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1.  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
2.  Type-2 Diabetes Risk Variants and Colorectal Cancer Risk: The Multiethnic Cohort and PAGE Studies 
Gut  2011;60(12):1703-1711.
Background
Diabetes has been positively associated with the risk of colorectal cancer. We investigated whether recently established risk variants for diabetes also have effects on colorectal cancer.
Methods
Nineteen SNPs associated with type-2 diabetes (T2D) in genome-wide association studies were tested in a case-control study of 2,011 colorectal cancer cases and 6,049 controls nested in the Multiethnic Cohort as part of the Population Architecture using Genomics and Epidemiology (PAGE) initiative. Odds ratios (OR) and 95% Confidence Intervals (CI) were estimated by unconditional logistic regression to evaluate the association between SNPs and colorectal cancer risk, adjusting for age, sex, and race/ethnicity. Permutation testing was conducted to correct for multiple hypothesis testing.
Results
Four type 2 diabetes SNPs were associated with colorectal cancer risk: rs7578597 (THADA), rs864745 (JAZF1), rs5219 (KCNJ11), and rs7961581 (TSPAN8, LGR5). The strongest association was for the rs7578597 (THADA) Thr1187Ala missense polymorphism (Ptrend = 0.004 adjusted for multiple testing) with the high risk allele for colorectal cancer being the low risk allele for diabetes. Similar patterns of associations were seen with further adjustment for diabetes status and body mass index. The association of diabetes status with colorectal cancer risk was somewhat weakened after adjustment for these SNPs.
Conclusion
Our findings suggest that diabetes risk variants also influence colorectal cancer susceptibility, possibly through different mechanisms than for diabetes.
doi:10.1136/gut.2011.237727
PMCID: PMC4332884  PMID: 21602532
colorectal cancer; SNPs; type 2 diabetes
3.  Trans-ethnic genome-wide association study of colorectal cancer identifies a new susceptibility locus in VTI1A 
Nature communications  2014;5:4613.
The genetic basis of sporadic colorectal cancer (CRC) is not well explained by known risk polymorphisms. Here we perform a meta-analysis of two genome-wide association studies in 2,627 cases and 3,797 controls of Japanese ancestry and 1,894 cases and 4,703 controls of African ancestry, to identify genetic variants that contribute to CRC susceptibility. We replicate genome-wide statistically significant associations (P < 5×10−8) in 16,823 cases and 18,211 controls of European ancestry. This study reveals a new pan-ethnic CRC risk locus at 10q25 (rs12241008, intronic to VTI1A; P=1.4×10−9), providing additional insight into the etiology of CRC and highlighting the value of association mapping in diverse populations.
doi:10.1038/ncomms5613
PMCID: PMC4180879  PMID: 25105248
4.  Fine-mapping of genome-wide association study-identified risk loci for colorectal cancer in African Americans 
Human Molecular Genetics  2013;22(24):5048-5055.
Genome-wide association studies of colorectal cancer (CRC) in Europeans and Asians have identified 21 risk susceptibility regions [29 index single-nucleotide polymorphisms (SNPs)]. Characterizing these risk regions in diverse racial groups with different linkage disequilibrium (LD) structure can help localize causal variants. We examined associations between CRC and all 29 index SNPs in 6597 African Americans (1894 cases and 4703 controls). Nine SNPs in eight regions (5q31.1, 6q26-q27, 8q23.3, 8q24.21, 11q13.4, 15q13.3, 18q21.1 and 20p12.3) formally replicated in our data with one-sided P-values <0.05 and the same risk directions as reported previously. We performed fine-mapping of the 21 risk regions (including 250 kb on both sides of the index SNPs) using genotyped and imputed markers at the density of the 1000 Genomes Project to search for additional or more predictive risk markers. Among the SNPs correlated with the index variants, two markers, rs12759486 (or rs7547751, a putative functional variant in perfect LD with it) in 1q41 and rs7252505 in 19q13.1, were more strongly and statistically significantly associated with CRC (P < 0.0006). The average per allele risk was improved using the replicated index variants and the two new markers (odds ratio = 1.14, P = 6.5 × 10−16) in African Americans, compared with using all index SNPs (odds ratio = 1.07, P = 3.4 × 10−10). The contribution of the two new risk SNPs to CRC heritability was estimated to be 1.5% in African Americans. This study highlights the importance of fine-mapping in diverse populations.
doi:10.1093/hmg/ddt337
PMCID: PMC3836473  PMID: 23851122
5.  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
6.  A Pooled Analysis of Body Mass Index and Mortality among African Americans 
PLoS ONE  2014;9(11):e111980.
