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1.  Additive Interactions Between Susceptibility Single-Nucleotide Polymorphisms Identified in Genome-Wide Association Studies and Breast Cancer Risk Factors in the Breast and Prostate Cancer Cohort Consortium 
Joshi, Amit D. | Lindström, Sara | Hüsing, Anika | Barrdahl, Myrto | VanderWeele, Tyler J. | Campa, Daniele | Canzian, Federico | Gaudet, Mia M. | Figueroa, Jonine D. | Baglietto, Laura | Berg, Christine D. | Buring, Julie E. | Chanock, Stephen J. | Chirlaque, María-Dolores | Diver, W. Ryan | Dossus, Laure | Giles, Graham G. | Haiman, Christopher A. | Hankinson, Susan E. | Henderson, Brian E. | Hoover, Robert N. | Hunter, David J. | Isaacs, Claudine | Kaaks, Rudolf | Kolonel, Laurence N. | Krogh, Vittorio | Le Marchand, Loic | Lee, I-Min | Lund, Eiliv | McCarty, Catherine A. | Overvad, Kim | Peeters, Petra H. | Riboli, Elio | Schumacher, Fredrick | Severi, Gianluca | Stram, Daniel O. | Sund, Malin | Thun, Michael J. | Travis, Ruth C. | Trichopoulos, Dimitrios | Willett, Walter C. | Zhang, Shumin | Ziegler, Regina G. | Kraft, Peter | Joshi, Amit D. | Lindström, Sara | Hunter, David J. | Kraft, Peter | Hüsing, Anika | Barrdahl, Myrto | Kaaks, Rudolf | Kraft, Peter | VanderWeele, Tyler J. | Trichopoulos, Dimitrios | Campa, Daniele | VanderWeele, Tyler J. | Campa, Daniele | Canzian, Federico | Gaudet, Mia M. | Figueroa, Jonine D. | Chanock, Stephen J. | Hoover, Robert N. | Ziegler, Regina G. | Baglietto, Laura | Giles, Graham G. | Severi, Gianluca | Baglietto, Laura | Giles, Graham G. | Severi, Gianluca | Berg, Christine D. | Buring, Julie E. | Lee, I-Min | Zhang, Shumin | Chirlaque, María-Dolores | Chirlaque, María-Dolores | Diver, W. Ryan | Thun, Michael J. | Dossus, Laure | Dossus, Laure | Giles, Graham G. | Haiman, Christopher A. | Schumacher, Fredrick | Stram, Daniel O. | Henderson, Brian E. | Hankinson, Susan E. | Isaacs, Claudine | Kolonel, Laurence N. | Krogh, Vittorio | Marchand, Loic Le | Lund, Eiliv | McCarty, Catherine A. | Overvad, Kim | Peeters, Petra H. | Peeters, Petra H. | Riboli, Elio | Sund, Malin | Travis, Ruth C. | Trichopoulos, Dimitrios | Trichopoulos, Dimitrios | Willett, Walter C.
American Journal of Epidemiology  2014;180(10):1018-1027.
Additive interactions can have public health and etiological implications but are infrequently reported. We assessed departures from additivity on the absolute risk scale between 9 established breast cancer risk factors and 23 susceptibility single-nucleotide polymorphisms (SNPs) identified from genome-wide association studies among 10,146 non-Hispanic white breast cancer cases and 12,760 controls within the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium. We estimated the relative excess risk due to interaction and its 95% confidence interval for each pairwise combination of SNPs and nongenetic risk factors using age- and cohort-adjusted logistic regression models. After correction for multiple comparisons, we identified a statistically significant relative excess risk due to interaction (uncorrected P = 4.51 × 10−5) between a SNP in the DNA repair protein RAD51 homolog 2 gene (RAD51L1; rs10483813) and body mass index (weight (kg)/height (m)2). We also compared additive and multiplicative polygenic risk prediction models using per-allele odds ratio estimates from previous studies for breast-cancer susceptibility SNPs and observed that the multiplicative model had a substantially better goodness of fit than the additive model.
doi:10.1093/aje/kwu214
PMCID: PMC4224360  PMID: 25255808
additive interactions; breast cancer; genome-wide association studies; single-nucleotide polymorphisms
2.  Plasma Coenzyme Q10 levels and Prostate Cancer Risk: The Multiethnic Cohort Study 
Background
Coenzyme Q10 (CoQ10) is considered to be a potential anti-cancer agent, but epidemiological evidence regarding CoQ10 and prostate cancer risk is lacking. We examined the association of circulating CoQ10 levels with prostate cancer risk using pre-diagnostic blood samples.
Methods
Each of the 307 cases was individually-matched to approximately 2 controls on age, ethnicity, geographic location, date/time of specimen collection, and hours of fasting, for a total of 596 controls. Logistic regression was used to compute odds ratios and 95% confidence intervals.
Results
There was no overall statistically significant association of plasma CoQ10 levels with prostate cancer risk (Ptrend = 0.50). However, after matched sets in which controls had possible undiagnosed prostate cancer (PSA > 4.0) were excluded, the odds ratios for quintiles 2–5 were all <1.0.
Conclusions
The results suggest the possibility that moderate levels of circulating CoQ10 may be optimal for the reduction of prostate cancer risk; however, the findings were weak and not statistically significant. Since this is the first epidemiologic study of the association between CoQ10 and prostate cancer, further research on this topic is needed.
Impact
If a nutritional factor like CoQ10 were determined to reduce prostate cancer risk, it would have considerable public health significance because of the very high incidence of this cancer.
doi:10.1158/1055-9965.EPI-10-1309
PMCID: PMC4439209  PMID: 21297042
Coenzyme Q10 prostate cancer
3.  Type I and II Endometrial Cancers: Have They Different Risk Factors? 
Journal of Clinical Oncology  2013;31(20):2607-2618.
Purpose
Endometrial cancers have long been divided into estrogen-dependent type I and the less common clinically aggressive estrogen-independent type II. Little is known about risk factors for type II tumors because most studies lack sufficient cases to study these much less common tumors separately. We examined whether so-called classical endometrial cancer risk factors also influence the risk of type II tumors.
Patients and Methods
Individual-level data from 10 cohort and 14 case-control studies from the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 14,069 endometrial cancer cases and 35,312 controls were included. We classified endometrioid (n = 7,246), adenocarcinoma not otherwise specified (n = 4,830), and adenocarcinoma with squamous differentiation (n = 777) as type I tumors and serous (n = 508) and mixed cell (n = 346) as type II tumors.
Results
Parity, oral contraceptive use, cigarette smoking, age at menarche, and diabetes were associated with type I and type II tumors to similar extents. Body mass index, however, had a greater effect on type I tumors than on type II tumors: odds ratio (OR) per 2 kg/m2 increase was 1.20 (95% CI, 1.19 to 1.21) for type I and 1.12 (95% CI, 1.09 to 1.14) for type II tumors (Pheterogeneity < .0001). Risk factor patterns for high-grade endometrioid tumors and type II tumors were similar.
