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1.
Nat Commun ; 11(1): 27, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31911640

RESUMO

Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV1: rg = 0.098, p = 2.3 × 10-8) and the ratio of FEV1 to forced vital capacity (FEV1/FVC: rg = 0.137, p = 2.0 × 10-12). Mendelian randomization analyses demonstrate that reduced FEV1 increases squamous cell carcinoma risk (odds ratio (OR) = 1.51, 95% confidence intervals: 1.21-1.88), while reduced FEV1/FVC increases the risk of adenocarcinoma (OR = 1.17, 1.01-1.35) and lung cancer in never smokers (OR = 1.56, 1.05-2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis.

2.
J Natl Cancer Inst ; 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31917448

RESUMO

BACKGROUND: Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies (GWAS) in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. METHODS: To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study (TWAS) in Europeans using three approaches, FUSION, MetaXcan and SMulTiXcan. We integrated GWAS summary statistics from 9,040 pancreatic cancer cases and 12,496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics, LTG (n = 95) and Genotype-Tissue Expression, GTEx v7 (n = 174) datasets), and data from 48 different tissues (GTEx v7, n = 74-421 samples). RESULTS: We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (FDR < 0.05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12:, PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at 6 known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci, and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1 and BCAR1 at known loci) remained statistically significant after Bonferroni correction. CONCLUSIONS: By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.

3.
Int J Cancer ; 146(3): 664-670, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30895617

RESUMO

Breast cancer is the most common cancer and the second-leading cause of cancer-related death among women. Inconsistent findings for the relationship between melatonin levels, sleep duration and breast cancer have been reported. We investigated the association of sleep duration at cohort entry and its interaction with body mass index (BMI) with risk of developing breast cancer in the large population-based Multiethnic Cohort study. Among the 74,481 at-risk participants, 5,790 breast cancer cases were identified during the study period. Although we detected no significant association between sleep duration and breast cancer incidence, higher risk estimates for short (HR = 1.03; 95% CI: 0.97-1.09) and long sleep (HR = 1.05; 95% CI: 0.95-1.15) compared to normal sleep (7-8 hr) were found. The patterns for models stratified by age, BMI, ethnicity and hormone receptor status were similar but did not indicate significant interaction effects. When examining the combined sleep duration and BMI interaction effect, in comparison to the normal BMI-normal sleep group, risk estimates for underweight, overweight and obesity were similar across categories of sleep duration (≤6, 7-8, and ≥9 hr). The underweight-normal sleep group had lower breast cancer incidence (HR = 0.66, 95% CI: 0.50-0.86), whereas the overweight-short sleep, overweight-normal sleep group and all obese women experienced elevated breast cancer incidence. The respective HRs for short, normal and long sleep among obese women were 1.35 (95% CI: 1.20-1.53), 1.27 (95% CI: 1.15-1.42) and 1.46 (95% CI: 1.21-1.76). Future perspectives need to examine the possibility that sleep quality, variations in circadian rhythm and melatonin are involved in breast cancer etiology.

4.
Int J Cancer ; 146(3): 699-711, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30924138

RESUMO

Previous studies using different exposure methods to assess air pollution and breast cancer risk among primarily whites have been inconclusive. Air pollutant exposures of particulate matter and oxides of nitrogen were estimated by kriging (NOx , NO2 , PM10 , PM2.5 ), land use regression (LUR, NOx , NO2 ) and California Line Source Dispersion model (CALINE4, NOx , PM2.5 ) for 57,589 females from the Multiethnic Cohort, residing largely in Los Angeles County from recruitment (1993-1996) through 2010. Cox proportional hazards models were used to examine the associations between time-varying air pollution and breast cancer incidence adjusting for confounding factors. Stratified analyses were conducted by race/ethnicity and distance to major roads. Among all women, breast cancer risk was positively but not significantly associated with NOx (per 50 parts per billion [ppb]) and NO2 (per 20 ppb) determined by kriging and LUR and with PM2.5 and PM10 (per 10 µg/m3 ) determined by kriging. However, among women who lived within 500 m of major roads, significantly increased risks were observed with NOx (hazard ratio [HR] = 1.35, 95% confidence interval [95% CI]: 1.02-1.79), NO2 (HR = 1.44, 95% CI: 1.04-1.99), PM10 (HR = 1.29, 95% CI: 1.07-1.55) and PM2.5 (HR = 1.85, 95% CI: 1.15-2.99) determined by kriging and NOx (HR = 1.21, 95% CI:1.01-1.45) and NO2 (HR = 1.26, 95% CI: 1.00-1.59) determined by LUR. No overall associations were observed with exposures assessed by CALINE4. Subgroup analyses suggested stronger associations of NOx and NO2 among African Americans and Japanese Americans. Further studies of multiethnic populations to confirm the effects of air pollution, particularly near-roadway exposures, on the risk of breast cancer is warranted.