Pooled analyses among whites and East Asians have demonstrated positive associations between all-cause mortality and body mass index (BMI), but studies of African Americans have yielded less consistent results. We examined the association between BMI and all-cause mortality in a sample of African Americans pooled from seven prospective cohort studies: NIH-AARP, 1995–2009; Adventist Health Study 2, 2002–2008; Black Women's Health Study, 1995–2009; Cancer Prevention Study II, 1982–2008; Multiethnic Cohort Study, 1993–2007; Prostate, Lung, Colorectal and Ovarian Screening Trial, 1993–2009; Southern Community Cohort Study, 2002–2009. 239,526 African Americans (including 100,175 never smokers without baseline heart disease, stroke, or cancer), age 30–104 (mean 52) and 71% female, were followed up to 26.5 years (mean 11.7). Hazard ratios (HR) and 95% confidence intervals (CI) for mortality were derived from multivariate Cox proportional hazards models. Among healthy, never smokers (11,386 deaths), HRs (CI) for BMI 25–27.4, 27.5–29.9, 30–34.9, 35–39.9, 40–49.9, and 50–60 kg/m2 were 1.02 (0.92–1.12), 1.06 (0.95–1.18), 1.32 (1.18–1.47), 1.54 (1.29–1.83), 1.93 (1.46–2.56), and 1.93 (0.80–4.69), respectively among men and 1.06 (0.99–1.15), 1.15 (1.06–1.25), 1.24 (1.15–1.34), 1.58 (1.43–1.74), 1.80 (1.60–2.02), and 2.31 (1.74–3.07) respectively among women (reference category 22.5–24.9). HRs were highest among those with the highest educational attainment, longest follow-up, and for cardiovascular disease mortality. Obesity was associated with a higher risk of mortality in African Americans, similar to that observed in pooled analyses of whites and East Asians. This study provides compelling evidence to support public health efforts to prevent excess weight gain and obesity in African Americans.
doi:10.1371/journal.pone.0111980
PMCID: PMC4234271  PMID: 25401742
7.  Prediagnostic serum tocopherol levels and the risk of Non-Hodgkin Lymphoma: The Multiethnic Cohort 
Background
Compromised immunity and chronic inflammation are thought to contribute to the development of non-Hodgkin lymphoma (NHL). Because tocopherols protect cells through antioxidant mechanisms, they may play a role in NHL etiology.
Methods
This nested case-control study within the Multiethnic Cohort examined the association of prediagnostic serum tocopherols levels measured in 271 NHL cases and 538 matched controls by high pressure liquid chromatography/photodiode-array detection with NHL risk. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CI).
Results
We observed U-shaped associations with NHL for total and α-tocopherols (Ptrend<0.01 for polynomial terms [3 df]). The ORs (95% CI) for total tocopherols, which consisted primarily of α-tocopherol, were 0.41 (0.25–0.68), 0.52 (0.32–0.85), 0.39 (0.23–0.65), and 0.78 (0.47–1.29) for the 2nd-5th quintiles as compared to the 1st. The risk estimates were similar for α-tocopherol but non-significant for β- and γ-tocopherol combined and for δ-tocopherol. Adjustment for serum lipids strengthened the non-linear associations for total and α-tocopherols. Serum total tocopherol levels were higher for vitamin E supplement users at cohort entry than non-users (21.32±9.04 vs 17.72±7.43 μg/mL; P <0.0001), but supplement use was not associated with NHL risk. No heterogeneity in risk estimates was detected by sex, ethnicity, vitamin E supplement use, or NHL subtype.
Conclusions
Circulating tocopherols, at levels likely reflecting adequate dietary intakes, may be protective against NHL, whereas higher intakes from supplementation may not be beneficial.
Impact
The association between serum tocopherol levels and NHL risk provides possible new insights into the etiology of NHL.
doi:10.1158/1055-9965.EPI-13-0522
PMCID: PMC3819232  PMID: 24045922
non-Hodgkin lymphoma; tocopherols; ethnicity; prospective cohort; nested case-control study
8.  Genetic Variation in the Inflammation and Innate Immunity Pathways and Colorectal Cancer Risk 
Background
It is widely accepted that chronic inflammation plays a role in the etiology of colorectal cancer. Using a two-stage design, we examined the associations between colorectal cancer and common variation in 37 key genes in the inflammation and innate immunity pathways.
Methods
In the discovery stage, 2,322 discordant sibships (2,535 cases, 3,915 sibling controls) from the Colorectal Cancer Family Registry were genotyped for over 600 tagSNPs and 99 SNPs were selected for further examination based on strength of association. In the second stage, 351 SNPs tagging gene regions covered by the 99 SNPs were tested in 4,783 Multiethnic Cohort subjects (2,153 cases, 2,630 controls).
