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1. Four-Day Food Record Macronutrient Intake, With and Without Biomarker Calibration, and Chronic Disease Risk in Postmenopausal Women

Author

Prentice, Ross L, Pettinger, Mary, Neuhouser, Marian L, Raftery, Daniel, Zheng, Cheng, Gowda, G A Nagana, Huang, Ying, Tinker, Lesley F, Howard, Barbara V, Manson, JoAnn E, Wallace, Robert, Mossavar-Rahmani, Yasmin, Johnson, Karen C, and Lampe, Johanna W

Subjects
Epidemiology, Carbohydrates, Original Contribution, Nutrients, Diet Records, Postmenopause, Eating, Surveys and Questionnaires, Calibration, Chronic Disease, Humans, Female, Energy Intake, Biomarkers
Abstract

We recently evaluated associations of biomarker-calibrated protein intake, protein density, carbohydrate intake, and carbohydrate density with the incidence of cardiovascular disease, cancer, and diabetes among postmenopausal women in the Women’s Health Initiative (1993–present, 40 US clinical centers). The biomarkers relied on serum and urine metabolomics profiles, and biomarker calibration used regression of biomarkers on food frequency questionnaires. Here we develop corresponding calibration equations using food records and dietary recalls. In addition, we use calibrated intakes based on food records in disease association estimation in a cohort subset (n = 29,294) having food records. In this analysis, more biomarker variation was explained by food records than by FFQs for absolute macronutrient intake, with 24-hour recalls being intermediate. However, the percentage of biomarker variation explained was similar for each assessment approach for macronutrient densities. Invasive breast cancer risk was related inversely to carbohydrate and protein densities using food records, in analyses that included (calibrated) total energy intake and body mass index. Corresponding analyses for absolute intakes did not differ from the null, nor did absolute or relative intakes associate significantly with colorectal cancer or coronary heart disease. These analyses do not suggest major advantages for food records or dietary recalls in comparison with less costly and logistically simpler food frequency questionnaires for these nutritional variables.

Published
2022

2. Adherence to Recommended Eating Patterns Is Associated With Lower Risk of Peripheral Arterial Disease: Results From the Women's Health Initiative

Author

Chen, Guo-Chong, Arthur, Rhonda, Mossavar-Rahmani, Yasmin, Xue, Xiaonan, Haring, Bernhard, Shadyab, Aladdin H, Allison, Matthew A, Liu, Simin, Tinker, Lesley F, Saquib, Nazmus, Coday, Mace, Shikany, James M, Neuhouser, Marian L, Snetselaar, Linda G, Van Horn, Linda, Rohan, Thomas E, Wassertheil-Smoller, Sylvia, Kaplan, Robert C, and Qi, Qibin

Subjects
Risk, Clinical Sciences, Cardiorespiratory Medicine and Haematology, Cardiovascular, Peripheral Arterial Disease, peripheral arterial disease, Clinical Research, Surveys and Questionnaires, Humans, risk factors, Aged, Nutrition, nutrition policy, Healthy, Incidence, Prevention, Feeding Behavior, Middle Aged, Diet, Postmenopause, Cardiovascular System & Hematology, lower extremity, Public Health and Health Services, Women's Health, Female, atherosclerosis, diet
Abstract

The potential role of nutritional factors in the development of peripheral arterial disease (PAD) remains poorly understood. We evaluated multiple recommended eating patterns as reflected by predefined diet quality indices in relation to long-term risk of PAD. We included 138 506 US postmenopausal women in the Women’s Health Initiative who had no known PAD at baseline (1993–1998). Four diet quality indices, including alternate Mediterranean diet index, alternate Healthy Eating Index-2010, Dietary Approaches to Stop Hypertension diet index, and Healthy Eating Index-2015, were derived using dietary information collected by a validated food frequency questionnaire at baseline. Incident cases of symptomatic PAD in the lower extremities were ascertained and adjudicated through March 2019 via medical record review. During a median 18.6 years of follow-up, 1036 incident PAD cases were identified. After multivariable adjustment, all diet quality scores were significantly and inversely associated with 21% (for alternate Healthy Eating Index 2010) to 34% (for Dietary Approaches to Stop Hypertension index) lower risk of PAD when comparing the highest with the lowest quartiles (all P-fortrend values ≤0.010). Among contributing food groups and nutrients, intakes of legumes, dietary fiber, and vegetable protein were associated lower risk of PAD, while intakes of unprocessed red meat, processed meat, and regular soft drinks were associated with higher risk. In a broad sample of US postmenopausal women, adhering to different recommended eating patterns is associated with lower risk of PAD. Our findings suggest that current clinical and public health strategies that recommend healthful eating patterns may also be applicable to PAD prevention. (

Published
2021

3. Differential DNA methylation in blood as a mediator of the association between cigarette smoking and bladder cancer risk among postmenopausal women

Author

Jordahl, Kristina M., Phipps, Amanda I., Randolph, Timothy W., Tindle, Hilary A., Liu, Simin, Tinker, Lesley F., Kelsey, Karl T., White, Emily, and Bhatti, Parveen

