Nina, Montgomery, Grant W., Mook-Kanamori, Dennis O., Mychaleckyj, Josyf C., Nadkarni, Girish N, Nalls, Mike A., Nauck, Matthias, Nikus, Kjell, Ning, Boting, Nolte, ilja M., Noordam, Raymond, O’Connell, Jeffrey, O’Donoghue, Michelle L., Olafsson, Isleifur, Oldehinkel, Albertine J., Orho-Melander, Marju, Ouwehand, Willem H., Padmanabhan, Sandosh, Palmer, Nicholette D., Palsson, Runolfur, Penninx, Brenda W. J. H., Perls, Thomas, Perola, Markus, Pirastu, Mario, Pirastu, Nicola, Pistis, Giorgio, Podgornaia, Anna I., Polasek, Ozren, Ponte, Belen, Porteous, David J., Poulain, Tanja, Pramstaller, Peter P., Preuss, Michael H., Prins, Bram P., Province, Michael A., Rabelink, Ton J., Raffield, Laura M., Raitakari, Olli T., Reilly, Dermot F., Rettig, Rainer, Rheinberger, Myriam, Rice, Kenneth M., Ridker, Paul M., Rivadeneira, Fernando, Rizzi, Federica, Roberts, David J., Robino, Antonietta, Rossing, Peter, Rudan, Igor, Rueedi, Rico, Ruggiero, Daniela, Ryan, Kathleen A., Saba, Yasaman, Sabanayagam, Charumathi, Salomaa, Veikko, Salvi, Erika, Saum, Kai-Uwe, Schmidt, Helena, Schmidt, Reinhold, Schöttker, Ben, Schulz, Christina-Alexandra, Schupf, Nicole, Shaffer, Christian M., Shi, Yuan, Smith, Albert V., Smith, Blair H., Soranzo, Nicole, Spracklen, Cassandra N., Strauch, Konstantin, Stringham, Heather M., Stumvoll, Michael, Svensson, Per O., Szymczak, Silke, Tai, E-Shyong, Tajuddin, Salman M., Tan, Nicholas Y. Q., Taylor, Kent D., Teren, Andrej, Tham, Yih-Chung, Thiery, Joachim, Thio, Chris H. L., Thomsen, Hauke, Thorleifsson, Gudmar, Toniolo, Daniela, Tönjes, Anke, Tremblay, Johanne, Tzoulaki, Ioanna, Uitterlinden, André G., Vaccargiu, Simona, van Dam, Rob M., van der Harst, Pim, van Duijn, Cornelia M., Velez Edward, Digna R., Verweij, Niek, Vogelezang, suzanne, Völker, üwe, Vollenweider, Peter, Waeber, Gerard, Waldenberger, Melanie, Wallentin, Lars, Wang, Ya Xing, Wang, Chaolong, Waterworth, Dawn M., Bin Wei, Wen, White, Harvey, Whitfield, John B., Wild, Sarah H., Wilson, James F., Wojczynski, Mary K., Wong, Charlene, Wong, Tien-Yin, Xu, Liang, Yang, Qiong, Yasuda, Masayuki, Yerges-Armstrong, Laura M., Zhang, Weihua, Zonderman, Alan B., Rotter, Jerome I., Bochud, Murielle, Psaty, Bruce M., Vitart, Veronique, Wilson, James G., Dehghan, Abbas, Parsa, Afshin, Chasman, Daniel I., Ho, Kevin, Morris, Andrew P., Devuyst, Olivier, Akilesh, Shreeram, Pendergrass, Sarah A., Sim, Xueling, Böger, Carsten A., Okada, Yukinori, Edwards, Todd L., Snieder, Harold, Stefansson, Kari, Hung, Adriana M., Heid, Iris M., Markus Scholz, Teumer, Alexander, Köttgen, Anna, Pattaro, Cristian, Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Internal Medicine, Epidemiology, Erasmus MC other, Pediatrics, Psychiatry, APH - Mental Health, APH - Digital Health, Wuttke, M, Li, Y, Li, M, Sieber, Kb, Feitosa, Mf, Gorski, M, Tin, A, Wang, L, Chu, Ay, Hoppmann, A, Kirsten, H, Giri, A, Chai, Jf, Sveinbjornsson, G, Tayo, Bo, Nutile, T, Fuchsberger, C, Marten, J, Cocca, M, Ghasemi, S, Xu, Y, Horn, K, Noce, D, van der Most, Pj, Sedaghat, S, Yu, Z, Akiyama, M, Afaq, S, Ahluwalia, T, Almgren, P, Amin, N, Ärnlöv, J, Bakker, Sjl, Bansal, N, Baptista, D, Bergmann, S, Biggs, Ml, Biino, G, Boehnke, M, Boerwinkle, E, Boissel, M, Bottinger, Ep, Boutin, T, Brenner, H, Brumat, M, Burkhardt, R, Butterworth, A, Campana, Eric, Campbell, A, Campbell, H, Canouil, M, Carroll, Rj, Catamo, E, Chambers, Jc, Chee, Ml, Chen, X, Cheng, Cy, Cheng, Y, Christensen, K, Cifkova, R, Ciullo, M, Concas, Mp, Cook, Jp, Coresh, J, Corre, T, Sala, Cf, Cusi, D, Danesh, J, Daw, Ew, de Borst, Mh, De Grandi, A, de Mutsert, R, de Vries, Apj, Degenhardt, F, Delgado, G, Demirkan, A, Di Angelantonio, E, Dittrich, K, Divers, J, Dorajoo, R, Eckardt, Ku, Ehret, G, Elliott, P, Endlich, K, Evans, Mk, Felix, Jf, Foo, Vhx, Franco, Oh, Franke, A, Freedman, Bi, Freitag-Wolf, S, Friedlander, Y, Froguel, P, Gansevoort, Rt, Gao, H, Gasparini, P, Gaziano, Jm, Giedraitis, V, Gieger, C, Girotto, G, Giulianini, F, Gögele, M, Gordon, Sd, Gudbjartsson, Df, Gudnason, V, Haller, T, Hamet, P, Harris, Tb, Hartman, Ca, Hayward, C, Hellwege, Jn, Heng, Ck, Hicks, Aa, Hofer, E, Huang, W, Hutri-Kähönen, N, Hwang, Sj, Ikram, Ma, Indridason, O, Ingelsson, E, Ising, M, Jaddoe, Vwv, Jakobsdottir, J, Jonas, Jb, Joshi, Pk, Josyula, N, Jung, B, Kähönen, M, Kamatani, Y, Kammerer, Cm, Kanai, M, Kastarinen, M, Kerr, Sm, Khor, Cc, Kiess, W, Kleber, Me, Koenig, W, Kooner, J, Körner, A, Kovacs, P, Kraja, At, Krajcoviechova, A, Kramer, H, Krämer, Bk, Kronenberg, F, Kubo, M, Kühnel, B, Kuokkanen, M, Kuusisto, J, La Bianca, M, Laakso, M, Lange, La, Langefeld, Cd, Lee, Jj, Lehne, B, Lehtimäki, T, Lieb, W, Lifelines Cohort, Study, Lim, Sc, Lind, L, Lindgren, Cm, Liu, J, Loeffler, M, Loos, Rjf, Lucae, S, Lukas, Ma, Lyytikäinen, Lp, Mägi, R, Magnusson, Pke, Mahajan, A, Martin, Ng, Martins, J, März, W, Mascalzoni, D, Matsuda, K, Meisinger, C, Meitinger, T, Melander, O, Metspalu, A, Mikaelsdottir, Ek, Milaneschi, Y, Miliku, K, Mishra, Pp, V. A., Million Veteran Program, Mohlke, Kl, Mononen, N, Montgomery, Gw, Mook-Kanamori, Do, Mychaleckyj, Jc, Nadkarni, Gn, Nalls, Ma, Nauck, M, Nikus, K, Ning, B, Nolte, Im, Noordam, R, O'Connell, J, O'Donoghue, Ml, Olafsson, I, Oldehinkel, Aj, Orho-Melander, M, Ouwehand, Wh, Padmanabhan, S, Palmer, Nd, Palsson, R, Penninx, Bwjh, Perls, T, Perola, M, Pirastu, M, Pirastu, N, Pistis, G, Podgornaia, Ai, Polasek, O, Ponte, B, Porteous, Dj, Poulain, T, Pramstaller, Pp, Preuss, Mh, Prins, Bp, Province, Ma, Rabelink, Tj, Raffield, Lm, Raitakari, Ot, Reilly, Df, Rettig, R, Rheinberger, M, Rice, Km, Ridker, Pm, Rivadeneira, F, Rizzi, F, Roberts, Dj, Robino, A, Rossing, P, Rudan, I, Rueedi, R, Ruggiero, D, Ryan, Ka, Saba, Y, Sabanayagam, C, Salomaa, V, Salvi, E, Saum, Ku, Schmidt, H, Schmidt, R, Schöttker, B, Schulz, Ca, Schupf, N, Shaffer, Cm, Shi, Y, Smith, Av, Smith, Bh, Soranzo, N, Spracklen, Cn, Strauch, K, Stringham, Hm, Stumvoll, M, Svensson, Po, Szymczak, S, Tai, E, Tajuddin, Sm, Tan, Nyq, Taylor, Kd, Teren, A, Tham, Yc, Thiery, J, Thio, Chl, Thomsen, H, Thorleifsson, G, Toniolo, D, Tönjes, A, Tremblay, J, Tzoulaki, I, Uitterlinden, Ag, Vaccargiu, S, van Dam, Rm, van der Harst, P, van Duijn, Cm, Velez Edward, Dr, Verweij, N, Vogelezang, S, Völker, U, Vollenweider, P, Waeber, G, Waldenberger, M, Wallentin, L, Wang, Yx, Wang, C, Waterworth, Dm, Bin Wei, W, White, H, Whitfield, Jb, Wild, Sh, Wilson, Jf, Wojczynski, Mk, Wong, C, Wong, Ty, Xu, L, Yang, Q, Yasuda, M, Yerges-Armstrong, Lm, Zhang, W, Zonderman, Ab, Rotter, Ji, Bochud, M, Psaty, Bm, Vitart, V, Wilson, Jg, Dehghan, A, Parsa, A, Chasman, Di, Ho, K, Morris, Ap, Devuyst, O, Akilesh, S, Pendergrass, Sa, Sim, X, Böger, Ca, Okada, Y, Edwards, Tl, Snieder, H, Stefansson, K, Hung, Am, Heid, Im, Scholz, M, Teumer, A, Köttgen, A, and Pattaro, C.