5.
Int J Cancer ; 146(3): 861-873, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31037736

RESUMO

Alcohol consumption is an established risk factor for colorectal cancer (CRC). However, while studies have consistently reported elevated risk of CRC among heavy drinkers, associations at moderate levels of alcohol consumption are less clear. We conducted a combined analysis of 16 studies of CRC to examine the shape of the alcohol-CRC association, investigate potential effect modifiers of the association, and examine differential effects of alcohol consumption by cancer anatomic site and stage. We collected information on alcohol consumption for 14,276 CRC cases and 15,802 controls from 5 case-control and 11 nested case-control studies of CRC. We compared adjusted logistic regression models with linear and restricted cubic splines to select a model that best fit the association between alcohol consumption and CRC. Study-specific results were pooled using fixed-effects meta-analysis. Compared to non-/occasional drinking (≤1 g/day), light/moderate drinking (up to 2 drinks/day) was associated with a decreased risk of CRC (odds ratio [OR]: 0.92, 95% confidence interval [CI]: 0.88-0.98, p = 0.005), heavy drinking (2-3 drinks/day) was not significantly associated with CRC risk (OR: 1.11, 95% CI: 0.99-1.24, p = 0.08) and very heavy drinking (more than 3 drinks/day) was associated with a significant increased risk (OR: 1.25, 95% CI: 1.11-1.40, p < 0.001). We observed no evidence of interactions with lifestyle risk factors or of differences by cancer site or stage. These results provide further evidence that there is a J-shaped association between alcohol consumption and CRC risk. This overall pattern was not significantly modified by other CRC risk factors and there was no effect heterogeneity by tumor site or stage.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31826910

RESUMO

BACKGROUND: Risk variants identified so far for colorectal cancer (CRC) explain only a small proportion of familial risk of this cancer, particularly in Asians. METHODS: We performed a genome-wide association study (GWAS) of CRC in East Asians including 23,572 CRC cases and 48,700 controls. To identify novel risk loci, we selected sixty promising risk variants for replication using data from 58,131 CRC cases and 67,347 controls of European descent. To identify additional risk variants in known CRC loci, we performed conditional analyses in East Asians. RESULTS: An indel variant, rs67052019 at 1p13.3, was found to be associated with CRC risk at P=3.9 x 10-8 in Asians (OR per allele deletion=1.13, 95%CI=1.08-1.18). This association was replicated in European descendants using a variant (rs2938616) in complete linkage disequilibrium with rs67052019 (P=7.7 x 10-3). Of the remaining 59 variants, 12 showed an association at P<0.05 in the European-ancestry study, including rs11108175 and rs9634162 at P<5×10-8 and two variants with an association near the genome-wide significance level (rs60911071, P=5.8×10-8; rs62558833, P=7.5×10-8) in the combined analyses of Asian- and European-ancestry data. In addition, using data from East Asians, we identified 13 new risk variants at 11 loci reported from previous GWAS. CONCLUSIONS: In this large GWAS, we identified three novel risk loci and two highly suggestive loci for CRC risk and provided evidence for potential roles of multiple genes and pathways in the etiology of CRC. IMPACT: Our study provides novel data to improve the understanding of the genetic basis for CRC risk.