Abstract

Smoking accounts for approximately 52% of bladder cancer incidence among postmenopausal women, but the underlying mechanism is poorly understood. Our study investigates whether changes in DNA methylation, as measured in blood, mediate the impact of smoking on bladder cancer risk among postmenopausal women. We conducted analyses among 206 cases and 251 controls that were current or never smokers at baseline from a previous case-control study of bladder cancer and genome-wide DNA methylation nested within the Women’s Health Initiative. Separate mediation analyses were conducted for three CpG sites demonstrating robust associations with smoking in prior methylome-wide association studies: cg05575921 (AhRR), cg03636183 (F2RL3), and cg19859270 (GPR15). We estimated causal effects using the regression-based, four-way decomposition approach, which addresses the interaction between smoking and each CpG site. The overall proportion of the excess relative risk mediated by cg05575921 was 92% (p-value = 0.004) and by cg19859270 was 79% (p-value = 0.02). The largest component of the excess relative risk of bladder cancer due to 30 pack-years of smoking history in current smokers was the mediated interaction for both cg05575921 (72%, p = 0.02) and cg19859270 (72%, p-value = 0.04), where the mediated interaction is the effect of smoking on bladder cancer that both acts through differential methylation and depends on smoking history. There was little evidence that smoking was mediated through cg03636183. Our results suggest that differential methylation of cg05575921 and cg19859270 mediate the effects of smoking on bladder cancer, potentially revealing downstream effects of smoking relevant for carcinogenesis.

Published
2019
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4. A Low-Fat Dietary Pattern and Diabetes: A Secondary Analysis From the Women's Health Initiative Dietary Modification Trial

Author

Howard, Barbara V, Aragaki, Aaron K, Tinker, Lesley F, Allison, Matthew, Hingle, Melanie D, Johnson, Karen C, Manson, JoAnn E, Shadyab, Aladdin H, Shikany, James M, Snetselaar, Linda G, Thomson, Cynthia A, Zaslavsky, Oleg, and Prentice, Ross L

Subjects
Aging, Clinical Trials and Supportive Activities, Reproductive health and childbirth, Medical and Health Sciences, Endocrinology & Metabolism, Risk Factors, Clinical Research, Fat-Restricted, Vegetables, Complementary and Integrative Health, Diabetes Mellitus, Humans, Insulin, Obesity, Metabolic and endocrine, Aged, Nutrition, Cancer, Incidence, Prevention, Diabetes, Feeding Behavior, Middle Aged, Dietary Fats, Diet, Postmenopause, Fruit, Female, Type 2, Diet Therapy, Follow-Up Studies
Abstract

ObjectiveWe performed a secondary analysis to evaluate the effect of the Women's Health Initiative dietary intervention on incident diabetes and diabetes treatment in postmenopausal women.Research design and methodsA total of 48,835 women were randomized to a comparison group or an intervention group that underwent a behavioral/nutritional modification program to decrease fat and increase vegetable, fruit, and grain intake for an average of 8.1 years. Ninety-three percent of participants completed the intervention, and 71% participated in active follow-up through 30 September 2015 (median 17.3 years). We measured time to development of treated diabetes and progression from oral antihyperglycemic agents to insulin. Serum glucose and insulin were measured in a subsample of women (N = 2,324) at baseline and years 1, 3, and 6.ResultsDuring the trial, intervention group women had lower rates of initiation of insulin therapy (hazard ratio [HR] 0.74 [95% CI 0.59, 0.94]; P = 0.01). Moreover, women with baseline waist circumference ≥88 cm (P interaction = 0.01) and worse metabolic syndrome scores (P interaction = 0.02) had the greatest reduction in risk of initiating insulin therapy. The decreased risk from the intervention was present during the cumulative follow-up (HR 0.88 [95% CI 0.78, 0.99]; P = 0.04). In participants with measured biomarkers (5.8% subsample) who had baseline glucose

Published
2018

5. Genome-wide association study and meta-analysis identify loci associated with ventricular and supraventricular ectopy

Author

Napier, Melanie D, Franceschini, Nora, Gondalia, Rahul, Stewart, James D, Méndez-Giráldez, Raúl, Sitlani, Colleen M, Seyerle, Amanda A, Highland, Heather M, Li, Yun, Wilhelmsen, Kirk C, Yan, Song, Duan, Qing, Roach, Jeffrey, Yao, Jie, Guo, Xiuqing, Taylor, Kent D, Heckbert, Susan R, Rotter, Jerome I, North, Kari E, Reiner, Alexander P, Zhang, Zhu-Ming, Tinker, Lesley F, Liao, Duanping, Laurie, Cathy C, Gogarten, Stephanie M, Lin, Henry J, Brody, Jennifer A, Bartz, Traci M, Psaty, Bruce M, Sotoodehnia, Nona, Soliman, Elsayed Z, Avery, Christy L, and Whitsel, Eric A

Subjects
Male, Supraventricular, Clinical Trials as Topic, Genotype, Human Genome, Bayes Theorem, Single Nucleotide, Middle Aged, Ventricular Premature Complexes, Cohort Studies, Electrocardiography, Phenotype, Tachycardia, Genetics, Humans, Female, Atrial Premature Complexes, Polymorphism, Aged, Genome-Wide Association Study
Abstract

The genetic basis of supraventricular and ventricular ectopy (SVE, VE) remains largely uncharacterized, despite established genetic mechanisms of arrhythmogenesis. To identify novel genetic variants associated with SVE/VE in ancestrally diverse human populations, we conducted a genome-wide association study of electrocardiographicallyidentified SVE and VE in five cohorts including approximately 43,000 participants of African, European and Hispanic/Latino ancestry. In thirteen ancestry-stratified subgroups, we tested multivariable-adjusted associations of SVE and VE with single nucleotide polymorphism (SNP) dosage. We combined subgroup-specific association estimates in inverse variance-weighted, fixed-effects and Bayesian meta-analyses. We also combined fixed-effects meta-analytic t-test statistics for SVE and VE in multi-trait SNP association analyses. No loci reached genome-wide significance in trans-ethnic meta-analyses. However, we found genome-wide significant SNPs intronic to an apoptosis-enhancing gene previously associated with QRS interval duration (FAF1; lead SNP rs7545860; effect allele frequency = 0.02; P = 2.0 × 10-8) in multi-trait analysis among European ancestry participants and near a locus encoding calcium-dependent glycoproteins (DSC3; lead SNP rs8086068; effect allele frequency = 0.17) in meta-analysis of SVE (P = 4.0 × 10-8) and multi-trait analysis (P = 2.9 × 10-9) among African ancestry participants. The novel findings suggest several mechanisms by which genetic variation may predispose to ectopy in humans and highlight the potential value of leveraging pleiotropy in future studies of ectopy-related phenotypes.

