Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.

• MeSH
• celogenomová asociační studie MeSH
• Evropané * genetika   MeSH
• genetická predispozice k nemoci MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• kolorektální nádory * genetika   MeSH
• lidé MeSH
• multiomika MeSH
• východní Asiaté * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

• Publikační typ
• tisková chyba MeSH

BACKGROUND: Glycemic traits-such as hyperinsulinemia, hyperglycemia, and type 2 diabetes-have been associated with higher colorectal cancer risk in observational studies; however, causality of these associations is uncertain. We used Mendelian randomization (MR) to estimate the causal effects of fasting insulin, 2-hour glucose, fasting glucose, glycated hemoglobin (HbA1c), and type 2 diabetes with colorectal cancer. METHODS: Genome-wide association study summary data were used to identify genetic variants associated with circulating levels of fasting insulin (n = 34), 2-hour glucose (n = 13), fasting glucose (n = 70), HbA1c (n = 221), and type 2 diabetes (n = 268). Using 2-sample MR, we examined these variants in relation to colorectal cancer risk (48 214 case patient and 64 159 control patients). RESULTS: In inverse-variance models, higher fasting insulin levels increased colorectal cancer risk (odds ratio [OR] per 1-SD = 1.65, 95% confidence interval [CI] = 1.15 to 2.36). We found no evidence of any effect of 2-hour glucose (OR per 1-SD = 1.02, 95% CI = 0.86 to 1.21) or fasting glucose (OR per 1-SD = 1.04, 95% CI = 0.88 to 1.23) concentrations on colorectal cancer risk. Genetic liability to type 2 diabetes (OR per 1-unit increase in log odds = 1.04, 95% CI = 1.01 to 1.07) and higher HbA1c levels (OR per 1-SD = 1.09, 95% CI = 1.00 to 1.19) increased colorectal cancer risk, although these findings may have been biased by pleiotropy. Higher HbA1c concentrations increased rectal cancer risk in men (OR per 1-SD = 1.21, 95% CI = 1.05 to 1.40), but not in women. CONCLUSIONS: Our results support a causal effect of higher fasting insulin, but not glucose traits or type 2 diabetes, on increased colorectal cancer risk. This suggests that pharmacological or lifestyle interventions that lower circulating insulin levels may be beneficial in preventing colorectal tumorigenesis.

• MeSH
• celogenomová asociační studie MeSH
• diabetes mellitus 2. typu * komplikace   epidemiologie   genetika   MeSH
• glykovaný hemoglobin analýza   MeSH
• hyperinzulinismus * komplikace   genetika   MeSH
• inzulin MeSH
• jednonukleotidový polymorfismus MeSH
• kolorektální nádory * komplikace   epidemiologie   genetika   MeSH
• krevní glukóza analýza   genetika   MeSH
• lidé MeSH
• mendelovská randomizace MeSH
• rizikové faktory MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Background: Observational studies indicate that periodontal disease may increase the risk of colorectal, lung, and pancreatic cancers. Using a 2-sample Mendelian randomization (MR) analysis, we assessed whether a genetic predisposition index for periodontal disease was associated with colorectal, lung, or pancreatic cancer risks. Methods: Our primary instrument included single nucleotide polymorphisms with strong genome-wide association study evidence for associations with chronic, aggressive, and/or severe periodontal disease (rs729876, rs1537415, rs2738058, rs12461706, rs16870060, rs2521634, rs3826782, and rs7762544). We used summary-level genetic data for colorectal cancer (n = 58 131 cases; Genetics and Epidemiology of Colorectal Cancer Consortium, Colon Cancer Family Registry, and Colorectal Transdisciplinary Study), lung cancer (n = 18 082 cases; International Lung Cancer Consortium), and pancreatic cancer (n = 9254 cases; Pancreatic Cancer Consortia). Four MR approaches were employed for this analysis: random-effects inverse-variance weighted (primary analyses), Mendelian Randomization-Pleiotropy RESidual Sum and Outlier, simple median, and weighted median. We conducted secondary analyses to determine if associations varied by cancer subtype (colorectal cancer location, lung cancer histology), sex (colorectal and pancreatic cancers), or smoking history (lung and pancreatic cancer). All statistical tests were 2-sided. Results: The genetic predisposition index for chronic or aggressive periodontitis was statistically significantly associated with a 3% increased risk of colorectal cancer (per unit increase in genetic index of periodontal disease; P = .03), 3% increased risk of colon cancer (P = .02), 4% increased risk of proximal colon cancer (P = .01), and 3% increased risk of colorectal cancer among females (P = .04); however, it was not statistically significantly associated with the risk of lung cancer or pancreatic cancer, overall or within most subgroups. Conclusions: Genetic predisposition to periodontitis may be associated with colorectal cancer risk. Further research should determine whether increased periodontitis prevention and increased cancer surveillance of patients with periodontitis is warranted.