Results
The association between rs9858822 in the PPARG gene and colorectal cancer was statistically significant at the end of the second stage (odds ratio per allele = 1.36, Bonferroni-adjusted P = 0.045), based on the “effective” number of markers in Stage 2 (n = 306). The risk allele C was common (frequency 0.3) in African Americans but rare (frequency < 0.03) in whites, Japanese Americans, Latinos and Native Hawaiians. No statistically significant heterogeneity of effects across race/ethnicity, BMI levels, regular aspirin use or pack-years of smoking was detected for this SNP. Suggestive associations were also observed for several SNPs in close vicinity to rs9858822.
Conclusions
Our results provide new evidence of association between PPARG variants and colorectal cancer risk.
Impact
Further replication in independent samples is warranted.
doi:10.1158/1055-9965.EPI-13-0694
PMCID: PMC3836607  PMID: 24045924
pathway approach; inflammation; colorectal cancer; minority population; immunity
9.  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
10.  No association of risk variants for diabetes and obesity with breast cancer: the Multiethnic Cohort and PAGE studies 
Body mass index is an established risk factor for post-menopausal breast cancer. Epidemiologic studies have also reported a positive association between type 2 diabetes (T2D) and breast cancer risk. To investigate a genetic basis linking these common phenotypes with breast cancer, we tested 31 common variants for T2D and obesity in a case-control study of 1,915 breast cancer cases and 2,884 controls nested within the Multiethnic Cohort (MEC) study. Following adjustment for multiple tests, we found no significant association between any variant and breast cancer risk. Summary scores comprised of the numbers of risk alleles for T2D and/or obesity were also not found to be significantly associated with breast cancer risk.
doi:10.1158/1055-9965.EPI-11-0135
PMCID: PMC4201112  PMID: 21357383
type 2 diabetes; obesity; GWAS; SNPs; breast cancer
11.  Insufficient and excessive amounts of sleep increase the risk of premature death from cardiovascular and other diseases: the Multiethnic Cohort Study 
Preventive medicine  2013;57(4):377-385.
Objective
To explore an independent association between self-reported sleep duration and cause-specific mortality.
Methods
Data were obtained from the Multiethnic Cohort Study conducted in Los Angeles and Hawaii.
Results
Among 61,936 men and 73,749 women with no history of cancer, heart attack or stroke, 19,335 deaths occurred during an average 12.9 year follow-up. Shorter (≤5 h/day) and longer (≥9 h/day) sleepers of both sexes (vs. 7 h/day) had an increased risk of all-cause and cardiovascular disease (CVD) mortality, but not of cancer mortality. Multivariable hazard ratios for CVD mortality were 1.13 (95% CI 1.00-1.28) for ≤5 h/day and 1.22 (95% CI 1.09-1.35) for ≥9 h/day among men; and 1.20 (95% CI 1.05-1.36) for ≤5 h/day and 1.29 (95% CI 1.13-1.47) for ≥9 h/day among women. This risk pattern was not heterogeneous across specific causes of CVD death among men (Phetero 0.53) or among women (Phetero 0.72). The U-shape association for all-cause and CVD mortality was observed in all five ethnic groups included in the study and by subgroups of age, smoking status, and body mass index.
Conclusion
Insufficient or excessive amounts of sleep were associated with increased risk of mortality from CVD and other diseases in a multiethnic population.
doi:10.1016/j.ypmed.2013.06.017
PMCID: PMC3947517  PMID: 23811525
Sleep; mortality; cardiovascular disease; ethnic groups; prospective studies
12.  The association of cigarette smoking with gastric cancer: the multiethnic cohort study 
Cancer causes & control : CCC  2011;23(1):51-58.
Purpose
The purpose of this study is to investigate the association of cigarette smoking with gastric cancer.
Methods
Over 215,000 men and women, representing five ethnic groups (African Americans, Japanese Americans, Latino Americans, Native Hawaiians, and Whites), completed a mailed questionnaire, 1993–1996. After an average follow-up of 7.3 years, 454 men and 242 women were diagnosed with gastric adenocarcinoma. Cox proportional hazard models were used to calculate multivariate-adjusted hazard ratios and 95% confidence intervals.
Results
Current cigarette smokers had elevated hazard ratios compared with never smokers among men (HR = 1.98; 95% CI 1.46–2.70) and women (HR = 1.78; 95% CI 1.23–2.57). This positive association was consistent across all five ethnicities. Former smokers had an elevated risk among men, but not among women. There was a significant trend by intensity (cigarettes per day) and duration (years) of smoking among all current smokers. After separation by anatomic location of their tumor, ever smokers had a higher risk for gastric cardia cancer (HR = 2.86; 95% CI 1.66–4.93) than for distal gastric cancer (HR = 1.52; 95% CI 1.25–1.86) among men and women combined. Analysis by histologic tumor type showed a stronger association between current smoking and the intestinal type.
