Publications by authors named "Xiao-Ou Shu"

834 Publications

Racial disparity in taxane-induced neutropenia among cancer patients.

Cancer Med 2021 Sep 21. Epub 2021 Sep 21.

Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.

Background: Large interindividual variations have been reported in chemotherapy-induced toxicities. Little is known whether racial disparities exist in neutropenia associated with taxanes.

Methods: Patients with a diagnosis of primary cancer who underwent chemotherapy with taxanes were identified from Vanderbilt University Medical Center's Synthetic Derivative. Multinomial regression models were applied to evaluate odds ratios (ORs) and 95% confidence intervals (CIs) of neutropenia associated with race, with adjustments for demographic variables, baseline neutrophil count, chemotherapy-related information, prior treatments, and cancer site.

Results: A total of 3492 patients were included in the study. Compared with White patients, grade 2 or higher neutropenia was more frequently recorded among Black patients who received taxanes overall (42.2% vs. 32.7%, p < 0.001) or paclitaxel (43.0% vs. 36.7%, p < 0.001) but not among those who received docetaxel (32.0% vs. 30.2%, p = 0.821). After adjustments for multiple covariates, Black patients who received chemotherapy with any taxanes had significantly higher risk of grade 2 (OR = 1.53; 95% CI = 1.09-2.14) and grade 3 (OR = 1.91; 95% CI = 1.36-2.67) neutropenia but comparable risk of grade 4 neutropenia (OR = 1.19; 95% CI = 0.79-1.79). Similar association patterns were observed for Black patients who specifically received paclitaxel, but a null association was found for those treated with docetaxel.

Conclusion: Black cancer patients treated with taxanes for any cancer had a higher risk of neutropenia compared with their White counterparts, especially those who received paclitaxel. More research is needed to understand the mechanism(s) underlying this racial disparity in order to enhance the delivery of patient-centered oncology.
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http://dx.doi.org/10.1002/cam4.4181DOI Listing
September 2021

Body mass index and type 2 diabetes and breast cancer survival: a Mendelian randomization study.

Am J Cancer Res 2021 15;11(8):3921-3934. Epub 2021 Aug 15.

Institute of Biomedical Sciences, Academia Sinica Taipei, Taiwan.

The causal relationship between body mass index (BMI) and type 2 diabetes (T2D) and breast cancer prognosis is still ambiguous. The aim of this study was to investigate the prognostic effect of BMI and T2D on breast cancer disease-free survival (DFS) among Asian individuals. In this two-sample Mendelian randomization (MR) study, the instrumental variables (IVs) were identified using a genome-wide association study (GWAS) among 24,000 participants in the Taiwan Biobank. Importantly, the validity of these IVs was confirmed with a previous large-scale GWAS (Biobank Japan Project, BBJ). In this study, we found that a genetic predisposition toward higher BMI (as indicated by BMI IVs, F = 86.88) was associated with poor breast cancer DFS (hazard ratio [HR] = 6.11; P < 0.001). Furthermore, higher level of genetically predicted T2D (as indicated by T2D IVs) was associated with an increased risk of recurrence of and mortality from breast cancer (HR = 1.43; P < 0.001). Sensitivity analyses, including the weighted-median approach, MR-Egger regression, Radial regression and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) supported the consistency of our findings. Finally, the causal relationship between BMI and poor breast cancer prognosis was confirmed in a prospective cohort study. Our MR analyses demonstrated the causal relationship between the genetic prediction of elevated BMI and a greater risk of T2D with poor breast cancer prognosis. BMI and T2D have important clinical implications and may be used as prognostic indicators of breast cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8414374PMC
August 2021

Genetic variations of DNA bindings of FOXA1 and co-factors in breast cancer susceptibility.

Nat Commun 2021 Sep 13;12(1):5318. Epub 2021 Sep 13.

Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Identifying transcription factors (TFs) whose DNA bindings are altered by genetic variants that regulate susceptibility genes is imperative to understand transcriptional dysregulation in disease etiology. Here, we develop a statistical framework to analyze extensive ChIP-seq and GWAS data and identify 22 breast cancer risk-associated TFs. We find that, by analyzing genetic variations of TF-DNA bindings, the interaction of FOXA1 with co-factors such as ESR1 and E2F1, and the interaction of TFs with chromatin features (i.e., enhancers) play a key role in breast cancer susceptibility. Using genetic variants occupied by the 22 TFs, transcriptome-wide association analyses identify 52 previously unreported breast cancer susceptibility genes, including seven with evidence of essentiality from functional screens in breast relevant cell lines. We show that FOXA1 and co-factors form a core TF-transcriptional network regulating the susceptibility genes. Our findings provide additional insights into genetic variations of TF-DNA bindings (particularly for FOXA1) underlying breast cancer susceptibility.
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http://dx.doi.org/10.1038/s41467-021-25670-9DOI Listing
September 2021

Integrating genome and methylome data to identify candidate DNA methylation biomarkers for pancreatic cancer risk.

Cancer Epidemiol Biomarkers Prev 2021 Sep 8. Epub 2021 Sep 8.

University of Hawaii at Manoa

Background The role of methylation in pancreatic cancer (PC) risk remains unclear. We integrated genome and methylome data to identify CpG sites (CpGs) with the genetically predicted methylation to be associated with PC risk. We also studied gene expression to understand the identified associations. Methods Using genetic data and white blood cell methylation data from 1,595 subjects of European descent, we built genetic models to predict DNA methylation levels. After internal and external validation, we applied prediction models with satisfactory performance to the genetic data of 8,280 PC cases and 6,728 controls of European ancestry to investigate the associations of predicted methylation with PC risk. For associated CpGs, we compared their measured levels in pancreatic tumor vs benign tissue. Results We identified 45 CpGs at nine loci showing an association with PC risk, including 15 CpGs showing an association independent from identified risk variants. We observed significant correlations between predicted methylation of 16 of the 45 CpGs and predicted expression of eight adjacent genes, of which six genes showed associations with PC risk. Of the 45 CpGs, we were able to compare measured methylation of 16 in pancreatic tumor versus benign pancreatic tissue. Of them, six showed differentiated methylation. Conclusions We identified methylation biomarker candidates associated with PC using genetic instruments and added additional insights into the role of methylation in regulating gene expression in PC development. Impact: A comprehensive study using genetic instruments identifies 45 CpG sites at nine genomic loci for PC risk.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0400DOI Listing
September 2021

Discovery of structural deletions in breast cancer predisposition genes using whole genome sequencing data from > 2000 women of African-ancestry.

Hum Genet 2021 Aug 27. Epub 2021 Aug 27.