Subjects
catalog, Inheritance Patterns, Hasso-Plattner-Institut für Digital Engineering GmbH, Genome-wide association study, Disease, Kidney Function Tests, Bioinformatics, DISEASE, 0302 clinical medicine, Uromodulin/urine, kidney function, 11 Medical and Health Sciences, Genetics & Heredity, ddc:616, 0303 health sciences, Kidney, Genome-wide association, HERITABILITY, GENOME-WIDE ASSOCIATION, COMMON VARIANTS, RENAL-FUNCTION, TRANS-EQTLS, METAANALYSIS, TRANSPORTER, CLASSIFICATION, INTEGRATION, Chromosome Mapping, 3. Good health, Phenotype, medicine.anatomical_structure, Medical genetics, Common variants, Renal function, Trans-EQTLS, Metaanalysis, Heritability, Transporter, Life Sciences & Biomedicine, Glomerular Filtration Rate, Metaanalysi, medicine.medical_specialty, Genotype, European Continental Ancestry Group, Quantitative Trait Loci, Common variant, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Article, White People, V. A. Million Veteran Program, 03 medical and health sciences, Quantitative Trait, Heritable, Lifelines Cohort Study, Uromodulin, Genetics, medicine, Humans, Genetic Predisposition to Disease, Renal Insufficiency, Chronic, Genetic Association Studies, 030304 developmental biology, Genetic association, Science & Technology, urogenital system, association, genetic loci, 06 Biological Sciences, medicine.disease, Renal Insufficiency, Chronic/genetics/physiopathology/urine, Genetic Association Studies/methods, ddc:000, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study, Kidney disease
Abstract

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

Published
2019

40. Equalization of four cardiovascular risk algorithms after systematic recalibration: individual-participant meta-analysis of 86 prospective studies