Conclusion
The results of this pooled analysis suggest that the two endometrial cancer types share many common etiologic factors. The etiology of type II tumors may, therefore, not be completely estrogen independent, as previously believed.
doi:10.1200/JCO.2012.48.2596
PMCID: PMC3699726  PMID: 23733771
4.  Tobacco and Alcohol in Relation to Male Breast Cancer: An Analysis of the Male Breast Cancer Pooling Project Consortium 
Background
The etiology of male breast cancer is poorly understood, partly due to its relative rarity. Although tobacco and alcohol exposures are known carcinogens, their association with male breast cancer risk remains ill-defined.
Methods
The Male Breast Cancer Pooling Project consortium provided 2,378 cases and 51,959 controls for analysis from 10 case-control and 10 cohort studies. Individual participant data were harmonized and pooled. Unconditional logistic regression was used to estimate study design-specific (case-control/cohort) odds ratios (OR) and 95% confidence intervals (CI), which were then combined using fixed effects meta-analysis.
Results
Cigarette smoking status, smoking pack-years, duration, intensity, and age at initiation were not associated with male breast cancer risk. Relations with cigar and pipe smoking, tobacco chewing, and snuff use were also null. Recent alcohol consumption and average grams of alcohol consumed per day were also not associated with risk; only one sub-analysis of very high recent alcohol consumption (>60 grams/day) was tentatively associated with male breast cancer (ORunexposed referent=1.29, 95%CI:0.97–1.71; OR>0–<7 g/day referent=1.36, 95%CI:1.04–1.77). Specific alcoholic beverage types were not associated with male breast cancer. Relations were not altered when stratified by age or body mass index.
Conclusions
In this analysis of the Male Breast Cancer Pooling Project we found little evidence that tobacco and alcohol exposures were associated with risk of male breast cancer.
Impact
Tobacco and alcohol do not appear to be carcinogenic for male breast cancer. Future studies should aim to assess these exposures in relation to subtypes of male breast cancer.
doi:10.1158/1055-9965.EPI-14-1009
PMCID: PMC4355041  PMID: 25515550
Alcohol Drinking; Breast Neoplasms; Male; Ethanol; Tobacco; Tobacco Use; Smoking
5.  Risk factors for endometrial cancer in black and white women: A pooled analysis from the Epidemiology of Endometrial Cancer Consortium (E2C2) 
Cancer causes & control : CCC  2014;26(2):287-296.
Purpose
Endometrial cancer (EC) is the most common gynecologic cancer in the United States. Over the last decade, the incidence rate has been increasing, with a larger increase among blacks. The aim of this study was to compare risk factors for EC in black and white women.
Methods
Data from 7 cohort and 4 case-control studies were pooled. Unconditional logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals for each risk factor in blacks and whites separately.
Results
Data were pooled for 2,011 black women (516 cases and 1,495 controls) and 19,297 white women (5,693 cases and 13,604 controls). BMI ≥ 30 was associated with an approximate 3-fold increase in risk of EC in both black and white women (ORblack=2.93, 95% CI: 2.11, 4.07 and ORwhite=2.99, 95% CI: 2.74, 3.26). Diabetes was associated with a 30–40% increase in risk among both groups. Increasing parity was associated with decreasing risk of EC in blacks and whites (p-value=0.02 and <0.001, respectively). Current and former smoking was associated with decreased risk of EC among all women. Both black and white women who used oral contraceptives for 10+ years were also at reduced risk of EC (OR=0.49, 95% CI: 0.27, 0.88 and OR=0.69, 95% CI: 0.58, 0.83, respectively). Previous history of hypertension was not associated with EC risk in either group.
Conclusions
The major known risk factors for EC exert similar effects on black and white women. Differences in the incidence rates between the two populations may be due to differences in the prevalence of risk factors.
doi:10.1007/s10552-014-0510-3
PMCID: PMC4528374  PMID: 25534916
endometrial neoplasms; race/ethnicity; obesity; parity; diabetes
6.  Common Breast Cancer Susceptibility Variants in LSP1 and RAD51L1 Are Associated with Mammographic Density Measures that Predict Breast Cancer Risk 
Vachon, Celine M. | Scott, Christopher G. | Fasching, Peter A. | Hall, Per | Tamimi, Rulla M. | Li, Jingmei | Stone, Jennifer | Apicella, Carmel | Odefrey, Fabrice | Gierach, Gretchen L. | Jud, Sebastian M. | Heusinger, Katharina | Beckmann, Matthias W. | Pollan, Marina | Fernández-Navarro, Pablo | González-Neira, Anna | Benítez, Javier | van Gils, Carla H. | Lokate, Mariëtte | Onland-Moret, N. Charlotte | Peeters, Petra H.M. | Brown, Judith | Leyland, Jean | Varghese, Jajini S. | Easton, Douglas F. | Thompson, Deborah J. | Luben, Robert N. | Warren, Ruth ML | Wareham, Nicholas J. | Loos, Ruth JF | Khaw, Kay-Tee | Ursin, Giske | Lee, Eunjung | Gayther, Simon A. | Ramus, Susan J. | Eeles, Rosalind A. | Leach, Martin O. | Kwan-Lim, Gek | Couch, Fergus J. | Giles, Graham G. | Baglietto, Laura | Krishnan, Kavitha | Southey, Melissa C. | Le Marchand, Loic | Kolonel, Laurence N. | Woolcott, Christy | Maskarinec, Gertraud | Haiman, Christopher A | Walker, Kate | Johnson, Nichola | McCormack, Valerie A. | Biong, Margarethe | Alnæs, Grethe I.G. | Gram, Inger Torhild | Kristensen, Vessela N. | Børresen-Dale, Anne-Lise | Lindström, Sara | Hankinson, Susan E. | Hunter, David J. | Andrulis, Irene L. | Knight, Julia A. | Boyd, Norman F. | Figueroa, Jonine D. | Lissowska, Jolanta | Wesolowska, Ewa | Peplonska, Beata | Bukowska, Agnieszka | Reszka, Edyta | Liu, JianJun | Eriksson, Louise | Czene, Kamila | Audley, Tina | Wu, Anna H. | Pankratz, V. Shane | Hopper, John L. | dos-Santos-Silva, Isabel
Background
Mammographic density adjusted for age and body mass index (BMI) is a heritable marker of breast cancer susceptibility. Little is known about the biological mechanisms underlying the association between mammographic density and breast cancer risk. We examined whether common low-penetrance breast cancer susceptibility variants contribute to inter-individual differences in mammographic density measures.
Methods
We established an international consortium (DENSNP) of 19 studies from 10 countries, comprising 16,895 Caucasian women, to conduct a pooled cross-sectional analysis of common breast cancer susceptibility variants in 14 independent loci and mammographic density measures. Dense and non-dense areas, and percent density, were measured using interactive-thresholding techniques. Mixed linear models were used to assess the association between genetic variants and the square roots of mammographic density measures adjusted for study, age, case status, body mass index (BMI) and menopausal status.
Results
Consistent with their breast cancer associations, the C-allele of rs3817198 in LSP1 was positively associated with both adjusted dense area (p=0.00005) and adjusted percent density (p=0.001) whereas the A-allele of rs10483813 in RAD51L1 was inversely associated with adjusted percent density (p=0.003), but not with adjusted dense area (p=0.07).