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, TN, 37203-1738, Nashville, USA.

Single germline nucleotide pathogenic variants have been identified in 12 breast cancer predisposition genes, but structural deletions in these genes remain poorly characterized. We conducted in-depth whole genome sequencing (WGS) in genomic DNA samples obtained from 1340 invasive breast cancer cases and 675 controls of African ancestry. We identified 25 deletions in the intragenic regions of ten established breast cancer predisposition genes based on a consensus call from six state-of-the-art SV callers. Overall, no significant case-control difference was found in the frequency of these deletions. However, 1.0% of cases and 0.3% of controls carried any of the eight putative protein-truncating rare deletions located in BRCA1, BRCA2, CDH1, TP53, NF1, RAD51D, RAD51C and CHEK2, resulting in an odds ratio (OR) of 3.29 (95% CI 0.74-30.16). We also identified a low-frequency deletion in NF1 associated with breast cancer risk (OR 1.93, 95% CI 1.14-3.42). In addition, we detected 56 deletions, including six putative protein-truncating deletions, in suspected breast predisposition genes. This is the first large study to systematically search for structural deletions in breast cancer predisposition genes. Many of the deletions, particularly those resulting in protein truncations, are likely to be pathogenic. Results from this study, if confirmed in future large-scale studies, could have significant implications for genetic testing for this common cancer.
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http://dx.doi.org/10.1007/s00439-021-02342-8DOI Listing
August 2021

Association of Sleep Duration With All- and Major-Cause Mortality Among Adults in Japan, China, Singapore, and Korea.

JAMA Netw Open 2021 Sep 1;4(9):e2122837. Epub 2021 Sep 1.

Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tsukiji, Chuo-ku, Tokyo, Japan.

Importance: The association between long sleep duration and mortality appears stronger in East Asian populations than in North American or European populations.

Objectives: To assess the sex-specific association between sleep duration and all-cause and major-cause mortality in a pooled longitudinal cohort and to stratify the association by age and body mass index.

Design, Setting, And Participants: This cohort study of individual-level data from 9 cohorts in the Asia Cohort Consortium was performed from January 1, 1984, to December 31, 2002. The final population included participants from Japan, China, Singapore, and Korea. Mean (SD) follow-up time was 14.0 (5.0) years for men and 13.4 (5.3) years for women. Data analysis was performed from August 1, 2018, to May 31, 2021.

Exposures: Self-reported sleep duration, with 7 hours as the reference category.

Main Outcomes And Measures: Mortality, including deaths from all causes, cardiovascular disease, cancer, and other causes. Sex-specific hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards regression with shared frailty models adjusted for age and the key self-reported covariates of marital status, body mass index, smoking status, alcohol consumption, physical activity, history of diabetes and hypertension, and menopausal status (for women).

Results: For 322 721 participants (mean [SD] age, 54.5 [9.2] years; 178 542 [55.3%] female), 19 419 deaths occurred among men (mean [SD] age of men, 53.6 [9.0] years) and 13 768 deaths among women (mean [SD] age of women, 55.3 [9.2] years). A sleep duration of 7 hours was the nadir for associations with all-cause, cardiovascular disease, and other-cause mortality in both men and women, whereas 8 hours was the mode sleep duration among men and the second most common sleep duration among women. The association between sleep duration and all-cause mortality was J-shaped for both men and women. The greatest association for all-cause mortality was with sleep durations of 10 hours or longer for both men (hazard ratio [HR], 1.34; 95% CI, 1.26-1.44) and women (HR, 1.48; 95% CI, 1.36-1.61). Sex was a significant modifier of the association between sleep duration and mortality from cardiovascular disease (χ25 = 13.47, P = .02), cancer (χ25 = 16.04, P = .007), and other causes (χ25 = 12.79, P = .03). Age was a significant modifier of the associations among men only (all-cause mortality: χ25 = 41.49, P < .001; cancer: χ25 = 27.94, P < .001; other-cause mortality: χ25 = 24.51, P < .001).

Conclusions And Relevance: The findings of this cohort study suggest that sleep duration is a behavioral risk factor for mortality in both men and women. Age was a modifier of the association between sleep duration in men but not in women. Sleep duration recommendations in these populations may need to be considered in the context of sex and age.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.22837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417759PMC
September 2021

Coffee and tea consumption and mortality from all causes, cardiovascular disease and cancer: a pooled analysis of prospective studies from the Asia Cohort Consortium.

Int J Epidemiol 2021 Sep 1. Epub 2021 Sep 1.

Department of Public Health Sciences, University of Chicago, Chicago, IL, USA.

Background: Accumulating evidence suggests that consuming coffee may lower the risk of death, but evidence regarding tea consumption in Asians is limited. We examined the association between coffee and tea consumption and mortality in Asian populations.

Methods: We used data from 12 prospective cohort studies including 248 050 men and 280 454 women from the Asia Cohort Consortium conducted in China, Japan, Korea and Singapore. We estimated the study-specific association of coffee, green tea and black tea consumption with mortality using Cox proportional-hazards regression models and the pooled study-specific hazard ratios (HRs) using a random-effects model.

Results: In total, 94 744 deaths were identified during the follow-up, which ranged from an average of 6.5 to 22.7 years. Compared with coffee non-drinkers, men and women who drank at least five cups of coffee per day had a 24% [95% confidence interval (CI) 17%, 29%] and a 28% (95% CI 19%, 37%) lower risk of all-cause mortality, respectively. Similarly, we found inverse associations for coffee consumption with cardiovascular disease (CVD)-specific and cancer-specific mortality among both men and women. Green tea consumption was associated with lower risk of mortality from all causes, CVD and other causes but not from cancer. The association of drinking green tea with CVD-specific mortality was particularly strong, with HRs (95% CIs) of 0.79 (0.68, 0.91) for men and 0.78 (0.68, 0.90) for women who drank at least five cups per day of green tea compared with non-drinkers. The association between black tea consumption and mortality was weak, with no clear trends noted across the categories of consumption.

Conclusions: In Asian populations, coffee consumption is associated with a lower risk of death overall and with lower risks of death from CVD and cancer. Green tea consumption is associated with lower risks of death from all causes and CVD.
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http://dx.doi.org/10.1093/ije/dyab161DOI Listing
September 2021

Association of oral microbiota with lung cancer risk in a low-income population in the Southeastern USA.

Cancer Causes Control 2021 Aug 25. Epub 2021 Aug 25.

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, 1161 21st Avenue South, Nashville, TN, USA.