Conclusions
Overall, this study shows an association of current cigarette smoking with gastric cancer in both sexes, consistency of this effect across five ethnic groups, evidence for a dose–response effect of smoking in both sexes, a stronger effect for cardia than for distal gastric cancer, and a stronger association for intestinal than for diffuse gastric cancer.
doi:10.1007/s10552-011-9854-0
PMCID: PMC4166441  PMID: 22037905
Gastric cancer; Cohort study; Cigarette smoking
13.  Magnesium Intake and Risk of Amyotrophic Lateral Sclerosis: Results From Five Large Cohort Studies 
Objective
A low magnesium intake has been suggested to be associated with amyotrophic lateral sclerosis (ALS) in pathological and case-control studies, but prospective studies in humans are lacking.
Methods
The relation between dietary intake of magnesium and ALS risk was explored in five large prospective cohort studies [the Nurses’ Health Study, the Health Professionals Follow-up Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort Study, and the National Institutes of Health – AARP Diet and Health Study], comprising over 1,050,000 men and women contributing 1,093 cases of ALS during a mean of 15 years of follow-up. Cox proportional hazards models were used within each cohort, and cohort-specific estimates were subsequently pooled using a random-effects model.
Results
Dietary magnesium intake was not associated with ALS risk, relative risk 1.07, 95% confidence interval: 0.88– 1.31 comparing the highest quintile of intake with the lowest.
Conclusions
This finding does not support a protective effect of magnesium intake on ALS risk. Further analyses should explore magnesium intake in combination with heavy metal exposure and genetic variants affecting magnesium absorption.
doi:10.3109/21678421.2013.803577
PMCID: PMC3743429  PMID: 23777266
amyotrophic lateral sclerosis; motor neuron disease; longitudinal cohort studies; epidemiology; magnesium
14.  Association of the FTO Obesity Risk Variant rs8050136 With Percentage of Energy Intake From Fat in Multiple Racial/Ethnic Populations 
American Journal of Epidemiology  2013;178(5):780-790.
Common obesity risk variants have been associated with macronutrient intake; however, these associations' generalizability across populations has not been demonstrated. We investigated the associations between 6 obesity risk variants in (or near) the NEGR1, TMEM18, BDNF, FTO, MC4R, and KCTD15 genes and macronutrient intake (carbohydrate, protein, ethanol, and fat) in 3 Population Architecture using Genomics and Epidemiology (PAGE) studies: the Multiethnic Cohort Study (1993–2006) (n = 19,529), the Atherosclerosis Risk in Communities Study (1987–1989) (n = 11,114), and the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) Study, which accesses data from the Third National Health and Nutrition Examination Survey (1991–1994) (n = 6,347). We used linear regression, with adjustment for age, sex, and ethnicity, to estimate the associations between obesity risk genotypes and macronutrient intake. A fixed-effects meta-analysis model showed that the FTO rs8050136 A allele (n = 36,973) was positively associated with percentage of calories derived from fat (βmeta = 0.2244 (standard error, 0.0548); P = 4 × 10−5) and inversely associated with percentage of calories derived from carbohydrate (βmeta = −0.2796 (standard error, 0.0709); P = 8 × 10−5). In the Multiethnic Cohort Study, percentage of calories from fat assessed at baseline was a partial mediator of the rs8050136 effect on body mass index (weight (kg)/height (m)2) obtained at 10 years of follow-up (mediation of effect = 0.0823 kg/m2, 95% confidence interval: 0.0559, 0.1128). Our data provide additional evidence that the association of FTO with obesity is partially mediated by dietary intake.
doi:10.1093/aje/kwt028
PMCID: PMC3755639  PMID: 23820787
energy intake; fat mass and obesity-associated (FTO) gene; obesity; percent calories from fat; race/ethnicity
15.  Body Mass Index and Non-Hodgkin's Lymphoma Survival in an Ethnically Diverse Population: The Multiethnic Cohort Study 
Introduction:
Obesity increases the risk of death from several malignancies including breast and colon cancer. However, for non-Hodgkin's lymphoma (NHL), the association between pre-diagnostic body mass index (BMI) and survival is unclear. We examined the association between pre-diagnostic BMI 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=1348). Body mass index (BMI) was based on self-reported weight and height at cohort entry. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for pre-diagnostic BMI categories in relation to all-cause and NHL-specific mortality while adjusting for known confounders.
