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Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.

BackgroundIn addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear.MethodsWe conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium.ResultsAll sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p  =  5.09  ×  10-4], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p  =  4.02  ×  10-4), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p  =  5.05  ×  10-19) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p  =  9.22  ×  10-6). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2-h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer.ConclusionsWe confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer.

ObjectiveLarger social networks have been associated with better breast cancer survival. To investigate potential mediators, we evaluated associations of social network size and diversity with lifestyle and treatment factors associated with prognosis.MethodsWe included 9331 women from the After Breast Cancer Pooling Project who provided data on social networks within approximately two years following diagnosis. A social network index was derived from information about the presence of a spouse or intimate partner, religious ties, community participation, friendship ties, and numbers of living relatives. Diversity was assessed as variety of ties, independent of size. We used logistic regression to evaluate associations with outcomes and evaluated whether effect estimates differed using meta-analytic techniques.ResultsAssociations were similar across cohorts though analyses of smoking and alcohol included US cohorts only because of low prevalence of these behaviors in the Shanghai cohort. Socially isolated women were more likely to be obese (OR = 1.21, 95% CI:1.03-1.42), have low physical activity (

Endogenous estradiol and estrone are linked causally to increased risks of breast cancer. In this study, we evaluated multiple competing hypotheses for how metabolism of these parent estrogens may influence risk. Prediagnostic concentrations of estradiol, estrone, and 13 metabolites were measured in 1,298 postmenopausal cases of breast cancer and 1,524 matched controls in four separate patient cohorts. The median time between sample collection and diagnosis was 4.4 to 12.7 years across the cohorts. Estrogen analytes were measured in serum or urine by liquid chromatography-tandem mass spectrometry. Total estrogen levels (summing all 15 estrogens/estrogen metabolites) were associated strongly and positively with breast cancer risk. Normalizing total estrogen levels, we also found that a relative increase in levels of 2-hydroxylation pathway metabolites, or in the ratio of 2-hydroxylation:16-hydroxylation pathway metabolites, were associated inversely with breast cancer risk. These associations varied by total estrogen levels, with the largest risk reductions occurring in women in the highest tertile. With appropriate validation, these findings suggest opportunities for breast cancer prevention by modifying individual estrogen metabolism profiles through either lifestyle alterations or chemopreventive strategies. Cancer Res; 77(4); 918-25. ©2017 AACR.

BackgroundObservational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.MethodsWe applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases  =  46,325, controls  =  42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively.ResultsIn the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR]  =  0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56-0.75, p = 3.32 × 10-10). The associations were similar for both premenopausal (OR   =   0.44, 95% CI:0.31-0.62, p  =  9.91 × 10-8) and postmenopausal breast cancer (OR  =  0.57, 95% CI: 0.46-0.71, p  =  1.88 × 10-8). This association was replicated in the data from the DRIVE consortium (OR  =  0.72, 95% CI: 0.60-0.84, p   =   1.64 × 10-7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p

PurposeType 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors.MethodsWe constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D susceptibility loci and evaluated its relation to breast cancer risk using the data from two consortia, including 62,328 breast cancer patients and 83,817 controls of European ancestry. Unconditional logistic regression models were used to derive adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) to measure the association of breast cancer risk with T2D GRS or T2D-associated genetic risk variants. Meta-analyses were conducted to obtain summary ORs across all studies.ResultsThe T2D GRS was not found to be associated with breast cancer risk, overall, by menopausal status, or for estrogen receptor positive or negative breast cancer. Three T2D associated risk variants were individually associated with breast cancer risk after adjustment for multiple comparisons using the Bonferroni method (at p < 0.001), rs9939609 (FTO) (OR 0.94, 95 % CI = 0.92-0.95, p = 4.13E-13), rs7903146 (TCF7L2) (OR 1.04, 95 % CI = 1.02-1.06, p = 1.26E-05), and rs8042680 (PRC1) (OR 0.97, 95 % CI = 0.95-0.99, p = 8.05E-04).ConclusionsWe have shown that several genetic risk variants were associated with the risk of both T2D and breast cancer. However, overall genetic susceptibility to T2D may not be related to breast cancer risk.

BACKGROUND:BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. METHODS:We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. RESULTS:The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). CONCLUSIONS:These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.