Published
2018

6. A pilot study combining Go4Life® materials with an interactive voice response system to promote physical activity in older women

Author

Saquib, Juliann, King, Abby C, Castro, Cynthia M, Tinker, Lesley F, Sims, Stacy, Shikany, James M, Bea, Jennifer W, Lacroix, Andrea Z, Van Horn, Linda, and Stefanick, Marcia L

Subjects
Aging, physical activity, Pilot Projects, Other Studies In Human Society, Health Promotion, Middle Aged, Patient Acceptance of Health Care, Public Health And Health Services, Telemedicine, United States, Patient Education as Topic, Clinical Research, Humans, Feasibility Studies, Female, women, Go4Life®, interactive voice response, Exercise, Gerontology, intervention, Aged
Abstract

Telephone-based interactive voice response (IVR) systems could be an effective tool for promotion of physical activity among older women. To test IVR feasibility, we enrolled 30 older women in a 10-week physical activity intervention designed around National Institute on Aging (NIA) Go4Life® educational materials with IVR coaching. Participants (mean age = 76 years) significantly increased physical activity by a mean 79 ± 116 (SD) minutes/week (p

Published
2016

7. A genome-wide association study of marginal zone lymphoma shows association to the HLA region

Author

Vijai, Joseph, Wang, Zhaoming, Berndt, Sonja I, Skibola, Christine F, Slager, Susan L, de Sanjose, Silvia, Melbye, Mads, Glimelius, Bengt, Bracci, Paige M, Conde, Lucia, Birmann, Brenda M, Wang, Sophia S, Brooks-Wilson, Angela R, Lan, Qing, de Bakker, Paul IW, Vermeulen, Roel CH, Portlock, Carol, Ansell, Stephen M, Link, Brian K, Riby, Jacques, North, Kari E, Gu, Jian, Hjalgrim, Henrik, Cozen, Wendy, Becker, Nikolaus, Teras, Lauren R, Spinelli, John J, Turner, Jenny, Zhang, Yawei, Purdue, Mark P, Giles, Graham G, Kelly, Rachel S, Zeleniuch-Jacquotte, Anne, Ennas, Maria Grazia, Monnereau, Alain, Bertrand, Kimberly A, Albanes, Demetrius, Lightfoot, Tracy, Yeager, Meredith, Chung, Charles C, Burdett, Laurie, Hutchinson, Amy, Lawrence, Charles, Montalvan, Rebecca, Liang, Liming, Huang, Jinyan, Ma, Baoshan, Villano, Danylo J, Maria, Ann, Corines, Marina, Thomas, Tinu, Novak, Anne J, Dogan, Ahmet, Liebow, Mark, Thompson, Carrie A, Witzig, Thomas E, Habermann, Thomas M, Weiner, George J, Smith, Martyn T, Holly, Elizabeth A, Jackson, Rebecca D, Tinker, Lesley F, Ye, Yuanqing, Adami, Hans-Olov, Smedby, Karin E, De Roos, Anneclaire J, Hartge, Patricia, Morton, Lindsay M, Severson, Richard K, Benavente, Yolanda, Boffetta, Paolo, Brennan, Paul, Foretova, Lenka, Maynadie, Marc, McKay, James, Staines, Anthony, Diver, W Ryan, Vajdic, Claire M, Armstrong, Bruce K, Kricker, Anne, Zheng, Tongzhang, Holford, Theodore R, Severi, Gianluca, Vineis, Paolo, Ferri, Giovanni M, Ricco, Rosalia, Miligi, Lucia, Clavel, Jacqueline, Giovannucci, Edward, Kraft, Peter, Virtamo, Jarmo, Smith, Alex, Kane, Eleanor, Roman, Eve, Chiu, Brian CH, Fraumeni, Joseph F, Wu, Xifeng, Cerhan, James R, Offit, Kenneth, and Chanock, Stephen J

Subjects
Membrane Glycoproteins, Genotype, Lymphoma, Butyrophilins, European Continental Ancestry Group, Human Genome, B-Cell, Computational Biology, Marginal Zone, Single Nucleotide, Hematology, White People, Major Histocompatibility Complex, Rare Diseases, Genetics, Humans, 2.1 Biological and endogenous factors, Polymorphism, Aetiology, Genome-Wide Association Study, Cancer
Abstract