Results:
The mean time from cohort entry to NHL diagnosis was 7.2±3.9 years (range: 0.0–15.0 years). The mean age at NHL diagnosis was 70.6 (range 45–89) years and the mean BMI at cohort entry was 26.5±4.7 kg/m2. After a mean follow-up of 4.3±3.5 years, 679 deaths including 457 NHL-specific deaths occurred. In multivariable models, obese patients (BMI ≥ 30.0) had higher all-cause (HR = 1.55, 95%CI = 1.21 −2.00) and NHL-specific (HR = 1.84, 95%CI = 1.35 – 2.52) mortality compared to patients with high-normal BMI (22.5–24.9 kg/m2). For overweight patients (BMI 25.0 – 29.9), the respective HRs were 1.29 (95%CI = 1.05 – 1.58) and 1.47 (95%CI = 1.14 – 1.89). Stratification by NHL type suggested higher NHL-specific mortality risk for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) than for diffuse large B-cell lymphoma (DLBCL).
Conclusions:
Pre-diagnostic obesity may be related to poorer overall and NHL-specific survival in NHL patients. Therefore, pre-diagnostic BMI may be a suitable prognostic marker for NHL patients.
PMCID: PMC4175946
16.  Genome-wide association study of age at menarche in African-American women 
Human Molecular Genetics  2013;22(16):3329-3346.
African-American (AA) women have earlier menarche on average than women of European ancestry (EA), and earlier menarche is a risk factor for obesity and type 2 diabetes among other chronic diseases. Identification of common genetic variants associated with age at menarche has a potential value in pointing to the genetic pathways underlying chronic disease risk, yet comprehensive genome-wide studies of age at menarche are lacking for AA women. In this study, we tested the genome-wide association of self-reported age at menarche with common single-nucleotide polymorphisms (SNPs) in a total of 18 089 AA women in 15 studies using an additive genetic linear regression model, adjusting for year of birth and population stratification, followed by inverse-variance weighted meta-analysis (Stage 1). Top meta-analysis results were then tested in an independent sample of 2850 women (Stage 2). First, while no SNP passed the pre-specified P < 5 × 10−8 threshold for significance in Stage 1, suggestive associations were found for variants near FLRT2 and PIK3R1, and conditional analysis identified two independent SNPs (rs339978 and rs980000) in or near RORA, strengthening the support for this suggestive locus identified in EA women. Secondly, an investigation of SNPs in 42 previously identified menarche loci in EA women demonstrated that 25 (60%) of them contained variants significantly associated with menarche in AA women. The findings provide the first evidence of cross-ethnic generalization of menarche loci identified to date, and suggest a number of novel biological links to menarche timing in AA women.
doi:10.1093/hmg/ddt181
PMCID: PMC3723312  PMID: 23599027
17.  Association between various sedentary behaviours and all-cause, cardiovascular disease and cancer mortality: the Multiethnic Cohort Study 
Background It has been proposed that time spent sitting increases all-cause mortality, but evidence to support this hypothesis, especially the relative effects of various sitting activities alone or in combination, is very limited.
Methods The association between various sedentary behaviours (time spent: sitting watching television (TV); in other leisure activities; in a car/bus; at work; and at meals) and mortality (all-cause and cause-specific) was examined in the Multiethnic Cohort Study, which included 61 395 men and 73 201 women aged 45–75 years among five racial/ethnic groups (African American, Latino, Japanese American, Native Hawaiian and White) from Hawaii and Los Angeles, USA.
Results Median follow-up was 13.7 years and 19 143 deaths were recorded. Total daily sitting was not associated with mortality in men, whereas in women the longest sitting duration (≥10 h/day vs <5 h/day) was associated with increased all-cause (11%) and cardiovascular (19%) mortality. Multivariate hazard ratios (HR) for ≥5 h/day vs <1 h/day of sitting watching TV were 1.19 in men (95% confidence interval (CI) 1.10–1.29) and 1.32 in women (95% CI 1.21–1.44) for all-cause mortality. This association was consistent across four racial/ethnic groups, but was not seen in Japanese Americans. Sitting watching TV was associated with an increased risk for cardiovascular mortality, but not for cancer mortality. Time spent sitting in a car/bus and at work was not related to mortality.