IntroductionChina has the largest population of Parkinson's disease (PD) patients; however few etiological studies of PD have been conducted in China.MethodsThe Shanghai Women's Health Study recruited 74,941 women in urban Shanghai, aged 40 to 70, from 1996 to 2000. Self-reported PD cases were invited for a neurological examination and diagnoses were made by a movement disorder specialist.ResultsThis cohort had very few smokers (2.7%), alcohol drinkers (2.3%), and post-menopausal hormone users (4.3%); however, tea drinking (29.9%) and exposure to tobacco smoke from husbands (61.8%) were common. A total of 301 participants reported PD diagnosis during the follow-up. The diagnosis was confirmed in 76 (57%) of the 133 clinically examined patients. An additional 19 (53%) PD cases were identified out of 36 participants who self-confirmed the diagnosis and provided a history on PD symptoms and treatments. As expected, increasing age was strongly associated with PD risk. Further, PD risk appears to be inversely associated with exposures to second-hand tobacco smoke from husbands and tea drinking, and positively with education, although none of these reached statistical significance. The age-adjusted odds ratio (OR) was 0.7 (95% confidence interval: 0.4-1.1) for participants whose husbands were current smokers at baseline and 0.8 (0.5-1.3) for ever tea-drinkers. Compared with primary education or lower, the age-adjusted OR was 1.3 (0.7-2.4) for middle school and 1.6 (1.0-2.7) for high school or above.ConclusionPD research in this unique cohort is feasible and, with extended follow-up, will allow for prospective PD etiological research in China.

BackgroundHormone therapy has been shown to increase risk of ischemic stroke in women. Plant-derived estrogens, particularly soy isoflavones, are known to have some estrogenic effects and have been marketed as natural alternatives to hormone therapy. Concerns have been raised about whether high isoflavone exposure may be related to ischemic stroke risk as well.ObjectiveWe examined the dietary intake of isoflavones and the urinary excretion of isoflavonoids in relation to risk of ischemic stroke in women.DesignA prospective cohort study was conducted in 66,832 Chinese women (aged 40-70 y) who had no cardiovascular disease or cancer at baseline. Usual dietary intakes were assessed via in-person interviews with the use of a validated food-frequency questionnaire. Incident strokes were ascertained during follow-up home visits and confirmed by medical records. We also conducted a nested case-control study in postmenopausal women who had never used hormone therapy, including 1422 incident ischemic stroke cases and 1422 controls individually matched by age, date and time of urine sample collection, time since last meal, and use of antibiotics. Urinary isoflavonoids were measured with the use of high-performance liquid chromatography coupled with mass spectrometry.ResultsDuring a mean follow-up of 10 y, 3110 incident ischemic strokes were verified. Dietary isoflavone intake was associated with increased risk of ischemic stroke; multivariable-adjusted HRs from lowest to highest quintiles were 1.00, 1.05, 1.10, 1.11, and 1.24, respectively (95% CI: 1.08, 1.42; P-trend = 0.002). In the case-control study, a similar positive association was observed for dietary isoflavones, but no significant associations were shown for the urinary isoflavonoid concentration [OR: 1.01 (95% CI: 0.77, 1.32) for comparison of extreme quintiles].ConclusionsA habitually high intake of soy isoflavones may be associated with a modest but significant increase in risk of ischemic stroke in women. However, no association was shown for the urinary excretion of isoflavonoids.

Human height is associated with risk of multiple diseases and is profoundly determined by an individual's genetic makeup and shows a high degree of ethnic heterogeneity. Large-scale genome-wide association (GWA) analyses of adult height in Europeans have identified nearly 180 genetic loci. A recent study showed high replicability of results from Europeans-based GWA studies in Asians; however, population-specific loci may exist due to distinct linkage disequilibrium patterns. We carried out a GWA meta-analysis in 93 926 individuals from East Asia. We identified 98 loci, including 17 novel and 81 previously reported loci, associated with height at P < 5 × 10(-8), together explaining 8.89% of phenotypic variance. Among the newly identified variants, 10 are commonly distributed (minor allele frequency, MAF > 5%) in Europeans, with comparable frequencies with in Asians, and 7 single-nucleotide polymorphisms are with low frequency (MAF < 5%) in Europeans. In addition, our data suggest that novel biological pathway such as the protein tyrosine phosphatase family is involved in regulation of height. The findings from this study considerably expand our knowledge of the genetic architecture of human height in Asians.