7.
Neurology ; 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31796528

RESUMO

OBJECTIVE: To examine the association between prediagnostic plasma polyunsaturated fatty acids levels (PUFA) and amyotrophic lateral sclerosis (ALS). METHODS: We identified 275 individuals who developed ALS while enrolled in 5 US prospective cohorts, and randomly selected 2 controls, alive at the time of the case diagnosis, matched on cohort, birth year, sex, ethnicity, fasting status, and time of blood draw. We measured PUFA, expressed as percentages of total fatty acids, using gas liquid chromatography and used conditional logistic regression to estimate risk ratios (RR) and 95% confidence intervals (CI) for the association between PUFA and ALS. RESULTS: There was no association between total, n-3, and n-6 PUFA, eicosapentaenoic acid, or docosapentaenoic acid levels and ALS. Higher plasma α-linolenic acid (ALA) in men was associated with lower risk of ALS in age- and matching factor-adjusted analyses (top vs bottom quartile: RR = 0.21 [95% CI 0.07, 0.58], p for trend = 0.004). In women, higher plasma arachidonic acid was associated with higher risk (top vs bottom quartile: RR = 1.65 [95% CI 0.99, 2.76], p for trend = 0.052). Multivariable adjustment, including correlated PUFA, did not change the findings for ALA and arachidonic acid. In men and women combined, higher plasma docosahexaenoic acid (DHA) was associated with higher risk of ALS (top vs bottom quartile: RR = 1.56 [95% CI 1.01, 2.41], p for trend = 0.054), but in multivariable models the association was only evident in men. CONCLUSIONS: The majority of individual PUFAs were not associated with ALS. In men, ALA was inversely and DHA was positively related to risk of ALS, while in women arachidonic acid was positively related. These findings warrant confirmation in future studies.

8.
Gastroenterology ; 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31884074

RESUMO

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 and other proteins 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 level associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% 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 x 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 x 10-5). Colorectal cancer risk was associated with only 1 variant in IGFBP3 (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.

9.
Breast Cancer Res ; 21(1): 144, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31847907

RESUMO

BACKGROUND: Breast cancer survivors are at risk for contralateral breast cancer (CBC), with the consequent burden of further treatment and potentially less favorable prognosis. We aimed to develop and validate a CBC risk prediction model and evaluate its applicability for clinical decision-making. METHODS: We included data of 132,756 invasive non-metastatic breast cancer patients from 20 studies with 4682 CBC events and a median follow-up of 8.8 years. We developed a multivariable Fine and Gray prediction model (PredictCBC-1A) including patient, primary tumor, and treatment characteristics and BRCA1/2 germline mutation status, accounting for the competing risks of death and distant metastasis. We also developed a model without BRCA1/2 mutation status (PredictCBC-1B) since this information was available for only 6% of patients and is routinely unavailable in the general breast cancer population. Prediction performance was evaluated using calibration and discrimination, calculated by a time-dependent area under the curve (AUC) at 5 and 10 years after diagnosis of primary breast cancer, and an internal-external cross-validation procedure. Decision curve analysis was performed to evaluate the net benefit of the model to quantify clinical utility. RESULTS: In the multivariable model, BRCA1/2 germline mutation status, family history, and systemic adjuvant treatment showed the strongest associations with CBC risk. The AUC of PredictCBC-1A was 0.63 (95% prediction interval (PI) at 5 years, 0.52-0.74; at 10 years, 0.53-0.72). Calibration-in-the-large was -0.13 (95% PI: -1.62-1.37), and the calibration slope was 0.90 (95% PI: 0.73-1.08). The AUC of Predict-1B at 10 years was 0.59 (95% PI: 0.52-0.66); calibration was slightly lower. Decision curve analysis for preventive contralateral mastectomy showed potential clinical utility of PredictCBC-1A between thresholds of 4-10% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. CONCLUSIONS: We developed a reasonably calibrated model to predict the risk of CBC in women of European-descent; however, prediction accuracy was moderate. Our model shows potential for improved risk counseling, but decision-making regarding contralateral preventive mastectomy, especially in the general breast cancer population where limited information of the mutation status in BRCA1/2 is available, remains challenging.