Author

Pennells, Lisa, Kaptoge, Stephen, Wood, Angela, Sweeting, Mike, Zhao, Xiaohui, White, Ian, Burgess, Stephen, Willeit, Peter, Bolton, Thomas, Moons, Karel G M, van der Schouw, Yvonne T, Selmer, Randi, Khaw, Kay-Tee, Gudnason, Vilmundur, Assmann, Gerd, Amouyel, Philippe, Salomaa, Veikko, Kivimaki, Mika, Nordestgaard, Børge G, Blaha, Michael J, Kuller, Lewis H, Brenner, Hermann, Gillum, Richard F, Meisinger, Christa, Ford, Ian, Knuiman, Matthew W, Rosengren, Annika, Lawlor, Debbie A, Völzke, Henry, Cooper, Cyrus, Marín Ibañez, Alejandro, Casiglia, Edoardo, Kauhanen, Jussi, Cooper, Jackie A, Rodriguez, Beatriz, Sundström, Johan, Barrett-Connor, Elizabeth, Dankner, Rachel, Nietert, Paul J, Davidson, Karina W, Wallace, Robert B, Blazer, Dan G, Björkelund, Cecilia, Donfrancesco, Chiara, Krumholz, Harlan M, Nissinen, Aulikki, Davis, Barry R, Coady, Sean, Whincup, Peter H, Jørgensen, Torben, Ducimetiere, Pierre, Trevisan, Maurizio, Engström, Gunnar, Crespo, Carlos J, Meade, Tom W, Visser, Marjolein, Kromhout, Daan, Kiechl, Stefan, Daimon, Makoto, Price, Jackie F, Gómez de la Cámara, Agustin, Wouter Jukema, J, Lamarche, Benoît, Onat, Altan, Simons, Leon A, Kavousi, Maryam, Ben-Shlomo, Yoav, Gallacher, John, Dekker, Jacqueline M, Arima, Hisatomi, Shara, Nawar, Tipping, Robert W, Roussel, Ronan, Brunner, Eric J, Koenig, Wolfgang, Sakurai, Masaru, Pavlovic, Jelena, Gansevoort, Ron T, Nagel, Dorothea, Goldbourt, Uri, Barr, Elizabeth L M, Palmieri, Luigi, Njølstad, Inger, Sato, Shinichi, Monique Verschuren, W M, Varghese, Cherian V, Graham, Ian, Onuma, Oyere, Greenland, Philip, Woodward, Mark, Ezzati, Majid, Psaty, Bruce M, Sattar, Naveed, Jackson, Rod, Ridker, Paul M, Cook, Nancy R, D'Agostino, Ralph B, Thompson, Simon G, Danesh, John, Di Angelantonio, Emanuele, Simpson, Lara M, Pressel, Sara L, Couper, David J, Nambi, Vijay, Matsushita, Kunihiro, Folsom, Aaron R, Shaw, Jonathan E, Magliano, Dianna J, Zimmet, Paul Z, Wannamethee, S Goya, Willeit, Johann, Santer, Peter, Egger, Georg, Casas, Juan Pablo, Amuzu, Antointtte, Tikhonoff, Valérie, Sutherland, Susan E, Cushman, Mary, Søgaard, Anne Johanne, Håheim, Lise Lund, Ariansen, Inger, Tybjærg-Hansen, Anne, Jensen, Gorm B, Schnohr, Peter, Giampaoli, Simona, Vanuzzo, Diego, Panico, Salvatore, Balkau, Beverley, Bonnet, Fabrice, Marre, Michel, de la Cámara, Agustin Gómez, Rubio Herrera, Miguel Angel, Friedlander, Yechiel, McCallum, John, McLachlan, Stela, Guralnik, Jack, Phillips, Caroline L, Wareham, Nick, Schöttker, Ben, Saum, Kai-Uwe, Holleczek, Bernd, Tolonen, Hanna, Vartiainen, Erkki, Jousilahti, Pekka, Harald, Kennet, D’Agostino, Ralph B, Massaro, Joseph M, Pencina, Michael, Vasan, Ramachandran, Kayama, Takamasa, Kato, Takeo, Oizumi, Toshihide, Jespersen, Jørgen, Møller, Lars, Bladbjerg, Else Marie, Chetrit, A, Wilhelmsen, Lars, Lissner, Lauren, Dennison, Elaine, Kiyohara, Yutaka, Ninomiya, Toshiharu, Doi, Yasufumi, Nijpels, Giel, Stehouwer, Coen D A, Kazumasa, Yamagishi, Iso, Hiroyasu, Kurl, Sudhir, Tuomainen, Tomi-Pekka, Salonen, Jukka T, Deeg, Dorly J H, Nilsson, Peter M, Hedblad, Bo, Melander, Olle, De Boer, Ian H, DeFilippis, Andrew Paul, Verschuren, W M Monique, Watt, Graham, Tverdal, Aage, Kirkland, Susan, Shimbo, Daichi, Shaffer, Jonathan, Bakker, Stephan J L, van der Harst, Pim, Hillege, Hans L, Dallongeville, Jean, Schulte, Helmut, Trompet, Stella, Smit, Roelof A J, Stott, David J, Després, Jean-Pierre, Cantin, Bernard, Dagenais, Gilles R, Laughlin, Gail, Wingard, Deborah, Aspelund, Thor, Eiriksdottir, Gudny, Gudmundsson, Elias Freyr, Ikram, Arfan, van Rooij, Frank J A, Franco, Oscar H, Rueda-Ochoa, Oscar L, Muka, Taulant, Glisic, Marija, Tunstall-Pedoe, Hugh, Howard, Barbara V, Zhang, Ying, Jolly, Stacey, Davey-Smith, George, Can, Günay, Yüksel, Hüsniye, Nakagawa, Hideaki, Morikawa, Yuko, Miura, Katsuyuki, Ingelsson, Martin, Giedraitis, Vilmantas, Gaziano, J Michael, Shipley, Martin, Arndt, Volker, Cook, Nancy, Ibañez, Alejandro Marín, Geleijnse, Johanna M, Epidemiology, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Pennells, Lisa [0000-0002-8594-3061], Kaptoge, Stephen [0000-0002-1155-4872], Wood, Angela [0000-0002-7937-304X], Sweeting, Michael [0000-0003-0980-8965], Zhao, Xiaohui [0000-0001-9922-2815], Burgess, Stephen [0000-0001-5365-8760], Danesh, John [0000-0003-1158-6791], Di Angelantonio, Emanuele [0000-0001-8776-6719], Apollo - University of Cambridge Repository, Nutrition and Health, APH - Aging & Later Life, APH - Societal Participation & Health, APH - Health Behaviors & Chronic Diseases, Cardiovascular Centre (CVC), Groningen Kidney Center (GKC), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Life Course Epidemiology (LCE), AGEM - Endocrinology, metabolism and nutrition, Internal medicine, Epidemiology and Data Science, İÜC, Lisa, Pennell, Stephen, Kaptoge, Angela, Wood, Mike, Sweeting, Xiaohui, Zhao, Ian, White, Stephen, Burge, Peter, Willeit, Thomas, Bolton, Karel G M, Moon, Yvonne T, van der Schouw, Randi, Selmer, Kay-Tee, Khaw, Vilmundur, Gudnason, Gerd, Assmann, Philippe, Amouyel, Veikko, Salomaa, Mika, Kivimaki, Børge G, Nordestgaard, Michael J, Blaha, Lewis H, Kuller, Hermann, Brenner, Richard F, Gillum, Christa, Meisinger, Ian, Ford, Matthew W, Knuiman, Annika, Rosengren, Debbie A, Lawlor, Henry, Völzke, Cyrus, Cooper, Alejandro, Marín Ibañez, Edoardo, Casiglia, Jussi, Kauhanen, Jackie A, Cooper, Beatriz, Rodriguez, Johan, Sundström, Elizabeth, Barrett-Connor, Rachel, Dankner, Paul J, Nietert, Karina W, Davidson, Robert B, Wallace, Dan G, Blazer, Cecilia, Björkelund, Chiara, Donfrancesco, Harlan M, Krumholz, Aulikki, Nissinen, Barry R, Davi, Sean, Coady, Peter H, Whincup, Torben, Jørgensen, Pierre, Ducimetiere, Maurizio, Trevisan, Gunnar, Engström, Carlos J, Crespo, Tom W, Meade, Marjolein, Visser, Daan, Kromhout, Stefan, Kiechl, Makoto, Daimon, Jackie F, Price, Agustin, Gómez de la Cámara, J, Wouter Jukema, Benoît, Lamarche, Altan, Onat, Leon A, Simon, Maryam, Kavousi, Yoav, Ben-Shlomo, John, Gallacher, Jacqueline M, Dekker, Hisatomi, Arima, Nawar, Shara, Robert W, Tipping, Ronan, Roussel, Eric J, Brunner, Wolfgang, Koenig, Masaru, Sakurai, Jelena, Pavlovic, Ron T, Gansevoort, Dorothea, Nagel, Uri, Goldbourt, Elizabeth L M, Barr, Luigi, Palmieri, Inger, Njølstad, Shinichi, Sato, W M, Monique Verschuren, Cherian V, Varghese, Ian, Graham, Oyere, Onuma, Philip, Greenland, Mark, Woodward, Majid, Ezzati, Bruce M, Psaty, Sattar, W Tipping, Naveerobert, M Simpson, Lara, L Pressel, Sara, J Couper, David, Nambi, Vijay, Matsushita, Kunihiro, R Folsom, Aaron, E Shaw, Jonathan, J Magliano, Dianna, Z Zimmet, Paul, W Knuiman, Matthew, H Whincup, Peter, Goya Wannamethee, S, Willeit, Johann, Santer, Peter, Egger, Georg, Pablo Casas, Juan, Amuzu, Antoinette, Ben-Shlomo, Yoav, Gallacher, John, Tikhonoff, Valérie, Casiglia, Edoardo, E Sutherland, Susan, J Nietert, Paul, Cushman, Mary, M Psaty, Bruce, Johanne Søgaard, Anne, Lund Håheim, Lise, Ariansen, Inger, Tybjærg-Hansen, Anne, B Jensen, Gorm, Schnohr, Peter, Giampaoli, Simona, Vanuzzo, Diego, Panico, Salvatore, Palmieri, Luigi, Balkau, Beverley, Bonnet, Fabrice, Marre, Michel, Gómez de la Cámara, Agustin, Angel Rubio Herrera, Miguel, Friedlander, Yechiel, Mccallum, John, Mclachlan, Stela, Guralnik, Jack, L Phillips, Caroline, Khaw, Kay-Tee, Wareham, Nick, Schöttker, Ben, Saum, Kai-Uwe, Holleczek, Bernd, Nissinen, Aulikki, Tolonen, Hanna, Donfrancesco, Chiara, Vartiainen, Erkki, Jousilahti, Pekka, Harald, Kennet, B D’Agostino, Ralph, M Massaro, Joseph, Pencina, Michael, Vasan, Ramachandran, Kayama, Takamasa, Kato, Takeo, Oizumi, Toshihide, Jespersen, Jørgen, Møller, Lar, Marie Bladbjerg, Else, Chetrit, A, Rosengren, Annika, Wilhelmsen, Lar, Björkelund, Cecilia, Lissner, Lauren, Nagel, Dorothea, Dennison, Elaine, Kiyohara, Yutaka, Ninomiya, Toshiharu, Doi, Yasufumi, Rodriguez, Beatriz, Nijpels, Giel, A Stehouwer, Coen D, Sato, Shinichi, Kazumasa, Yamagishi, Iso, Hiroyasu, Goldbourt, Uri, Salomaa, Veikko, Kurl, Sudhir, Tuomainen, Tomi-Pekka, T Salonen, Jukka, Visser, Marjolein, H Deeg, Dorly J, W Meade, Tom, M Nilsson, Peter, Hedblad, Bo, Melander, Olle, H De Boer, Ian, Paul DeFilippis, Andrew, M Monique Verschuren, W, Sattar, Naveed, Watt, Graham, Meisinger, Christa, Koenig, Wolfgang, H Kuller, Lewi, Tverdal, Aage, F Gillum, Richard, A Cooper, Jackie, Kirkland, Susan, Shimbo, Daichi, Shaffer, Jonathan, Ducimetiere, Pierre, L Bakker, Stephan J, van der Harst, Pim, L Hillege, Han, J Crespo, Carlo, Amouyel, Philippe, Dallongeville, Jean, Assmann, Gerd, Schulte, Helmut, Trompet, Stella, J Smit, Roelof A, J Stott, David, T van der Schouw, Yvonne, Després, Jean-Pierre, Cantin, Bernard, R Dagenais, Gille, Laughlin, Gail, Wingard, Deborah, Trevisan, Maurizio, Aspelund, Thor, Eiriksdottir, Gudny, Freyr Gudmundsson, Elia, Ikram, Arfan, A van Rooij, Frank J, H Franco, Oscar, L Rueda-Ochoa, Oscar, Muka, Taulant, Glisic, Marija, Tunstall-Pedoe, Hugh, Völzke, Henry, V Howard, Barbara, Zhang, Ying, Jolly, Stacey, Davey-Smith, George, Can, Günay, Yüksel, Hüsniye, Nakagawa, Hideaki, Morikawa, Yuko, Miura, Katsuyuki, Njølstad, Inger, Ingelsson, Martin, Giedraitis, Vilmanta, M Ridker, Paul, Michael Gaziano, J, Kivimaki, Mika, Shipley, Martin, J Brunner, Eric, Arndt, Volker, Brenner, Hermann, Cook, Nancy, Ford, Ian, Marín Ibañez, Alejandro, M Geleijnsed, Johanna, Rod, Jackson, Paul M, Ridker, Nancy R, Cook, Ralph B, D'Agostino, Simon G, Thompson, John, Danesh, and Emanuele, Di Angelantonio