Conclusions Leisure time spent sitting, particularly watching television, may increase overall and cardiovascular mortality. Sitting at work or during transportation was not related to mortality.
doi:10.1093/ije/dyt108
PMCID: PMC3781003  PMID: 24062293
Sedentary lifestyle; mortality; television; exercise; prospective studies
18.  Alcohol consumption and breast cancer risk among women from five ethnic groups with light to moderate intakes: the Multiethnic Cohort Study 
Higher alcohol consumption, even at moderate levels, has been associated with an increased risk of breast cancer in epidemiological studies. However, prior studies were conducted in mostly white populations. To assess the relationship of alcohol consumption to postmenopausal breast cancer risk in a multiethnic population of largely never, light, or moderate drinkers, we prospectively examined the association in 85,089 women enrolled in the Multiethnic Cohort in Hawaii and California. During a mean follow-up of 12.4 years, 3,885 incident invasive breast cancer cases were identified. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models, controlling for potential confounders. Higher alcohol consumption was associated with increased risk of breast cancer: compared to nondrinkers, HRs were 1.23 (95% CI: 1.06-1.42), 1.21 (95% CI: 1.00-1.45), 1.12 (95% CI: 0.95-1.31), and 1.53 (95% CI: 1.32-1.77) for 5-9.9, 10-14.9, 15-29.9, and ≥30 g/day of alcohol, respectively. The positive association was seen in African American, Japanese American, Latino, and white, but not Native Hawaiian, women, and in those with tumors that were both positive and negative for estrogen and progesterone receptors (ER/PR). This prospective study supports previous findings that light to moderate alcohol consumption increases breast cancer risk, demonstrates this association in several ethnic groups besides whites, independent of ER/PR status.
doi:10.1002/ijc.28476
PMCID: PMC4102309  PMID: 24037751
alcohol; breast cancer; multiethnic population; prospective study
19.  Insulin-like growth factor pathway genes and blood concentrations, dietary protein, and risk of prostate cancer in the NCI Breast and Prostate Cancer Cohort Consortium (BPC3) 
It has been hypothesized that a high intake of dairy protein may increase prostate cancer risk by increasing the production of insulin-like growth factor 1 (IGF-1). Several single nucleotide polymorphisms (SNPs) have been weakly associated with circulating concentrations of IGF-1 and IGF binding protein 3 (IGFBP-3), but none of these SNPs was associated with risk of prostate cancer. We examined whether an association between 16 SNPs associated with circulating IGF-1 or IGFBP-3 concentrations and prostate cancer exists within subgroups defined by dietary protein intake in 5,253 cases and 4,963 controls of European ancestry within the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). The BPC3 includes nested case-control studies within large North-American and European cohorts. Per allele odds ratios for prostate cancer for the SNPs were compared across tertiles of protein intake, which was expressed as the percentage of energy derived from total, animal, dairy or plant protein sources, using conditional logistic regression models. Total, animal, dairy and plant protein intakes were significantly positively associated with blood IGF-1 (P<0.01), but not with IGFBP-3 concentrations (P>0.10) or with risk of prostate cancer (P>0.20). After adjusting for multiple testing, the SNP-prostate cancer associations did not differ by intakes of protein, although two interactions by intake of plant protein were of marginal statistical significance (SSTR5 (somatostatin receptor 5) -rs197056 [uncorrected P for interaction, 0.001]; SSTR5-rs197057 [uncorrected P for interaction, 0.002]). We found no strong evidence that the associations between 16 IGF pathway SNPs and prostate cancer differed by intakes of dietary protein.
doi:10.1002/ijc.28042
PMCID: PMC3656134  PMID: 23341348
gene*environment interaction; genetic epidemiology; insulin-like growth factor; diet; prostate cancer
20.  Testicular germ cell tumor susceptibility associated with the UCK2 locus on chromosome 1q23 
Human Molecular Genetics  2013;22(13):2748-2753.
Genome-wide association studies (GWASs) have identified multiple common genetic variants associated with an increased risk of testicular germ cell tumors (TGCTs). A previous GWAS reported a possible TGCT susceptibility locus on chromosome 1q23 in the UCK2 gene, but failed to reach genome-wide significance following replication. We interrogated this region by conducting a meta-analysis of two independent GWASs including a total of 940 TGCT cases and 1559 controls for 122 single-nucleotide polymorphisms (SNPs) on chromosome 1q23 and followed up the most significant SNPs in an additional 2202 TGCT cases and 2386 controls from four case–control studies. We observed genome-wide significant associations for several UCK2 markers, the most significant of which was for rs3790665 (PCombined = 6.0 × 10−9). Additional support is provided from an independent familial study of TGCT where a significant over-transmission for rs3790665 with TGCT risk was observed (PFBAT = 2.3 × 10−3). Here, we provide substantial evidence for the association between UCK2 genetic variation and TGCT risk.
doi:10.1093/hmg/ddt109
PMCID: PMC3674801  PMID: 23462292
21.  C-Reactive Protein, Lipid-soluble Micronutrients, and Survival in Colorectal Cancer Patients 
Background
Identification of biomarkers associated with survival in cancer patients is important for elucidating the underlying mechanisms of cancer progression and identifying possible interventions to reduce cancer morbidity and mortality.
