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1.  Rationale and Design of the International Lymphoma Epidemiology Consortium (InterLymph) Non-Hodgkin Lymphoma Subtypes Project 
Background
Non-Hodgkin lymphoma (NHL), the most common hematologic malignancy, consists of numerous subtypes. The etiology of NHL is incompletely understood, and increasing evidence suggests that risk factors may vary by NHL subtype. However, small numbers of cases have made investigation of subtype-specific risks challenging. The International Lymphoma Epidemiology Consortium therefore undertook the NHL Subtypes Project, an international collaborative effort to investigate the etiologies of NHL subtypes. This article describes in detail the project rationale and design.
Methods
We pooled individual-level data from 20 case-control studies (17471 NHL cases, 23096 controls) from North America, Europe, and Australia. Centralized data harmonization and analysis ensured standardized definitions and approaches, with rigorous quality control.
Results
The pooled study population included 11 specified NHL subtypes with more than 100 cases: diffuse large B-cell lymphoma (N = 4667), follicular lymphoma (N = 3530), chronic lymphocytic leukemia/small lymphocytic lymphoma (N = 2440), marginal zone lymphoma (N = 1052), peripheral T-cell lymphoma (N = 584), mantle cell lymphoma (N = 557), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (N = 374), mycosis fungoides/Sézary syndrome (N = 324), Burkitt/Burkitt-like lymphoma/leukemia (N = 295), hairy cell leukemia (N = 154), and acute lymphoblastic leukemia/lymphoma (N = 152). Associations with medical history, family history, lifestyle factors, and occupation for each of these 11 subtypes are presented in separate articles in this issue, with a final article quantitatively comparing risk factor patterns among subtypes.
Conclusions
The International Lymphoma Epidemiology Consortium NHL Subtypes Project provides the largest and most comprehensive investigation of potential risk factors for a broad range of common and rare NHL subtypes to date. The analyses contribute to our understanding of the multifactorial nature of NHL subtype etiologies, motivate hypothesis-driven prospective investigations, provide clues for prevention, and exemplify the benefits of international consortial collaboration in cancer epidemiology.
doi:10.1093/jncimonographs/lgu005
PMCID: PMC4155460  PMID: 25174022
2.  Medical History, Lifestyle, Family History, and Occupational Risk Factors for Mycosis Fungoides and Sézary Syndrome: The InterLymph Non-Hodgkin Lymphoma Subtypes Project 
Background
Mycosis fungoides and Sézary syndrome (MF/SS) are rare cutaneous T-cell lymphomas. Their etiology is poorly understood.
Methods
A pooled analysis of 324 MF/SS cases and 17217 controls from 14 case–control studies from Europe, North America, and Australia, as part of the International Lymphoma Epidemiology Consortium (InterLymph) Non-Hodgkin Lymphoma (NHL) Subtypes Project, was carried out to investigate associations with lifestyle, medical history, family history, and occupational risk factors. Multivariate logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (CI).
Results
We found an increased risk of MF/SS associated with body mass index equal to or larger than 30kg/m2 (OR = 1.57, 95% CI = 1.03 to 2.40), cigarette smoking for 40 years or more (OR = 1.55, 95% CI = 1.04 to 2.31), eczema (OR = 2.38, 95% CI = 1.73 to 3.29), family history of multiple myeloma (OR = 8.49, 95% CI = 3.31 to 21.80), and occupation as crop and vegetable farmers (OR = 2.37, 95% CI = 1.14 to 4.92), painters (OR = 3.71, 95% CI = 1.94 to 7.07), woodworkers (OR = 2.20, 95% CI = 1.18 to 4.08), and general carpenters (OR = 4.07, 95% CI = 1.54 to 10.75). We also found a reduced risk of MF/SS associated with moderate leisure time physical activity (OR = 0.46, 95% CI = 0.22 to 0.97).
Conclusions
Our study provided the first detailed analysis of risk factors for MF/SS and further investigation is needed to confirm these findings in prospective data and in other populations.
doi:10.1093/jncimonographs/lgu008
PMCID: PMC4155463  PMID: 25174030
3.  Medical History, Lifestyle, Family History, and Occupational Risk Factors for Diffuse Large B-Cell Lymphoma: The InterLymph Non-Hodgkin Lymphoma Subtypes Project 
Background
Although risk factors for diffuse large B-cell lymphoma (DLBCL) have been suggested, their independent effects, modification by sex, and association with anatomical sites are largely unknown.
Methods
In a pooled analysis of 4667 cases and 22639 controls from 19 studies, we used stepwise logistic regression to identify the most parsimonious multivariate models for DLBCL overall, by sex, and for selected anatomical sites.
Results
DLBCL was associated with B-cell activating autoimmune diseases (odds ratio [OR] = 2.36, 95% confidence interval [CI] = 1.80 to 3.09), hepatitis C virus seropositivity (OR = 2.02, 95% CI = 1.47 to 2.76), family history of non-Hodgkin lymphoma (OR = 1.95, 95% CI = 1.54 to 2.47), higher young adult body mass index (OR = 1.58, 95% CI = 1.12 to 2.23, for 35+ vs 18.5 to 22.4 kg/m2), higher recreational sun exposure (OR = 0.78, 95% CI = 0.69 to 0.89), any atopic disorder (OR = 0.82, 95% CI = 0.76 to 0.89), and higher socioeconomic status (OR = 0.86, 95% CI = 0.79 to 0.94). Additional risk factors for women were occupation as field crop/vegetable farm worker (OR = 1.78, 95% CI = 1.22 to 2.60), hairdresser (OR = 1.65, 95% CI = 1.12 to 2.41), and seamstress/embroider (OR = 1.49, 95% CI = 1.13 to 1.97), low adult body mass index (OR = 0.46, 95% CI = 0.29 to 0.74, for <18.5 vs 18.5 to 22.4 kg/m2), hormone replacement therapy started age at least 50 years (OR = 0.68, 95% CI = 0.52 to 0.88), and oral contraceptive use before 1970 (OR = 0.78, 95% CI = 0.62 to 1.00); and for men were occupation as material handling equipment operator (OR = 1.58, 95% CI = 1.02 to 2.44), lifetime alcohol consumption (OR = 0.57, 95% CI = 0.44 to 0.75, for >400kg vs nondrinker), and previous blood transfusion (OR = 0.69, 95% CI = 0.57 to 0.83). Autoimmune disease, atopy, and family history of non-Hodgkin lymphoma showed similar associations across selected anatomical sites, whereas smoking was associated with central nervous system, testicular and cutaneous DLBCLs; inflammatory bowel disease was associated with gastrointestinal DLBCL; and farming and hair dye use were associated with mediastinal DLBCL.