10.
Int J Cancer ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31696517

RESUMO

We have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of our study has been to integrate the complete GWAS results with a large-scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n = 1,038) to identify candidate causal genes for lung cancer. We performed transcriptome-wide association study (TWAS) for lung cancer overall, by histology (adenocarcinoma, squamous cell carcinoma and small cell lung cancer) and smoking subgroups (never- and ever-smokers). We performed replication analysis using lung data from the Genotype-Tissue Expression (GTEx) project. DNA damage assays were performed in human lung fibroblasts for selected TWAS genes. As expected, the main TWAS signal for all histological subtypes and ever-smokers was on chromosome 15q25. The gene most strongly associated with lung cancer at this locus using the TWAS approach was IREB2 (pTWAS = 1.09E-99), where lower predicted expression increased lung cancer risk. A new lung adenocarcinoma susceptibility locus was revealed on 9p13.3 and associated with higher predicted expression of AQP3 (pTWAS = 3.72E-6). Among the 45 previously described lung cancer GWAS loci, we mapped candidate target gene for 17 of them. The association AQP3-adenocarcinoma on 9p13.3 was replicated using GTEx (pTWAS = 6.55E-5). Consistent with the effect of risk alleles on gene expression levels, IREB2 knockdown and AQP3 overproduction promote endogenous DNA damage. These findings indicate genes whose expression in lung tissue directly influences lung cancer risk.

12.
Artigo em Inglês | MEDLINE | ID: mdl-31727725

RESUMO

BACKGROUND: As the stronger association of obesity with postmenopausal breast cancer in Asian than white women may be due to body fat distribution, we examined the relation of adiposity measures with percent mammographic density (PMD), a strong predictor of breast cancer incidence. METHODS: A total of 938 women from five ethnic groups (69.1±2.7 years) in the Adiposity Phenotype Study (APS) underwent DXA and MRI imaging. PMD was assessed in routine mammograms using a computer-assisted method. Spearman correlation coefficients were computed and general linear models were applied to estimate regression coefficients (ß) for PMD per 0.5 SD units of adiposity measures while adjusting for known confounders including DXA total body fat. RESULTS: For 701 (75%) of the participants (69.1±2.7 years), valid mammograms were obtained. Whereas total body fat, the trunk-to-periphery-fat ratio (TPFR), visceral fat (VAT), and subcutaneous fat (SAT) were inversely correlated with PMD (p<0.0001), the VAT/SAT ratio correlated positively (rspearman=0.10; p=0.01). In fully adjusted models, PMD remained inversely related to TPFR and SAT and disappeared for VAT, while it was strengthened for VAT/SAT (ß=0.51; p=0.009). This relation was stronger in Japanese Americans than other ethnic groups. CONCLUSION: This is the first study to show an association of a high VAT/SAT ratio with greater PMD, a marker of breast cancer risk after taking into account total body fat. IMPACT: The results indicate a link between the propensity to accumulate VAT and the amount of fat in the breast (1-PMD), which may influence the relation of obesity with breast cancer incidence.

13.
J Acad Nutr Diet ; 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31732484

RESUMO

BACKGROUND: For some quantitative food frequency questionnaire (QFFQ) items, data may be insufficient to set gram weights for multiple portion size (PS) categories. Ratios of food amounts across PS categories may be used to quantify these PS for less frequently consumed food items. OBJECTIVE: To explore the ratios of food amounts reported in 24-hour dietary recalls (24HDRs) by a sample of participants in a cohort study who chose the A (smallest) or C (largest) PS category on the QFFQ, relative to the food amounts for those who chose the B PS category. DESIGN: This study was conducted as a cross-sectional design. PARTICIPANTS/SETTING: Data were from participants (n=2,360) who completed three 24HDRs and the QFFQ in a calibration study of the Multiethnic Cohort Study in 1994-1997. MAIN OUTCOME MEASURES: Median food amounts were calculated from 24HDRs for participants who selected each PS category (A, smallest; B; and C, largest) of items on the QFFQ. A-to-B and C-to-B ratios were computed if reported by five or more people in the 24HDRs: A-to-B ratios for 68 items (men) and 88 items (women); C-to-B ratios for 93 items (men) and 79 items (women). STATISTICAL ANALYSES PERFORMED: The t test was used to compare the mean A-to-B ratios and C-to-B ratios as preset on the QFFQ with those from the 24HDRs and to examine sex differences. Analysis of variance was used to compare the mean ratios among race and ethnicity groups. RESULTS: Mean A-to-B and C-to-B ratios were 0.71±0.15 and 1.45±0.35 in men and 0.71±0.15 and 1.44±0.40 in women based on the 24HDRs. Compared with the original QFFQ PS (A-to-B ratio=0.5±0.07; C-to-B ratio=1.8±0.30), the ratios were closer to 1 both in men and women (P<0.001). There were no significant sex differences or racial or ethnic differences. CONCLUSIONS: These results provide guidance on appropriate ratios to use to set values for small and large PS categories on a QFFQ, particularly for items with insufficient information on usual PS.