Methods
Using stored patient plasma samples from a multiethnic population-based case-control study of invasive colorectal cancer, we measured post-treatment blood levels of C-reactive protein (CRP) and lipid-soluble micronutrients. Patients (n=368) were followed after phlebotomy (mean of 8 years), during which time 47% died (25% colorectal cancer-specific). Hazard ratios (HR) were estimated by Cox proportional hazards regression with adjustment for stage, age at diagnosis, ethnicity, sex, smoking status, and month of blood draw.
Results
A positive association with overall risk of death was observed for CRP (HR for highest vs. lowest quintile: 1.80; 95% CI: 1.07-3.04; Ptrend=0.01) whereas, inverse associations were generally observed for retinol and carotenoids (HRs for overall risk of death for the highest quintile ranging from 0.5-0.8); these associations were significant for retinol (Ptrend=0.0002), α-carotene (Ptrend=0.02), and total carotenoids (Ptrend=0.02) and were generally consistent across subgroups (sex, ethnicity, cancer anatomical subtype, and stage). Hazard ratios for retinol and carotenoids were attenuated somewhat after adjustment for CRP. Similar trends for CRP were observed for colorectal cancer-specific deaths (HR for highest vs. lowest tertile: 2.06; 95% CI: 1.18-3.61; Ptrend=0.01) as for deaths from all other causes (Pheterogeneity=0.78).
Conclusion
These observations are consistent with a direct relationship between circulating CRP and overall survival among colorectal cancer patients.
Impact
These results, if reproduced, suggest that reduction of inflammation should be explored as a potential complementary treatment strategy.
doi:10.1158/1055-9965.EPI-13-0199
PMCID: PMC3834261  PMID: 23677577
Survival; colorectal cancer; carotenoids; coenzyme Q10; C-reactive protein
22.  The Influence of Obesity-Related Single Nucleotide Polymorphisms on BMI Across the Life Course 
Diabetes  2013;62(5):1763-1767.
Evidence is limited as to whether heritable risk of obesity varies throughout adulthood. Among >34,000 European Americans, aged 18–100 years, from multiple U.S. studies in the Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we examined evidence for heterogeneity in the associations of five established obesity risk variants (near FTO, GNPDA2, MTCH2, TMEM18, and NEGR1) with BMI across four distinct epochs of adulthood: 1) young adulthood (ages 18–25 years), adulthood (ages 26–49 years), middle-age adulthood (ages 50–69 years), and older adulthood (ages ≥70 years); or 2) by menopausal status in women and stratification by age 50 years in men. Summary-effect estimates from each meta-analysis were compared for heterogeneity across the life epochs. We found heterogeneity in the association of the FTO (rs8050136) variant with BMI across the four adulthood epochs (P = 0.0006), with larger effects in young adults relative to older adults (β [SE] = 1.17 [0.45] vs. 0.09 [0.09] kg/m2, respectively, per A allele) and smaller intermediate effects. We found no evidence for heterogeneity in the association of GNPDA2, MTCH2, TMEM18, and NEGR1 with BMI across adulthood. Genetic predisposition to obesity may have greater effects on body weight in young compared with older adulthood for FTO, suggesting changes by age, generation, or secular trends. Future research should compare and contrast our findings with results using longitudinal data.
doi:10.2337/db12-0863
PMCID: PMC3636619  PMID: 23300277
23.  Plasma carotenoid- and retinol-weighted multi-SNP scores and risk of breast cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium 
Background
Dietary and circulating carotenoids have been inversely associated with breast cancer risk, but observed associations may be due to confounding. Single nucleotide polymorphisms (SNPs) in β-carotene 15,15′-monooxygenase 1 (BCMO1), a gene encoding the enzyme involved in the first step of synthesizing vitamin A from dietary carotenoids, have been associated with circulating carotenoid concentrations and may serve as unconfounded surrogates for those biomarkers. We determined associations between variants in BCMO1 and breast cancer risk in a large cohort consortium.
Methods
We used unconditional logistic regression to test four SNPs in BCMO1 for associations with breast cancer risk in 9,226 cases and 10,420 controls from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3). We also tested weighted multi-SNP scores composed of the two SNPs with strong, confirmed associations with circulating carotenoid concentrations.
Results
Neither the individual SNPs nor the weighted multi-SNP scores were associated with breast cancer risk (odds ratio (95% confidence interval) comparing extreme quintiles of weighted multi-SNP scores =1.04 (0.94–1.16) for β-carotene, 1.08 (0.98–1.20) for α-carotene, 1.04 (0.94–1.16) for β-cryptoxanthin, 0.95 (0.87–1.05) for lutein/zeaxanthin, and 0.92 (0.83–1.02) for retinol). Furthermore, no associations were observed when stratifying by estrogen receptor status, but power was limited.