Conclusion
Our results support a complex and multifactorial etiology for DLBCL with some variation in risk observed by sex and anatomical site.
doi:10.1093/jncimonographs/lgu010
PMCID: PMC4155465  PMID: 25174023
4.  Medical History, Lifestyle, Family History, and Occupational Risk Factors for Peripheral T-Cell Lymphomas: The InterLymph Non-Hodgkin Lymphoma Subtypes Project 
Background
Accounting for 10%–15% of all non-Hodgkin lymphomas in Western populations, peripheral T-cell lymphomas (PTCL) are the most common T-cell lymphoma but little is known about their etiology. Our aim was to identify etiologic risk factors for PTCL overall, and for specific PTCL subtypes, by analyzing data from 15 epidemiologic studies participating in the InterLymph Consortium.
Methods
A pooled analysis of individual-level data for 584 histologically confirmed PTCL cases and 15912 controls from 15 case–control studies conducted in Europe, North America, and Australia was undertaken. Data collected from questionnaires were harmonized to permit evaluation of a broad range of potential risk factors. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression.
Results
Risk factors associated with increased overall PTCL risk with a P value less than .05 included: a family history of hematologic malignancies (OR = 1.92, 95% CI = 1.30 to 2.84); celiac disease (OR = 17.8, 95% CI = 8.61 to 36.79); eczema (OR = 1.41, 95% CI = 1.07 to 1.85); psoriasis (OR = 1.97, 95% CI = 1.17 to 3.32); smoking 40 or more years (OR = 1.92, 95% CI = 1.41 to 2.62); and employment as a textile worker (ever) (OR = 1.58, 95% CI = 1.05 to 2.38) and electrical fitter (ever) (OR = 2.89, 95% CI = 1.41 to 5.95). Exposures associated with reduced overall PTCL risk included a personal history of allergies (OR = 0.69, 95% CI = 0.54 to 0.87), alcohol consumption (ever) (OR = 0.64, 95% CI = 0.49 to 0.82), and having ever lived or worked on a farm (OR = 0.72, 95% CI = 0.55% to 0.95%). We also observed the well-established risk elevation for enteropathy-type PTCL among those with celiac disease in our data.
Conclusions Our pooled analyses identified a number of new potential risk factors for PTCL and require further validation in independent series.
doi:10.1093/jncimonographs/lgu012
PMCID: PMC4155466  PMID: 25174027
5.  Etiologic Heterogeneity Among Non-Hodgkin Lymphoma Subtypes: The InterLymph Non-Hodgkin Lymphoma Subtypes Project 
Morton, Lindsay M. | Slager, Susan L. | Cerhan, James R. | Wang, Sophia S. | Vajdic, Claire M. | Skibola, Christine F. | Bracci, Paige M. | de Sanjosé, Silvia | Smedby, Karin E. | Chiu, Brian C. H. | Zhang, Yawei | Mbulaiteye, Sam M. | Monnereau, Alain | Turner, Jennifer J. | Clavel, Jacqueline | Adami, Hans-Olov | Chang, Ellen T. | Glimelius, Bengt | Hjalgrim, Henrik | Melbye, Mads | Crosignani, Paolo | di Lollo, Simonetta | Miligi, Lucia | Nanni, Oriana | Ramazzotti, Valerio | Rodella, Stefania | Costantini, Adele Seniori | Stagnaro, Emanuele | Tumino, Rosario | Vindigni, Carla | Vineis, Paolo | Becker, Nikolaus | Benavente, Yolanda | Boffetta, Paolo | Brennan, Paul | Cocco, Pierluigi | Foretova, Lenka | Maynadié, Marc | Nieters, Alexandra | Staines, Anthony | Colt, Joanne S. | Cozen, Wendy | Davis, Scott | de Roos, Anneclaire J. | Hartge, Patricia | Rothman, Nathaniel | Severson, Richard K. | Holly, Elizabeth A. | Call, Timothy G. | Feldman, Andrew L. | Habermann, Thomas M. | Liebow, Mark | Blair, Aaron | Cantor, Kenneth P. | Kane, Eleanor V. | Lightfoot, Tracy | Roman, Eve | Smith, Alex | Brooks-Wilson, Angela | Connors, Joseph M. | Gascoyne, Randy D. | Spinelli, John J. | Armstrong, Bruce K. | Kricker, Anne | Holford, Theodore R. | Lan, Qing | Zheng, Tongzhang | Orsi, Laurent | Dal Maso, Luigino | Franceschi, Silvia | La Vecchia, Carlo | Negri, Eva | Serraino, Diego | Bernstein, Leslie | Levine, Alexandra | Friedberg, Jonathan W. | Kelly, Jennifer L. | Berndt, Sonja I. | Birmann, Brenda M. | Clarke, Christina A. | Flowers, Christopher R. | Foran, James M. | Kadin, Marshall E. | Paltiel, Ora | Weisenburger, Dennis D. | Linet, Martha S. | Sampson, Joshua N.
Background
Non-Hodgkin lymphoma (NHL) comprises biologically and clinically heterogeneous subtypes. Previously, study size has limited the ability to compare and contrast the risk factor profiles among these heterogeneous subtypes.
Methods
We pooled individual-level data from 17 471 NHL cases and 23 096 controls in 20 case–control studies from the International Lymphoma Epidemiology Consortium (InterLymph). We estimated the associations, measured as odds ratios, between each of 11 NHL subtypes and self-reported medical history, family history of hematologic malignancy, lifestyle factors, and occupation. We then assessed the heterogeneity of associations by evaluating the variability (Q value) of the estimated odds ratios for a given exposure among subtypes. Finally, we organized the subtypes into a hierarchical tree to identify groups that had similar risk factor profiles. Statistical significance of tree partitions was estimated by permutation-based P values (P NODE).