Conclusion
We identified two common breast cancer susceptibility variants associated with mammographic measures of radio-dense tissue in the breast gland.
Impact
We examined the association of 14 established breast cancer susceptibility loci with mammographic density phenotypes within a large genetic consortium and identified two breast cancer susceptibility variants, LSP1-rs3817198 and RAD51L1-rs10483813, associated with mammographic measures and in the same direction as the breast cancer association.
doi:10.1158/1055-9965.EPI-12-0066
PMCID: PMC3569092  PMID: 22454379
breast density; breast cancer; genetics; biomarkers; mammography
7.  Obesity and breast cancer survival in ethnically diverse postmenopausal women: The Multiethnic Cohort Study 
Breast cancer survival has been found to be lower in obese women, but few studies have evaluated ethnic variations in this association. This study examined all-cause and breast cancer-specific survival by body mass index (BMI) in the Multiethnic Cohort (MEC) study for African American, Native Hawaiian, Japanese American, Latino, and Caucasian women. Female MEC participants free of breast cancer, aged ≥ 50 years at cohort entry, and diagnosed with primary invasive breast cancer during follow-up were included in the analyses (n = 3,842). Cox proportional hazards regression was used to estimate the effect of pre-diagnostic adult BMI (<22.5, 22.5–24.9, 25.0–29.9, ≥30 kg/m2) on the risk of mortality. Mean age at diagnosis was 68.8 years (range 50–89 years). During a mean follow-up of 6.2 ± 3.8 years after diagnosis, there were 804 deaths that included 376 breast cancer-specific deaths. After adjustment for breast cancer characteristics, including hormone receptor status, stage at diagnosis, and treatment, obese women had a higher risk of all-cause [hazard ratio (HR) = 1.54; 95% confidence interval (CI): 1.23, 1.91] and breast cancer-specific (HR = 1.45; 95% CI: 1.05, 2.00) mortality compared to women with high-normal BMI; however, being overweight did not affect survival. There was no evidence of ethnic differences in the BMI effect on all-cause (Pinteraction = 0.87) or breast cancer-specific (Pinteraction = 0.63) mortality. Our findings are consistent with the literature that maintaining moderate weight throughout adult life may be beneficial for breast cancer survival in women and this appears to hold for all ethnic groups.
doi:10.1007/s10549-011-1468-4
PMCID: PMC3164157  PMID: 21499688
Breast carcinoma; ethnicity; obesity; survival; prognosis
8.  A priori-defined Diet Quality Indexes and Risk of Type 2 diabetes: The Multiethnic Cohort 
Diabetologia  2014;58(1):98-112.
Aim
Dietary patterns have been associated with type 2 diabetes incidence, but little is known about the impact of ethnicity on this relation. This study evaluated the association of four a priori dietary quality indexes and type 2 diabetes risk among whites, Japanese Americans, and Native Hawaiians in the Hawaii component of the Multiethnic Cohort (MEC).
Methods
After excluding participants with prevalent diabetes and missing values, the analysis included 89,185 participants (11,217 cases). Dietary intake was assessed at baseline with a quantitative food frequency questionnaire designed for use in the relevant ethnic populations. Sex- and ethnicity-specific hazard ratios were calculated for the Healthy Eating Index-2010 (HEI-2010), the alternative HEI-2010 (AHEI-2010), the alternate Mediterranean diet score (aMED), and the Dietary Approaches to Stop Hypertension (DASH).
Results
We observed significant inverse associations between higher scores of the DASH index and type 2 diabetes risk in white men and women, as well as in Japanese American women and Native Hawaiian men with respective risk reductions of 37, 31, 19 and 21% (highest compared to lowest index category). A higher adherence to the AHEI-2010 and aMED diet was related to a 13–28% lower type 2 diabetes risk in white participants but not in other ethnic groups. No significant associations with type 2 diabetes risk were observed for the HEI-2010 index.
Conclusions
The small ethnic differences in type 2 diabetes risk associated with scores of a priori-defined dietary patterns may be due to different consumption patterns of food components and the fact that the original indexes were not based on Asians and Pacific Islanders.
doi:10.1007/s00125-014-3404-8
PMCID: PMC4258157  PMID: 25319012
Alternative Healthy Eating Index; Healthy Eating Index; Alternate Mediterranean diet score; Dietary Approaches to Stop Hypertension; Dietary patterns; Multiethnic Cohort; Type 2 diabetes
9.  Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33 
Wang, Zhaoming | Zhu, Bin | Zhang, Mingfeng | Parikh, Hemang | Jia, Jinping | Chung, Charles C. | Sampson, Joshua N. | Hoskins, Jason W. | Hutchinson, Amy | Burdette, Laurie | Ibrahim, Abdisamad | Hautman, Christopher | Raj, Preethi S. | Abnet, Christian C. | Adjei, Andrew A. | Ahlbom, Anders | Albanes, Demetrius | Allen, Naomi E. | Ambrosone, Christine B. | Aldrich, Melinda | Amiano, Pilar | Amos, Christopher | Andersson, Ulrika | Andriole, Gerald | Andrulis, Irene L. | Arici, Cecilia | Arslan, Alan A. | Austin, Melissa A. | Baris, Dalsu | Barkauskas, Donald A. | Bassig, Bryan A. | Beane Freeman, Laura E. | Berg, Christine D. | Berndt, Sonja I. | Bertazzi, Pier Alberto | Biritwum, Richard B. | Black, Amanda | Blot, William | Boeing, Heiner | Boffetta, Paolo | Bolton, Kelly | Boutron-Ruault, Marie-Christine | Bracci, Paige M. | Brennan, Paul | Brinton, Louise A. | Brotzman, Michelle | Bueno-de-Mesquita, H. Bas | Buring, Julie E. | Butler, Mary