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

Published
2015

8. Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma

Author

Cerhan, James R, Berndt, Sonja I, Vijai, Joseph, Ghesquières, Hervé, McKay, James, Wang, Sophia S, Wang, Zhaoming, Yeager, Meredith, Conde, Lucia, de Bakker, Paul IW, Nieters, Alexandra, Cox, David, Burdett, Laurie, Monnereau, Alain, Flowers, Christopher R, De Roos, Anneclaire J, Brooks-Wilson, Angela R, Lan, Qing, Severi, Gianluca, Melbye, Mads, Gu, Jian, Jackson, Rebecca D, Kane, Eleanor, Teras, Lauren R, Purdue, Mark P, Vajdic, Claire M, Spinelli, John J, Giles, Graham G, Albanes, Demetrius, Kelly, Rachel S, Zucca, Mariagrazia, Bertrand, Kimberly A, Zeleniuch-Jacquotte, Anne, Lawrence, Charles, Hutchinson, Amy, Zhi, Degui, Habermann, Thomas M, Link, Brian K, Novak, Anne J, Dogan, Ahmet, Asmann, Yan W, Liebow, Mark, Thompson, Carrie A, Ansell, Stephen M, Witzig, Thomas E, Weiner, George J, Veron, Amelie S, Zelenika, Diana, Tilly, Hervé, Haioun, Corinne, Molina, Thierry Jo, Hjalgrim, Henrik, Glimelius, Bengt, Adami, Hans-Olov, Bracci, Paige M, Riby, Jacques, Smith, Martyn T, Holly, Elizabeth A, Cozen, Wendy, Hartge, Patricia, Morton, Lindsay M, Severson, Richard K, Tinker, Lesley F, North, Kari E, Becker, Nikolaus, Benavente, Yolanda, Boffetta, Paolo, Brennan, Paul, Foretova, Lenka, Maynadie, Marc, Staines, Anthony, Lightfoot, Tracy, Crouch, Simon, Smith, Alex, Roman, Eve, Diver, W Ryan, Offit, Kenneth, Zelenetz, Andrew, Klein, Robert J, Villano, Danylo J, Zheng, Tongzhang, Zhang, Yawei, Holford, Theodore R, Kricker, Anne, Turner, Jenny, Southey, Melissa C, Clavel, Jacqueline, Virtamo, Jarmo, Weinstein, Stephanie, Riboli, Elio, Vineis, Paolo, Kaaks, Rudolph, Trichopoulos, Dimitrios, Vermeulen, Roel CH, Boeing, Heiner, Tjonneland, Anne, Angelucci, Emanuele, Di Lollo, Simonetta, Rais, Marco, and Birmann, Brenda M

Subjects
Likelihood Functions, Genotype, Lymphoma, Quantitative Trait Loci, Human Genome, Chromosome Mapping, Computational Biology, Single Nucleotide, Hematology, Biological Sciences, Diffuse, Medical and Health Sciences, White People, Rare Diseases, Genetic Loci, Large B-Cell, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Polymorphism, Aetiology, Genome-Wide Association Study, Cancer, Developmental Biology
Abstract

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

Published
2014

9. Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma

Author

Cerhan, James R, Berndt, Sonja I, Vijai, Joseph, Ghesquières, Hervé, McKay, James, Wang, Sophia S, Wang, Zhaoming, Yeager, Meredith, Conde, Lucia, de Bakker, Paul IW, Nieters, Alexandra, Cox, David, Burdett, Laurie, Monnereau, Alain, Flowers, Christopher R, De Roos, Anneclaire J, Brooks-Wilson, Angela R, Lan, Qing, Severi, Gianluca, Melbye, Mads, Gu, Jian, Jackson, Rebecca D, Kane, Eleanor, Teras, Lauren R, Purdue, Mark P, Vajdic, Claire M, Spinelli, John J, Giles, Graham G, Albanes, Demetrius, Kelly, Rachel S, Zucca, Mariagrazia, Bertrand, Kimberly A, Zeleniuch-Jacquotte, Anne, Lawrence, Charles, Hutchinson, Amy, Zhi, Degui, Habermann, Thomas M, Link, Brian K, Novak, Anne J, Dogan, Ahmet, Asmann, Yan W, Liebow, Mark, Thompson, Carrie A, Ansell, Stephen M, Witzig, Thomas E, Weiner, George J, Veron, Amelie S, Zelenika, Diana, Tilly, Hervé, Haioun, Corinne, Molina, Thierry Jo, Hjalgrim, Henrik, Glimelius, Bengt, Adami, Hans-Olov, Bracci, Paige M, Riby, Jacques, Smith, Martyn T, Holly, Elizabeth A, Cozen, Wendy, Hartge, Patricia, Morton, Lindsay M, Severson, Richard K, Tinker, Lesley F, North, Kari E, Becker, Nikolaus, Benavente, Yolanda, Boffetta, Paolo, Brennan, Paul, Foretova, Lenka, Maynadie, Marc, Staines, Anthony, Lightfoot, Tracy, Crouch, Simon, Smith, Alex, Roman, Eve, Diver, W Ryan, Offit, Kenneth, Zelenetz, Andrew, Klein, Robert J, Villano, Danylo J, Zheng, Tongzhang, Zhang, Yawei, Holford, Theodore R, Kricker, Anne, Turner, Jenny, Southey, Melissa C, Clavel, Jacqueline, Virtamo, Jarmo, Weinstein, Stephanie, Riboli, Elio, Vineis, Paolo, Kaaks, Rudolph, Trichopoulos, Dimitrios, Vermeulen, Roel CH, Boeing, Heiner, Tjonneland, Anne, Angelucci, Emanuele, Di Lollo, Simonetta, Rais, Marco, and Birmann, Brenda M