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

BackgroundCholine deficiency has been shown to induce liver fat accumulation in both rodent and human studies. However, it is unclear whether dietary choline intake is related to fatty liver in the general population.ObjectiveWe examined the association between choline intake and nonalcoholic fatty liver.MethodsParticipants included 56,195 Chinese women and men, 40-75 y of age, with no or negligible alcohol consumption and with no history of hepatitis, cardiovascular disease, or cancer. All participants reported undergoing liver ultrasonography. Fatty liver was defined by self-report of a physician diagnosis. Habitual dietary intakes were assessed via validated food-frequency questionnaires.ResultsThe average total choline intakes were 289 ± 85 mg/d in women and 318 ± 92 mg/d in men. Major food sources were eggs, soy foods, red meat, fish, and vegetables. A higher choline intake was associated with lower risk of fatty liver; after adjustment for sociodemographic characteristics, lifestyle factors, and other dietary intakes, the ORs (95% CIs) for the highest vs. the lowest quintiles of choline intake were 0.68 (0.59, 0.79) in women and 0.75 (0.60, 0.93) in men (both P-trend < 0.01). The inverse association was attenuated after further adjustment for history of metabolic disease and, in particular, BMI. The corresponding ORs (95% CIs) were 0.88 (0.75, 1.03) in women (P-trend = 0.05) and 0.85 (0.68, 1.06) in men (P-trend = 0.09). Stratified analyses suggested a potential effect modification by obesity status in women; the OR (95% CI) across extreme quintiles was 0.72 (0.57, 0.91) in normal-weight women vs. 1.05 (0.84, 1.31) in overweight or obese women (P-trend = 0.007 vs. 0.99, P-interaction < 0.0001).ConclusionHigher dietary choline intake may be associated with lower risk of nonalcoholic fatty liver only in normal-weight Chinese women.

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

BackgroundA higher adherence to dietary recommendations, such as the Dietary Approaches to Stop Hypertension (DASH) and the Alternative Healthy Eating Index (AHEI), has been associated with lower morbidity and mortality from chronic diseases in Western populations. However, the health benefits of following the Dietary Guidelines for Chinese remain unknown.ObjectiveWe examined adherence to the Chinese Food Pagoda (CHFP) in association with total and cause-specific mortality and compared associations with those of the DASH and AHEI.DesignParticipants included 61,239 men and 73,216 women (aged 40-74 y) from 2 population-based prospective studies in Shanghai, China. Habitual dietary intakes were assessed at baseline in-person interviews by using validated food-frequency questionnaires. Deaths and underlying causes were identified through the Shanghai Vital Statistics Registry and follow-up home visits.ResultsWe documented 2954 deaths in men and 4348 deaths in women during mean follow-ups of 6.5 and 12.0 y, respectively. A higher CHFP score was associated with lower total mortality with multivariable-adjusted HRs of 0.67 (95% CI: 0.60, 0.75) in men and 0.87 (95% CI: 0.80, 0.95) in women when extreme quartiles were compared (both P-trend < 0.005). Decreased risks associated with a higher CHFP score were observed for cardiovascular disease, cancer, and diabetes mortality, particularly in men. A significantly lower total mortality was shown for adherence to specific recommendations on vegetables, fruit, legumes, fish, and eggs but not grains, dairy, meat, fat, and salt. A higher DASH score and AHEI also predicted lower mortality from all causes, cardiovascular disease, and diabetes but not cancer.ConclusionsA greater compliance with Chinese or US dietary guidelines is associated with lower total mortality in Chinese adults. Favorable associations are more evident in men than women and more consistent for cardiometabolic mortality than cancer mortality.

Glycated hemoglobin A1c (HbA1c) is used as a measure of glycemic control and also as a diagnostic criterion for diabetes. To discover novel loci harboring common variants associated with HbA1c in East Asians, we conducted a meta-analysis of 13 genome-wide association studies (GWAS; N = 21,026). We replicated our findings in three additional studies comprising 11,576 individuals of East Asian ancestry. Ten variants showed associations that reached genome-wide significance in the discovery data set, of which nine (four novel variants at TMEM79 [P value = 1.3 × 10(-23)], HBS1L/MYB [8.5 × 10(-15)], MYO9B [9.0 × 10(-12)], and CYBA [1.1 × 10(-8)] as well as five variants at loci that had been previously identified [CDKAL1, G6PC2/ABCB11, GCK, ANK1, and FN3KI]) showed consistent evidence of association in replication data sets. These variants explained 1.76% of the variance in HbA1c. Several of these variants (TMEM79, HBS1L/MYB, CYBA, MYO9B, ANK1, and FN3K) showed no association with either blood glucose or type 2 diabetes. Among individuals with nondiabetic levels of fasting glucose (