Ann | Cai, Qiuyin | Cancel-Tassin, Geraldine | Canzian, Federico | Cao, Guangwen | Caporaso, Neil E. | Carrato, Alfredo | Carreon, Tania | Carta, Angela | Chang, Gee-Chen | Chang, I-Shou | Chang-Claude, Jenny | Che, Xu | Chen, Chien-Jen | Chen, Chih-Yi | Chen, Chung-Hsing | Chen, Constance | Chen, Kuan-Yu | Chen, Yuh-Min | Chokkalingam, Anand P. | Chu, Lisa W. | Clavel-Chapelon, Francoise | Colditz, Graham A. | Colt, Joanne S. | Conti, David | Cook, Michael B. | Cortessis, Victoria K. | Crawford, E. David | Cussenot, Olivier | Davis, Faith G. | De Vivo, Immaculata | Deng, Xiang | Ding, Ti | Dinney, Colin P. | Di Stefano, Anna Luisa | Diver, W. Ryan | Duell, Eric J. | Elena, Joanne W. | Fan, Jin-Hu | Feigelson, Heather Spencer | Feychting, Maria | Figueroa, Jonine D. | Flanagan, Adrienne M. | Fraumeni, Joseph F. | Freedman, Neal D. | Fridley, Brooke L. | Fuchs, Charles S. | Gago-Dominguez, Manuela | Gallinger, Steven | Gao, Yu-Tang | Gapstur, Susan M. | Garcia-Closas, Montserrat | Garcia-Closas, Reina | Gastier-Foster, Julie M. | Gaziano, J. Michael | Gerhard, Daniela S. | Giffen, Carol A. | Giles, Graham G. | Gillanders, Elizabeth M. | Giovannucci, Edward L. | Goggins, Michael | Gokgoz, Nalan | Goldstein, Alisa M. | Gonzalez, Carlos | Gorlick, Richard | Greene, Mark H. | Gross, Myron | Grossman, H. Barton | Grubb, Robert | Gu, Jian | Guan, Peng | Haiman, Christopher A. | Hallmans, Goran | Hankinson, Susan E. | Harris, Curtis C. | Hartge, Patricia | Hattinger, Claudia | Hayes, Richard B. | He, Qincheng | Helman, Lee | Henderson, Brian E. | Henriksson, Roger | Hoffman-Bolton, Judith | Hohensee, Chancellor | Holly, Elizabeth A. | Hong, Yun-Chul | Hoover, Robert N. | Hosgood, H. Dean | Hsiao, Chin-Fu | Hsing, Ann W. | Hsiung, Chao Agnes | Hu, Nan | Hu, Wei | Hu, Zhibin | Huang, Ming-Shyan | Hunter, David J. | Inskip, Peter D. | Ito, Hidemi | Jacobs, Eric J. | Jacobs, Kevin B. | Jenab, Mazda | Ji, Bu-Tian | Johansen, Christoffer | Johansson, Mattias | Johnson, Alison | Kaaks, Rudolf | Kamat, Ashish M. | Kamineni, Aruna | Karagas, Margaret | Khanna, Chand | Khaw, Kay-Tee | Kim, Christopher | Kim, In-Sam | Kim, Jin Hee | Kim, Yeul Hong | Kim, Young-Chul | Kim, Young Tae | Kang, Chang Hyun | Jung, Yoo Jin | Kitahara, Cari M. | Klein, Alison P. | Klein, Robert | Kogevinas, Manolis | Koh, Woon-Puay | Kohno, Takashi | Kolonel, Laurence N. | Kooperberg, Charles | Kratz, Christian P. | Krogh, Vittorio | Kunitoh, Hideo | Kurtz, Robert C. | Kurucu, Nilgun | Lan, Qing | Lathrop, Mark | Lau, Ching C. | Lecanda, Fernando | Lee, Kyoung-Mu | Lee, Maxwell P. | Le Marchand, Loic | Lerner, Seth P. | Li, Donghui | Liao, Linda M. | Lim, Wei-Yen | Lin, Dongxin | Lin, Jie | Lindstrom, Sara | Linet, Martha S. | Lissowska, Jolanta | Liu, Jianjun | Ljungberg, Börje | Lloreta, Josep | Lu, Daru | Ma, Jing | Malats, Nuria | Mannisto, Satu | Marina, Neyssa | Mastrangelo, Giuseppe | Matsuo, Keitaro | McGlynn, Katherine A. | McKean-Cowdin, Roberta | McNeill, Lorna H. | McWilliams, Robert R. | Melin, Beatrice S. | Meltzer, Paul S. | Mensah, James E. | Miao, Xiaoping | Michaud, Dominique S. | Mondul, Alison M. | Moore, Lee E. | Muir, Kenneth | Niwa, Shelley | Olson, Sara H. | Orr, Nick | Panico, Salvatore | Park, Jae Yong | Patel, Alpa V. | Patino-Garcia, Ana | Pavanello, Sofia | Peeters, Petra H. M. | Peplonska, Beata | Peters, Ulrike | Petersen, Gloria M. | Picci, Piero | Pike, Malcolm C. | Porru, Stefano | Prescott, Jennifer | Pu, Xia | Purdue, Mark P. | Qiao, You-Lin | Rajaraman, Preetha | Riboli, Elio | Risch, Harvey A. | Rodabough, Rebecca J. | Rothman, Nathaniel | Ruder, Avima M. | Ryu, Jeong-Seon | Sanson, Marc | Schned, Alan | Schumacher, Fredrick R. | Schwartz, Ann G. | Schwartz, Kendra L. | Schwenn, Molly | Scotlandi, Katia | Seow, Adeline | Serra, Consol | Serra, Massimo | Sesso, Howard D. | Severi, Gianluca | Shen, Hongbing | Shen, Min | Shete, Sanjay | Shiraishi, Kouya | Shu, Xiao-Ou | Siddiq, Afshan | Sierrasesumaga, Luis | Sierri, Sabina | Loon Sihoe, Alan Dart | Silverman, Debra T. | Simon, Matthias | Southey, Melissa C. | Spector, Logan | Spitz, Margaret | Stampfer, Meir | Stattin, Par | Stern, Mariana C. | Stevens, Victoria L. | Stolzenberg-Solomon, Rachael Z. | Stram, Daniel O. | Strom, Sara S. | Su, Wu-Chou | Sund, Malin | Sung, Sook Whan | Swerdlow, Anthony | Tan, Wen | Tanaka, Hideo | Tang, Wei | Tang, Ze-Zhang | Tardon, Adonina | Tay, Evelyn | Taylor, Philip R. | Tettey, Yao | Thomas, David M. | Tirabosco, Roberto | Tjonneland, Anne | Tobias, Geoffrey S. | Toro, Jorge R. | Travis, Ruth C. | Trichopoulos, Dimitrios | Troisi, Rebecca | Truelove, Ann | Tsai, Ying-Huang | Tucker, Margaret A. | Tumino, Rosario | Van Den Berg, David | Van Den Eeden, Stephen K. | Vermeulen, Roel | Vineis, Paolo | Visvanathan, Kala | Vogel, Ulla | Wang, Chaoyu | Wang, Chengfeng | Wang, Junwen | Wang, Sophia S. | Weiderpass, Elisabete | Weinstein, Stephanie J. | Wentzensen, Nicolas | Wheeler, William | White, Emily | Wiencke, John K. | Wolk, Alicja | Wolpin, Brian M. | Wong, Maria Pik | Wrensch, Margaret | Wu, Chen | Wu, Tangchun | Wu, Xifeng | Wu, Yi-Long | Wunder, Jay S. | Xiang, Yong-Bing | Xu, Jun | Yang, Hannah P. | Yang, Pan-Chyr | Yatabe, Yasushi | Ye, Yuanqing | Yeboah, Edward D. | Yin, Zhihua | Ying, Chen | Yu, Chong-Jen | Yu, Kai | Yuan, Jian-Min | Zanetti, Krista A. | Zeleniuch-Jacquotte, Anne | Zheng, Wei | Zhou, Baosen | Mirabello, Lisa | Savage, Sharon A. | Kraft, Peter | Chanock, Stephen J. | Yeager, Meredith | Landi, Maria Terese | Shi, Jianxin | Chatterjee, Nilanjan | Amundadottir, Laufey T.
Human Molecular Genetics  2014;23(24):6616-6633.
Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10−39; Region 3: rs2853677, P = 3.30 × 10−36 and PConditional = 2.36 × 10−8; Region 4: rs2736098, P = 3.87 × 10−12 and PConditional = 5.19 × 10−6, Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10−6; and Region 6: rs10069690, P = 7.49 × 10−15 and PConditional = 5.35 × 10−7) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10−18 and PConditional = 7.06 × 10−16). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
doi:10.1093/hmg/ddu363
PMCID: PMC4240198  PMID: 25027329
10.  No evidence of gene-calcium interactions from genome-wide analysis of colorectal cancer risk 
Background
Calcium intake may reduce risk of colorectal cancer (CRC), but the mechanisms remain unclear. Studies of interaction between calcium intake and single nucleotide polymorphisms (SNPs) in calcium-related pathways have yielded inconsistent results.
Methods
To identify gene-calcium interactions, we tested interactions between ~2.7 million SNPs across the genome with self-reported calcium intake (from dietary or supplemental sources) in 9,006 CRC cases and 9,503 controls of European ancestry. To test for multiplicative interactions, we used multivariable logistic regression and defined statistical significance using the conventional genome-wide α=5E-08.
Results
After accounting for multiple comparisons, there were no statistically significant SNP-interactions with total, dietary, or supplemental calcium intake.
Conclusions
We found no evidence of SNP-interactions with calcium intake for CRC risk in a large population of 18,509 individuals.
Impact
These results suggest that in genome-wide analysis common genetic variants do not strongly modify the association between calcium intake and CRC in European populations.
doi:10.1158/1055-9965.EPI-14-0893
PMCID: PMC4257872  PMID: 25192705
11.  Obesity and Non-Hodgkin Lymphoma Survival in an Ethnically Diverse Population: The Multiethnic Cohort Study 
Cancer causes & control : CCC  2014;25(11):1449-1459.
Purpose
Obesity increases mortality for several malignancies, but for non-Hodgkin lymphoma (NHL) the association between body mass index (BMI) and survival is unclear. We examined the association of pre-diagnostic BMI with overall and NHL-specific survival in the Multiethnic Cohort (MEC) study of African Americans, Native Hawaiians, Japanese Americans, Latinos, and Caucasians.
Methods
MEC participants free of NHL at cohort entry and diagnosed with NHL during follow-up were included in the analyses (N=1331). BMI was based on self-reported weight and height at cohort entry and after 6.1 years of cohort entry. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) with BMI as time-varying exposure in relation to all-cause and NHL-specific mortality while adjusting for known confounders.
Results
The mean age at NHL diagnosis was 70.5 (range 45–89) years. After a mean follow-up of 4.3±3.5 years, 667 deaths including 450 NHL-specific deaths occurred. In multivariable models, obese patients (BMI ≥30.0 kg/m2) had higher all-cause (HR=1.46, 95%CI 1.13–1.87) and NHL-specific (HR=1.77, 95%CI 1.30–2.41) mortality compared to patients with high-normal BMI (22.5–24.9 kg/m2). For overweight patients (BMI=25.0–29.9 kg/m2), the respective HRs were 1.21 (95%CI 0.99–1.49) and 1.36 (95%CI 1.06–1.75). Cases with low-normal BMI (<22.5 kg/m2) experienced a significant 45% higher all-cause and a 40% higher NHL-specific mortality. After stratification by NHL type, the adverse effect of BMI was stronger for chronic lymphocytic leukemia/small lymphocytic lymphoma than for diffuse large B-cell lymphoma and follicular lymphoma.
Conclusions
Pre-diagnostic BMI may be a suitable prognostic marker for NHL patients.
doi:10.1007/s10552-014-0447-6
PMCID: PMC4230453  PMID: 25070667
Non-Hodgkin Lymphoma; Ethnicity; Obesity; Survival; Prognosis
12.  Ethnic differences in serum adipokine and C-reactive protein levels: The Multiethnic Cohort 
Background
Ethnic disparities in metabolic disease risk may be the result of differences in circulating adipokines and inflammatory markers related to ethnic variations in obesity and body fat distribution.
Subjects/Methods
In a cross-sectional design, we compared serum levels of leptin, adiponectin, C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in control subjects (321 men and 930 women) from two nested case-control studies conducted within the Multiethnic Cohort Study consisting of whites, Japanese Americans (JA), Latinos, African Americans (AA), and Native Hawaiians (NH). General linear models were applied to evaluate ethnic differences in log-transformed serum biomarker levels before and after adjusting for body mass index (BMI) at cohort entry.
Results
In comparison to whites, significant ethnic differences were observed for all biomarkers except TNF-α. JA men and women had significantly lower leptin and CRP levels than whites and JA women also had lower adiponectin levels. Leptin was significantly higher in AA women (p<0.01), adiponectin was significantly lower in AA men and women (p=0.02 and p<0.001), and CRP and IL-6 were significantly higher in AA men and women. Lower adiponectin (p<0.0001) and CRP (p=0.03) levels were the only biomarkers in NH women that differed from whites; no statistically significant differences were seen for NH men and for Latino men and women. When adjusted for BMI at cohort entry, the differences between the lowest and highest values across ethnic groups decreased for all biomarkers except adiponectin in men indicating that ethnic differences were partially due to weight status.
Conclusions
These findings demonstrate ethnic variations in circulating adipokine and CRP levels before and after adjustment for BMI. Given the limitation of BMI as a general measure of obesity, further investigation with visceral and subcutaneous adiposity measures are warranted to elucidate ethnicity-related differences in adiposity in relation to disparities in obesity-related disease risk.
doi:10.1038/ijo.2014.25
PMCID: PMC4247246  PMID: 24522245
body mass index; ethnicity; leptin; adiponectin; inflammatory markers; C-reactive protein
13.  A comprehensive examination of breast cancer risk loci in African American women 
Human Molecular Genetics  2014;23(20):5518-5526.
Genome-wide association studies have identified 73 breast cancer risk variants mainly in European populations. Given considerable differences in linkage disequilibrium structure between populations of European and African ancestry, the known risk variants may not be informative for risk in African ancestry populations. In a previous fine-mapping investigation of 19 breast cancer loci, we were able to identify SNPs in four regions that better captured risk associations in African American women. In this study of breast cancer in African American women (3016 cases, 2745 controls), we tested an additional 54 novel breast cancer risk variants. Thirty-eight variants (70%) were found to have an association with breast cancer in the same direction as previously reported, with eight (15%) replicating at P < 0.05. Through fine-mapping, in three regions (1q32, 3p24, 10q25), we identified variants that better captured associations with overall breast cancer or estrogen receptor positive disease. We also observed suggestive associations with variants (at P < 5 × 10−6) in three separate regions (6q25, 14q13, 22q12) that may represent novel risk variants. Directional consistency of association observed for ∼65–70% of currently known genetic variants for breast cancer in women of African ancestry implies a shared functional common variant at most loci. To validate and enhance the spectrum of alleles that define associations at the known breast cancer risk loci, as well as genome-wide, will require even larger collaborative efforts in women of African ancestry.
doi:10.1093/hmg/ddu252
PMCID: PMC4168823  PMID: 24852375
14.  Parity, Lactation, and Breast Cancer Subtypes in African American Women: Results from the AMBER Consortium 
Background
African American (AA) women have a disproportionately high incidence of estrogen receptor–negative (ER-) breast cancer, a subtype with a largely unexplained etiology. Because childbearing patterns also differ by race/ethnicity, with higher parity and a lower prevalence of lactation in AA women, we investigated the relation of parity and lactation to risk of specific breast cancer subtypes.