14.
Int J Cancer ; 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31577861

RESUMO

Genome-wide association studies (GWAS) have identified 45 susceptibility loci associated with lung cancer. Only less than SNPs, small insertions and deletions (INDELs) are the second most abundant genetic polymorphisms in the human genome. INDELs are highly associated with multiple human diseases, including lung cancer. However, limited studies with large-scale samples have been available to systematically evaluate the effects of INDELs on lung cancer risk. Here, we performed a large-scale meta-analysis to evaluate INDELs and their risk for lung cancer in 23,202 cases and 19,048 controls. Functional annotations were performed to further explore the potential function of lung cancer risk INDELs. Conditional analysis was used to clarify the relationship between INDELs and SNPs. Four new risk loci were identified in genome-wide INDEL analysis (1p13.2: rs5777156, Insertion, OR = 0.92, p = 9.10 × 10-8 ; 4q28.2: rs58404727, Deletion, OR = 1.19, p = 5.25 × 10-7 ; 12p13.31: rs71450133, Deletion, OR = 1.09, p = 8.83 × 10-7 ; and 14q22.3: rs34057993, Deletion, OR = 0.90, p = 7.64 × 10-8 ). The eQTL analysis and functional annotation suggested that INDELs might affect lung cancer susceptibility by regulating the expression of target genes. After conducting conditional analysis on potential causal SNPs, the INDELs in the new loci were still nominally significant. Our findings indicate that INDELs could be potentially functional genetic variants for lung cancer risk. Further functional experiments are needed to better understand INDEL mechanisms in carcinogenesis.

15.
Br J Cancer ; 121(10): 869-876, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31551580

RESUMO

BACKGROUND: Type 2 diabetes mellitus and high total cholesterol and triglycerides are known to be associated with increased colorectal cancer risk for the general population. These associations are unknown for people with a germline DNA mismatch repair gene mutation (Lynch syndrome), who are at high risk of colorectal cancer. METHODS: This study included 2023 (56.4% female) carriers with a mismatch repair gene mutation (737 in MLH1, 928 in MSH2, 230 in MSH6, 106 in PMS2, 22 in EPCAM) recruited by the Colon Cancer Family Registry between 1998 and 2012. Weighted Cox regression was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for the associations between self-reported type 2 diabetes, high cholesterol, triglyceride and colorectal cancer risk. RESULTS:  Overall, 802 carriers were diagnosed with colorectal cancer at a median age of 42 years. A higher risk of colorectal cancer was observed in those with self-reported type-2 diabetes (HR 1.92; 95% CI, 1.03-3.58) and high cholesterol (HR 1.76; CI 1.23-2.52) compared with those without these conditions. There was no evidence of high triglyceride being associated with colorectal cancer risk. CONCLUSION: For people with Lynch syndrome, self-reported type-2 diabetes mellitus and high cholesterol were associated with increased colorectal cancer risk.