Triple-negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study of TN breast cancer (stage 1: 1529 TN cases, 3399 controls; stage 2: 2148 cases, 1309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (P < 5 × 10(-) (8)) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the single nucleotide polymorphisms (SNPs) analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (P < 0.05). Associations with TN breast cancer were confirmed for 10 loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (P < 0.05: PEX14, 2q24.1, 2q31.1, ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of previously reported signals in ESR1 [rs12525163 odds ratio (OR) = 1.15, P = 4.9 × 10(-) (4)] and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 × 10(-) (9)) were associated with TN breast cancer. A polygenic risk score (PRS) for TN breast cancer based on known breast cancer risk variants showed a 4-fold difference in risk between the highest and lowest PRS quintiles (OR = 4.03, 95% confidence interval 3.46-4.70, P = 4.8 × 10(-) (69)). This translates to an absolute risk for TN breast cancer ranging from 0.8% to 3.4%, suggesting that genetic variation may be used for TN breast cancer risk prediction.

The protective effects of fruits and vegetables against CHD have been suggested by many epidemiological studies among Western populations. However, prospective data are lacking for Asian populations. In the present study, we examined the associations of fruit and vegetable intake with CHD incidence among 67 211 women (aged 40-70 years) and 55 474 men (aged 40-74 years) living in Shanghai, China. Food intake was assessed using validated FFQ through in-person interviews. Coronary events (non-fatal myocardial infarction or fatal CHD) were identified by biennial home visits and further confirmed by medical record review. During a mean follow-up period of 9·8 and 5·4 years, 148 events in women and 217 events in men were documented and verified. After adjustment for potential confounders, women in the highest quartile of total fruit and vegetable intake (median 814 g/d) had a hazard ratio (HR) of 0·62 (95 % CI 0·38, 1·02) for CHD (P for trend = 0·04) compared with those in the lowest quartile (median 274 g/d). This association was primarily driven by fruits (HR for the highest v. the lowest intake in women: 0·62, 95 % CI 0·37, 1·03). The strength of the association was attenuated after further controlling for history of diabetes or hypertension. For men, no significant association was found for fruit and vegetable intake when analysed either in combination or individually. The present findings suggest that a high consumption of fruits may reduce CHD risk in Chinese women.

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

BackgroundThere is controversy on whether former smokers have increased risk for breast cancer recurrence or all-cause mortality, regardless of how much they smoked.MethodsData were from three US cohorts in the After Breast Cancer Pooling Project, with detailed information on smoking among 9975 breast cancer survivors. Smoking was assessed an average of 2 years after diagnosis. Delayed entry Cox proportional hazards models were used to examine the relationships of smoking status, cigarettes per day, years of smoking, and pack years with breast cancer prognosis. Endpoints included breast cancer recurrence (n = 1727), breast cancer mortality (n = 1059), and overall mortality (n = 1803).ResultsCompared with never smokers, former smokers with less than 20 pack-years of exposure had no increased risk of any outcome. However, former smokers with 20 to less than 34.9 pack-years of exposure had a 22% increased risk of breast cancer recurrence (hazard ratio [HR] = 1.22; 95% confidence interval [CI] = 1.01 to 1.48) and a 26% increased risk of all-cause mortality (HR = 1.26; 95% CI = 1.07 to 1.48). For former smokers with 35 or more pack-years of exposure, the probability of recurrence increased by 37% (HR = 1.37; 95% CI = 1.13 to 1.66), breast cancer mortality increased by 54% (HR = 1.54; 95% CI = 1.24 to 1.91), and all-cause mortality increased by 68% (HR = 1.68; 95% CI = 1.44 to 1.96). Current smoking increased the probability of recurrence by 41% (HR = 1.41; 95% CI = 1.16 to 1.71), increased breast cancer mortality by 60% (HR = 1.61; 95% CI = 1.28 to 2.03), and doubled the risk of all-cause mortality (HR = 2.17; 95% CI = 1.85 to 2.54).ConclusionsLifetime cigarette smoking was statistically significantly associated with a poor prognosis among women diagnosed with breast cancer, dose-dependent increased risks of recurrence, and breast cancer and all-cause mortality.