Methods
Questionnaire data from two cohort and two case-control studies of breast cancer in AA women were combined and harmonized. Case patients were classified as ER+ (n = 2446), ER- (n = 1252), or triple negative (ER-, PR-, HER2-; n = 567) based on pathology data; there were 14180 control patients. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated in polytomous logistic regression analysis with adjustment for study, age, reproductive and other risk factors.
Results
ORs for parity relative to nulliparity was 0.92 (95% CI = 0.81 to 1.03) for ER+, 1.33 (95% CI = 1.11 to 1.59) for ER-, and 1.37 (95% CI = 1.06 to 1.70) for triple-negative breast cancer. Lactation was associated with a reduced risk of ER- (OR = 0.81, 95% CI = 0.69 to 0.95) but not ER+ cancer. ER- cancer risk increased with each additional birth in women who had not breastfed, with an OR of 1.68 (95% CI = 1.15 to 2.44) for 4 or more births relative to one birth with lactation.
Conclusions
The findings suggest that parous women who have not breastfed are at increased risk of ER- and triple-negative breast cancer. Promotion of lactation may be an effective tool for reducing occurrence of the subtypes that contribute disproportionately to breast cancer mortality.
doi:10.1093/jnci/dju237
PMCID: PMC4271113  PMID: 25224496
15.  A pooled analysis of body mass index and pancreatic cancer mortality in African Americans 
Background
Pancreatic cancer is a leading cause of cancer-related mortality in the U.S. and both incidence and mortality are highest in African Americans. Obesity is also disproportionately high in African Americans, but limited data are available on the relation of obesity to pancreatic cancer in this population.
Methods
Seven large prospective cohort studies pooled data from African American participants. Body mass index (BMI) was calculated from self-reported height and weight at baseline. Cox regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for levels of BMI relative to BMI 18.5–24.9, with adjustment for covariates. Primary analyses were restricted to participants with ≥5 years of follow-up because weight loss prior to diagnosis may have influenced baseline BMI in cases who died during early follow-up.
Results
In follow-up of 239,597 participants, 897 pancreatic cancer deaths occurred. HRs were 1.08 (95% CI, 0.90–1.31) for BMI 25.0–29.9, 1.25 (95% CI, 0.99–1.57) for BMI 30.0–34.9, and 1.31 (95% CI, 0.97–1.77) for BMI ≥35.0 among those with ≥5 years of follow-up (Ptrend = 0.03). The association was evident among both sexes and was independent of a history of diabetes. A stronger association was observed among never-smokers (BMI ≥30 vs. referent: HR = 1.44; 95% CI, 1.02–2.03) than among smokers (HR = 1.16; 95% CI, 0.87–1.54; Pinteraction = 0.02).
Conclusion
The findings suggest that obesity is independently associated with increased pancreatic cancer mortality in African Americans.
Impact
Interventions to reduce obesity may also reduce risk of pancreatic cancer mortality, particularly among never-smokers.
doi:10.1158/1055-9965.EPI-14-0422
PMCID: PMC4184984  PMID: 25017247
body mass index; obesity; pancreatic cancer mortality; African American
16.  Dietary isoflavone intake is not statistically significantly associated with breast cancer risk in the Multiethnic Cohort 
The British journal of nutrition  2014;112(6):976-983.
Given high soy intake and low incidence rates in Asian countries, isoflavones, substances with an estrogen-like structure occurring principally in soybeans, are postulated to be cancer-protective. We examined the association of dietary isoflavone intake with breast cancer risk in 84,450 women (896 in situ and 3,873 invasive cases) who were part of the Multiethnic Cohort (Japanese Americans, whites, Latinos, African Americans, and Native Hawaiians) with wide ranges of soy intake. The absolute amount of dietary isoflavone consumption estimated from a baseline food frequency questionnaire was categorized into quartiles, with the top quartile further subdivided to examine high dietary intake. The respective intakes for the quartiles (Q1, Q2, Q3, lower and upper Q4s) were 0-<3.2, 3.2-<6.7, 6.7-<12.9, 12.9-<20.3, and 20.3-178.7 mg/day. After a mean follow-up of 13 years, hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression stratified by age and adjusted for known confounders. Linear trends were tested by modeling continuous variables of interest assigned the median value within the corresponding quartile. We observed no statistically significant association between dietary isoflavone intake and overall breast cancer risk (HR [and 95% CI] for upper Q4 vs. Q1: 0.96 [0.85-1.08]; P-trend=0.40). While the test for interaction was not significant (P=0.14), stratified analyses suggested possible ethnic/racial differences in risk estimates, with a suggestion that higher isoflavone intake may be protective in Latina, African American, and Japanese American women. These results agree with previous meta-analyses showing no protection at low intake levels but suggesting inverse associations in high-soy consuming populations.
doi:10.1017/S0007114514001780
PMCID: PMC4237401  PMID: 25201305
isoflavones; breast cancer; ethnicity; prospective cohort
17.  Dietary n-3 polyunsaturated fatty acid intake and risk of amyotrophic lateral sclerosis 
JAMA neurology  2014;71(9):1102-1110.
Importance
Amyotrophic lateral sclerosis (ALS) is a severe progressive disease that cannot be prevented or cured. Diet-derived long chain polyunsaturated fatty acids (PUFA) are incorporated in brain lipids and modulate oxidative and inflammatory processes, and could thus affect ALS risk and progression.
Objective
To examine the association between n-6 and n-3 PUFA consumption and ALS risk.
Design, setting, and participants
Longitudinal analyses based on 1,002,082 participants (479,114 women; 522,968 men) in five prospective cohorts: the National Institutes of Health-AARP Diet and Health Study, the Cancer Prevention Study II Nutrition Cohort, the Health Professionals Follow-up Study, the Multiethnic Cohort Study, and the Nurses’ Health Study. Diet was assessed via food frequency questionnaire developed or modified for each cohort. Participants were categorized into cohort-specific quintiles of intake of energy-adjusted dietary variables.
Main outcomes and measures
Cohort-specific multivariable-adjusted risk ratios (RR) of ALS incidence or death estimated by Cox proportional hazards regression and pooled using random-effects methods.
Results
A total of 995 ALS cases were documented during the follow-up. A greater n-3 PUFA intake was associated with a reduced risk of ALS – the pooled, multivariable-adjusted RR for the highest to the lowest quintile was 0.66 (95% CI: 0.53–0.81; P trend<0.001). Consumption of both α-linolenic acid (RR = 0.73; 95% CI: 0.59 to 0.89; P trend=0.003) and marine n-3 PUFAs (RR=0.84; 95% CI: 0.65–1.08, P trend=0.03) contributed to this inverse association. Intakes of n-6 PUFA were not associated with ALS risk.