Conclusions
Our results do not support an association between SNPs associated with circulating carotenoid concentrations and breast cancer risk.
Impact
Future studies will need additional genetic surrogates and/or sample sizes at least three times larger to contribute evidence of a causal link between carotenoids and breast cancer.
doi:10.1158/1055-9965.EPI-13-0017
PMCID: PMC3650115  PMID: 23515144
breast cancer; BCMO1; β-carotene 15,15′-monooxygenase 1; carotenoids; single nucleotide polymorphism
24.  Genome-Wide Diet-Gene Interaction Analyses for Risk of Colorectal Cancer 
PLoS Genetics  2014;10(4):e1004228.
Dietary factors, including meat, fruits, vegetables and fiber, are associated with colorectal cancer; however, there is limited information as to whether these dietary factors interact with genetic variants to modify risk of colorectal cancer. We tested interactions between these dietary factors and approximately 2.7 million genetic variants for colorectal cancer risk among 9,287 cases and 9,117 controls from ten studies. We used logistic regression to investigate multiplicative gene-diet interactions, as well as our recently developed Cocktail method that involves a screening step based on marginal associations and gene-diet correlations and a testing step for multiplicative interactions, while correcting for multiple testing using weighted hypothesis testing. Per quartile increment in the intake of red and processed meat were associated with statistically significant increased risks of colorectal cancer and vegetable, fruit and fiber intake with lower risks. From the case-control analysis, we detected a significant interaction between rs4143094 (10p14/near GATA3) and processed meat consumption (OR = 1.17; p = 8.7E-09), which was consistently observed across studies (p heterogeneity = 0.78). The risk of colorectal cancer associated with processed meat was increased among individuals with the rs4143094-TG and -TT genotypes (OR = 1.20 and OR = 1.39, respectively) and null among those with the GG genotype (OR = 1.03). Our results identify a novel gene-diet interaction with processed meat for colorectal cancer, highlighting that diet may modify the effect of genetic variants on disease risk, which may have important implications for prevention.
Author Summary
High intake of red and processed meat and low intake of fruits, vegetables and fiber are associated with a higher risk of colorectal cancer. We investigate if the effect of these dietary factors on colorectal cancer risk is modified by common genetic variants across the genome (total of about 2.7 million genetic variants), also known as gene-diet interactions. We included over 9,000 colorectal cancer cases and 9,000 controls that were not diagnosed with colorectal cancer. Our results provide strong evidence for a gene-diet interaction and colorectal cancer risk between a genetic variant (rs4143094) on chromosome 10p14 near the gene GATA3 and processed meat consumption (p = 8.7E-09). This genetic locus may have interesting biological significance given its location in the genome. Our results suggest that genetic variants may interact with diet and in combination affect colorectal cancer risk, which may have important implications for personalized cancer care and provide novel insights into prevention strategies.
doi:10.1371/journal.pgen.1004228
PMCID: PMC3990510  PMID: 24743840
25.  Premorbid Body Mass Index and Risk of Amyotrophic Lateral Sclerosis 
Objective
To determine if Amyotrophic Lateral Sclerosis (ALS) risk varies according to body mass index (BMI) captured up to three decades earlier.
Methods
At baseline 537,968 women and 562,942 men in five ongoing cohorts reported height, current weight and weight at age 18/21. During 14-28 years of follow-up 1,153 participants developed ALS. Cohort-specific Cox proportional hazards models were used to estimate rates that were then pooled with random effects models.
Results
Lower BMI at baseline was associated with ALS; for each 5-unit increase in BMI, ALS rates were 21% lower (95%CI: 14% to 27%). Compared to individuals with healthy BMI, ALS rates were significantly lower among the overweight (RR=0.76 [95%CI: 0.62-0.93]) and obese (RR=0.73 [95%CI: 0.55-0.96]). Among never-smokers the association persisted: RR=0.75 (95%CI: 0.65-0.85) for each 5-unit increase. Excluding the first seven years of follow-up, the associations were materially unchanged suggesting that weight loss from undiagnosed disease does not fully explain the findings. Overall, 75% of men and women had a healthy BMI at age 18/21, 15% of men and 8% of women were overweight or obese; there was no association with ALS risk although power was limited.
Conclusion
These findings support an association between lower premorbid BMI and ALS.
doi:10.3109/21678421.2012.735240
PMCID: PMC3615420  PMID: 23134505
Amyotrophic Lateral Sclerosis; Body Mass Index; Risk; Epidemiology; Cohort; Nutrition

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