The potential long-term association between carbohydrate intake and the risk of coronary heart disease (CHD) remains unclear, especially among populations who habitually have high-carbohydrate diets. We prospectively examined intakes of carbohydrates and staple grains as well as glycemic index and glycemic load in relation to CHD among 117,366 Chinese women and men (40-74 years of age) without history of diabetes, CHD, stroke, or cancer at baseline in Shanghai, China. Diet was assessed using validated food frequency questionnaires. Incident CHD cases were ascertained during follow-ups (in women, the mean was 9.8 years and in men, the mean was 5.4 years) and confirmed by medical records. Carbohydrate intake accounted for 67.5% of the total energy intake in women and 68.5% in men. Seventy percent of total carbohydrates came from white rice and 17% were from refined wheat products. Positive associations between carbohydrate intakess and CHD were found in both sexes (all P for heterogeneity > 0.35). The combined multivariate-adjusted hazard ratios for the lowest to highest quartiles of carbohydrate intake, respectively, were 1.00, 1.38, 2.03, and 2.88 (95% confidence interval: 1.44, 5.78; P for trend = 0.001). The combined hazard ratios comparing the highest quartile with the lowest were 1.80 (95% confidence interval: 1.01, 3.17) for refined grains and 1.87 (95% confidence interval: 1.00, 3.53) for glycemic load (both P for trend = 0.03). High carbohydrate intake, mainly from refined grains, is associated with increased CHD risk in Chinese adults.

Background & aimsHeritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis.MethodsWe conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent.ResultsBased on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 × 10(-8): an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 × 10(-8)). We also found evidence for 3 additional loci with P values less than 5.0 × 10(-7): a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 × 10(-8)), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 × 10(-8)), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 × 10(-7)).ConclusionsIn a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to β-catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.

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

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

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

A recent genome-wide association study (PanScan) identified significant associations at the ABO gene locus with risk of pancreatic cancer, but the influence of specific ABO genotypes remains unknown. We determined ABO genotypes (OO, AO, AA, AB, BO, and BB) in 1,534 cases and 1,583 controls from 12 prospective cohorts in PanScan, grouping participants by genotype-derived serologic blood type (O, A, AB, and B). Adjusted odds ratios (ORs) for pancreatic cancer by ABO alleles were calculated using logistic regression. Compared with blood type O, the ORs for pancreatic cancer in subjects with types A, AB, and B were 1.38 [95% confidence interval (95% CI), 1.18-1.62], 1.47 (95% CI, 1.07-2.02), and 1.53 (95% CI, 1.21-1.92), respectively. The incidence rates for blood types O, A, AB, and B were 28.9, 39.9, 41.8, and 44.5 cases per 100,000 subjects per year. An increase in risk was noted with the addition of each non-O allele. Compared with OO genotype, subjects with AO and AA genotype had ORs of 1.33 (95% CI, 1.13-1.58) and 1.61 (95% CI, 1.22-2.18), whereas subjects with BO and BB genotypes had ORs of 1.45 (95% CI, 1.14-1.85) and 2.42 (1.28-4.57). The population attributable fraction for non-O blood type was 19.5%. In a joint model with smoking, current smokers with non-O blood type had an adjusted OR of 2.68 (95% CI, 2.03-3.54) compared with nonsmokers of blood type O. We concluded that ABO genotypes were significantly associated with pancreatic cancer risk.

Smoking is an established risk factor for pancreatic cancer; however, detailed examination of the association of smoking intensity, smoking duration, and cumulative smoking dose with pancreatic cancer is limited. The authors analyzed pooled data from the international Pancreatic Cancer Cohort Consortium nested case-control study (1,481 cases, 1,539 controls). Odds ratios and 95% confidence intervals were calculated by using unconditional logistic regression. Smoking intensity effects were examined with an excess odds ratio model that was linear in pack-years and exponential in cigarettes smoked per day and its square. When compared with never smokers, current smokers had a significantly elevated risk (odds ratio (OR) = 1.77, 95% confidence interval (CI): 1.38, 2.26). Risk increased significantly with greater intensity (> or =30 cigarettes/day: OR = 1.75, 95% CI: 1.27, 2.42), duration (> or =50 years: OR = 2.13, 95% CI: 1.25, 3.62), and cumulative smoking dose (> or =40 pack-years: OR = 1.78, 95% CI: 1.35, 2.34). Risk more than 15 years after smoking cessation was similar to that for never smokers. Estimates of excess odds ratio per pack-year declined with increasing intensity, suggesting greater risk for total exposure delivered at lower intensity for longer duration than for higher intensity for shorter duration. This finding and the decline in risk after smoking cessation suggest that smoking has a late-stage effect on pancreatic carcinogenesis.