Subjects
Likelihood Functions, Genotype, Lymphoma, Quantitative Trait Loci, European Continental Ancestry Group, Chromosome Mapping, Computational Biology, Single Nucleotide, Biological Sciences, Diffuse, Medical and Health Sciences, Genetic Loci, Large B-Cell, Humans, Genetic Predisposition to Disease, Polymorphism, Genome-Wide Association Study, Developmental Biology
Abstract

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

Published
2014

10. Genome-wide association study identifies five susceptibility loci for follicular lymphoma outside the HLA region

Author

Skibola, Christine F, Berndt, Sonja I, Vijai, Joseph, Conde, Lucia, Wang, Zhaoming, Yeager, Meredith, de Bakker, Paul IW, Birmann, Brenda M, Vajdic, Claire M, Foo, Jia-Nee, Bracci, Paige M, Vermeulen, Roel CH, Slager, Susan L, de Sanjose, Silvia, Wang, Sophia S, Linet, Martha S, Salles, Gilles, Lan, Qing, Severi, Gianluca, Hjalgrim, Henrik, Lightfoot, Tracy, Melbye, Mads, Gu, Jian, Ghesquières, Hervé, Link, Brian K, Morton, Lindsay M, Holly, Elizabeth A, Smith, Alex, Tinker, Lesley F, Teras, Lauren R, Kricker, Anne, Becker, Nikolaus, Purdue, Mark P, Spinelli, John J, Zhang, Yawei, Giles, Graham G, Vineis, Paolo, Monnereau, Alain, Bertrand, Kimberly A, Albanes, Demetrius, Zeleniuch-Jacquotte, Anne, Gabbas, Attilio, Chung, Charles C, Burdett, Laurie, Hutchinson, Amy, Lawrence, Charles, Montalvan, Rebecca, Liang, Liming, Huang, Jinyan, Ma, Baoshan, Liu, Jianjun, Adami, Hans-Olov, Glimelius, Bengt, Ye, Yuanqing, Nowakowski, Grzegorz S, Dogan, Ahmet, Thompson, Carrie A, Habermann, Thomas M, Novak, Anne J, Liebow, Mark, Witzig, Thomas E, Weiner, George J, Schenk, Maryjean, Hartge, Patricia, De Roos, Anneclaire J, Cozen, Wendy, Zhi, Degui, Akers, Nicholas K, Riby, Jacques, Smith, Martyn T, Lacher, Mortimer, Villano, Danylo J, Maria, Ann, Roman, Eve, Kane, Eleanor, Jackson, Rebecca D, North, Kari E, Diver, W Ryan, Turner, Jenny, Armstrong, Bruce K, Benavente, Yolanda, Boffetta, Paolo, Brennan, Paul, Foretova, Lenka, Maynadie, Marc, Staines, Anthony, McKay, James, Brooks-Wilson, Angela R, Zheng, Tongzhang, Holford, Theodore R, Chamosa, Saioa, Kaaks, Rudolph, Kelly, Rachel S, Ohlsson, Bodil, Travis, Ruth C, Weiderpass, Elisabete, Clavel, Jacqueline, Giovannucci, Edward, Kraft, Peter, and Virtamo, Jarmo

Subjects
Lymphoma, Medical and Health Sciences, Chromosomes, Rare Diseases, HLA Antigens, Clinical Research, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Polymorphism, Aetiology, Alleles, Cancer, Genetics & Heredity, Tumor, Human Genome, Follicular, Single Nucleotide, Hematology, Biological Sciences, Haplotypes, Case-Control Studies, Biomarkers, Human, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non-HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 × 10(-20)) near CXCR5; 11q24.3 (rs4937362, p = 6.76 × 10(-11)) near ETS1; 3q28 (rs6444305, p = 1.10 × 10(-10)) in LPP; 18q21.33 (rs17749561, p = 8.28 × 10(-10)) near BCL2; and 8q24.21 (rs13254990, p = 1.06 × 10(-8)) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DRβ1 multiallelic amino acids at positions 11, 13, 28, and 30 that were associated with FL risk (pomnibus = 4.20 × 10(-67) to 2.67 × 10(-70)). Additional independent signals included rs17203612 in HLA class II (odds ratio [OR(per-allele)] = 1.44; p = 4.59 × 10(-16)) and rs3130437 in HLA class I (OR(per-allele) = 1.23; p = 8.23 × 10(-9)). Our findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk.