Subjects
Male, Cardiac & Cardiovascular Systems, Nutrition and Disease, Prevention and Epidemiology, PREDICTION, Áhættuþættir, 030204 cardiovascular system & hematology, GUIDELINES, 0302 clinical medicine, Risk Factors, Voeding en Ziekte, FRAMINGHAM, Discrimination, Medicine, Cardiac and Cardiovascular Systems, Blóðrásarsjúkdómar, Prospective Studies, Prospective cohort study, Non-U.S. Gov't, 1102 Cardiorespiratory Medicine and Haematology, CALIBRATION, Kardiologi, Framingham Risk Score, Emerging Risk Factors Collaboration, SCORES, Research Support, Non-U.S. Gov't, Incidence (epidemiology), Middle Aged, Cardiovascular disease, Justice and Strong Institutions, Risk prediction, ddc, 3. Good health, Cardiovascular Diseases, Meta-analysis, Cohort, Calibration, Female, Risk assessment, Cardiology and Cardiovascular Medicine, Algorithm, Life Sciences & Biomedicine, Algorithms, SDG 16 - Peace, Risk algorithms, DISEASE PREVENTION, Research Support, Risk Assessment, VALIDATION, 03 medical and health sciences, Clinical Research, Journal Article, Humans, ddc:610, Risk factor, VLAG, Aged, Science & Technology, business.industry, SDG 16 - Peace, Justice and Strong Institutions, 030229 sport sciences, R1, STATIN USE, Cardiovascular System & Hematology, Cardiovascular System & Cardiology, business, PRIMARY PREVENTION, TASK-FORCE
Abstract

Publisher's version (útgefin grein), Aims: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after 'recalibration', a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied. Methods and results: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at 'high' 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29-39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22-24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44-51 such individuals using original algorithms, in contrast to 37-39 individuals with recalibrated algorithms. Conclusion: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need., The work of the co-ordinating centre was funded by the UK Medical Research Council (G0800270), British Heart Foundation (SP/09/ 002), British Heart Foundation Cambridge Cardiovascular Centre of Excellence, UK National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council (268834), and European Commission Framework Programme 7 (HEALTH-F2-2012-279233). The Emerging Risk Factor Collaboration’s website https://www.phpc.cam.ac.uk/ceu/erfc/list-of-studies/ has compiled a list provided by investigators of some of the funders of the component studies in this analysis. I.W. was supported by the Medical Research Council Unit Programme MC_UU_12023/21. M.K. is supported by the Netherlands Organization for Scientific Research (NWO) Veni grant (Veni, 91616079). J.P. is supported by Erasmus Mundus Western Balkans (ERAWEB), a project funded by the European Commission.

Published
2019

41. Circulating high sensitivity C reactive protein concentrations and risk of lung cancer : nested case-control study within Lung Cancer Cohort Consortium

Author

Muller, David C, Larose, Tricia L, Hodge, Allison, Guida, Florence, Langhammer, Arnulf, Grankvist, Kjell, Meyer, Klaus, Cai, Qiuyin, Arslan, Alan A, Zeleniuch-Jacquotte, Anne, Albanes, Demetrius, Giles, Graham G, Sesso, Howard D, Lee, I-Min, Gaziano, J Michael, Yuan, Jian-Min, Hoffman Bolton, Judith, Buring, Julie E, Visvanathan, Kala, Le Marchand, Loic, Purdue, Mark P, Caporaso, Neil E, Midttun, Øivind, Ueland, Per M, Prentice, Ross L, Weinstein, Stephanie J, Stevens, Victoria L, Zheng, Wei, Blot, William J, Shu, Xiao-Ou, Zhang, Xuehong, Xiang, Yong-Bing, Koh, Woon-Puay, Hveem, Kristian, Thomson, Cynthia A, Pettinger, Mary, Engström, Gunnar, Brunnström, Hans, Milne, Roger L, Stampfer, Meir J, Han, Jiali, Johansson, Mikael, Brennan, Paul, Severi, Gianluca, and Johansson, Mattias

Subjects
Adult, Male, Lung Neoplasms, Adolescent, Risk Assessment, Sensitivity and Specificity, Young Adult, Biomarkers, Tumor, Odds Ratio, Humans, Prospective Studies, cardiovascular diseases, Carcinoma, Small Cell, Aged, Aged, 80 and over, Cancer och onkologi, Smokers, Research, Smoking, Non-Smokers, Middle Aged, C-Reactive Protein, Case-Control Studies, Cancer and Oncology, Carcinoma, Squamous Cell, Carcinoma, Large Cell, Female, Ex-Smokers, Biomarkers
Abstract

Objectives: Inflammation may play an important role in lung cancer pathogenesis. Previous studies have suggested an association between C-reactive protein (CRP) as a marker of inflammation, and risk of lung cancer, but have lacked power to comprehensively investigate associations by smoking status and histological subtype. Our objective was to conduct a comprehensive analysis of prospectively measured circulating high-sensitivity CRP (hs-CRP) concentration and risk of lung cancer overall, by smoking status (current, former and never smokers), and histological sub-type. Design: Pooled analysis of prospective case-control studies nested within 20 population cohort studies. Setting: Population-based cohort studies in the Asia, Europe, Australia, and the United States. Participants: 5299 incident lung cancer cases, with individually incidence-density matched controls. Exposure: Circulating hs-CRP concentrations in pre-diagnostic serum/plasma samples. Main Outcome Measure: Incident lung cancer diagnosis. Results: We observed a positive association between circulating hs-CRP concentration and risk of lung cancer for current (OR per doubling in hs-CRP [ORlog2CRP]: 1.09, 95% CI: 1.05 to 1.13) and former smokers (ORlog2CRP 1.09, 95% CI: 1.04 to 1.14), but not never smokers (p-interaction