Purpose: Oral microbiome plays an important role in oral health and systemic diseases, including cancer. We aimed to prospectively investigate the association of oral microbiome with lung cancer risk.

Methods: We analyzed 156 incident lung cancer cases (73 European Americans and 83 African Americans) and 156 individually matched controls nested within the Southern Community Cohort Study. Oral microbiota were assessed using 16S rRNA gene sequencing in pre-diagnostic mouth rinse samples. Paired t test and the permutational multivariate analysis of variance test were used to evaluate lung cancer risk association with alpha diversity or beta diversity, respectively. Conditional logistic regression models were used to evaluate the association of individual bacterial abundance or prevalence with lung cancer risk.

Results: No significant differences were observed for alpha or beta diversity between lung cancer cases and controls. Abundance of families Lachnospiraceae_[XIV], Peptostreptococcaceae_[XI], and Erysipelotrichaceae and species Parvimonas micra was associated with decreased lung cancer risk, with odds ratios (ORs) and 95% confidence intervals (CIs) of 0.76 (0.59-0.98), 0.80 (0.66-0.97), 0.81 (0.67-0.99), and 0.83 (0.71-0.98), respectively (all p < 0.05). Prevalence of five pre-defined oral pathogens were not significantly associated with overall lung cancer risk. Prevalence of genus Bacteroidetes_[G-5] and species Alloprevotella sp._oral_taxon_912, Capnocytophaga sputigena, Lactococcus lactis, Peptoniphilaceae_[G-1] sp._oral_taxon_113, Leptotrichia sp._oral_taxon_225, and Fretibacterium fastidiosum was associated with decreased lung cancer risk, with ORs and 95% CIs of 0.55 (0.30-1.00), 0.36 (0.17-0.73), 0.53 (0.31-0.92), 0.43 (0.21-0.88), 0.43 (0.19-0.94), 0.57 (0.34-0.99), and 0.54 (0.31-0.94), respectively (all p < 0.05). Species L. sp._oral_taxon_225 was significantly associated with decreased lung cancer risk in African Americans (OR [95% CIs] 0.28 [0.12-0.66]; p = 0.00012).

Conclusion: Results from this study suggest that oral microbiota may play a role in the development of lung cancer.
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http://dx.doi.org/10.1007/s10552-021-01490-6DOI Listing
August 2021

Lung Cancer in Vietnam.

J Thorac Oncol 2021 09;16(9):1443-1448

Multidisciplinary Thoracic Oncology Program, Baptist Cancer Center, Memphis, Tennessee.

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http://dx.doi.org/10.1016/j.jtho.2021.06.002DOI Listing
September 2021

Comprehensive Characterization of COVID-19 Patients with Repeatedly Positive SARS-CoV-2 Tests Using a Large U.S. Electronic Health Record Database.

Microbiol Spectr 2021 09 18;9(1):e0032721. Epub 2021 Aug 18.

Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

In the absence of genome sequencing, two positive molecular tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) separated by negative tests, prolonged time, and symptom resolution remain the best surrogate measure of possible reinfection. Using a large electronic health record database, we characterized clinical and testing data for 23 patients with repeatedly positive SARS-CoV-2 PCR test results ≥60 days apart, separated by ≥2 consecutive negative test results. The prevalence of chronic medical conditions, symptoms, and severe outcomes related to coronavirus disease 19 (COVID-19) illness were ascertained. The median age of patients was 64.5 years, 40% were Black, and 39% were female. A total of 83% smoked within the prior year, 61% were overweight/obese, 83% had immunocompromising conditions, and 96% had ≥2 comorbidities. The median interval between the two positive tests was 77 days. Among the 19 patients with 60 to 89 days between positive tests, 17 (89%) exhibited symptoms or clinical manifestations consistent with COVID-19 at the time of the second positive test and 14 (74%) were hospitalized at the second positive test. Of the four patients with ≥90 days between two positive tests (patient 2 [PT2], PT8, PT14, and PT19), two had mild or no symptoms at the second positive test and one, an immunocompromised patient, had a brief hospitalization at the first diagnosis, followed by intensive care unit (ICU) admission at the second diagnosis 3 months later. Our study demonstrated a high prevalence of compromised immune systems, comorbidities, obesity, and smoking among patients with repeatedly positive SARS-CoV-2 tests. Despite limitations, including a lack of semiquantitative estimates of viral load, these data may help prioritize suspected cases of reinfection for investigation and continued surveillance. The comprehensive characterization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing and clinical data for patients with repeatedly positive SARS-CoV-2 tests can help prioritize suspected cases of reinfection for investigation in the absence of genome sequencing data and for continued surveillance of the potential long-term health consequences of SARS-CoV-2 infection.
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http://dx.doi.org/10.1128/Spectrum.00327-21DOI Listing
September 2021

Using Risk Stratification to Optimize Mammography Screening in Chinese Women.

JNCI Cancer Spectr 2021 Aug 7;5(4):pkab060. Epub 2021 Jun 7.

Division of Epidemiology and Biostatistics, School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong.

Background: The cost-effectiveness of mammography screening among Chinese women remains contentious. Here, we characterized breast cancer (BC) epidemiology in Hong Kong and evaluated the cost-effectiveness of personalized risk-based screening.

Methods: We used the Hong Kong Breast Cancer Study (a case-control study with 3501 cases and 3610 controls) and Hong Kong Cancer Registry to develop a risk stratification model based on well-documented risk factors. We used the Shanghai Breast Cancer Study to validate the model. We considered risk-based programs with different screening age ranges and risk thresholds under which women were eligible to join if their remaining BC risk at the starting age exceeded the threshold.

Results: The lifetime risk (15-99 years) of BC ranged from 1.8% to 26.6% with a mean of 6.8%. Biennial screening was most cost-effective when the starting age was 44 years, and screening from age 44 to 69 years would reduce breast cancer mortality by 25.4% (95% credible interval [CrI] = 20.5%-29.4%) for all risk strata. If the risk threshold for this screening program was 8.4% (the average remaining BC risk among US women at their recommended starting age of 50 years), the coverage was 25.8%, and the incremental cost-effectiveness ratio (ICER) was US$18 151 (95% CrI = $10 408-$27 663) per quality-of-life-year (QALY) compared with no screening. The ICER of universal screening was $34 953 (95% CrI = $22 820-$50 268) and $48 303 (95% CrI = $32 210-$68 000) per QALY compared with no screening and risk-based screening with 8.4% threshold, respectively.