Conclusion and relevance
Consumption of foods high in n-3 PUFAs may help prevent or delay onset of ALS.
doi:10.1001/jamaneurol.2014.1214
PMCID: PMC4160351  PMID: 25023276
18.  Gene-environment interaction involving recently identified colorectal cancer susceptibility loci 
BACKGROUND
Genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) that are associated with risk of colorectal cancer (CRC). Prior research has evaluated the presence of gene-environment interaction involving the first 10 identified susceptibility loci, but little work has been conducted on interaction involving SNPs at recently identified susceptibility loci, including: rs10911251, rs6691170, rs6687758, rs11903757, rs10936599, rs647161, rs1321311, rs719725, rs1665650, rs3824999, rs7136702, rs11169552, rs59336, rs3217810, rs4925386, and rs2423279.
METHODS
Data on 9160 cases and 9280 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and Colon Cancer Family Registry (CCFR) were used to evaluate the presence of interaction involving the above-listed SNPs and sex, body mass index (BMI), alcohol consumption, smoking, aspirin use, post-menopausal hormone (PMH) use, as well as intake of dietary calcium, dietary fiber, dietary folate, red meat, processed meat, fruit, and vegetables. Interaction was evaluated using a fixed-effects meta-analysis of an efficient Empirical Bayes estimator, and permutation was used to account for multiple comparisons.
RESULTS
None of the permutation-adjusted p-values reached statistical significance.
CONCLUSIONS
The associations between recently identified genetic susceptibility loci and CRC are not strongly modified by sex, BMI, alcohol, smoking, aspirin, PMH use, and various dietary factors.
IMPACT
Results suggest no evidence of strong gene-environment interactions involving the recently identified 16 susceptibility loci for CRC taken one at a time.
doi:10.1158/1055-9965.EPI-14-0062
PMCID: PMC4209726  PMID: 24994789
Colorectal Cancer; Gene-Environment Interaction; Polymorphism; Single Nucleotide; Genetic Predisposition to Disease; Diet
19.  Estimating the heritability of colorectal cancer 
Human Molecular Genetics  2014;23(14):3898-3905.
A sizable fraction of colorectal cancer (CRC) is expected to be explained by heritable factors, with heritability estimates ranging from 12 to 35% twin and family studies. Genome-wide association studies (GWAS) have successfully identified a number of common single-nucleotide polymorphisms (SNPs) associated with CRC risk. Although it has been shown that these CRC susceptibility SNPs only explain a small proportion of the genetic risk, it is not clear how much of the heritability these SNPs explain and how much is left to be detected by other, yet to be identified, common SNPs. Therefore, we estimated the heritability of CRC under different scenarios using Genome-Wide Complex Trait Analysis in the Genetics and Epidemiology of Colorectal Cancer Consortium including 8025 cases and 10 814 controls. We estimated that the heritability explained by known common CRC SNPs identified in GWAS was 0.65% (95% CI:0.3–1%; P = 1.11 × 10−16), whereas the heritability explained by all common SNPs was at least 7.42% (95% CI: 4.71–10.12%; P = 8.13 × 10−8), suggesting that many common variants associated with CRC risk remain to be detected. Comparing the heritability explained by the common variants with that from twin and family studies, a fraction of the heritability may be explained by other genetic variants, such as rare variants. In addition, our analysis showed that the gene × smoking interaction explained a significant proportion of the CRC variance (P = 1.26 × 10−2). In summary, our results suggest that known CRC SNPs only explain a small proportion of the heritability and more common SNPs have yet to be identified.
doi:10.1093/hmg/ddu087
PMCID: PMC4065150  PMID: 24562164
20.  Dietary Fat and Breast Cancer in Postmenopausal Women According to Ethnicity and Hormone Receptor Status: The Multiethnic Cohort Study 
Dietary fat has been widely studied as a risk factor for breast cancer, with little consistency in results. The Multiethnic Cohort Study (MEC) provides an opportunity to assess this relationship for possible hetero-geneity across different racial/ethnic groups, as well as by stratification on several other variables associated with risk. Therefore, we investigated the associations between dietary fat, overall and by type, and breast cancer risk among 85,089 postmenopausal women who entered the MEC by completing a comprehensive dietary questionnaire in 1993 to 1996. During a mean follow-up of 12 years, 3,885 incident invasive breast cancer cases were identified. The multivariate HR [95% confidence interval (CI)] for the highest versus lowest quintile of intake was 0.94 (95% CI, 0.85–1.05) for total fat and 0.93 (95% CI, 0.83–1.04) for saturated fat. Other specific types of dietary fat, including individual fatty acids, were not related to risk of postmenopausal breast cancer. We found no heterogeneity in these null findings across the five ethnic groups. Furthermore, we found no evidence that the association between dietary fat and postmenopausal breast cancer risk differed by estrogen/progesterone receptor status, tumor stage, body mass index, hormone replacement therapy use, follow-up period, family history of breast cancer, and smoking status at baseline. In conclusion, this comprehensive prospective analysis in the MEC does not support a role of adult intake of dietary fat in the etiology of postmenopausal breast cancer.
doi:10.1158/1940-6207.CAPR-11-0260
PMCID: PMC4495954  PMID: 22166249
21.  Genetic Variants, Prediagnostic Circulating Levels of Insulin-like Growth Factors, Insulin, and Glucose and the Risk of Colorectal Cancer: The Multiethnic Cohort Study 
Background
Increased exposure of colonic and rectal epithelial cells to the promitotic and antiapoptotic effects of insulin and insulin-like growth factors (IGF) is hypothesized to increase colorectal cancer risk.
Methods
In a case–control study nested within the Multiethnic Cohort, we attempted to replicate associations for five genetic variants associated with IGF system biomarkers, insulin, or glucose and to examine their association with the risk of colorectal cancer. In a subset of participants, the association between circulating biomarkers and colorectal cancer risk was examined. Unconditional logistic regression was used to calculate ORs and 95% confidence intervals (CI) for genetic variants (1,954 cases/2,587 controls) and serum biomarkers (258 cases/1,701 controls).
Results
Associations with circulating biomarkers were replicated in the Multiethnic Cohort for IGF1 rs35767 and for IGFBP3 rs2854744, rs2854746, and rs3110697 (P < 0.05). Homozygous carriers of the glucokinase regulator (GCKR) rs780094 variant T-allele were at a decreased risk of colorectal cancer (OR, 0.77; 95% CI, 0.64–0.92). In risk factor–adjusted models, participants with the highest prediagnostic IGF-II levels were at an increased risk [OR (T1 vs. T3), 1.58; 95% CI, 1.09–2.28; Ptrend = 0.011] and participants with the highest prediagnostic IGF-binding protein (IGFBP)-3 levels were at a decreased risk of colorectal cancer (OR, 0.53; 95% CI, 0.34–0.83; Ptrend = 0.003).
Conclusion
These data provide further support for a role of prediagnostic IGF and insulin levels in the etiology of colorectal cancer.
Impact
Future studies attempting to replicate the association between the GCKR rs780094 variant and the risk of colorectal cancer are warranted.
doi:10.1158/1055-9965.EPI-11-1105
PMCID: PMC4494075  PMID: 22354904
22.  Body mass index and mortality in an ethnically diverse population: the Multiethnic Cohort Study 
European journal of epidemiology  2012;27(7):489-497.