Published
2019

42. Agnostic Pathway/Gene Set Analysis of Genome-Wide Association Data Identifies Associations for Pancreatic Cancer

Author

Walsh, Naomi, Zhang, Han, Hyland, Paula L, Yang, Qi, Mocci, Evelina, Zhang, Mingfeng, Childs, Erica J, Collins, Irene, Wang, Zhaoming, Arslan, Alan A, Beane-Freeman, Laura, Bracci, Paige M, Brennan, Paul, Canzian, Federico, Duell, Eric J, Gallinger, Steven, Giles, Graham G, Goggins, Michael, Goodman, Gary E, Goodman, Phyllis J, Hung, Rayjean J, Kooperberg, Charles, Kurtz, Robert C, Malats, Núria, LeMarchand, Loic, Neale, Rachel E, Olson, Sara H, Scelo, Ghislaine, Shu, Xiao O, Van Den Eeden, Stephen K, Visvanathan, Kala, White, Emily, Zheng, Wei, PanScan and PanC4 consortia, Albanes, Demetrius, Andreotti, Gabriella, Babic, Ana, Bamlet, William R, Berndt, Sonja I, Borgida, Ayelet, Boutron-Ruault, Marie-Christine, Brais, Lauren, Bueno-de-Mesquita, Bas, Buring, Julie, Chaffee, Kari G, Chanock, Stephen, Cleary, Sean, Cotterchio, Michelle, Foretova, Lenka, Fuchs, Charles, M Gaziano, J Michael, Giovannucci, Edward, Hackert, Thilo, Haiman, Christopher, Hartge, Patricia, Hasan, Manal, Helzlsouer, Kathy J, Herman, Joseph, Holcatova, Ivana, Holly, Elizabeth A, Hoover, Robert, Janout, Vladimir, Klein, Eric A, Laheru, Daniel, Lee, I-Min, Lu, Lingeng, Mannisto, Satu, Milne, Roger L, Oberg, Ann L, Orlow, Irene, Patel, Alpa V, Peters, Ulrike, Porta, Miquel, Real, Francisco X, Rothman, Nathaniel, Sesso, Howard D, Severi, Gianluca, Silverman, Debra, Strobel, Oliver, Sund, Malin, Thornquist, Mark D, Tobias, Geoffrey S, Wactawski-Wende, Jean, Wareham, Nick, Weiderpass, Elisabete, Wentzensen, Nicolas, Wheeler, William, Yu, Herbert, Zeleniuch-Jacquotte, Anne, Kraft, Peter, Li, Donghui, Jacobs, Eric J, Petersen, Gloria M, Wolpin, Brian M, Risch, Harvey A, Amundadottir, Laufey T, Yu, Kai, Klein, Alison P, Stolzenberg-Solomon, Rachael Z, Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository

Subjects
Pancreatic Neoplasms, Models, Statistical, Case-Control Studies, Humans, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Carcinoma, Pancreatic Ductal, Genome-Wide Association Study
Abstract

Background: Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes. Methods: We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided. Results: We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P ≤ 1.3 × 10-5), the strongest associations were detected in five pathways and gene sets, including maturity-onset diabetes of the young, regulation of beta-cell development, role of epidermal growth factor (EGF) receptor transactivation by G protein-coupled receptors in cardiac hypertrophy pathways, and the Nikolsky breast cancer chr17q11-q21 amplicon and Pujana ATM Pearson correlation coefficient (PCC) network gene sets. We identified and validated rs876493 and three correlating SNPs (PGAP3) and rs3124737 (CASP7) from the Pujana ATM PCC gene set as eQTLs in two normal derived pancreas tissue datasets. Conclusion: Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified.

Published
2018

43. Genetics of blood lipids among ~300,000 multi-ethnic participants of the Million Veteran Program

Author

Klarin, Derek, Damrauer, Scott M, Cho, Kelly, Sun, Yan V, Teslovich, Tanya M, Honerlaw, Jacqueline, Gagnon, David R, DuVall, Scott L, Li, Jin, Peloso, Gina M, Chaffin, Mark, Small, Aeron M, Huang, Jie, Tang, Hua, Lynch, Julie A, Ho, Yuk-Lam, Liu, Dajiang J, Emdin, Connor A, Li, Alexander H, Huffman, Jennifer E, Lee, Jennifer S, Natarajan, Pradeep, Chowdhury, Rajiv, Saleheen, Danish, Vujkovic, Marijana, Baras, Aris, Pyarajan, Saiju, Di Angelantonio, Emanuele, Neale, Benjamin M, Naheed, Aliya, Khera, Amit V, Danesh, John, Chang, Kyong-Mi, Abecasis, Gonçalo, Willer, Cristen, Dewey, Frederick E, Carey, David J, Global Lipids Genetics Consortium, Myocardial Infarction Genetics (MIGen) Consortium, Geisinger-Regeneron DiscovEHR Collaboration, VA Million Veteran Program, Concato, John, Gaziano, J Michael, O'Donnell, Christopher J, Tsao, Philip S, Kathiresan, Sekar, Rader, Daniel J, Wilson, Peter WF, Assimes, Themistocles L, Gagnon, David R [0000-0002-6367-3179], Chaffin, Mark [0000-0002-1234-5562], Emdin, Connor A [0000-0002-2385-8259], Huffman, Jennifer E [0000-0002-9672-2491], Vujkovic, Marijana [0000-0003-4924-5714], Neale, Benjamin M [0000-0003-1513-6077], Willer, Cristen [0000-0001-5645-4966], Kathiresan, Sekar [0000-0002-6724-032X], Assimes, Themistocles L [0000-0003-2349-0009], and Apollo - University of Cambridge Repository

Subjects
Male, Genotype, Black People, Hispanic or Latino, Middle Aged, Lipid Metabolism, Lipids, Polymorphism, Single Nucleotide, White People, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Ethnicity, Humans, Female, Aged, Genome-Wide Association Study, Veterans
Abstract

The Million Veteran Program (MVP) was established in 2011 as a national research initiative to determine how genetic variation influences the health of US military veterans. Here we genotyped 312,571 MVP participants using a custom biobank array and linked the genetic data to laboratory and clinical phenotypes extracted from electronic health records covering a median of 10.0 years of follow-up. Among 297,626 veterans with at least one blood lipid measurement, including 57,332 black and 24,743 Hispanic participants, we tested up to around 32 million variants for association with lipid levels and identified 118 novel genome-wide significant loci after meta-analysis with data from the Global Lipids Genetics Consortium (total n > 600,000). Through a focus on mutations predicted to result in a loss of gene function and a phenome-wide association study, we propose novel indications for pharmaceutical inhibitors targeting PCSK9 (abdominal aortic aneurysm), ANGPTL4 (type 2 diabetes) and PDE3B (triglycerides and coronary disease).

Published
2018

44. Genetic analysis of over one million people identifies 535 novel loci for blood pressure

Author

Evangelou, Evangelos, Warren, Helen R, Mosen-Ansorena, David, Mifsud, Borbala, Pazoki, Raha, Gao, He, Ntritsos, Georgios, Dimou, Niki, Cabrera, Claudia P, Karaman, Ibrahim, Ng, Fu Liang, Evangelou, Marina, Witkowska, Katarzyna, Tzanis, Evan, Hellwege, Jacklyn N, Giri, Ayush, Edwards, Jacklyn N Hellwege, Sun, Yan V, Cho, Kelly, Gaziano, J Michael, Wilson, Peter WF, Tsao, Philip S, Kovesdy, Csaba P, Esko, Tonu, Magi, Reedik, Milani, Lili, Almgren, Peter, Levy, Daniel, Munroe, Patricia B, Newton-Cheh, Christopher, Brown, Morris J, Metspalu, Andres, Hung, Adriana M, O'Donnell, Christopher, Edwards, Todd L, Psaty, Bruce M, Tzoulaki, Ioanna, Barnes, Michael R, Wain, Louise V, Elliott, Paul, Caulfield, Mark J, and Apollo - University of Cambridge Repository

Subjects
Adult, Aged, 80 and over, Male, Quantitative Trait Loci, Blood Pressure, Middle Aged, Polymorphism, Single Nucleotide, Genetics, Population, Cardiovascular Diseases, Genetic Loci, Risk Factors, Hypertension, Human Umbilical Vein Endothelial Cells, Humans, Female, Genetic Predisposition to Disease, Genetic Testing, Life Style, Cells, Cultured, Aged, Genome-Wide Association Study
Abstract

High blood pressure is the foremost heritable global risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits to date (systolic, diastolic, pulse pressure) in over one million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also reveal shared loci influencing lifestyle exposures. Our findings offer the potential for a precision medicine strategy for future cardiovascular disease prevention.

Published
2018

45. Impaired functional vitamin B6 status is associated with increased risk of lung cancer

Author

Theofylaktopoulou, Despoina, Midttun, Øivind, Ueland, Per M., Meyer, Klaus, Fanidi, Anouar, Zheng, Wei, Shu, Xiao Ou, Xiang, Yong Bing, Prentice, Ross, Pettinger, Mary, Thomson, Cynthia A., Giles, Graham G., Hodge, Allison, Cai, Qiuyin, Blot, William J., Wu, Jie, Johansson, Mikael, Hultdin, Johan, Grankvist, Kjell, Stevens, Victoria L., McCullough, Marjorie M., Weinstein, Stephanie J., Albanes, Demetrius, Ziegler, Regina, Freedman, Neal D., Langhammer, Arnulf, Hveem, Kristian, Næss, Marit, Sesso, Howard D., Gaziano, J. Michael, Buring, Julie E., Lee, I. Min, Severi, Gianluca, Zhang, Xuehong, Stampfer, Meir J., Han, Jiali, Smith-Warner, Stephanie A., Zeleniuch-Jacquotte, Anne, Le Marchand, Loic, Yuan, Jian Min, Wang, Renwei, Butler, Lesley M., Koh, Woon Puay, Gao, Yu Tang, Rothman, Nathaniel, Ericson, Ulrika, Sonestedt, Emily, Visvanathan, Kala, Jones, Miranda R., Relton, Caroline, Brennan, Paul, Johansson, Mattias, and Ulvik, Arve

Subjects
Male, Lung Cancer Cohort Consortium, Lung Neoplasms, pyridoxal 5′-phosphate, functional vitamin B6 marker, Middle Aged, Vitamin B 6, Article, Cohort Studies, xanthurenic acid [3-hydroxykynurenine], Risk Factors, Case-Control Studies, Carcinoma, Squamous Cell, Odds Ratio, Humans, Female, ICEP, Biomarkers, Aged
Abstract

Circulating vitamin B6 levels have been found to be inversely associated with lung cancer. Most studies have focused on the B6 form pyridoxal 5′-phosphate (PLP), a direct biomarker influenced by inflammation and other factors. Using a functional B6 marker allows further investigation of the potential role of vitamin B6 status in the pathogenesis of lung cancer. We prospectively evaluated the association of the functional marker of vitamin B6 status, the 3-hydroxykynurenine:xanthurenic acid (HK:XA) ratio, with risk of lung cancer in a nested case–control study consisting of 5,364 matched case–control pairs from the Lung Cancer Cohort Consortium (LC3). We used conditional logistic regression to evaluate the association between HK:XA and lung cancer, and random effect models to combine results from different cohorts and regions. High levels of HK:XA, indicating impaired functional B6 status, were associated with an increased risk of lung cancer, the odds ratio comparing the fourth and the first quartiles (OR4th vs. 1st) was 1.25 (95% confidence interval, 1.10–1.41). Stratified analyses indicated that this association was primarily driven by cases diagnosed with squamous cell carcinoma. Notably, the risk associated with HK:XA was approximately 50% higher in groups with a high relative frequency of squamous cell carcinoma, i.e., men, former and current smokers. This risk of squamous cell carcinoma was present in both men and women regardless of smoking status.

Published
2017

46. Long-Term Outcomes in Patients With Acute Coronary Syndromes Related to Prolonging Dual Antiplatelet Therapy More Than 12 Months After Coronary Stenting

Author

Wimmer, Neil J., Dufour, Alyssa B., Cho, Kelly, Gagnon, David R., Quach, Lien, Ly, Samantha, Do, Jacquelyn-My, Ostrowski, Simon, Gaziano, J. Michael, Faxon, David P., and Kinlay, Scott

Subjects
Male, Ticlopidine, Time Factors, Databases, Factual, Hospitals, Veterans, Myocardial Infarction, Hemorrhage, Prosthesis Design, Article, Drug Administration Schedule, Percutaneous Coronary Intervention, Risk Factors, Humans, Acute Coronary Syndrome, Propensity Score, Aged, Proportional Hazards Models, Aspirin, Middle Aged, United States, Clopidogrel, United States Department of Veterans Affairs, Logistic Models, Treatment Outcome, Multivariate Analysis, Drug Therapy, Combination, Female, Stents, Platelet Aggregation Inhibitors
Abstract

To assess the impact of stent type on the risk of death or myocardial infarction (MI) related to dual antiplatelet therapy (DAPT) more than 12 months (prolonged DAPT) versus 12 or less months after PCI for an acute coronary syndrome (ACS).The recent DAPT study reported lower recurrent ischemic events from prolonged DAPT in patients treated with PCI for an ACS, but was underpowered to determine the impact of stent type.We determined clinical outcomes after PCI for an ACS (median follow-up: DES = 26 months, BMS = 46 months) in 18,484 patients in the Veterans Affairs system treated with first generation drug-eluting stents (DES) or bare-metal stents (BMS). We used landmark analyses starting 1 year after the index PCI to assess the risk of prolonged DAPT on the primary endpoint of death or MI. Multivariable and propensity models adjusted for confounding.There was a significant interaction between stent type and prolonged DAPT for death and MI (P = 0.0036), death (P = 0.054), and major bleeding (P = 0.0013). Patients treated with prolonged DAPT had lower risks of death or MI (HR = 0.71, 95% CI = 0.61, 0.82) and death (HR = 0.74, 95%CI = 0.62, 0.89) with DES, but not BMS, and higher risks of major bleeding, particularly with BMS (HR = 1.67, P 0.001) than DES (HR = 1.24, p = 0.01).Prolonging DAPT more than 12 months after PCI for ACS only associated with a lower risk of ischemic events in the 1-4 years after PCI in those receiving first generation DES. Stent type may influence the benefit of prolonged DAPT. © 2016 Wiley Periodicals, Inc.

Published
2016

47. Multivitamin Use and the Risk of Cardiovascular Disease in Men12

Author

Rautiainen, Susanne, Rist, Pamela M, Glynn, Robert J, Buring, Julie E, Gaziano, J Michael, and Sesso, Howard D

Subjects
Adult, Aged, 80 and over, Male, food and beverages, Vitamins, Middle Aged, Body Mass Index, Cardiovascular Diseases, Risk Factors, Dietary Supplements, Nutritional Epidemiology, Humans, Prospective Studies, Aged, Follow-Up Studies, Proportional Hazards Models
Abstract

Although multivitamins are widely used by US adults, few prospective studies have investigated their association with the long- and short-term risks of cardiovascular disease (CVD).The aim of this study was to investigate how multivitamin use is associated with the risk of CVD in initially healthy men at baseline.We studied 18,530 male physicians aged ≥40 y from the Physicians' Health Study I cohort who were free of CVD and cancer at baseline (1982). All men provided a wide range of self-reported lifestyle and clinical factors plus intake of selected foods and dietary supplements. Cox proportional hazards models were used to calculate multivariable-adjusted HRs (95% CIs).During a mean follow-up of 12.2 y (total of 225,287 person-years), there were 1697 incident cases of major CVD (defined as nonfatal myocardial infarction, nonfatal stroke, and CVD death). In multivariable-adjusted analyses, no significant associations were observed among baseline multivitamin users compared with nonusers for the risk of major CVD events (HR: 0.94; 95% CI: 0.84, 1.05), whereas a self-reported duration of ≥20 y at baseline was associated with lower risk (HR: 0.56; 95% CI: 0.35, 0.90; P-trend = 0.05). Baseline multivitamin use was also significantly inversely associated with the risk of cardiac revascularization (HR: 0.86; 95% CI: 0.75, 0.98). Baseline use of multivitamins was not significantly associated with other CVD endpoints.In this long-term prospective study in initially healthy men, multivitamin use for ≥20 y was associated with a lower risk of major CVD events.