Conclusion: Organized BC screening in Chinese women should commence as risk-based programs. Outcome data (e.g., QALY loss because of false-positive mammograms) should be systemically collected for optimizing the risk threshold.
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http://dx.doi.org/10.1093/jncics/pkab060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346705PMC
August 2021

Racial Differences in Hepatocellular Carcinoma Incidence and Risk Factors among a Low Socioeconomic Population.

Cancers (Basel) 2021 Jul 23;13(15). Epub 2021 Jul 23.

Division of Epidemiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.

The purpose of this study was to examine differences in risk factors associated with hepatocellular carcinoma (HCC) among White and African Americans from low socioeconomic backgrounds in the Southern Community Cohort Study (SCCS). The SCCS is a prospective cohort study with participants from the southeastern US. HCC incidence rates were calculated. Multivariable Cox regression was used to calculate HCC-adjusted hazard ratios (aHR) associated with known baseline HCC risk factors for White and African Americans, separately. There were 294 incident HCC. The incidence rate ratio for HCC was higher (IRR = 1.4, 95%CI: 1.1-1.9) in African Americans compared to White Americans. White Americans saw a stronger association between self-reported hepatitis C virus (aHR = 19.24, 95%CI: 10.58-35.00) and diabetes (aHR = 3.55, 95%CI: 1.96-6.43) for the development of HCC compared to African Americans (aHR = 7.73, 95%CI: 5.71-10.47 and aHR = 1.48, 95%CI: 1.06-2.06, respectively) even though the prevalence of these risk factors was similar between races. Smoking (aHR = 2.91, 95%CI: 1.87-4.52) and heavy alcohol consumption (aHR = 1.59, 95%CI: 1.19-2.11) were significantly associated with HCC risk among African Americans only. In this large prospective cohort, we observed racial differences in HCC incidence and risk factors associated with HCC among White and African Americans.
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http://dx.doi.org/10.3390/cancers13153710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345125PMC
July 2021

Association between body mass index and colorectal adenomas: Findings from a case-control study in Vietnam.

Int J Cancer 2021 Aug 4. Epub 2021 Aug 4.

Vietnam Colorectal Cancer and Polyps Research Program, Vinmec Healthcare System, Hanoi, Vietnam.

Colorectal cancer is a leading cancer worldwide and in Vietnam. Adenomas (adenomatous polyps) is an important precursor of colorectal cancer. There is currently no study to determine the modifiable risk factors for colorectal adenomas, including body mass index (BMI) in Vietnam. We conducted an individually matched case-control study of 1149 colorectal adenomas and 1145 controls in a large-scale colorectal screening program involving 103 542 individuals aged 40-75 years old in Hanoi, Vietnam. Conditional logistic regression was used to evaluate the association between BMI and colorectal adenomas prevalence, after controlling for potential confounders. Overall, comparing to normal weight (ie, 18.5-22.9 kg/m ), underweight (ie, BMI < 18.5) was associated with a non-statistically significant increased prevalence of colorectal adenomas (odd ratio [OR] = 1.29 and 95% confident interval [CI]: 0.88-1.87). This association became significant among male (OR = 1.98, 95% CI: 1.20-3.27), male who were ever smokers (OR = 2.59, 95% CI: 1.33-5.03), nonregular exercise (OR = 2.44, 95% CI: 1.26-4.73) and individuals with cardiometabolic disorders (OR = 3.46, 95% CI: 1.19-10.00). The association between underweight and colorectal adenomas did not vary by smoking status, drinking status, family history of cancer, adenomas types or cardiometabolic disorders. No association was observed among obese individuals (BMI ≥ 25). In the population with low prevalence of obesity, we found that the association between BMI and colorectal adenomas followed a reversed J-shape that underweight was associated with increased prevalence. Further studies are, therefore, warranted to replicate our results and to investigate the biologic mechanism the effect of underweight on colorectal adenomas prevalence.
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http://dx.doi.org/10.1002/ijc.33757DOI Listing
August 2021

Mendelian randomisation study of smoking exposure in relation to breast cancer risk.

Br J Cancer 2021 Aug 2. Epub 2021 Aug 2.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.

Background: Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk.

Methods: We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy.

Results: Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07-1.30, P = 0.11 × 10), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78-1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect.

Conclusion: Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.
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http://dx.doi.org/10.1038/s41416-021-01432-8DOI Listing
August 2021

Impact of molecular subtype and race on HR+, HER2- breast cancer survival.

Breast Cancer Res Treat 2021 Jul 31. Epub 2021 Jul 31.

Vanderbilt University Medical Center (VUMC)/Vanderbilt-Ingram Cancer Center (VICC), 2220 Pierce Ave. 777 PRB, Nashville, TN, 37232, USA.

Purpose: There is an urgent need to understand the biological factors contributing to the racial survival disparity among women with hormone receptor-positive (HR+), HER2- breast cancer. In this study, we examined the impact of PAM50 subtype on 10-year mortality rate in women with HR+, HER2- breast cancer by race.

Methods: Women with localized, HR+, HER2- breast cancer diagnosed between 2002 and 2012 from two population-based cohorts were evaluated. Archival tumors were obtained and classified by PAM50 into four molecular subtypes (i.e., luminal A, luminal B, HER2-enriched, and basal-like). The molecular subtypes within HR+, HER2- breast cancers and corresponding 10-year mortality rate were compared between Black and Non-Hispanic White (NHW) women using Cox proportional hazard ratios and survival analysis, adjusting for covariates.

Results: In this study, 318 women with localized, HR+, HER2- breast cancer were included-227 Black (71%) and 91 NHW (29%). Young Black women (age ≤ 50) had the highest proportion of HR+, non-luminal A tumors (47%), compared to young NHW (10%), older Black women (31%), and older NHW (30%). Overall, women with HR+, non-luminal A subtypes had a higher 10-year mortality rate compared to HR+, luminal A subtypes after adjustment for age, stage, and income (HR 4.21 for Blacks, 95% CI 1.74-10.18 and HR 3.44 for NHW, 95% CI 1.31-9.03). Among HR+, non-luminal A subtypes there was, however, no significant racial difference in 10-yr mortality observed (Black vs. NHW: HR 1.23, 95% CI 0.58-2.58).

Conclusion: Molecular subtype classification highlights racial disparities in PAM50 subtype distribution among women with HR+, HER2- breast cancer. Among women with HR+, HER2- breast cancer, racial survival disparities are ameliorated after adjusting for molecular subtype.
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http://dx.doi.org/10.1007/s10549-021-06342-0DOI Listing
July 2021

Associations of Subtype and Isomeric Plasma Carotenoids with Prostate Cancer Risk in Low-Income African and European Americans.

Cancer Epidemiol Biomarkers Prev 2021 Jul 16. Epub 2021 Jul 16.