16.
Hepatology ; 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31553803

RESUMO

Epidemiological data on dietary risk factors for NAFLD from population-based studies, particularly in an ethnically diverse population, are scarce. We examined dietary factors in relation to NAFLD risk in African Americans, Japanese Americans, Latinos, Native Hawaiians, and whites in the Multiethnic Cohort (MEC). A nested case-control analysis was conducted within the MEC, a large prospective study with >215,000 older-adult participants in Hawaii and California. NAFLD was identified using Medicare claims data, and controls were selected among participants without liver disease and individually matched to cases by birth year, sex, ethnicity, and length of Medicare enrollment. Diet was assessed at baseline via a validated quantitative food frequency questionnaire. Diet-NAFLD associations were quantified by odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable conditional logistic regression. The study consisted of 2,974 NAFLD cases (518 with cirrhosis; 2,456 without cirrhosis) and 29,474 matched controls. Red meat (P trend=0.010), processed red meat (P trend= 0.004), poultry (P trend= 0.005) and cholesterol (P trend= 0.005) intakes were positively associated with NAFLD, while dietary fiber intake (P trend=0.003) was inversely associated with risk. Stronger associations were observed between red meat and cholesterol and NAFLD with cirrhosis than without cirrhosis (P heterogeneity ≤0.014). Conclusion Dietary factors are independently associated with NAFLD and NAFLD-related cirrhosis in a multiethnic population. Decreasing the consumption of cholesterol, red and processed meat and poultry and increasing consumption of fiber may reduce the risk for NAFLD and related advanced liver disease.

17.
Int J Cancer ; 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31469419

RESUMO

Women of African ancestry have lower incidence of epithelial ovarian cancer (EOC) yet worse survival compared to women of European ancestry. We conducted a genome-wide association study in African ancestry women with 755 EOC cases, including 537 high-grade serous ovarian carcinomas (HGSOC) and 1,235 controls. We identified four novel loci with suggestive evidence of association with EOC (p < 1 × 10-6 ), including rs4525119 (intronic to AKR1C3), rs7643459 (intronic to LOC101927394), rs4286604 (12 kb 3' of UGT2A2) and rs142091544 (5 kb 5' of WWC1). For HGSOC, we identified six loci with suggestive evidence of association including rs37792 (132 kb 5' of follistatin [FST]), rs57403204 (81 kb 3' of MAGEC1), rs79079890 (LOC105376360 intronic), rs66459581 (5 kb 5' of PRPSAP1), rs116046250 (GABRG3 intronic) and rs192876988 (32 kb 3' of GK2). Among the identified variants, two are near genes known to regulate hormones and diseases of the ovary (AKR1C3 and FST), and two are linked to cancer (AKR1C3 and MAGEC1). In follow-up studies of the 10 identified variants, the GK2 region SNP, rs192876988, showed an inverse association with EOC in European ancestry women (p = 0.002), increased risk of ER positive breast cancer in African ancestry women (p = 0.027) and decreased expression of GK2 in HGSOC tissue from African ancestry women (p = 0.004). A European ancestry-derived polygenic risk score showed positive associations with EOC and HGSOC in women of African ancestry suggesting shared genetic architecture. Our investigation presents evidence of variants for EOC shared among European and African ancestry women and identifies novel EOC risk loci in women of African ancestry.

18.
Int J Cancer ; 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31276202

RESUMO

Cell-mediated immune suppression may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), quinolinic acid (QA) and neopterin as markers of immune regulation and inflammation with lung cancer risk in 5,364 smoking-matched case-control pairs from 20 prospective cohorts included in the international Lung Cancer Cohort Consortium. All biomarkers were quantified by mass spectrometry-based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with individual biomarkers were calculated using conditional logistic regression with adjustment for circulating cotinine. Compared to the lowest quintile, the highest quintiles of kynurenine, KTR, QA and neopterin were associated with a 20-30% higher risk, and tryptophan with a 15% lower risk of lung cancer (all ptrend < 0.05). The strongest associations were seen for current smokers, where the adjusted ORs (95% CIs) of lung cancer for the highest quintile of KTR, QA and neopterin were 1.42 (1.15-1.75), 1.42 (1.14-1.76) and 1.45 (1.13-1.86), respectively. A stronger association was also seen for KTR and QA with risk of lung squamous cell carcinoma followed by adenocarcinoma, and for lung cancer diagnosed within the first 2 years after blood draw. This study demonstrated that components of the tryptophan-kynurenine pathway with immunomodulatory effects are associated with risk of lung cancer overall, especially for current smokers. Further research is needed to evaluate the role of these biomarkers in lung carcinogenesis and progression.