Results
Risks differed statistically significantly among NHL subtypes for medical history factors (autoimmune diseases, hepatitis C virus seropositivity, eczema, and blood transfusion), family history of leukemia and multiple myeloma, alcohol consumption, cigarette smoking, and certain occupations, whereas generally homogeneous risks among subtypes were observed for family history of NHL, recreational sun exposure, hay fever, allergy, and socioeconomic status. Overall, the greatest difference in risk factors occurred between T-cell and B-cell lymphomas (P NODE < 1.0×10−4), with increased risks generally restricted to T-cell lymphomas for eczema, T-cell-activating autoimmune diseases, family history of multiple myeloma, and occupation as a painter. We further observed substantial heterogeneity among B-cell lymphomas (P NODE < 1.0×10−4). Increased risks for B-cell-activating autoimmune disease and hepatitis C virus seropositivity and decreased risks for alcohol consumption and occupation as a teacher generally were restricted to marginal zone lymphoma, Burkitt/Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and/or lymphoplasmacytic lymphoma/Waldenström macroglobulinemia.
Conclusions
Using a novel approach to investigate etiologic heterogeneity among NHL subtypes, we identified risk factors that were common among subtypes as well as risk factors that appeared to be distinct among individual or a few subtypes, suggesting both subtype-specific and shared underlying mechanisms. Further research is needed to test putative mechanisms, investigate other risk factors (eg, other infections, environmental exposures, and diet), and evaluate potential joint effects with genetic susceptibility.
doi:10.1093/jncimonographs/lgu013
PMCID: PMC4155467  PMID: 25174034
6.  Human Nail Clippings as a Source of DNA for Genetic Studies 
Open journal of epidemiology  2015;5(1):41-50.
Blood samples have traditionally been used as the main source of DNA for genetic analysis. However, this source can be difficult in terms of collection, transportation, and long-term storage. In this study, we investigated whether human nail clippings could be used as a source of DNA for SNP genotyping, null-allele detection, and whole-genome amplification. From extracted nail DNA, we achieved amplicons up to a length of ~400 bp and >96% concordance for SNP genotyping and 100% concordance for null-allele detection compared to DNA derived from matched blood samples. For whole-genome amplification, OmniPlex performed better than Multiple Displacement Amplification with a success rate of 89.3% and 76.8% for SNP genotyping and null-allele detection, respectively. Concordance was ~98% for both methods. When combined with OmniPlex whole-genome amplification, human nail clippings could potentially be used as an alternative to whole blood as a less invasive and more convenient source of DNA for genotyping studies.
doi:10.4236/ojepi.2015.51006
PMCID: PMC4499506  PMID: 26180661
Single Nucleotide Polymorphism (SNP); Nail Clippings; Genotyping; Whole Genome Amplification (WGA)
7.  Medical History, Lifestyle, Family History, and Occupational Risk Factors for Marginal Zone Lymphoma: The InterLymph Non-Hodgkin Lymphoma Subtypes Project 
Background
Marginal zone lymphoma (MZL), comprised of nodal, extranodal, and splenic subtypes, accounts for 5%–10% of non-Hodgkin lymphoma cases. A detailed evaluation of the independent effects of risk factors for MZL and its subtypes has not been conducted.
Methods
Data were pooled from 1052 MZL cases (extranodal [EMZL] = 633, nodal [NMZL] = 157, splenic [SMZL] = 140) and 13766 controls from 12 case–control studies. Adjusted unconditional logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs).
Results
Novel findings for MZL subtypes include increased risk for B-cell activating autoimmune conditions (EMZL OR = 6.40, 95% CI = 4.24 to 9.68; NMZL OR = 7.80, 95% CI = 3.32 to 18.33; SMZL OR = 4.25, 95% CI = 1.49 to 12.14), hepatitis C virus seropositivity (EMZL OR = 5.29, 95% CI = 2.48 to 11.28), self-reported peptic ulcers (EMZL OR = 1.83, 95% CI = 1.35 to 2.49), asthma without other atopy (SMZL OR = 2.28, 95% CI = 1.23 to 4.23), family history of hematologic cancer (EMZL OR = 1.90, 95% CI = 1.37 to 2.62) and of non-Hodgkin lymphoma (NMZL OR = 2.82, 95% CI = 1.33 to 5.98), permanent hairdye use (SMZL OR = 6.59, 95% CI = 1.54 to 28.17), and occupation as a metalworker (NMZL OR = 3.56, 95% CI = 1.67 to 7.58). Reduced risks were observed with consumption of any alcohol (EMZL fourth quartile OR = 0.48, 95% CI = 0.28 to 0.82) and lower consumption of wine (NMZL first to third quartile ORs < 0.45) compared with nondrinkers, and occupation as a teacher (EMZL OR = 0.58, 95% CI = 0.37 to 0.88).
Conclusion
Our results provide new data suggesting etiologic heterogeneity across MZL subtypes although a common risk of MZL associated with B-cell activating autoimmune conditions was found.
doi:10.1093/jncimonographs/lgu011
PMCID: PMC4207869  PMID: 25174026
8.  A genome-wide association study of marginal zone lymphoma shows association to the HLA region 
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 I W | Vermeulen, Roel C H | 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 C H | Fraumeni, Joseph F | Wu, Xifeng | Cerhan, James R | Offit, Kenneth | Chanock, Stephen J | Rothman, Nathaniel | Nieters, Alexandra
Nature communications  2015;6:5751.
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.
doi:10.1038/ncomms6751
PMCID: PMC4287989  PMID: 25569183
10.  Genome-wide association study identifies multiple susceptibility loci for diffuse large B-cell lymphoma 
Cerhan, James R | Berndt, Sonja I | Vijai, Joseph | Ghesquières, Hervé | McKay, James | Wang, Sophia S | Wang, Zhaoming | Yeager, Meredith | Conde, Lucia | de Bakker, Paul I W | 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 C H | Boeing, Heiner | Tjonneland, Anne | Angelucci, Emanuele | Di Lollo, Simonetta | Rais, Marco | Birmann, Brenda M | Laden, Francine | Giovannucci, Edward | Kraft, Peter | Huang, Jinyan | Ma, Baoshan | Ye, Yuanqing | Chiu, Brian C H | Sampson, Joshua | Liang, Liming | Park, Ju-Hyun | Chung, Charles C | Weisenburger, Dennis D | Chatterjee, Nilanjan | Fraumeni, Joseph F | Slager, Susan L | Wu, Xifeng | de Sanjose, Silvia | Smedby, Karin E | Salles, Gilles | Skibola, Christine F | Rothman, Nathaniel | Chanock, Stephen J
Nature genetics  2014;46(11):1233-1238.
doi:10.1038/ng.3105
PMCID: PMC4213349  PMID: 25261932
11.  Racial Disparities in Uncorrected and Undercorrected Refractive Error in the United States 
Purpose.