Division of Epidemiology, Vanderbilt Epidemiology Center, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.

Background: Various carotenoids in circulation, including isomers, may have different influences on cancer risk.

Methods: We conducted a nested case-control study including 343 incident prostate cancer cases and 640 controls individually matched on age, race, study site, and time of blood collection. Carotenoids investigated were carotene, cryptoxanthin, lycopene, dihydrolycopene, lutein, anhydrolutein, and zeaxanthin, including α versus β configurations and versus isomers. General linear model and conditional logistic regression were applied to evaluate associations for prostate cancer risk, with adjustment for potential confounders. We conducted additional analyses with further stratification by race, multivitamin use, and smoking status.

Results: Case-control differences were found in carotenoid subtype levels, although not all reached the multiple comparison adjusted threshold for significance. Plasma lycopene [OR = 0.51; 95% confidence interval (CI), 0.29-0.87; = 0.014], dihydrolycopene (OR = 0.37; 95% CI, 0.18-0.74; = 0.006), and -anhydrolutein (OR = 0.57; 95% CI, 0.33-0.96; = 0.037) were inversely, while β--carotene (OR = 2.13; 95% CI, 1.32-3.43; = 0.002) and -lutein (OR, 1.86; 95% CI, 1.20-2.88; = 0.006) were positively associated with prostate cancer risk. Stratified analyses showed inverse associations of lycopene, dihydrolycopene, and -anhydrolutein with prostate cancer risk in subjects without multivitamin use; lycopene and dihydrolycopene in African-Americans and current smokers; and dihydrolycopene in nonsmokers. Positive associations of β--carotene and -lutein were observed in African-Americans, nonsmokers, and multivitamin users.

Conclusions: The associations of carotenoids with risk of prostate cancer differed by carotenoid subtypes.

Impact: Public health recommendations on carotenoid intakes for prostate cancer prevention should take subtypes and isomers into consideration.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1785DOI Listing
July 2021

Hepcidin-regulating iron metabolism genes and pancreatic ductal adenocarcinoma: a pathway analysis of genome-wide association studies.

Am J Clin Nutr 2021 Jul 13. Epub 2021 Jul 13.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

Background: Epidemiological studies have suggested positive associations for iron and red meat intake with risk of pancreatic ductal adenocarcinoma (PDAC). Inherited pathogenic variants in genes involved in the hepcidin-regulating iron metabolism pathway are known to cause iron overload and hemochromatosis.

Objectives: The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC.

Methods: We conducted a pathway analysis of the hepcidin-regulating genes using single nucleotide polymorphism (SNP) summary statistics generated from 4 genome-wide association studies in 2 large consortium studies using the summary data-based adaptive rank truncated product method. Our population consisted of 9253 PDAC cases and 12,525 controls of European descent. Our analysis included 11 hepcidin-regulating genes [bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 6 (BMP6), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), hepcidin (HAMP), homeostatic iron regulator (HFE), hemojuvelin (HJV), nuclear factor erythroid 2-related factor 2 (NRF2), ferroportin 1 (SLC40A1), transferrin receptor 1 (TFR1), and transferrin receptor 2 (TFR2)] and their surrounding genomic regions (±20 kb) for a total of 412 SNPs.

Results: The hepcidin-regulating gene pathway was significantly associated with PDAC (P = 0.002), with the HJV, TFR2, TFR1, BMP6, and HAMP genes contributing the most to the association.

Conclusions: Our results support that genetic susceptibility related to the hepcidin-regulating gene pathway is associated with PDAC risk and suggest a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate effect modification by intake of iron-rich foods on this association.
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http://dx.doi.org/10.1093/ajcn/nqab217DOI Listing
July 2021

Epidemiology of 40 blood biomarkers of one-carbon metabolism, vitamin status, inflammation, and renal and endothelial function among cancer-free older adults.

Sci Rep 2021 Jul 5;11(1):13805. Epub 2021 Jul 5.

Duke - NUS Medical School, Singapore, Singapore.

Imbalances of blood biomarkers are associated with disease, and biomarkers may also vary non-pathologically across population groups. We described variation in concentrations of biomarkers of one-carbon metabolism, vitamin status, inflammation including tryptophan metabolism, and endothelial and renal function among cancer-free older adults. We analyzed 5167 cancer-free controls aged 40-80 years from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). Centralized biochemical analyses of 40 biomarkers in plasma or serum were performed. We fit multivariable linear mixed effects models to quantify variation in standardized biomarker log-concentrations across four factors: age, sex, smoking status, and body mass index (BMI). Differences in most biomarkers across most factors were small, with 93% (186/200) of analyses showing an estimated difference lower than 0.25 standard-deviations, although most were statistically significant due to large sample size. The largest difference was for creatinine by sex, which was - 0.91 standard-deviations lower in women than men (95%CI - 0.98; - 0.84). The largest difference by age was for total cysteine (0.40 standard-deviation increase per 10-year increase, 95%CI 0.36; 0.43), and by BMI was for C-reactive protein (0.38 standard-deviation increase per 5-kg/m increase, 95%CI 0.34; 0.41). For 31 of 40 markers, the mean difference between current and never smokers was larger than between former and never smokers. A statistically significant (p < 0.05) association with time since smoking cessation was observed for 8 markers, including C-reactive protein, kynurenine, choline, and total homocysteine. We conclude that most blood biomarkers show small variations across demographic characteristics. Patterns by smoking status point to normalization of multiple physiological processes after smoking cessation.
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http://dx.doi.org/10.1038/s41598-021-93214-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257595PMC
July 2021

Cholesterol and Egg Intakes with Cardiometabolic and All-Cause Mortality among Chinese and Low-Income Black and White Americans.

Nutrients 2021 Jun 19;13(6). Epub 2021 Jun 19.

Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Department of Medicine, Division of Epidemiology, Nashville, TN 37203, USA.