• Publikační typ
• časopisecké články MeSH

BACKGROUND & AIMS: Human studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development. METHODS: Serum levels of IGF1 were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow-up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genome-wide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls]) RESULTS: After a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariable-adjusted model, circulating level of IGF1 associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% confidence interval [CI] 1.05-1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio 1.08; 95% CI 1.03-1.12; P = 3.3 × 10-4). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI 1.06-1.18; P = 4.2 × 10-5). Colorectal cancer risk was associated with only 1 variant in the IGFBP3 gene region (rs11977526), which also associated with anthropometric traits and circulating level of IGF2. CONCLUSIONS: In an analysis of blood samples from almost 400,000 participants in the UK Biobank, we found an association between circulating level of IGF1 and colorectal cancer. Using genetic data from 52,865 cases with colorectal cancer and 46,287 controls, a higher level of IGF1, determined by genetic factors, was associated with colorectal cancer. Further studies are needed to determine how this signaling pathway might contribute to colorectal carcinogenesis.

• MeSH
• hodnocení rizik metody   MeSH
• IGFBP-3 krev   genetika   MeSH
• incidence MeSH
• insulinu podobný růstový faktor I analýza   genetika   MeSH
• insulinu podobný růstový faktor II analýza   MeSH
• jednonukleotidový polymorfismus MeSH
• kolorektální nádory krev   epidemiologie   genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mendelovská randomizace MeSH
• nádorové biomarkery krev   genetika   MeSH
• následné studie MeSH
• registrace statistika a číselné údaje   MeSH
• rizikové faktory MeSH
• senioři MeSH
• sexuální faktory MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, N.I.H., Intramural MeSH
• Geografické názvy
• Spojené království MeSH

BACKGROUND: Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. METHODS: We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. RESULTS: In sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. CONCLUSIONS: Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.

• MeSH
• adipozita genetika   MeSH
• celogenomová asociační studie statistika a číselné údaje   MeSH
• dospělí MeSH
• genetická predispozice k nemoci MeSH
• index tělesné hmotnosti MeSH
• jednonukleotidový polymorfismus MeSH
• kolorektální nádory epidemiologie   etiologie   genetika   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mendelovská randomizace MeSH
• metabolom genetika   MeSH
• obezita komplikace   epidemiologie   genetika   metabolismus   MeSH
• poměr pasu a boků MeSH
• rizikové faktory MeSH
• sexuální faktory MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Geografické názvy
• Evropa MeSH