Body mass index (BMI) has been strongly related to overall mortality, but the consistency of this association across diverse ethnic groups and the effects of early adult BMI versus BMI in later adulthood have not been adequately studied. A prospective analysis was performed using data from 183,211 adults aged 45–75 who enrolled the population-based Multiethnic Cohort Study by completing a questionnaire that included self-reported weight and height information in 1993–1996. Participants were African Americans, Native Hawaiians, Japanese Americans, Latinos, and whites living in Hawaii and California. During an average 12.5 years of follow-up, 35,664 deaths were identified. To control for confounding caused by conditions that lead to weight loss and mortality, we excluded participants with a history of cancer or heart disease, who ever smoked, and who died within the first 3 years of follow-up. An increased risk of mortality was observed in participants with a BMI ≥ 27.5 in both men and women compared with the reference category of BMI 23.0–24.9; a BMI ≥ 35.0 carried a greater risk of mortality in men than in women. Although the findings were generally similar across ethnic groups, the association of higher BMI with mortality in Latino men appeared to be weaker than in the other groups. A BMI of 25.0–34.9 at age 21 showed a stronger positive association, with no further increase in risk for a BMI ≥ 35.0, than did BMI in later adulthood. These results indicate that the association of BMI with mortality is generally consistent across sex and ethnic groups, with some variation in the strength of the effect. Most notably, the effect of overweight in young adulthood appears to be much stronger than that of overweight in later adulthood on mortality in later life. This emphasizes the importance of weight management in childhood and adolescence.
doi:10.1007/s10654-012-9695-5
PMCID: PMC4494097  PMID: 22644110
Body mass index; Cohort studies; Mortality; Multiethnic population; Obesity
23.  Dietary sources of five nutrients in ethnic groups represented in the Multiethnic Cohort 
The British journal of nutrition  2012;109(8):1479-1489.
Data are limited on how dietary sources of energy and nutrient intakes differ among ethnic groups in the USA. The objective of the present study was to characterise dietary sources of energy, total fat, saturated fat, protein, dietary fibre and added sugar for five ethnic groups. A validated quantitative FFQ was used to collect dietary data from 186916 men and women aged 45–75 years who were living in Hawaii and Los Angeles between 1993 and 1996. Participants represented five ethnic groups: African-American; Japanese-American; Native Hawaiian; Latino; Caucasian. The top ten dietary sources of energy contributed 36·2–49·6 % to total energy consumption, with rice and bread contributing the most (11·4–27·8 %) across all ethnic–sex groups. Major dietary sources of total fat were chicken/turkey dishes and butter among most groups. Ice cream, ice milk or frozen yogurt contributed 4·6–6·2 % to saturated fat intake across all ethnic–sex groups, except Latino-Mexico women. Chicken/turkey and bread were among the top dietary sources of protein (13·9–19·4 %). The top two sources of dietary fibre were bread and cereals (18·1–22 %) among all groups, except Latino-Mexico men. Regular sodas contributed the most to added sugar consumption. The present study provides, for the first time, data on the major dietary sources of energy, fat, saturated fat, protein, fibre and added sugar for these five ethnic groups in the USA. Such data are valuable for identifying target foods for nutritional intervention programmes and directing public health strategies aimed at reducing dietary risk factors for chronic disease.
doi:10.1017/S0007114512003388
PMCID: PMC4489548  PMID: 22947145
Dietary sources; Nutrients; Ethnicity; Multiethnic Cohort
24.  Methodological Considerations in Estimation of Phenotype Heritability Using Genome-Wide SNP Data, Illustrated by an Analysis of the Heritability of Height in a Large Sample of African Ancestry Adults 
PLoS ONE  2015;10(6):e0131106.
Height has an extremely polygenic pattern of inheritance. Genome-wide association studies (GWAS) have revealed hundreds of common variants that are associated with human height at genome-wide levels of significance. However, only a small fraction of phenotypic variation can be explained by the aggregate of these common variants. In a large study of African-American men and women (n = 14,419), we genotyped and analyzed 966,578 autosomal SNPs across the entire genome using a linear mixed model variance components approach implemented in the program GCTA (Yang et al Nat Genet 2010), and estimated an additive heritability of 44.7% (se: 3.7%) for this phenotype in a sample of evidently unrelated individuals. While this estimated value is similar to that given by Yang et al in their analyses, we remain concerned about two related issues: (1) whether in the complete absence of hidden relatedness, variance components methods have adequate power to estimate heritability when a very large number of SNPs are used in the analysis; and (2) whether estimation of heritability may be biased, in real studies, by low levels of residual hidden relatedness. We addressed the first question in a semi-analytic fashion by directly simulating the distribution of the score statistic for a test of zero heritability with and without low levels of relatedness. The second question was addressed by a very careful comparison of the behavior of estimated heritability for both observed (self-reported) height and simulated phenotypes compared to imputation R2 as a function of the number of SNPs used in the analysis. These simulations help to address the important question about whether today's GWAS SNPs will remain useful for imputing causal variants that are discovered using very large sample sizes in future studies of height, or whether the causal variants themselves will need to be genotyped de novo in order to build a prediction model that ultimately captures a large fraction of the variability of height, and by implication other complex phenotypes. Our overall conclusions are that when study sizes are quite large (5,000 or so) the additive heritability estimate for height is not apparently biased upwards using the linear mixed model; however there is evidence in our simulation that a very large number of causal variants (many thousands) each with very small effect on phenotypic variance will need to be discovered to fill the gap between the heritability explained by known versus unknown causal variants. We conclude that today's GWAS data will remain useful in the future for causal variant prediction, but that finding the causal variants that need to be predicted may be extremely laborious.
doi:10.1371/journal.pone.0131106
PMCID: PMC4488332  PMID: 26125186
25.  Body size and breast cancer risk: the Multiethnic Cohort 
The influence of body size on postmenopausal breast cancer risk was investigated among five racial/ethnic groups in the Multiethnic Cohort. Participants were 45–75 years old at recruitment (1993–1996), living in Hawaii and California. Of the 82,971 White, African American, Native Hawaiian, Japanese and Latina women included in this analysis, 3,030 were diagnosed with invasive breast cancer. Body mass index (BMI), height, weight and adulthood weight gain were associated with a significantly higher risk and, with the exception of height, were found to vary across ethnic groups. Native Hawaiians and Japanese with a BMI ≥30.0 compared to 20.0–24.9 kg/m2 had the highest risk (hazard ratio = 1.82, 95% confidence interval: 1.31, 2.54, p-trend = 0.001, and hazard ratio = 1.59, 95% confidence interval: 1.24, 2.05, p-trend < 0.0001, respectively). Current hormone replacement therapy use modified the impact of a high BMI, as non- and former users had a significantly higher risk compared to current users. BMI also had a more pronounced risk for advanced tumors compared to localized tumors. When both BMI and adult weight gain were analyzed simultaneously, adult weight gain, rather than BMI, was a significant risk factor overall. These findings emphasize the significance of maintaining a healthy weight throughout adulthood for the prevention of postmenopausal breast cancer.
doi:10.1002/ijc.27373
PMCID: PMC4484854  PMID: 22120517
breast cancer; body size; body mass index

Results 1-25 (215)