We examined the associations of dietary cholesterol and egg intakes with cardiometabolic and all-cause mortality among Chinese and low-income Black and White Americans. Included were 47,789 Blacks, 20,360 Whites, and 134,280 Chinese aged 40-79 years at enrollment. Multivariable Cox models with restricted cubic splines were applied to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality outcomes using intakes of 150 mg cholesterol/day and 1 egg/week as the references. Cholesterol intake showed a nonlinear association with increased all-cause mortality and a linear association with increased cardiometabolic mortality among Black Americans: HRs (95% CIs) associated with 300 and 600 mg/day vs. 150 mg/day were 1.07 (1.03-1.11) and 1.13 (1.05-1.21) for all-cause mortality (-linearity = 0.04, -nonlinearity = 0.002, and -overall < 0.001) and 1.10 (1.03-1.16) and 1.21 (1.08-1.36) for cardiometabolic mortality (-linearity = 0.007, -nonlinearity = 0.07, and -overall = 0.005). Null associations with all-cause or cardiometabolic mortality were noted for White Americans (-linearity ≥ 0.13, -nonlinearity ≥ 0.06, and -overall ≥ 0.05 for both). Nonlinear inverse associations were observed among Chinese: HR (95% CI) for 300 vs. 150 mg/day was 0.94 (0.92-0.97) for all-cause mortality and 0.91 (0.87-0.95) for cardiometabolic mortality, but the inverse associations disappeared with cholesterol intake > 500 mg/day (-linearity ≥ 0.12; -nonlinearity ≤ 0.001; -overall < 0.001 for both). Similarly, we observed a positive association of egg intake with all-cause mortality in Black Americans, but a null association in White Americans and a nonlinear inverse association in Chinese. In conclusion, the associations of cholesterol and egg intakes with cardiometabolic and all-cause mortality may differ across ethnicities who have different dietary patterns and cardiometabolic risk profiles. However, residual confounding remains possible.
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http://dx.doi.org/10.3390/nu13062094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234137PMC
June 2021

Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element.

Am J Hum Genet 2021 07 18;108(7):1190-1203. Epub 2021 Jun 18.

Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.

A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10).
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http://dx.doi.org/10.1016/j.ajhg.2021.05.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322933PMC
July 2021

Legume Consumption and Gut Microbiome in Elderly Chinese Men and Women.

J Nutr 2021 Aug;151(8):2399-2408

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.

Background: Legumes, important components of a healthy diet, may exert their health benefits through the influence of the gut microbiome. However, this hypothesis has not been well investigated.

Objective: This study aimed to examine the associations between long-term legume consumption and the gut microbiome among elderly Chinese.

Methods: The gut microbiome was profiled by 16S ribosomal RNA sequencing in 2302 Chinese adults enrolled in 2 large cohort studies, the Shanghai Women's Health Study and Shanghai Men's Health Study. Legume consumption, including peanuts, soy foods, and other beans, was assessed by food-frequency questionnaires prior to the stool collection. The associations of legume consumption with microbiome diversity and taxa abundance were evaluated by linear or negative binomial hurdle models, adjusting for sociodemographics, lifestyle factors, and BMI. False discovery rate (FDR)-corrected P values (PFDR) < 0.1 were considered significant.

Results: Respectively, 52% and 48% of study participants were male and female. The mean age at stool collection was 68.03 y for females and 70.28 y for males. Total legume consumption was not associated with gut microbiome ɑ-diversity; however, male peanut consumers had a higher Chao1 index (β = 22.52, P = 0.01), whereas peanut consumption was associated with decreased Shannon (β = -0.03, P = 0.02) and Simpson (β = -0.002, P = 0.04) indexes among females. In female and male combined analyses, total legume consumption was associated with increased Enterobacteriales (β = 0.30, PFDR = 0.06). Within this order, an unclassified genus in the family Enterobacteriaceae was positively associated with total legume (β = 0.46, PFDR = 0.03) and peanut (β = 0.59, PFDR = 0.01) consumption. Stratified analyses showed significant associations were primarily confined to females and participants without metabolic conditions.

Conclusions: Legume consumption was associated with gut microbiome diversity and abundance of some bacteria in elderly Chinese. Associations were significant only among 1 sex group. Further research, including large-scale prospective studies and feeding trials, is needed to fully understand the role of the gut microbiome in legume-health associations.
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http://dx.doi.org/10.1093/jn/nxab139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435997PMC
August 2021

Systematic Review of Cancer Research Output From Africa, With Zambia as an Example.

JCO Glob Oncol 2021 05;7:802-810

Vanderbilt Institute for Global Health, Vanderbilt University Medical Center, Nashville, TN.

Purpose: Cancer occurrence is increasing in Africa, although research has lagged. The objective of this review was to analyze cancer research outputs from Africa, with a particular focus on Zambia.

Methods: We searched PubMed for published cancer-related articles from African countries. All articles reporting on cancer in Africa were considered. We conducted analyses to explore correlations between cancer research output and total population, gross domestic product, and new cancer cases recorded in 2020. For Zambia articles, we also analyzed cancer types and time trends.

Results: A total of 48,487 cancer-related publications from Africa were identified, with nearly half coming from Egypt (13,372; 28%) and South Africa (9,393; 19%). Cancer research output correlated significantly with country population (Spearman's correlation coefficient 0.74; < .001) and the number of new cancer cases recorded in 2020 (Spearman's correlation coefficient 0.77; < .001). Standardized by population size, Western Sahara (0.576), Seychelles (0.244), Tunisia (0.239), South Africa (0.158), and Egypt (0.131) had the highest overall output per 1,000 population. A total of 244 publications were from Zambia; the most studied cancers were cervical (25%), Kaposi sarcoma (24%), and breast (10%). Although an increase in cancer research output from Zambia was noted, only 33% of publications were first or last authored by Zambians. The major limitation of this review is that the evaluation was based on a single electronic database, PubMed.

Conclusion: Cancer research output from Africa is very low, with many of the publications concentrated in a few countries. There is an urgent need to invest in both human resources and infrastructure to increase cancer research output from African countries, particularly in less populous countries.
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http://dx.doi.org/10.1200/GO.21.00079DOI Listing
May 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Development and external validation of a breast cancer absolute risk prediction model in Chinese population.

Breast Cancer Res 2021 05 29;23(1):62. Epub 2021 May 29.

Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, 38 Xueyuan Road, Beijing, 100191, China.

Backgrounds: In contrast to developed countries, breast cancer in China is characterized by a rapidly escalating incidence rate in the past two decades, lower survival rate, and vast geographic variation. However, there is no validated risk prediction model in China to aid early detection yet.

Methods: A large nationwide prospective cohort, China Kadoorie Biobank (CKB), was used to evaluate relative and attributable risks of invasive breast cancer. A total of 300,824 women free of any prior cancer were recruited during 2004-2008 and followed up to Dec 31, 2016. Cox models were used to identify breast cancer risk factors and build a relative risk model. Absolute risks were calculated by incorporating national age- and residence-specific breast cancer incidence and non-breast cancer mortality rates. We used an independent large prospective cohort, Shanghai Women's Health Study (SWHS), with 73,203 women to externally validate the calibration and discriminating accuracy.