BACKGROUND: The association among gallbladder disease, cholecystectomy, and pancreatic cancer is unclear. Moreover, time interval between gallbladder disease or cholecystectomy and pancreatic cancer diagnosis is not considered in most previous studies. AIM: To quantify the association among gallbladder disease, cholecystectomy, and pancreatic cancer, considering time since first diagnosis of gallbladder disease or cholecystectomy. METHODS: We used data from nine case-control studies within the Pancreatic Cancer Case-Control Consortium, including 5760 cases of adenocarcinoma of the exocrine pancreas and 8437 controls. We estimated pooled odds ratios and the corresponding 95% confidence intervals by estimating study-specific odds ratios through multivariable unconditional logistic regression models, and then pooling the obtained estimates using fixed-effects models. RESULTS: Compared with patients with no history of gallbladder disease, the pooled odds ratio of pancreatic cancer was 1.69 (95% confidence interval, 1.51-1.88) for patients reporting a history of gallbladder disease. The odds ratio was 4.90 (95% confidence interval, 3.45-6.97) for gallbladder disease diagnosed <2 years before pancreatic cancer diagnosis and 1.11 (95% confidence interval, 0.96-1.29) when ≥2 years elapsed. The pooled odds ratio was 1.64 (95% confidence interval, 1.43-1.89) for patients who underwent cholecystectomy, as compared to those without cholecystectomy. The odds ratio was 7.00 (95% confidence interval, 4.13-11.86) for a surgery <2 years before pancreatic cancer diagnosis and 1.28 (95% confidence interval, 1.08-1.53) for a surgery ≥2 years before. CONCLUSIONS: There appears to be no long-term effect of gallbladder disease on pancreatic cancer risk, and at most a modest one for cholecystectomy. The strong short-term association can be explained by diagnostic bias and reverse causation.

• MeSH
• cholecystektomie škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mezinárodní agentury MeSH
• nádory slinivky břišní etiologie   patologie   MeSH
• nemoci žlučníku patologie   chirurgie   MeSH
• prognóza MeSH
• rizikové faktory MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Physical activity has been associated with lower risks of breast and colorectal cancer in epidemiological studies; however, it is unknown if these associations are causal or confounded. In two-sample Mendelian randomisation analyses, using summary genetic data from the UK Biobank and GWA consortia, we found that a one standard deviation increment in average acceleration was associated with lower risks of breast cancer (odds ratio [OR]: 0.51, 95% confidence interval [CI]: 0.27 to 0.98, P-value = 0.04) and colorectal cancer (OR: 0.66, 95% CI: 0.48 to 0.90, P-value = 0.01). We found similar magnitude inverse associations for estrogen positive (ER+ve) breast cancer and for colon cancer. Our results support a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer. Based on these data, the promotion of physical activity is probably an effective strategy in the primary prevention of these commonly diagnosed cancers.

• MeSH
• akcelerometrie MeSH
• cvičení * MeSH
• genetická predispozice k nemoci * MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• kolorektální nádory genetika   MeSH
• lidé MeSH
• mendelovská randomizace * MeSH
• nádory prsu genetika   MeSH
• odds ratio MeSH
• rizikové faktory MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND: Worldwide implementation of risk-based cardiovascular disease (CVD) prevention requires risk prediction tools that are contemporarily recalibrated for the target country and can be used where laboratory measurements are unavailable. We present two cardiovascular risk scores, with and without laboratory-based measurements, and the corresponding risk charts for 182 countries to predict 10-year risk of fatal and non-fatal CVD in adults aged 40-74 years. METHODS: Based on our previous laboratory-based prediction model (Globorisk), we used data from eight prospective studies to estimate coefficients of the risk equations using proportional hazard regressions. The laboratory-based risk score included age, sex, smoking, blood pressure, diabetes, and total cholesterol; in the non-laboratory (office-based) risk score, we replaced diabetes and total cholesterol with BMI. We recalibrated risk scores for each sex and age group in each country using country-specific mean risk factor levels and CVD rates. We used recalibrated risk scores and data from national surveys (using data from adults aged 40-64 years) to estimate the proportion of the population at different levels of CVD risk for ten countries from different world regions as examples of the information the risk scores provide; we applied a risk threshold for high risk of at least 10% for high-income countries (HICs) and at least 20% for low-income and middle-income countries (LMICs) on the basis of national and international guidelines for CVD prevention. We estimated the proportion of men and women who were similarly categorised as high risk or low risk by the two risk scores. FINDINGS: Predicted risks for the same risk factor profile were generally lower in HICs than in LMICs, with the highest risks in countries in central and southeast Asia and eastern Europe, including China and Russia. In HICs, the proportion of people aged 40-64 years at high risk of CVD ranged from 1% for South Korean women to 42% for Czech men (using a ≥10% risk threshold), and in low-income countries ranged from 2% in Uganda (men and women) to 13% in Iranian men (using a ≥20% risk threshold). More than 80% of adults were similarly classified as low or high risk by the laboratory-based and office-based risk scores. However, the office-based model substantially underestimated the risk among patients with diabetes. INTERPRETATION: Our risk charts provide risk assessment tools that are recalibrated for each country and make the estimation of CVD risk possible without using laboratory-based measurements. FUNDING: National Institutes of Health.