Published
2016

48. Walking and calcified atherosclerotic plaque in the coronary arteries: the NHLBI Family Heart Study

Author

Imran, Tasnim F., Patel, Yash, Ellison, R Curtis, Carr, J. Jeffrey, Arnett, Donna K., Pankow, James S., Heiss, Gerardo, Hunt, Steven C., Gaziano, J. Michael, and Djoussé, Luc

Subjects
Adult, Male, Computed Tomography Angiography, Aortic Diseases, Coronary Artery Disease, Walking, Coronary Angiography, Aortography, Risk Assessment, Article, Risk Factors, Surveys and Questionnaires, Multidetector Computed Tomography, Prevalence, Humans, Vascular Calcification, Aged, Middle Aged, Protective Factors, Coronary Vessels, Plaque, Atherosclerotic, United States, Cross-Sectional Studies, Female, National Heart, Lung, and Blood Institute (U.S.), Risk Reduction Behavior
Abstract

Studies have reported mixed findings on the association between physical activity and subclinical atherosclerosis. We sought to examine whether walking is associated with prevalent coronary artery calcification (CAC) and aortic calcification.In a cross-sectional design, we studied 2971 participants of the National Heart, Lung, and Blood Institute Family Heart Study without a history of myocardial infarction, coronary artery bypass grafting, or percutaneous transluminal angioplasty. A standardized questionnaire was used to ascertain the number of blocks walked daily to compute walking metabolic equivalent hours. CAC was measured by cardiac computed tomography. We defined prevalent CAC and aortic calcification using an Agatston score of at least 100 and used generalized estimating equations to calculate adjusted prevalence ratios. Mean age was 55 years, and 60% of participants were women. Compared with the ≤3.75-Met-h/wk group, prevalence ratios for CAC after adjusting for age, sex, race, smoking, alcohol use, total physical activity (excluding walking), and familial clustering were 0.53 (95% confidence interval, 0.35-0.79) for3.75 to 7.5 Met-h/wk, 0.72 (95% confidence interval, 0.52-0.99) for7.5 to 15 Met-h/wk, and 0.54 (95% confidence interval, 0.36-0.81) for15 to 22.5 Met-h/wk, (P trend=0.01). The walking-CAC relationship remained significant for those with body mass index ≥25 (P trend=0.02) and persisted with CAC cutoffs of 300, 200, 150, and 50 but not 0. When examined as a continuous variable, a J-shaped association between walking and CAC was found. The walking-aortic calcification association was not significant.Our findings suggest that walking is associated with lower prevalent CAC (but not aortic calcification) in adults without known heart disease.

Published
2016

49. Analysis of heritability and shared heritability based on Genome-Wide Association Studies for 13 Cancer Types

Author

Sampson, Joshua N., Wheeler, William A., Yeager, Meredith, Panagiotou, Orestis, Wang, Zhaoming, Berndt, Sonja I., Lan, Qing, Abnet, Christian C., Amundadottir, Laufey T., Figueroa, Jonine D., Landi, Maria Teresa, Mirabello, Lisa, Savage, Sharon A., Taylor, Philip R., Vivo, Immaculata De, McGlynn, Katherine A., Purdue, Mark P., Rajaraman, Preetha, Adami, Hans-Olov, Ahlbom, Anders, Albanes, Demetrius, Amary, Maria Fernanda, An, She-Juan, Andersson, Ulrika, Andriole, Gerald, Andrulis, Irene L., Angelucci, Emanuele, Ansell, Stephen M., Arici, Cecilia, Armstrong, Bruce K., Arslan, Alan A., Austin, Melissa A., Baris, Dalsu, Barkauskas, Donald A., Bassig, Bryan A., Becker, Nikolaus, Benavente, Yolanda, Benhamou, Simone, Berg, Christine, Van Den Berg, David, Bernstein, Leslie, Bertrand, Kimberly A., Birmann, Brenda M., Black, Amanda, Boeing, Heiner, Boffetta, Paolo, Boutron-Ruault, Marie-Christine, Bracci, Paige M., Brinton, Louise, Brooks-Wilson, Angela R., Bueno-de-Mesquita, H. Bas, Burdett, Laurie, Buring, Julie, Butler, Mary Ann, Cai, Qiuyin, Cancel-Tassin, Geraldine, Canzian, Federico, Carrato, Alfredo, Carreon, Tania, Carta, Angela, Chan, John K. C., Chang, Ellen T., Chang, Gee-Chen, Chang, I-Shou, Chang, Jiang, Chang-Claude, Jenny, Chen, Chien-Jen, Chen, Chih-Yi, Chen, Chu, Chen, Chung-Hsing, Chen, Constance, Chen, Hongyan, Chen, Kexin, Chen, Kuan-Yu, Chen, Kun-Chieh, Chen, Ying, Chen, Ying-Hsiang, Chen, Yi-Song, Chen, Yuh-Min, Chien, Li-Hsin, Chirlaque, María-Dolores, Choi, Jin Eun, Choi, Yi Young, Chow, Wong-Ho, Chung, Charles C., Clavel, Jacqueline, Clavel-Chapelon, Françoise, Cocco, Pierluigi, Colt, Joanne S., Comperat, Eva, Conde, Lucia, Connors, Joseph M., Conti, David, Cortessis, Victoria K., Cotterchio, Michelle, Cozen, Wendy, Crouch, Simon, Crous-Bou, Marta, Cussenot, Olivier, Davis, Faith G., Ding, Ti, Diver, W. Ryan, Dorronsoro, Miren, Dossus, Laure, Duell, Eric J., Ennas, Maria Grazia, Erickson, Ralph L., Feychting, Maria, Flanagan, Adrienne M., Foretova, Lenka, Fraumeni, Joseph F., Freedman, Neal D., Beane Freeman, Laura E., Fuchs, Charles, Gago-Dominguez, Manuela, Gallinger, Steven, Gao, Yu-Tang, Gapstur, Susan M., Garcia-Closas, Montserrat, García-Closas, Reina, Gascoyne, Randy D., Gastier-Foster, Julie, Gaudet, Mia M., Gaziano, J. Michael, Giffen, Carol, Giles, Graham G., Giovannucci, Edward, Glimelius, Bengt, Goggins, Michael, Gokgoz, Nalan, Goldstein, Alisa M., Gorlick, Richard, Gross, Myron, Grubb, Robert, Gu, Jian, Guan, Peng, Gunter, Marc, Guo, Huan, Habermann, Thomas M., Haiman, Christopher A., Halai, Dina, Hallmans, Goran, Hassan, Manal, Hattinger, Claudia, He, Qincheng, He, Xingzhou, Helzlsouer, Kathy, Henderson, Brian, Henriksson, Roger, Hjalgrim, Henrik, Hoffman-Bolton, Judith, Hohensee, Chancellor, Holford, Theodore R., Holly, Elizabeth A., Hong, Yun-Chul, Hoover, Robert N., Horn-Ross, Pamela L., Hosain, G. M. Monawar, Hosgood, H. Dean, Hsiao, Chin-Fu, Hu, Nan, Hu, Wei, Hu, Zhibin, Huang, Ming-Shyan, Huerta, Jose-Maria, Hung, Jen-Yu, Hutchinson, Amy, Inskip, Peter D., Jackson, Rebecca D., Jacobs, Eric J., Jenab, Mazda, Jeon, Hyo-Sung, Ji, Bu-Tian, Jin, Guangfu, Jin, Li, Johansen, Christoffer, Johnson, Alison, Jung, Yoo Jin, Kaaks, Rudolph, Kamineni, Aruna, Kane, Eleanor, Kang, Chang Hyun, Karagas, Margaret R., Kelly, Rachel S., Khaw, Kay-Tee, Kim, Christopher, Kim, Hee Nam, Kim, Jin Hee, Kim, Jun Suk, Kim, Yeul Hong, Kim, Young Tae, Kim, Young-Chul, Kitahara, Cari M., Klein, Alison P., Klein, Robert J., Kogevinas, Manolis, Kohno, Takashi, Kolonel, Laurence N., Kooperberg, Charles, Kricker, Anne, Krogh, Vittorio, Kunitoh, Hideo, Kurtz, Robert C., Kweon, Sun-Seog, LaCroix, Andrea, Lawrence, Charles, Lecanda, Fernando, Lee, Victor Ho Fun, Li, Donghui, Li, Haixin, Li, Jihua, Li, Yao-Jen, Li, Yuqing, Liao, Linda M., Liebow, Mark, Lightfoot, Tracy, Lim, Wei-Yen, Lin, Chien-Chung, Lin, Dongxin, Lindstrom, Sara, Linet, Martha S., Link, Brian K., Liu, Chenwei, Liu, Jianjun, Liu, Li, Ljungberg, Börje, Lloreta, Josep, Lollo, Simonetta Di, Lu, Daru, Lund, Eiluv, Malats, Nuria, Mannisto, Satu, Marchand, Loic Le, Marina, Neyssa, Masala, Giovanna, Mastrangelo, Giuseppe, Matsuo, Keitaro, Maynadie, Marc, McKay, James, McKean-Cowdin, Roberta, Melbye, Mads, Melin, Beatrice S., Michaud, Dominique S., Mitsudomi, Tetsuya, Monnereau, Alain, Montalvan, Rebecca, Moore, Lee E., Mortensen, Lotte Maxild, Nieters, Alexandra, North, Kari E., Novak, Anne J., Oberg, Ann L., Offit, Kenneth, Oh, In-Jae, Olson, Sara H., Palli, Domenico, Pao, William, Park, In Kyu, Park, Jae Yong, Park, Kyong Hwa, Patiño-Garcia, Ana, Pavanello, Sofia, Peeters, Petra H. M., Perng, Reury-Perng, Peters, Ulrike, Petersen, Gloria M., Picci, Piero, Pike, Malcolm C., Porru, Stefano, Prescott, Jennifer, Prokunina-Olsson, Ludmila, Qian, Biyun, Qiao, You-Lin, Rais, Marco, Riboli, Elio, Riby, Jacques, Risch, Harvey A., Rizzato, Cosmeri, Rodabough, Rebecca, Roman, Eve, Roupret, Morgan, Ruder, Avima M., de Sanjose, Silvia, Scelo, Ghislaine, Schned, Alan, Schumacher, Fredrick, Schwartz, Kendra, Schwenn, Molly, Scotlandi, Katia, Seow, Adeline, Serra, Consol, Serra, Massimo, Sesso, Howard D., Setiawan, Veronica Wendy, Severi, Gianluca, Severson, Richard K., Shanafelt, Tait D., Shen, Hongbing, Shen, Wei, Shin, Min-Ho, Shiraishi, Kouya, Shu, Xiao-Ou, Siddiq, Afshan, Sierrasesúmaga, Luis, Sihoe, Alan Dart Loon, Skibola, Christine F., Smith, Alex, Smith, Martyn T., Southey, Melissa C., Spinelli, John J., Staines, Anthony, Stampfer, Meir, Stern, Marianna C., Stevens, Victoria L., Stolzenberg-Solomon, Rachael S., Su, Jian, Su, Wu-Chou, Sund, Malin, Sung, Jae Sook, Sung, Sook Whan, Tan, Wen, Tang, Wei, Tardón, Adonina, Thomas, David, Thompson, Carrie A., Tinker, Lesley F., Tirabosco, Roberto, Tjønneland, Anne, Travis, Ruth C., Trichopoulos, Dimitrios, Tsai, Fang-Yu, Tsai, Ying-Huang, Tucker, Margaret, Turner, Jenny, Vajdic, Claire M., Vermeulen, Roel C. H., Villano, Danylo J., Vineis, Paolo, Virtamo, Jarmo, Visvanathan, Kala, Wactawski-Wende, Jean, Wang, Chaoyu, Wang, Chih-Liang, Wang, Jiu-Cun, Wang, Junwen, Wei, Fusheng, Weiderpass, Elisabete, Weiner, George J., Weinstein, Stephanie, Wentzensen, Nicolas, White, Emily, Witzig, Thomas E., Wolpin, Brian M., Wong, Maria Pik, Wu, Chen, Wu, Guoping, Wu, Junjie, Wu, Tangchun, Wu, Wei, Wu, Xifeng, Wu, Yi-Long, Wunder, Jay S., Xiang, Yong-Bing, Xu, Jun, Xu, Ping, Yang, Pan-Chyr, Yang, Tsung-Ying, Ye, Yuanqing, Yin, Zhihua, Yokota, Jun, Yoon, Ho-Il, Yu, Chong-Jen, Yu, Herbert, Yu, Kai, Yuan, Jian-Min, Zelenetz, Andrew, Zeleniuch-Jacquotte, Anne, Zhang, Xu-Chao, Zhang, Yawei, Zhao, Xueying, Zhao, Zhenhong, Zheng, Hong, Zheng, Tongzhang, Zheng, Wei, Zhou, Baosen, Zhu, Meng, Zucca, Mariagrazia, Boca, Simina M., Cerhan, James R., Ferri, Giovanni M., Hartge, Patricia, Hsiung, Chao Agnes, Magnani, Corrado, Miligi, Lucia, Morton, Lindsay M., Smedby, Karin E., Teras, Lauren R., Vijai, Joseph, Wang, Sophia S., Brennan, Paul, Caporaso, Neil E., Hunter, David J., Kraft, Peter, Rothman, Nathaniel, Silverman, Debra T., Slager, Susan L., Chanock, Stephen J., and Chatterjee, Nilanjan