Results: During a median of 10.2 years of follow-up in the CKB, 2287 cases were observed. The final model included age, residence area, education, BMI, height, family history of overall cancer, parity, and age at menarche. The model was well-calibrated in both the CKB and the SWHS, yielding expected/observed (E/O) ratios of 1.01 (95% confidence interval (CI), 0.94-1.09) and 0.94 (95% CI, 0.89-0.99), respectively. After eliminating the effect of age and residence, the model maintained moderate but comparable discriminating accuracy compared with those of some previous externally validated models. The adjusted areas under the receiver operating curve (AUC) were 0.634 (95% CI, 0.608-0.661) and 0.585 (95% CI, 0.564-0.605) in the CKB and the SWHS, respectively.

Conclusions: Based only on non-laboratory predictors, our model has a good calibration and moderate discriminating capacity. The model may serve as a useful tool to raise individuals' awareness and aid risk-stratified screening and prevention strategies.
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http://dx.doi.org/10.1186/s13058-021-01439-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164768PMC
May 2021

ABO genotypes and the risk of esophageal and gastric cancers.

BMC Cancer 2021 May 22;21(1):589. Epub 2021 May 22.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Dr. 6E3280, Rockville, MD, 20850, USA.

Background: Blood type has been associated with the risk of gastric cancer, but few studies have examined the association with esophageal squamous cell carcinoma (ESCC).

Methods: We conducted a case-control study using genotyping data of Chinese individuals, including cases of 2022 ESCC, 1189 gastric cardia adenocarcinoma, 1161 gastric noncardia adenocarcinoma, and 2696 controls. Genetic blood type was imputed using three single nucleotide polymorphisms. We used logistic regression to examine the association between blood type and the risk of each cancer.

Results: Compared to blood type O, the risk of ESCC was significantly elevated for blood type B and AB, with the highest risk for type AB (OR, 95%CI: 1.34, 1.07-1.67). Analysis of genotype suggested that the association of ESCC was from carrying the B allele. Similarly, blood type was significantly associated with gastric noncardia adenocarcinoma (P < 0.001) with risk significantly elevated in type A (1.37, 1.14-1.65) and AB (1.44, 1.10-1.89) compared to type O. Blood type was not associated with gastric cardia adenocarcinoma (P = 0.13).

Conclusions: This study provides novel insights into the association between blood type and the risk of ESCC and restricted previously observed association to only gastric noncardia cancer, providing important evidence to clarify the pattern of association and suggesting mechanisms of action.
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http://dx.doi.org/10.1186/s12885-021-08334-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141232PMC
May 2021

Associations of circulating choline and its related metabolites with cardiometabolic biomarkers: an international pooled analysis.

Am J Clin Nutr 2021 09;114(3):893-906

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA.

Background: Choline is an essential nutrient; however, the associations of choline and its related metabolites with cardiometabolic risk remain unclear.

Objective: We examined the associations of circulating choline, betaine, carnitine, and dimethylglycine (DMG) with cardiometabolic biomarkers and their potential dietary and nondietary determinants.

Methods: The cross-sectional analyses included 32,853 participants from 17 studies, who were free of cancer, cardiovascular diseases, chronic kidney diseases, and inflammatory bowel disease. In each study, metabolites and biomarkers were log-transformed and standardized by means and SDs, and linear regression coefficients (β) and 95% CIs were estimated with adjustments for potential confounders. Study-specific results were combined by random-effects meta-analyses. A false discovery rate <0.05 was considered significant.

Results: We observed moderate positive associations of circulating choline, carnitine, and DMG with creatinine [β (95% CI): 0.136 (0.084, 0.188), 0.106 (0.045, 0.168), and 0.128 (0.087, 0.169), respectively, for each SD increase in biomarkers on the log scale], carnitine with triglycerides (β = 0.076; 95% CI: 0.042, 0.109), homocysteine (β = 0.064; 95% CI: 0.033, 0.095), and LDL cholesterol (β = 0.055; 95% CI: 0.013, 0.096), DMG with homocysteine (β = 0.068; 95% CI: 0.023, 0.114), insulin (β = 0.068; 95% CI: 0.043, 0.093), and IL-6 (β = 0.060; 95% CI: 0.027, 0.094), but moderate inverse associations of betaine with triglycerides (β = -0.146; 95% CI: -0.188, -0.104), insulin (β = -0.106; 95% CI: -0.130, -0.082), homocysteine (β = -0.097; 95% CI: -0.149, -0.045), and total cholesterol (β = -0.074; 95% CI: -0.102, -0.047). In the whole pooled population, no dietary factor was associated with circulating choline; red meat intake was associated with circulating carnitine [β = 0.092 (0.042, 0.142) for a 1 serving/d increase], whereas plant protein was associated with circulating betaine [β = 0.249 (0.110, 0.388) for a 5% energy increase]. Demographics, lifestyle, and metabolic disease history showed differential associations with these metabolites.

Conclusions: Circulating choline, carnitine, and DMG were associated with unfavorable cardiometabolic risk profiles, whereas circulating betaine was associated with a favorable cardiometabolic risk profile. Future prospective studies are needed to examine the associations of these metabolites with incident cardiovascular events.
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http://dx.doi.org/10.1093/ajcn/nqab152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408854PMC
September 2021

Reduction in total and major cause-specific mortality from tobacco smoking cessation: a pooled analysis of 16 population-based cohort studies in Asia.

Int J Epidemiol 2021 Feb 5. Epub 2021 Feb 5.

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.

Background: Little is known about the time course of mortality reduction following smoking cessation in Asians who have smoking behaviours distinct from their Western counterparts. We evaluated the level of reduction in all-cause, cardiovascular disease (CVD) and lung cancer mortality by years since quitting smoking, in Asia.

Methods: Using Cox regression, we analysed individual participant data (n = 709 151) from 16 prospective cohorts conducted in China, Japan, Korea/Singapore, and India/Bangladesh, separately by cohorts. Cohort-specific hazard ratios (HRs) were combined using a random-effects meta-analysis.

Results: During a mean follow-up of 12.0 years, 108 287 deaths were ascertained-35 658 from CVD and 7546 from lung cancer. Among Asian men, a dose-response relationship of risk reduction in deaths from all causes, CVD and lung cancer was observed with an increase in years after smoking cessation. Compared with never smokers, however, all-cause and CVD mortality among former smokers remained elevated 10-14 years after quitting [multivariable-adjusted HR (95% confidence interval (CI) = 1.25 (1.13-1.37) and 1.20 (1.02-1.41), respectively]. Lung cancer mortality stayed almost 2-fold higher than among never smokers 15-19 years after smoking cessation [1.97 (1.41-2.73)], particularly among former heavy smokers [2.62 (1.71-4.00)]. Women who quitted for ≥5 years retained a significantly elevated mortality from all causes, CVD and lung cancer. Overall patterns of the cessation-mortality associations were similar across countries.

Conclusions: Our findings suggest that adverse effects of tobacco smoking persist for an extended time period, even for more than two decades, which is beyond the time windows defined in current clinical guidelines for risk assessment of lung cancer and CVD.
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http://dx.doi.org/10.1093/ije/dyab087DOI Listing
February 2021

Effects of Screenings in Reducing Colorectal Cancer Incidence and Mortality Differ by Polygenic Risk Scores.

Clin Transl Gastroenterol 2021 05 6;12(5):e00344. Epub 2021 May 6.

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Introduction: Colorectal cancer (CRC) screening reduces CRC incidence and mortality. However, it is unclear whether the reduction in CRC risk may differ by genetic susceptibility.

Methods: We evaluated this question in a cohort of 304,740 participants of European descent aged 50 years and older. Genetic susceptibility was measured using a polygenic risk score (PRS) constructed with risk variants identified in genomewide association studies. Cox models were used to estimate hazard ratios and 95% confidence intervals of CRC risk.

Results: Over a median follow-up of 7.0 years, 2,261 incident CRC cases and 528 CRC deaths were identified. CRC screening was associated with a significantly reduced CRC incidence among individuals with a high (hazard ratio, 0.80; 95% confidence interval, 0.71-0.92) and intermediate PRS (0.84, 0.71-0.98) but not among those with a low PRS (1.03, 0.86-1.25; Pinteraction, 0.005). A similar but more evident difference was observed for mortality (Pinteraction, 0.046), with more than 30% reduced mortality observed in the high PRS group (0.69, 0.52-0.91). Among the younger group (age 50-60 years), CRC screenings were associated with a slightly (but nonsignificantly) elevated incidence and mortality in the low PRS group but a reduced risk in the high PRS group (Pinteraction, 0.043 [incidence]; 0.092 [mortality]). No significant interaction was observed in the older group (age > 60 years).

Discussion: Individuals with a higher genetic risk benefited more substantially from CRC screenings than those with a lower risk. Our findings suggest that PRS may be used to develop personalized CRC screening to maximize its effect on CRC prevention.
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http://dx.doi.org/10.14309/ctg.0000000000000344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104134PMC
May 2021

A Pooled Case-only Analysis of Reproductive Risk Factors and Breast Cancer Subtype Among Black Women in the Southeastern United States.

Cancer Epidemiol Biomarkers Prev 2021 Jul 4;30(7):1416-1423. Epub 2021 May 4.

Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.

Background: We investigated the association between reproductive risk factors and breast cancer subtype in Black women. On the basis of the previous literature, we hypothesized that the relative prevalence of specific breast cancer subtypes might differ according to reproductive factors.

Methods: We conducted a pooled analysis of 2,188 (591 premenopausal, 1,597 postmenopausal) Black women with a primary diagnosis of breast cancer from four studies in the southeastern United States. Breast cancers were classified by clinical subtype. Case-only polytomous logistic regression models were used to estimate ORs and 95% confidence intervals (CI) for HER2 and triple-negative breast cancer (TNBC) status in relation to estrogen receptor-positive (ER)/HER2 status (referent) for reproductive risk factors.

Results: Relative to women who had ER/HER2 tumors, women who were age 19-24 years at first birth (OR, 1.78; 95% CI, 1.22-2.59) were more likely to have TNBC. Parous women were less likely to be diagnosed with HER2 breast cancer and more likely to be diagnosed with TNBC relative to ER/HER2 breast cancer. Postmenopausal parous women who breastfed were less likely to have TNBC [OR, 0.65 (95% CI, 0.43-0.99)].

Conclusions: This large pooled study of Black women with breast cancer revealed etiologic heterogeneity among breast cancer subtypes.

Impact: Black parous women who do not breastfeed are more likely to be diagnosed with TNBC, which has a worse prognosis, than with ER/HER2 breast cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254754PMC
July 2021

Long-term Diet Quality and Gut Microbiome Functionality: A Prospective, Shotgun Metagenomic Study among Urban Chinese Adults.

Curr Dev Nutr 2021 Apr 2;5(4):nzab026. Epub 2021 Apr 2.

Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Background: Diet is known to affect human gut microbiome composition; yet, how diet affects gut microbiome functionality remains unclear.

Objective: We compared the diversity and abundance/presence of fecal microbiome metabolic pathways among individuals according to their long-term diet quality.

Methods: In 2 longitudinal cohorts, we assessed participants' usual diets via repeated surveys during 1996-2011 and collected a stool sample in 2015-2018. Participants who maintained a healthy or unhealthy diet (i.e., stayed in the highest or lowest quintile of a healthy diet score throughout follow-up) were selected. Participants were excluded if they reported a history of cancer, cardiovascular disease, diabetes, or hypertension; had diarrhea or constipation in the last 7 d; or used antibiotics in the last 6 mo before stool collection. Functional profiling of shotgun metagenomics was performed using HUMAnN2. Associations of dietary variables and 420 microbial metabolic pathways were evaluated via multivariable-adjusted linear or logistic regression models.

Results: We included 144 adults (mean age = 64 y; 55% female); 66 had an unhealthy diet and 78 maintained a healthy diet. The healthy diet group had higher Shannon α-diversity indexes of microbial gene families and metabolic pathways (both < 0.02), whereas β-diversity, as evaluated by Bray-Curtis distance, did not differ between groups (both > 0.50). At < 0.01 [false discovery rate (FDR) <0.15], the healthy diet group showed enriched pathways for vitamin and carrier biosynthesis (e.g., tetrahydrofolate, acetyl-CoA, and l-methionine) and tricarboxylic acid (TCA) cycle, and increased degradation (or reduced biosynthesis) of certain sugars [e.g., cytidine monophosphate (CMP)-legionaminate, deoxythymidine diphosphate (dTDP)-l-rhamnose, and sucrose], nucleotides, 4-aminobutanoate, methylglyoxal, sulfate, and aromatic compounds (e.g., catechol and toluene). Meanwhile, several food groups were associated with the CMP-legionaminate biosynthesis pathway at FDR <0.05.

Conclusions: In a small longitudinal study of generally healthy, older Chinese adults, we found long-term healthy eating was associated with increased α-diversity of microbial gene families and metabolic pathways and altered symbiotic functions relevant to human nutrition and health.
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http://dx.doi.org/10.1093/cdn/nzab026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068758PMC
April 2021
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