Published
2014

11. Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia

Author

Berndt, Sonja I, Skibola, Christine F, Joseph, Vijai, Camp, Nicola J, Nieters, Alexandra, Wang, Zhaoming, Cozen, Wendy, Monnereau, Alain, Wang, Sophia S, Kelly, Rachel S, Lan, Qing, Teras, Lauren R, Chatterjee, Nilanjan, Chung, Charles C, Yeager, Meredith, Brooks-Wilson, Angela R, Hartge, Patricia, Purdue, Mark P, Birmann, Brenda M, Armstrong, Bruce K, Cocco, Pierluigi, Zhang, Yawei, Severi, Gianluca, Zeleniuch-Jacquotte, Anne, Lawrence, Charles, Burdette, Laurie, Yuenger, Jeffrey, Hutchinson, Amy, Jacobs, Kevin B, Call, Timothy G, Shanafelt, Tait D, Novak, Anne J, Kay, Neil E, Liebow, Mark, Wang, Alice H, Smedby, Karin E, Adami, Hans-Olov, Melbye, Mads, Glimelius, Bengt, Chang, Ellen T, Glenn, Martha, Curtin, Karen, Cannon-Albright, Lisa A, Jones, Brandt, Diver, W Ryan, Link, Brian K, Weiner, George J, Conde, Lucia, Bracci, Paige M, Riby, Jacques, Holly, Elizabeth A, Smith, Martyn T, Jackson, Rebecca D, Tinker, Lesley F, Benavente, Yolanda, Becker, Nikolaus, Boffetta, Paolo, Brennan, Paul, Foretova, Lenka, Maynadie, Marc, McKay, James, Staines, Anthony, Rabe, Kari G, Achenbach, Sara J, Vachon, Celine M, Goldin, Lynn R, Strom, Sara S, Lanasa, Mark C, Spector, Logan G, Leis, Jose F, Cunningham, Julie M, Weinberg, J Brice, Morrison, Vicki A, Caporaso, Neil E, Norman, Aaron D, Linet, Martha S, De Roos, Anneclaire J, Morton, Lindsay M, Severson, Richard K, Riboli, Elio, Vineis, Paolo, Kaaks, Rudolph, Trichopoulos, Dimitrios, Masala, Giovanna, Weiderpass, Elisabete, Chirlaque, María-Dolores, Vermeulen, Roel CH, Travis, Ruth C, Giles, Graham G, Albanes, Demetrius, Virtamo, Jarmo, Weinstein, Stephanie, Clavel, Jacqueline, Zheng, Tongzhang, Holford, Theodore R, Offit, Kenneth, Zelenetz, Andrew, Klein, Robert J, Spinelli, John J, and Bertrand, Kimberly A

Subjects
Risk, Leukemia, B-Cell, Single Nucleotide, Biological Sciences, Medical and Health Sciences, Chromosomes, Recombination, Linkage Disequilibrium, Lymphocytic, Genetic, Genetic Loci, Case-Control Studies, Pair 2, Humans, Genetic Predisposition to Disease, Polymorphism, Chronic, Human, Genome-Wide Association Study, Developmental Biology
Abstract

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

Published
2013

12. Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia

Author

Berndt, Sonja I, Skibola, Christine F, Joseph, Vijai, Camp, Nicola J, Nieters, Alexandra, Wang, Zhaoming, Cozen, Wendy, Monnereau, Alain, Wang, Sophia S, Kelly, Rachel S, Lan, Qing, Teras, Lauren R, Chatterjee, Nilanjan, Chung, Charles C, Yeager, Meredith, Brooks-Wilson, Angela R, Hartge, Patricia, Purdue, Mark P, Birmann, Brenda M, Armstrong, Bruce K, Cocco, Pierluigi, Zhang, Yawei, Severi, Gianluca, Zeleniuch-Jacquotte, Anne, Lawrence, Charles, Burdette, Laurie, Yuenger, Jeffrey, Hutchinson, Amy, Jacobs, Kevin B, Call, Timothy G, Shanafelt, Tait D, Novak, Anne J, Kay, Neil E, Liebow, Mark, Wang, Alice H, Smedby, Karin E, Adami, Hans-Olov, Melbye, Mads, Glimelius, Bengt, Chang, Ellen T, Glenn, Martha, Curtin, Karen, Cannon-Albright, Lisa A, Jones, Brandt, Diver, W Ryan, Link, Brian K, Weiner, George J, Conde, Lucia, Bracci, Paige M, Riby, Jacques, Holly, Elizabeth A, Smith, Martyn T, Jackson, Rebecca D, Tinker, Lesley F, Benavente, Yolanda, Becker, Nikolaus, Boffetta, Paolo, Brennan, Paul, Foretova, Lenka, Maynadie, Marc, McKay, James, Staines, Anthony, Rabe, Kari G, Achenbach, Sara J, Vachon, Celine M, Goldin, Lynn R, Strom, Sara S, Lanasa, Mark C, Spector, Logan G, Leis, Jose F, Cunningham, Julie M, Weinberg, J Brice, Morrison, Vicki A, Caporaso, Neil E, Norman, Aaron D, Linet, Martha S, De Roos, Anneclaire J, Morton, Lindsay M, Severson, Richard K, Riboli, Elio, Vineis, Paolo, Kaaks, Rudolph, Trichopoulos, Dimitrios, Masala, Giovanna, Weiderpass, Elisabete, Chirlaque, María-Dolores, Vermeulen, Roel CH, Travis, Ruth C, Giles, Graham G, Albanes, Demetrius, Virtamo, Jarmo, Weinstein, Stephanie, Clavel, Jacqueline, Zheng, Tongzhang, Holford, Theodore R, Offit, Kenneth, Zelenetz, Andrew, Klein, Robert J, Spinelli, John J, and Bertrand, Kimberly A

Subjects
Risk, Leukemia, B-Cell, Single Nucleotide, Biological Sciences, Medical and Health Sciences, Chromosomes, Recombination, Linkage Disequilibrium, Lymphocytic, Genetic, Genetic Loci, Case-Control Studies, Pair 2, Humans, Genetic Predisposition to Disease, Polymorphism, Chronic, Human, Genome-Wide Association Study, Cancer, Developmental Biology
Abstract

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

Published
2013

13. Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia

Author

Berndt, Sonja I., Skibola, Christine F., Joseph, Vijai, Camp, Nicola J., Nieters, Alexandra, Wang, Zhaoming, Cozen, Wendy, Monnereau, Alain, Wang, Sophia S., Kelly, Rachel S., Lan, Qing, Teras, Lauren R., Chatterjee, Nilanjan, Chung, Charles C., Yeager, Meredith, Brooks-Wilson, Angela R., Hartge, Patricia, Purdue, Mark P., Birmann, Brenda M., Armstrong, Bruce K., Cocco, Pierluigi, Zhang, Yawei, Severi, Gianluca, Zeleniuch-Jacquotte, Anne, Lawrence, Charles, Burdette, Laurie, Yuenger, Jeffrey, Hutchinson, Amy, Jacobs, Kevin B., Call, Timothy G., Shanafelt, Tait D., Novak, Anne J., Kay, Neil E., Liebow, Mark, Wang, Alice H., Smedby, Karin E., Adami, Hans-Olov, Melbye, Mads, Glimelius, Bengt, Chang, Ellen T., Glenn, Martha, Curtin, Karen, Cannon-Albright, Lisa A., Jones, Brandt, Diver, W. Ryan, Link, Brian K., Weiner, George J., Conde, Lucia, Bracci, Paige M., Riby, Jacques, Holly, Elizabeth A., Smith, Martyn T., Jackson, Rebecca D. J., Tinker, Lesley F., Benavente, Yolanda, Becker, Nikolaus, Boffetta, Paolo, Brennan, Paul, Foretova, Lenka, Maynadié, Marc, McKay, James D., and Staines, Anthony

Subjects
Genòmica, Leucèmia limfocítica crònica, Chronic lymphocytic leukemia, Genomics

14. Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia

Author

Berndt, Sonja I., Skibola, Christine F., Joseph, Vijai, Camp, Nicola J., Nieters, Alexandra, Wang, Zhaoming, Cozen, Wendy, Monnereau, Alain, Wang, Sophia S., Kelly, Rachel S., Lan, Qing, Teras, Lauren R., Chatterjee, Nilanjan, Chung, Charles C., Yeager, Meredith, Brooks-Wilson, Angela R., Hartge, Patricia, Purdue, Mark P., Birmann, Brenda M., Armstrong, Bruce K., Cocco, Pierluigi, Zhang, Yawei, Severi, Gianluca, Zeleniuch-Jacquotte, Anne, Lawrence, Charles, Burdette, Laurie, Yuenger, Jeffrey, Hutchinson, Amy, Jacobs, Kevin B., Call, Timothy G., Shanafelt, Tait D., Novak, Anne J., Kay, Neil E., Liebow, Mark, Wang, Alice H., Smedby, Karin E., Adami, Hans-Olov, Melbye, Mads, Glimelius, Bengt, Chang, Ellen T., Glenn, Martha, Curtin, Karen, Cannon-Albright, Lisa A., Jones, Brandt, Diver, W. Ryan, Link, Brian K., Weiner, George J., Conde, Lucia, Bracci, Paige M., Riby, Jacques, Holly, Elizabeth A., Smith, Martyn T., Jackson, Rebecca D., Tinker, Lesley F., Benavente, Yolanda, Becker, Nikolaus, Boffetta, Paolo, Brennan, Paul, Foretova, Lenka, Maynadie, Marc, McKay, James, and Staines, Anthony

Subjects
Genòmica, Leucèmia limfocítica crònica, Chronic lymphocytic leukemia, Genomics
Abstract

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

15. Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia

Author

Berndt, Sonja I., Skibola, Christine F., Joseph, Vijai, Camp, Nicola J., Nieters, Alexandra, Wang, Zhaoming, Cozen, Wendy, Monnereau, Alain, Wang, Sophia S., Kelly, Rachel S., Lan, Qing, Teras, Lauren R., Chatterjee, Nilanjan, Chung, Charles C., Yeager, Meredith, Brooks-Wilson, Angela R., Hartge, Patricia, Purdue, Mark P., Birmann, Brenda M., Armstrong, Bruce K., Cocco, Pierluigi, Zhang, Yawei, Severi, Gianluca, Zeleniuch-Jacquotte, Anne, Lawrence, Charles, Burdette, Laurie, Yuenger, Jeffrey, Hutchinson, Amy, Jacobs, Kevin B., Call, Timothy G., Shanafelt, Tait D., Novak, Anne J., Kay, Neil E., Liebow, Mark, Wang, Alice H., Smedby, Karin E., Adami, Hans-Olov, Melbye, Mads, Glimelius, Bengt, Chang, Ellen T., Glenn, Martha, Curtin, Karen, Cannon-Albright, Lisa A., Jones, Brandt, Diver, W. Ryan, Link, Brian K., Weiner, George J., Conde, Lucia, Bracci, Paige M., Riby, Jacques, Holly, Elizabeth A., Smith, Martyn T., Jackson, Rebecca D., Tinker, Lesley F., Benavente, Yolanda, Becker, Nikolaus, Boffetta, Paolo, Brennan, Paul, Foretova, Lenka, Maynadie, Marc, McKay, James, Staines, Anthony, and Universitat de Barcelona

Subjects
Genòmica, Leucèmia limfocítica crònica, Chronic lymphocytic leukemia, Genomics
Abstract

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

16. Genome-wide homozygosity and risk of four non-Hodgkin lymphoma subtypes

Author

Joseph Vijai, Henrik Hjalgrim, Roger L. Milne, Simonetta Bisanzi, Rebecca D. Jackson, Graham G. Giles, Mark Liebow, John J. Spinelli, Stephanie J. Weinstein, Wendy Cozen, Susan M. Gapstur, Michael Dean, Paolo Boffetta, Pierluigi Cocco, Paige M. Bracci, Nicola J. Camp, Amy Moore, Herve Ghesquieres, Federico Canzian, James McKay, Thomas M. Habermann, Nikolaus Becker, Kari E. North, Demetrius Albanes, Alain Monnereau, Marc Maynadié, Lesley F. Tinker, Christine F. Skibola, Vignesh Ravichandran, Susan L. Slager, Karin E. Smedby, Ruth C. Travis, Jacqueline Clavel, Lucia Miligi, Melissa C. Southey, Mary Carrington, Claire M. Vajdic, Karen Curtin, David G. Cox, Roel Vermeulen, Elio Riboli, Eleanor Kane, Weiyin Zhou, Nathaniel Rothman, Mitchell J. Machiela, Yolanda Benavente, Alan A. Arslan, Meredith Yeager, Paul Brennan, Tongzhang Zheng, Elisabete Weiderpass, Moara Machado, Qing Lan, Alpa V. Patel, James R. Cerhan, Sonja I. Berndt, Neil E. Caporaso, Silvia de Sanjosé, Stephen J. Chanock, Nicole Wong Doo, Lauren R. Teras, Sara Piro, Lenka Foretova, Chi Gao, Gilles Salles, Immaculata De Vivo, Alexandra Nieters, Bengt Glimelius, Sophia S. Wang, Richard K. Severson, Mads Melbye, Hans-Olov Adami, Yawei Zhang, Carolyn Stewart, Lucia Conde, Brenda M. Birmann, Angela Brooks-Wilson, Thierry Jo Molina, Kenneth Offit, Brian K. Link, Martha Glenn, Anthony Staines, Moore, Amy, Machiela, Mitchell J, Machado, Moara, Wang, Sophia S, Kane, Eleanor, Slager, Susan L, Zhou, Weiyin, Carrington, Mary, Lan, Qing, Milne, Roger L, Birmann, Brenda M, Adami, Hans-Olov, Albanes, Demetriu, Arslan, Alan A, Becker, Nikolau, Benavente, Yolanda, Bisanzi, Simonetta, Boffetta, Paolo, Bracci, Paige M, Brennan, Paul, Brooks-Wilson, Angela R, Canzian, Federico, Caporaso, Neil, Clavel, Jacqueline, Cocco, Pierluigi, Conde, Lucia, Cox, David G, Cozen, Wendy, Curtin, Karen, De Vivo, Immaculata, de Sanjose, Silvia, Foretova, Lenka, Gapstur, Susan M, Ghesquières, Hervè, Giles, Graham G, Glenn, Martha, Glimelius, Bengt, Gao, Chi, Habermann, Thomas M, Hjalgrim, Henrik, Jackson, Rebecca D, Liebow, Mark, Link, Brian K, Maynadie, Marc, McKay, Jame, Melbye, Mad, Miligi, Lucia, Molina, Thierry J, Monnereau, Alain, Nieters, Alexandra, North, Kari E, Offit, Kenneth, Patel, Alpa V, Piro, Sara, Ravichandran, Vignesh, Riboli, Elio, Salles, Gille, Severson, Richard K, Skibola, Christine F, Smedby, Karin E, Southey, Melissa C, Spinelli, John J, Staines, Anthony, Stewart, Carolyn, Teras, Lauren R, Tinker, Lesley F, Travis, Ruth C, Vajdic, Claire M, Vermeulen, Roel C H, Vijai, Joseph, Weiderpass, Elisabete, Weinstein, Stephanie, Doo, Nicole Wong, Zhang, Yawei, Zheng, Tongzhang, Chanock, Stephen J, Rothman, Nathaniel, Cerhan, James R, Dean, Michael, Camp, Nicola J, Yeager, Meredith, and Berndt, Sonja I

Subjects
Genetics, Chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Follicular lymphoma, Single-nucleotide polymorphism, Runs of Homozygosity, Biology, medicine.disease, marginal zone lymphoma, Article, follicular lymphoma, immune system diseases, hemic and lymphatic diseases, Genetic variation, medicine, chronic lymphocytic leukemia, homozygosity, Diffuse large B-cell lymphoma, Inbreeding, Non-Hodgkin lymphoma, Genetic association
Abstract

Aim: Recessive genetic variation is thought to play a role in non-Hodgkin lymphoma (NHL) etiology. Runs of homozygosity (ROH), defined based on long, continuous segments of homozygous SNPs, can be used to estimate both measured and unmeasured recessive genetic variation. We sought to examine genome-wide homozygosity and NHL risk.Methods: We used data from eight genome-wide association studies of four common NHL subtypes: 3061 chronic lymphocytic leukemia (CLL), 3814 diffuse large B-cell lymphoma (DLBCL), 2784 follicular lymphoma (FL), and 808 marginal zone lymphoma (MZL) cases, as well as 9374 controls. We examined the effect of homozygous variation on risk by: (1) estimating the fraction of the autosome containing runs of homozygosity (FROH); (2) calculating an inbreeding coefficient derived from the correlation among uniting gametes (F3); and (3) examining specific autosomal regions containing ROH. For each, we calculated beta coefficients and standard errors using logistic regression and combined estimates across studies using random-effects meta-analysis.Results: We discovered positive associations between FROH and CLL (β = 21.1, SE = 4.41, P = 1.6 × 10 -6) and FL (β = 11.4, SE = 5.82, P = 0.02) but not DLBCL ( P = 1.0) or MZL ( P = 0.91). For F3, we observed an association with CLL (β = 27.5, SE = 6.51, P = 2.4 × 10 -5). We did not find evidence of associations with specific ROH, suggesting that the associations observed with FROH and F3 for CLL and FL risk were not driven by a single region of homozygosity. Conclusion: Our findings support the role of recessive genetic variation in the etiology of CLL and FL; additional research is needed to identify the specific loci associated with NHL risk.

Published
2021

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