Subjects
Adult, Asian Continental Ancestry Group, Male, Lung Neoplasms, DATABASE, European Continental Ancestry Group, RELATIVES, Bone Neoplasms, Polymorphism, Single Nucleotide, Article, LUNG-CANCER, Testicular Neoplasms, Neoplasms, SWEDEN, LYMPHOMA, Humans, Genetic Predisposition to Disease, FAMILIAL RISK, Oncology & Carcinogenesis, Aged, Osteosarcoma, Science & Technology, MUTATIONS, Smoking, Middle Aged, Leukemia, Lymphocytic, Chronic, B-Cell, PANCREATIC-CANCER, Kidney Neoplasms, MULTIPLE SUSCEPTIBILITY LOCI, INDIVIDUALS, Oncology, Urinary Bladder Neoplasms, Tissue Array Analysis, Female, Lymphoma, Large B-Cell, Diffuse, Life Sciences & Biomedicine, 1112 Oncology And Carcinogenesis, Genome-Wide Association Study
Abstract

Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common SNPs for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49,492 cancer cases and 34,131 controls. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl2, on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% CI = 14% - 37%) and 7% (4% - 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ=0.73, SE=0.28), Diffuse Large B-Cell Lymphoma (DLBCL) and pediatric osteosarcoma (ρ=0.53, SE=0.21), DLBCL and Chronic Lymphocytic Leukemia (CLL) (ρ=0.51, SE=0.18), and bladder and lung (ρ=0.35, SE=0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a non-smoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.

Published
2015

50. Age-related Cataract in a Randomized Trial of Selenium and Vitamin E in Men: The SELECT Eye Endpoints (SEE) Study

Author

Christen, William G., Glynn, Robert J., Gaziano, J. Michael, Darke, Amy K., Crowley, John J., Goodman, Phyllis J., Lippman, Scott M., Lad, Thomas E., Bearden, James D., Goodman, Gary E., Minasian, Lori M., Thompson, Ian M., Blanke, Charles D., and Klein, Eric A.

Subjects
Male, Aging, Endpoint Determination, Incidence, Prostatic Neoplasms, Cataract Extraction, Middle Aged, Article, Antioxidants, Cataract, Drug Combinations, Double-Blind Method, Risk Factors, Surveys and Questionnaires, Humans, Vitamin E, Selenomethionine, Aged, Proportional Hazards Models
Abstract

Observational studies suggest a role for dietary nutrients such as vitamin E and selenium in cataract prevention. However, the results of randomized clinical trials of vitamin E supplements and cataract have been disappointing and are not yet available for selenium.To test whether long-term supplementation with selenium and vitamin E affects the incidence of cataract in a large cohort of men.The Selenium and Vitamin E Cancer Prevention Trial (SELECT) Eye Endpoints Study was an ancillary study of the Southwest Oncology Group-coordinated SELECT, a randomized placebo-controlled 4-arm trial of selenium and vitamin E conducted among 35,533 men, 50 years and older for African American participants and 55 years and older for all other men, at 427 participating sites in the United States, Canada, and Puerto Rico. A total of 11,267 SELECT participants from 128 SELECT sites participated in the SELECT Eye Endpoints ancillary study.Individual supplements of selenium (200 μg per day from L-selenomethionine) and vitamin E (400 IU per day of all rac-α-tocopheryl acetate).Incident cataract was defined as a lens opacity, age related in origin, and responsible for a reduction in best-corrected visual acuity to 20/30 or worse based on self-reports confirmed by medical record review. Cataract extraction was defined as the surgical removal of an incident cataract.During a mean (SD) of 5.6 (1.2) years of treatment and follow-up, 389 cases of cataract were documented. There were 185 cataracts in the selenium group and 204 in the no selenium group (hazard ratio, 0.91; 95 % CI, 0.75-1.11; P = .37). For vitamin E, there were 197 cases in the treated group and 192 in the placebo group (hazard ratio, 1.02; 95 % CI, 0.84-1.25; P = .81). Similar results were observed for cataract extraction.These data from a large cohort of apparently healthy men indicate that long-term daily supplementation with selenium and/or vitamin E is unlikely to have a large beneficial effect on age-related cataract.ClinicalTrials.gov Identifier: NCT00784225.

Published
2015

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