19.
J Am Coll Nutr ; : 1-8, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31291155

RESUMO

Objective: To understand how diet quality affects chronic disease etiology, the associations of 4 a priori diet quality indices with blood levels of lipid-soluble micronutrients and biomarkers of inflammation, lipid, and glucose metabolism were examined in 5 ethnic groups. Methods: In a cross-sectional design, the Adiposity Phenotype Study, a subset of the Multiethnic Cohort in Hawaii and Los Angeles, recruited participants of white, African American, Native Hawaiian, Japanese American, and Latino ancestry. A total of 896 men and 910 women completed a validated quantitative food frequency questionnaire and anthropometric measurements and donated a fasting blood sample. Using general linear models, covariate-adjusted mean levels of lipid-soluble micronutrients (total carotenes, lycopene, total tocopherols, total lutein, cryptoxanthins), biomarkers of inflammation (C-reactive protein [CRP], tumor necrosis factor- α ), adipokines (adiponectin, leptin), lipids (total cholesterol, high-density lipoprotein cholesterol [HDL-C], triglycerides), and glucose metabolism (glucose, insulin, homeostatic model assessment of insulin resistance [HOMA-IR]) were computed across tertiles of 4 a priori dietary indices Healthy Eating Index (HEI)-2010, Alternative HEI (AHEI)-2010, alternate Mediterranean Diet (aMED), Dietary Approaches to Stop Hypertension (DASH); trends were evaluated in models with diet quality scores as continuous variables. Results: With better diet quality, levels of carotenes, lutein, cryptoxanthin, adiponectin, and HDL-C were significantly higher (ptrend < 0.01), whereas levels of CRP, leptin, total cholesterol, triglycerides, glucose, insulin, and HOMA-IR were inversely associated (ptrend < 0.05) with diet quality. With the exception of cryptoxanthins and triglycerides, the associations were consistent across ethnic groups. Conclusions: These findings confirm the association between diet quality and nutrition-related biomarkers and support the idea that a high-quality diet positively influences biologic pathways involved in chronic disease etiology across different ethnic groups.

20.
J Nutr ; 149(9): 1575-1584, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31187868

RESUMO

BACKGROUND: Variation in gut microbial community structure is partly attributed to variations in diet. A priori dietary indexes capture diet quality and have been associated with chronic disease risk. OBJECTIVES: The aim of this study was to examine the association of diet quality, as assessed by the Healthy Eating Index, Alternative Healthy Eating Index-2010, alternate Mediterranean Diet, and the Dietary Approaches to Stop Hypertension Trial, with measures of fecal microbial community structure assessed in the Adiposity Phenotype Study (APS), an ethnically diverse study population with varied food intakes. METHODS: Multiethnic Cohort Study members completed a validated quantitative food frequency questionnaire (QFFQ) at cohort entry (1993-1996) and, for the APS subset, at clinic visit (2013-2015), when they also provided a stool sample. DNA was extracted from stool, and the V1-V3 region of the 16S rRNA gene was amplified and sequenced. Dietary index scores were computed based on the QFFQ and an extensive nutritional database. Using linear regression adjusted for relevant covariates, we estimated associations of dietary quality with microbiome measures and computed adjusted mean values of microbial measures by tertiles of dietary index scores. RESULTS: The 858 men and 877 women of white, Japanese American, Latino, Native Hawaiian, and African American ancestry had a mean age of 69.2 years at stool collection. Alpha diversity according to the Shannon index increased by 1-2% across tertiles of all 4 diet indexes measured at clinic visit. The mean relative abundance of the phylum Actinobacteria was 13-19% lower with higher diet quality across all 4 indexes (difference between tertile 3 and tertile 1 divided by tertile 1). Of the 104 bacterial genera tested, 21 (primarily from the phylum Firmicutes) were positively associated with at least 1 index after Bonferroni adjustment. CONCLUSION: Diet quality was strongly associated with fecal microbial alpha diversity and beta diversity and several genera previously associated with human health.

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