To identify risk factors for inadequately corrected refractive error in the United States.
Methods.
This cross-sectional study included 12,758 participants 12 years of age and older from the 2005 to 2008 National Health and Nutrition Examination Survey. The primary outcome was the proportion of individuals with inadequate refractive correction for whom refractive correction would result in a visual acuity of 20/40 or better. The primary predictor was race/ethnicity. Secondary predictors included age, sex, annual household income, education, insurance, type of refractive error, current corrective lens use, presenting and best corrected visual acuity, cataract surgery, glaucoma, and age-related macular degeneration.
Results.
Overall, 50.6% of subjects had a refractive error which was correctable to 20/40 or better with refraction. The percentage of subjects with correctable refractive error who were inadequately corrected was 11.7%. Odds of inadequate refractive correction were significantly greater in Mexican Americans and non-Hispanic blacks than in their non-Hispanic white counterparts in all age groups, with the greatest disparity in the 12- to 19-year-old group. Other risk factors associated with inadequate refractive correction in adults but not in teenagers included low annual household income, low education, and lack of health insurance.
Conclusions.
Racial disparities in refractive error correction were most pronounced in those under 20 years of age, as well as in adults with low annual household income, low education level, and lack of health insurance. Targeted efforts to provide culturally appropriate education, accessible vision screening, appropriate refractive correction, and routine follow-up to these medically underserved groups should be pursued as a public health strategy.
This US population-based study found Non-Caucasian race to be associated with inadequately corrected refractive error. The racial disparities were most pronounced in subjects under 20 years as well as in adults with low annual household income, low education level and lack of health insurance.
doi:10.1167/iovs.13-12662
PMCID: PMC4215743  PMID: 25249602
ethnic disparities; healthcare access; NHANES; racial disparities; refractive error
12.  Molecular characteristics of diffuse large B-cell lymphoma in human immunodeficiency virus-infected and -uninfected patients in the pre-highly active antiretroviral therapy and pre-rituximab era 
Leukemia & lymphoma  2013;55(3):551-557.
Human immunodeficiency virus (HIV) infection substantially elevates diffuse large B-cell lymphoma (DLBCL) risk, but its impact on the distinct DLBCL subtypes defined by cell of origin is unclear. We compared DLBCL molecular characteristics and prognosis in 51 HIV-infected and 116 HIV-uninfected cases diagnosed during 1977-2003. Using immunohistochemistry to classify cell of origin based on the Tally algorithm, activated B-cell (ABC)-DLBCL was substantially more common in HIV-infected (83%) than in HIV-uninfected (54%) cases (p< 0.001). Epstein-Barr virus (EBV) was detected in 63% of DLBCLs in HIV-infected cases, occurring almost exclusively in ABC-DLBCL (74% vs. 13% of germinal center B-cell [GCB]-DLBCL, p=0.002), but was rarely detected in DLBCLs among HIV-uninfected cases (3%). Among HIV-uninfected cases, MYC/IgH[t(8;14)(q24;q32)] and IgH/BCL2[t(14;18)(q32;q21)] translocations were significantly more common and BCL6/IgH[t(3;14)(q27;q32)] significantly less common in GCB-DLBCL than in ABC-DLBCL (p= 0.010, < 0.001 and = 0.039, respectively). Among HIV-infected cases, translocations other than MYC/IgH[t(8;14)(q24;q32)] (21%) were rare (≤6%) and unrelated to cell of origin. ABC-DLBCL was associated with adverse overall survival compared with GCB-DLBCL regardless of HIV status (pHIV-infected= 0.066;pHIV-uninfected= 0.038). Our data demonstrate key differences in the molecular characteristics, cell of origin and prognosis of DLBCL by HIV status in the pre-highly active antiretroviral therapy (HAART) and pre-rituximab era, supporting biologic differences in lymphomagenesis in the presence of HIV.
doi:10.3109/10428194.2013.813499
PMCID: PMC3936016  PMID: 23772639
Diffuse large B-cell lymphoma; Epstein-Barr virus; activated B-cell; germinal center B-cell
13.  Association between Visual Field Defects and Quality of Life in the United States 
Ophthalmology  2013;121(3):733-740.
Purpose
To investigate the association between visual field defects and quality of life in the United States population.
Design
Cross-sectional study
Participants
A total of 5,186participants in the 2005–2008 National Health and Nutrition Examination Survey (NHANES) aged 40 years and older without a self-reported history of age-related macular degeneration or prior refractive surgery who had undergone frequency doubling technology (FDT) perimetric testing.
Methods
FDT perimetry was performed in both eyes. Results from the better eye were used to categorize subjects as normal or having mild, moderate, or severe visual field loss. Subjects completed surveys about their visual and physical functioning ability.
Main outcome measures
Disability pertaining to six vision-related activities, two visual function questions, and five physical functioning domains.
Results
Eighty one percent of subjects had normal visual fields and 10%, 7% and 2% demonstrated mild, moderate and severe visual field defects, respectively. Subjects with greater severity of visual field defects had greater difficulty with vision-related activities. Subjects with severe visual field defects demonstrated the greatest odds of difficulty with all six activities. The two activities most adversely impacted were daytime driving in familiar places (Odds Ratio (OR): 12.4, 95% Confidence Interval (CI) 6.1–25.1) and noticing objects off to the side when walking (OR: 7.7, 95% CI: 4.7–12.7). Subjects with severe visual field defects had greater odds of worrying about eyesight (OR: 3.4, 95% CI 2.0–5.8) and being limited by vision in the time spent on daily activities (OR: 5.1, 95% CI 3.0–8.5). Subjects with severe visual field defects demonstrated the greatest odds of difficulty with three physical function domains including activities of daily living (OR: 2.45, 95% CI 1.37–4.38), instrumental activities of daily living (OR: 2.45, 95% CI: 1.37–4.38), as well as leisure and social activities (OR: 3.29, 95% CI: 1.87–5.77).
Conclusions
Greater severity of visual field abnormality was associated with significantly greater odds of disability with vision-related function and physical function. These findings support the necessity of routine screening to find those who may benefit from therapy to prevent progressive glaucomatous vision loss.
doi:10.1016/j.ophtha.2013.09.043
PMCID: PMC3943627  PMID: 24342021
14.  Body Mass Index and Risk of Death in Asian Americans 
American journal of public health  2014;104(3):520-525.
Objective
To investigate the association between body mass index (BMI) and mortality among Asian Americans
Methods
We pooled data from prospective cohort studies that included 20,672 Asian American adults with no history of cancer or heart disease at baseline. Hazard ratios and 95% confidence intervals (CI) were estimated using Cox proportional hazards models.
Results
A high, but not low, BMI was associated with an increased risk of total mortality among individuals 35–69 years old. BMI was not related to total mortality among individuals ≥70 years old. With a BMI 22.5–<25 as the reference category among 35–69 year old never smokers the hazard ratios (95% CI) for total mortality were 0.83 (0.47–1.47) for BMI 15–<18.5, 0.91 (0.62–1.32) for BMI 18.5–<20, 1.08 (0.86–1.36) for BMI 20–<22.5, 1.14 (0.90–1.44) for BMI 25–<27.5, 1.13 (0.79–1.62) for BMI 27.5–<30, 1.82 (1.25–2.64) for BMI 30–<35, and 2.09 (1.06–4.11) for BMI 35–50. Higher BMI was also related to an increased mortality from cardiovascular disease and cancer.
Conclusions
A high BMI is associated with increased risk of mortality among Asian Americans.
doi:10.2105/AJPH.2013.301573
PMCID: PMC3953786  PMID: 24432919
15.  A genome-wide association study of marginal zone lymphoma shows association to the HLA region 
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 I. W. | Vermeulen, Roel C. H. | 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 C. H. | Fraumeni, Joseph F. | Wu, Xifeng | Cerhan, James R. | Offit, Kenneth | Chanock, Stephen J. | Rothman, Nathaniel | Nieters, Alexandra
Nature Communications  2015;6:5751.
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.
Marginal zone lymphoma (MZL) is a common subtype of B-cell non-Hodgkin lymphoma. Here the authors carry out a two-stage genome-wide association study in over 8,000 Europeans and identify two new MZL risk loci at chromosome 6p, implicating the major histocompatibility complex in the disease for the first time.
doi:10.1038/ncomms6751
PMCID: PMC4287989  PMID: 25569183
16.  Evaluation of a multiplex panel of immune-related markers in cervical secretions: a methodologic study 
While persistent carcinogenic human papillomvirus (HPV) infection is necessary for cervical carcinogenesis, the co-factors involved in HPV persistence and disease progression are poorly understood. Chronic cervical inflammation may increase risk, but few studies have measured immune markers (cytokines/chemokines/soluble receptors) in cervical secretions. We evaluated the performance of 74 multiplexed, bead-based immune markers in cervical secretions from three groups of women with biopsy evaluation of cervical intraepithelial neoplasia (CIN): 1) 25% detectability and >80% interclass correlation coefficients (ICC) acceptable for epidemiologic studies. Within-batch coefficients of variation (CV) of ≥25% indicated room for assay improvement. Secondarily, we explored associations between marker levels and CIN/HPV status adjusted for matching variables, assay batch, age, and number of sexual partners. Sixty-two markers (84%) had >25% detectability and ICCs>80%. Of those, 53 (85%) had CVs<25%. Using these preliminary data, we found that HPV-positivity was associated with increased eotaxin-1 (OR: 15.63, 95% CI: 1.26–200.00) and G-CSF (OR: 12.99, 95% CI: 1.10–142.86) among CIN-negative women. There was suggestive evidence that higher chemoattractant marker levels were associated with CIN2/3 (e.g., MIP-1delta, OR: 4.48, 95% CI: 0.87–23.04 versus
doi:10.1002/ijc.28354
PMCID: PMC3872247  PMID: 23824624
Background
Brain glioma is a relatively rare and fatal malignancy in adulthood with few known risk factors. Some observational studies have reported inverse associations between diabetes and subsequent glioma risk, but possible mechanisms are unclear.
Methods
We conducted a pooled analysis of original data from five nested case-control studies and two case-control studies from the U.S. and China that included 962 glioma cases and 2,195 controls. We examined self-reported diabetes history in relation to glioma risk, as well as effect modification by seven glioma risk-associated single-nucleotide polymorphisms (SNPs). We also examined the associations between 13 diabetes risk-associated SNPs, identified from genome-wide association studies, and glioma risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable-adjusted logistic regression models.
Results
We observed a 42% reduced risk of glioma for individuals with a history of diabetes (OR=0.58, 95% CI: 0.40–0.84). The association did not differ by sex, study design, or after restricting to glioblastoma, the most common histological sub-type. We did not observe any significant per-allele trends among the 13 diabetes-related SNPs examined in relation to glioma risk.
Conclusion
These results support an inverse association between diabetes history and glioma risk. The role of genetic susceptibility to diabetes cannot be excluded, and should be pursued in future studies together with other factors that might be responsible for the diabetes-glioma association.
Impact
These data suggest the need for studies that can evaluate, separately, the association between type 1 and type 2 diabetes and subsequent risk of adult glioma.
doi:10.1158/1055-9965.EPI-13-0913
PMCID: PMC3947107  PMID: 24220915
diabetes mellitus; brain cancer; glioma; cancer; epidemiology
Cancer causes & control : CCC  2013;24(7):1279-1289.
Background
Risk of developing multiple myeloma (MM) rises with age and is greater among men and blacks than among women and whites, respectively, and possibly increased among obese persons. Other risk factors remain poorly understood. By pooling data from two complementary epidemiologic studies, we assessed whether obesity, smoking, or alcohol consumption alters MM risk and whether female reproductive history might explain the lower occurrence of MM in females than males.
Methods
The Los Angeles County MM Case-Control Study (1985-92) included 278 incident cases and 278 controls, matched on age, sex, race, and neighborhood of residence at case’s diagnosis. We estimated MM risk using conditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI). In the prospective California Teachers Study (CTS), 152 women were diagnosed with incident MM between 1995-2009; we calculated hazard ratios using Cox proportional hazards analysis. Data from the two studies were pooled using a stratified, nested case-control sampling scheme (10:1 match) for the CTS; conditional logistic regression among 430 cases and 1,798 matched controls was conducted.
Results
Obesity and smoking were not associated with MM risk in the individual or combined studies. Alcohol consumption was associated with decreased MM risk among whites only (pooled OR=0.66, 95% CI=0.49-0.90) for ever vs. never drinking). Higher gravidity and parity were associated with increased MM risk, with pooled ORs of 1.38 (95% CI=1.01-1.90) for ≥3 versus 1-2 pregnancies and 1.50 (95% CI=1.09-2.06) for ≥3 versus 1-2 live births.
Conclusions
Female reproductive history may modestly alter MM risk, but appears unlikely to explain the sex disparity in incidence. Further investigation in consortial efforts is warranted.
doi:10.1007/s10552-013-0206-0
PMCID: PMC3684420  PMID: 23568533
multiple myeloma; women; reproductive; modifiable; risk factors; association; pooling; case-control; cohort; epidemiology
Cancer causes & control : CCC  2013;24(10):1885-1891.
Common variants in two of the five genetic regions recently identified from genome-wide association studies (GWAS) of risk of glioma were reported to interact with a history of allergic symptoms. In a pooled analysis of five epidemiologic studies, we evaluated the association between the five GWAS implicated gene variants and allergies and autoimmune conditions (AIC) on glioma risk (851 adult glioma cases and 3,977 controls). We further evaluated the joint effects between allergies and AIC and these gene variants on glioma risk. Risk estimates were calculated as odds ratios (OR) and 95 % confidence intervals (95 % CI), adjusted for age, gender, and study. Joint effects were evaluated by conducting stratified analyses whereby the risk associations (OR and 95 % CI) with the allergy or autoimmune conditions for glioma were evaluated by the presence or absence of the ‘at-risk’ variant, and estimated p interaction by fitting models with the main effects of allergy or autoimmune conditions and genotype and an interaction (product) term between them. Four of the five SNPs previously reported by others were statistically significantly associated with increased risk of glioma in our study (rs2736100, rs4295627, rs4977756, and rs6010620); rs498872 was not associated with glioma in our study. Reporting any allergies or AIC was associated with reduced risks of glioma (allergy: adjusted OR = 0.71, 95 % CI 0.55–0.91; AIC: adjusted OR = 0.65, 95 % CI 0.47–0.90). We did not observe differential association between allergic or autoimmune conditions and glioma by genotype, and there were no statistically significant p interactions. Stratified analysis by glioma grade (low and high grade) did not suggest risk differences by disease grade. Our results do not provide evidence that allergies or AIC modulate the association between the four GWAS-identified SNPs examined and risk of glioma.
doi:10.1007/s10552-013-0244-7
PMCID: PMC4074857  PMID: 23903690
Single-nucleotide polymorphisms; Glioma; Allergies; Autoimmune conditions; Gene–environment interaction
Milne, Roger L. | Burwinkel, Barbara | Michailidou, Kyriaki | Arias-Perez, Jose-Ignacio | Zamora, M. Pilar | Menéndez-Rodríguez, Primitiva | Hardisson, David | Mendiola, Marta | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Dennis, Joe | Wang, Qin | Bolla, Manjeet K. | Swerdlow, Anthony | Ashworth, Alan | Orr, Nick | Schoemaker, Minouk | Ko, Yon-Dschun | Brauch, Hiltrud | Hamann, Ute | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Tchatchou, Sandrine | Matsuo, Keitaro | Ito, Hidemi | Iwata, Hiroji | Tajima, Kazuo | Li, Jingmei | Brand, Judith S. | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Lambrechts, Diether | Peuteman, Gilian | Christiaens, Marie-Rose | Smeets, Ann | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katazyna | Hartman, Mikael | Hui, Miao | Yen Lim, Wei | Wan Chan, Ching | Marme, Federick | Yang, Rongxi | Bugert, Peter | Lindblom, Annika | Margolin, Sara | García-Closas, Montserrat | Chanock, Stephen J. | Lissowska, Jolanta | Figueroa, Jonine D. | Bojesen, Stig E. | Nordestgaard, Børge G. | Flyger, Henrik | Hooning, Maartje J. | Kriege, Mieke | van den Ouweland, Ans M.W. | Koppert, Linetta B. | Fletcher, Olivia | Johnson, Nichola | dos-Santos-Silva, Isabel | Peto, Julian | Zheng, Wei | Deming-Halverson, Sandra | Shrubsole, Martha J. | Long, Jirong | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Cox, Angela | Cross, Simon S. | Reed, Malcolm W.R. | Schmidt, Marjanka K. | Broeks, Annegien | Cornelissen, Sten | Braaf, Linde | Kang, Daehee | Choi, Ji-Yeob | Park, Sue K. | Noh, Dong-Young | Simard, Jacques | Dumont, Martine | Goldberg, Mark S. | Labrèche, France | Fasching, Peter A. | Hein, Alexander | Ekici, Arif B. | Beckmann, Matthias W. | Radice, Paolo | Peterlongo, Paolo | Azzollini, Jacopo | Barile, Monica | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael | Miller, Nicola | Hopper, John L. | Schmidt, Daniel F. | Makalic, Enes | Southey, Melissa C. | Hwang Teo, Soo | Har Yip, Cheng | Sivanandan, Kavitta | Tay, Wan-Ting | Shen, Chen-Yang | Hsiung, Chia-Ni | Yu, Jyh-Cherng | Hou, Ming-Feng | Guénel, Pascal | Truong, Therese | Sanchez, Marie | Mulot, Claire | Blot, William | Cai, Qiuyin | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Wu, Anna H. | Tseng, Chiu-Chen | Van Den Berg, David | Stram, Daniel O. | Bogdanova, Natalia | Dörk, Thilo | Muir, Kenneth | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Shu, Xiao-Ou | Lu, Wei | Gao, Yu-Tang | Zhang, Ben | Couch, Fergus J. | Toland, Amanda E. | Yannoukakos, Drakoulis | Sangrajrang, Suleeporn | McKay, James | Wang, Xianshu | Olson, Janet E. | Vachon, Celine | Purrington, Kristen | Severi, Gianluca | Baglietto, Laura | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Devilee, Peter | Tollenaar, Robert A.E.M. | Seynaeve, Caroline | Czene, Kamila | Eriksson, Mikael | Humphreys, Keith | Darabi, Hatef | Ahmed, Shahana | Shah, Mitul | Pharoah, Paul D.P. | Hall, Per | Giles, Graham G. | Benítez, Javier | Dunning, Alison M. | Chenevix-Trench, Georgia | Easton, Douglas F. | Berchuck, Andrew | Eeles, Rosalind A. | Olama, Ali Amin Al | Kote-Jarai, Zsofia | Benlloch, Sara | Antoniou, Antonis | McGuffog, Lesley | Offit, Ken | Lee, Andrew | Dicks, Ed | Luccarini, Craig | Tessier, Daniel C. | Bacot, Francois | Vincent, Daniel | LaBoissière, Sylvie | Robidoux, Frederic | Nielsen, Sune F. | Cunningham, Julie M. | Windebank, Sharon A. | Hilker, Christopher A. | Meyer, Jeffrey | Angelakos, Maggie | Maskiell, Judi | van der Schoot, Ellen | Rutgers, Emiel | Verhoef, Senno | Hogervorst, Frans | Boonyawongviroj, Prat | Siriwanarungsan, Pornthep | Schrauder, Michael | Rübner, Matthias | Oeser, Sonja | Landrith, Silke | Williams, Eileen | Ryder-Mills, Elaine | Sargus, Kara | McInerney, Niall | Colleran, Gabrielle | Rowan, Andrew | Jones, Angela | Sohn, Christof | Schneeweiß, Andeas | Bugert, Peter | Álvarez, Núria | Lacey, James | Wang, Sophia | Ma, Huiyan | Lu, Yani | Deapen, Dennis | Pinder, Rich | Lee, Eunjung | Schumacher, Fred | Horn-Ross, Pam | Reynolds, Peggy | Nelson, David | Ziegler, Hartwig | Wolf, Sonja | Hermann, Volker | Lo, Wing-Yee | Justenhoven, Christina | Baisch, Christian | Fischer, Hans-Peter | Brüning, Thomas | Pesch, Beate | Rabstein, Sylvia | Lotz, Anne | Harth, Volker | Heikkinen, Tuomas | Erkkilä, Irja | Aaltonen, Kirsimari | von Smitten, Karl | Antonenkova, Natalia | Hillemanns, Peter | Christiansen, Hans | Myöhänen, Eija | Kemiläinen, Helena | Thorne, Heather | Niedermayr, Eveline | Bowtell, D | Chenevix-Trench, G | deFazio, A | Gertig, D | Green, A | Webb, P | Green, A. | Parsons, P. | Hayward, N. | Webb, P. | Whiteman, D. | Fung, Annie | Yashiki, June | Peuteman, Gilian | Smeets, Dominiek | Brussel, Thomas Van | Corthouts, Kathleen | Obi, Nadia | Heinz, Judith | Behrens, Sabine | Eilber, Ursula | Celik, Muhabbet | Olchers, Til | Manoukian, Siranoush | Peissel, Bernard | Scuvera, Giulietta | Zaffaroni, Daniela | Bonanni, Bernardo | Feroce, Irene | Maniscalco, Angela | Rossi, Alessandra | Bernard, Loris | Tranchant, Martine | Valois, Marie-France | Turgeon, Annie | Heguy, Lea | Sze Yee, Phuah | Kang, Peter | Nee, Kang In | Mariapun, Shivaani | Sook-Yee, Yoon | Lee, Daphne | Ching, Teh Yew | Taib, Nur Aishah Mohd | Otsukka, Meeri | Mononen, Kari | Selander, Teresa | Weerasooriya, Nayana | staff, OFBCR | Krol-Warmerdam, E. | Molenaar, J. | Blom, J. | Brinton, Louise | Szeszenia-Dabrowska, Neonila | Peplonska, Beata | Zatonski, Witold | Chao, Pei | Stagner, Michael | Bos, Petra | Blom, Jannet | Crepin, Ellen | Nieuwlaat, Anja | Heemskerk, Annette | Higham, Sue | Cross, Simon | Cramp, Helen | Connley, Dan | Balasubramanian, Sabapathy | Brock, Ian | Luccarini, Craig | Conroy, Don | Baynes, Caroline | Chua, Kimberley
Human Molecular Genetics  2014;23(22):6096-6111.
Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04–1.10, P = 2.9 × 10−6], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03–1.07, P = 1.7 × 10−6) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07–1.12, P = 5.1 × 10−17). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05–1.10, P = 1.0 × 10−8); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04–1.07, P = 2.0 × 10−10). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.
doi:10.1093/hmg/ddu311
PMCID: PMC4204770  PMID: 24943594
Familial cancer can be used to leverage genetic association studies. Recent genome-wide association studies have reported independent associations between seven single nucleotide polymorphisms (SNPs) and risk of glioma. The aim of this study was to investigate whether glioma cases with a positive family history of brain tumours, defined as having at least one first or second degree relative with a history of brain tumour, are associated with known glioma risk loci. 1431 glioma cases and 2868 cancer-free controls were identified from four case-control studies and two prospective cohorts from USA, Sweden, and Denmark and genotyped for seven SNPs previously reported to be associated with glioma risk in case-control designed studies. Odds ratios were calculated by unconditional logistic regression. In analyses including glioma cases with a family history of brain tumours (n=104) and control subjects free of glioma at baseline, three out of seven SNPs were associated with glioma risk; rs2736100 (5p15.33, TERT), rs4977756 (9p21.3, CDKN2A-CDKN2B), and rs6010620 (20q13.33, RTEL1). After Bonferroni correction for multiple comparisons, only one marker was statistically significantly associated with glioma risk, rs6010620 (ORtrend for the minor (A) allele, 0.39; 95% CI, 0.25–0.61; Bonferroni adjusted ptrend, 1.7×10−4). In conclusion, as previously shown for glioma regardless of family history of brain tumours, rs6010620 (RTEL1) was associated with an increased risk of glioma when restricting to cases with family history of brain tumours. These findings require confirmation in further studies with a larger number of glioma cases with a family history of brain tumours.
doi:10.1002/ijc.27922
PMCID: PMC3586297  PMID: 23115063
Glioma; brain tumours; genome-wide association study; single nucleotide polymorphism
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 C H | 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. | Bertrand, Kimberly A. | Laden, Francine | Giovannucci, Edward | Kraft, Peter | Kricker, Anne | Turner, Jenny | Vajdic, Claire M. | Ennas, Maria Grazia | Ferri, Giovanni M. | Miligi, Lucia | Liang, Liming | Sampson, Joshua | Crouch, Simon | Park, Ju-hyun | North, Kari E. | Cox, Angela | Snowden, John A. | Wright, Josh | Carracedo, Angel | Lopez-Otin, Carlos | Bea, Silvia | Salaverria, Itziar | Martin, David | Campo, Elias | Fraumeni, Joseph F. | de Sanjose, Silvia | Hjalgrim, Henrik | Cerhan, James R. | Chanock, Stephen J. | Rothman, Nathaniel | Slager, Susan L.
Nature genetics  2013;45(8):868-876.
doi:10.1038/ng.2652
PMCID: PMC3729927  PMID: 23770605
Factors associated with progression from cervical intraepithelial neoplasias (CIN) grade 2 and 3 to invasive cancer are not well understood; most CIN2 and CIN3 do not progress to cancer. Among carcinogenic HPV types, infections with HPV16 have the highest risk of progressing to cancer. We evaluated the heterogeneity of risk factors, lesion size, colposcopic impression, and colposcopic biopsy results in relation to HPV16 status among 627 women with CIN2 or CIN3 in women referred to colposcopy at the University of Oklahoma. Loop excision specimens were evaluated in 12 radial segments to estimate lesion size. The mean age at CIN3 was 27.7 years for HPV16-positive women (n=225) and 33.6 years for HPV16-negative women (n=104), respectively. The average lesion size did not differ by HPV16 status (p=0.83). Among HPV16-positive women with CIN3, lesions were significantly larger in women 30 years and older (p=0.03). Colposcopic impression was worse in women with HPV16 infections (p=0.009), but the detection of CIN3 at the preceding biopsy was not improved in HPV16-positive women. CIN3 is detected at the same lesion size, but at much younger age in women with HPV16 infections, suggesting faster growth. CIN2 lesion size in women without HPV16 peaks below 30 years and then decreases, suggesting frequent regression, while HPV16-related CIN2 is more likely to persist. Lesion size seems to be the most important determinant of colposcopy and biopsy performance. Genotyping for HPV16 in cervical cancer screening can improve risk stratification, but may pose challenges to finding small lesions in colposcopy.
doi:10.1002/ijc.27577
PMCID: PMC3409928  PMID: 22488167
HPV16; CIN3; biopsy; colposcopy; screening
Epilepsia  2012;54(1):187-193.
Purpose
Studies of seizure outcome in patients undergoing serial antiepileptic drug trials have all been uncontrolled, with no account made for the spontaneous changes in disease state that could confound the elucidation of drug effects. In addition, no study has ever looked at outcome following antiepileptic drug switch in seizure-free patients, despite the fact that this is done routinely in clinical practice. We aimed to address both of these issues using a matched case-cohort design.
Methods
We followed patients taking phenytoin or carbamazepine in monotherapy for focal epilepsy who were being crossed over to a newer agent as part of studies on the metabolic effects of anticonvulsant therapy. Many had been seizure-free but were being switched nonetheless due to side effects or concerns about long-term adverse consequences. Each patient was matched with two controls of the same seizure status who were on anticonvulsant monotherapy and whose drug was not switched. Seizure freedom over the ensuing 6 months was the primary endpoint.
Key Findings
There were 43 cases and 86 matched controls. Twenty-three case patients had been seizure-free on their old drug; 5 (21.7%) had seizure recurrence after drug switch compared to 2/46 matched controls (4.3%). Twenty case patients were having seizures on their old drug; 6 (30%) entered remission after drug switch, compared to 8/40 matched controls (20%). The two groups differed at baseline in number of anticonvulsants previously failed, which was the most important factor for prognosis. After statistical adjustment to account for this, seizure-free patients had 6.53 times higher odds of seizure recurrence if switched to a new drug (95% CI 1.02 – 61.19; p=0.06). Non-seizure-free patients had 1.66 times higher odds of remission if they remained on the same drug compared to switching, though this was not significant (95% CI 0.36 – 8.42; p=0.532). Neither dose changes, nor drug mechanism, nor duration of seizure-freedom had any bearing upon the results.
Significance
While the large majority of seizure-free patients remain so when switched to another agent, about one-sixth have a recurrence attributable to the change. Conversely, our study design provides the first evidence to suggest that most improvements in drug-resistant patients are likely due to spontaneous remissions, not new drug introductions. These findings have conflicting implications for two competing models of comparative antiepileptic drug efficacy, which will require further study to elaborate.
doi:10.1111/j.1528-1167.2012.03652.x
PMCID: PMC3519976  PMID: 22931161
antiepileptic drugs; seizure recurrence; seizure remission; crossover
Cancer causes & control : CCC  2012;24(1):125-134.
Purpose
Studies of smoking and risk of non-Hodgkin lymphoma (NHL) have yielded inconsistent results, possibly due to subtype heterogeneity and/or genetic variation impacting the metabolism of tobacco-derived carcinogens, including substrates of the N-acetyltransferase enzymes NAT1 and NAT2.
Methods
We conducted a pooled analysis of 5,026 NHL cases and 4,630 controls from seven case–control studies in the international lymphoma epidemiology consortium to examine associations between smoking, variation in the N-acetyltransferase genes NAT1 and NAT2, and risk of NHL subtypes. Smoking data were harmonized across studies, and genetic variants in NAT1 and NAT2 were used to infer acetylation phenotype of the NAT1 and NAT2 enzymes, respectively. Pooled odds ratios (ORs) and 95 % confidence intervals (95 % CIs) for risk of NHL and subtypes were calculated using joint fixed effects unconditional logistic regression models.
Results
Current smoking was associated with a significant 30 % increased risk of follicular lymphoma (n = 1,176) but not NHL overall or other NHL subtypes. The association was similar among NAT2 slow (OR 1.36; 95 % CI 1.07–1.75) and intermediate/rapid (OR 1.27; 95 % CI 0.95–1.69) acetylators (pinteraction = 0.82) and also did not differ by NAT1*10 allelotype. Neither NAT2 phenotype nor NAT1*10 allelotype was associated with risk of NHL overall or NHL subtypes.
Conclusion
The current findings provide further evidence for a modest association between current smoking and follicular lymphoma risk and suggest that this association may not be influenced by variation in the N-acetyltransferase enzymes.
doi:10.1007/s10552-012-0098-4
PMCID: PMC3529854  PMID: 23160945
Non-Hodgkin lymphoma; Gene environment interaction; Cigarette smoking; N-acetyltransferase; Follicular lymphoma

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