• MeSH
• celosvětové zdraví MeSH
• dospělí MeSH
• hodnocení rizik metody   MeSH
• kardiovaskulární nemoci diagnóza   epidemiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• prospektivní studie MeSH
• rizikové faktory MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND: Treatment of cardiovascular risk factors based on disease risk depends on valid risk prediction equations. We aimed to develop, and apply in example countries, a risk prediction equation for cardiovascular disease (consisting here of coronary heart disease and stroke) that can be recalibrated and updated for application in different countries with routinely available information. METHODS: We used data from eight prospective cohort studies to estimate coefficients of the risk equation with proportional hazard regressions. The risk prediction equation included smoking, blood pressure, diabetes, and total cholesterol, and allowed the effects of sex and age on cardiovascular disease to vary between cohorts or countries. We developed risk equations for fatal cardiovascular disease and for fatal plus non-fatal cardiovascular disease. We validated the risk equations internally and also using data from three cohorts that were not used to create the equations. We then used the risk prediction equation and data from recent (2006 or later) national health surveys to estimate the proportion of the population at different levels of cardiovascular disease risk in 11 countries from different world regions (China, Czech Republic, Denmark, England, Iran, Japan, Malawi, Mexico, South Korea, Spain, and USA). FINDINGS: The risk score discriminated well in internal and external validations, with C statistics generally 70% or more. At any age and risk factor level, the estimated 10 year fatal cardiovascular disease risk varied substantially between countries. The prevalence of people at high risk of fatal cardiovascular disease was lowest in South Korea, Spain, and Denmark, where only 5-10% of men and women had more than a 10% risk, and 62-77% of men and 79-82% of women had less than a 3% risk. Conversely, the proportion of people at high risk of fatal cardiovascular disease was largest in China and Mexico. In China, 33% of men and 28% of women had a 10-year risk of fatal cardiovascular disease of 10% or more, whereas in Mexico, the prevalence of this high risk was 16% for men and 11% for women. The prevalence of less than a 3% risk was 37% for men and 42% for women in China, and 55% for men and 69% for women in Mexico. INTERPRETATION: We developed a cardiovascular disease risk equation that can be recalibrated for application in different countries with routinely available information. The estimated percentage of people at high risk of fatal cardiovascular disease was higher in low-income and middle-income countries than in high-income countries. FUNDING: US National Institutes of Health, UK Medical Research Council, Wellcome Trust.

• MeSH
• cévní mozková příhoda epidemiologie   MeSH
• diagnostické techniky kardiovaskulární normy   MeSH
• dospělí MeSH
• hodnocení rizik metody   MeSH
• kalibrace MeSH
• kardiovaskulární nemoci epidemiologie   mortalita   MeSH
• koronární nemoc epidemiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• proporcionální rizikové modely MeSH
• prospektivní studie MeSH
• rizikové faktory MeSH
• senioři MeSH
• ukazatele zdravotního stavu MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH