Novel breast cancer susceptibility loci under linkage peaks identified in African ancestry consortia.

BACKGROUND: Expansion of genome-wide association studies across population groups is needed to improve our understanding of shared and unique genetic contributions to breast cancer. We performed association and replication studies guided by a priori linkage findings from African ancestry (AA) relative pairs. METHODS: We performed fixed-effect inverse-variance weighted meta-analysis under three significant AA breast cancer linkage peaks (3q26-27, 12q22-23, and 16q21-22) in 9241 AA cases and 10 193 AA controls. We examined associations with overall breast cancer as well as estrogen receptor (ER)-positive and negative subtypes (193,132 SNPs). We replicated associations in the African-ancestry Breast Cancer Genetic Consortium (AABCG). RESULTS: In AA women, we identified two associations on chr12q for overall breast cancer (rs1420647, OR = 1.15, p = 2.50×10-6; rs12322371, OR = 1.14, p = 3.15×10-6), and one for ER-negative breast cancer (rs77006600, OR = 1.67, p = 3.51×10-6). On chr3, we identified two associations with ER-negative disease (rs184090918, OR = 3.70, p = 1.23×10-5; rs76959804, OR = 3.57, p = 1.77×10-5) and on chr16q we identified an association with ER-negative disease (rs34147411, OR = 1.62, p = 8.82×10-6). In the replication study, the chr3 associations were significant and effect sizes were larger (rs184090918, OR: 6.66, 95% CI: 1.43, 31.01; rs76959804, OR: 5.24, 95% CI: 1.70, 16.16). CONCLUSION: The two chr3 SNPs are upstream to open chromatin ENSR00000710716, a regulatory feature that is actively regulated in mammary tissues, providing evidence that variants in this chr3 region may have a regulatory role in our target organ. Our study provides support for breast cancer variant discovery using prioritization based on linkage evidence.

Differential patterns of reproductive and lifestyle risk factors for breast cancer according to birth cohorts among women in China, Japan and Korea.

BACKGROUND: The birth cohort effect has been suggested to influence the rate of breast cancer incidence and the trends of associated reproductive and lifestyle factors. We conducted a cohort study to determine whether a differential pattern of associations exists between certain factors and breast cancer risk based on birth cohorts. METHODS: This was a cohort study using pooled data from 12 cohort studies. We analysed associations between reproductive (menarche age, menopause age, parity and age at first delivery) and lifestyle (smoking and alcohol consumption) factors and breast cancer risk. We obtained hazard ratios (HRs) with 95% confidence intervals (CIs) using the Cox proportional hazard regression analysis on the 1920s, 1930s, 1940s and 1950s birth cohorts. RESULTS: Parity was found to lower the risk of breast cancer in the older but not in the younger birth cohort, whereas lifestyle factors showed associations with breast cancer risk only among the participants born in the 1950s. In the younger birth cohort group, the effect size was lower for parous women compared to the other cohort groups (HR [95% CI] 0.86 [0.66-1.13] compared to 0.60 [0.49-0.73], 0.46 [0.38-0.56] and 0.62 [0.51-0.77]). Meanwhile, a higher effect size was found for smoking (1.45 [1.14-1.84] compared to 1.25 [0.99-1.58], 1.06 [0.85-1.32] and 0.86 [0.69-1.08]) and alcohol consumption (1.22 [1.01-1.48] compared to 1.10 [0.90-1.33], 1.15 [0.96-1.38], and 1.07 [0.91-1.26]). CONCLUSION: We observed different associations of parity, smoking and alcohol consumption with breast cancer risk across various birth cohorts.

Dietary intake, obesity, and physical activity in association with biliary tract cancer risk: Results from meta-analyses of individual-level data from prospective cohort studies of 723,326 adults.

Biliary tract cancer (BTC) is a rare and aggressive malignancy with increasing incidence. Most BTC cases are diagnosed with metastatic disease which carries a 5-year survival rate of <5%. Physical activity, diet, and obesity might be associated with BTC risk, but studies have been limited particularly in African descendants. We addressed this knowledge gap by evaluating associations of BTC risk with obesity, physical activity, and dietary intakes in 723,326 adult participants in four cohort studies conducted in China, the United Kingdom, and the United States. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) in each cohort; results were combined using meta-analysis. All cohorts had ≥11 median follow-up years with 839 incident BTC cases combined. BTC risk was positively associated with body mass index (BMI) and waist-to-hip ratio (WHR) whereas physical activity, fruit intake, and fish intake were inversely associated. HR and (95% CI) comparing BMI >35.0 to 18.5-24.9: 1.71 (1.26, 2.31), p-trend <.0001; comparing BMI-adjusted WHR top to bottom quartile: 1.20 (0.94, 1.53), p-trend = .05; comparing ≥15-0 metabolic equivalent task-hours/week 0.76 (0.61, 0.94), p-trend = .009; comparing highest to lowest intake tertile for fruit and fish 0.79 (0.66, 0.95), p-trend = .01; 0.82 (0.68, 0.98), p-trend = .04, respectively. Associations were, in general, similar across ancestry groups. Our study provides strong evidence for important roles of obesity, diet, and physical activity in BTC etiology and stresses the need for lifestyle modification to combat the rising incidence of this fatal malignancy.

Circulating microRNAs in association with pancreatic cancer risk within 5 years.

Early detection is critical for improving pancreatic cancer prognosis. Our study aims to identify circulating microRNAs (miRNAs) associated with pancreatic cancer risk. The two-stage study used plasma samples collected ≤5 years prior to cancer diagnosis, from case-control studies nested in five prospective cohort studies. The discovery stage included 185 case-control pairs from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Replication stage samples comprised 277 pairs from Shanghai Women's Health Study/Shanghai Men's Health Study, Southern Community Cohort Study, and Multiethnic Cohort Study. Seven hundred and ninety-eight miRNAs were measured using the NanoString nCounter Analysis System. Odds ratios (OR) and 95% confidence intervals (CI) for per 10% change in miRNAs in association with pancreatic cancer risk were derived from conditional logistic regression analysis in discovery and replication studies, separately, and then meta-analyzed. Stratified analysis was conducted by age at diagnosis (<65/≥65 years) and time interval between sample collection and diagnosis (≤2/>2 years). In the discovery stage, 120 risk associated miRNAs were identified at p < .05. Three were validated in the replication stage: hsa-miR-199a-3p/hsa-miR-199b-3p, hsa-miR-767-5p, and hsa-miR-191-5p, with respective ORs (95% CI) being 0.89 (0.84-0.95), 1.08 (1.02-1.13), and 0.90 (0.85-0.95). Five additional miRNAs, hsa-miR-640, hsa-miR-874-5p, hsa-miR-1299, hsa-miR-22-3p, and hsa-miR-449b-5p, were validated among patients diagnosed at ≥65 years, with OR (95% CI) of 1.23 (1.09-1.39), 1.33 (1.16-1.52), 1.25 (1.09-1.43), 1.28 (1.12-1.46), 0.76 (0.65-0.89), and 1.22 (1.07-1.39), respectively. The miRNA targets were enriched in pancreatic carcinogenesis/progression-related pathways. Our study suggests that circulating miRNAs may identify individuals at high risk for pancreatic cancer ≤5 years prior to diagnosis, indicating its potential utility in cancer screening and surveillance.

A nested case-control study of untargeted plasma metabolomics and lung cancer among never-smoking women within the prospective Shanghai Women's Health Study.

The etiology of lung cancer in never-smokers remains elusive, despite 15% of lung cancer cases in men and 53% in women worldwide being unrelated to smoking. Here, we aimed to enhance our understanding of lung cancer pathogenesis among never-smokers using untargeted metabolomics. This nested case-control study included 395 never-smoking women who developed lung cancer and 395 matched never-smoking cancer-free women from the prospective Shanghai Women's Health Study with 15,353 metabolic features quantified in pre-diagnostic plasma using liquid chromatography high-resolution mass spectrometry. Recognizing that metabolites often correlate and seldom act independently in biological processes, we utilized a weighted correlation network analysis to agnostically construct 28 network modules of correlated metabolites. Using conditional logistic regression models, we assessed the associations for both metabolic network modules and individual metabolic features with lung cancer, accounting for multiple testing using a false discovery rate (FDR) < 0.20. We identified a network module of 121 features inversely associated with all lung cancer (p = .001, FDR = 0.028) and lung adenocarcinoma (p = .002, FDR = 0.056), where lyso-glycerophospholipids played a key role driving these associations. Another module of 440 features was inversely associated with lung adenocarcinoma (p = .014, FDR = 0.196). Individual metabolites within these network modules were enriched in biological pathways linked to oxidative stress, and energy metabolism. These pathways have been implicated in previous metabolomics studies involving populations exposed to known lung cancer risk factors such as traffic-related air pollution and polycyclic aromatic hydrocarbons. Our results suggest that untargeted plasma metabolomics could provide novel insights into the etiology and risk factors of lung cancer among never-smokers.

Association between reproductive factors with lung cancer incidence and mortality: A pooled analysis of over 308,000 females in the Asia cohort consortium.

Previous studies have investigated the association between reproductive factors and lung cancer risk; however, findings have been inconsistent. In order to assess this association among Asian women, a total of 308,949 female participants from 11 prospective cohorts and four Asian countries (Japan, Korea, China, and Singapore) were included. Cox proportional hazards regression models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CIs). A total of 3,119 primary lung cancer cases and 2247 lung cancer deaths were identified with a mean follow-up of 16.4 years. Parous women had a lower risk of lung cancer incidence and mortality as compared with nulliparous women, with HRs of 0.82 (95% CI = 0.70-0.96) and 0.78 (95% CI = 0.65-0.94). The protective association of parity and lung cancer incidence was greater among ever-smokers (HR = 0.66, 95% CI = 0.49-0.87) than in never-smokers (HR = 0.90, 95% CI = 0.74-1.09) (P-interaction = 0.029). Compared with age at first delivery ≤20 years, older age at first delivery (21-25, ≥26 years) was associated with a lower risk of lung cancer incidence and mortality. Women who ever used hormone replacements had a higher likelihood of developing non-small cell lung cancer (HR = 1.31, 95% CI = 1.02-1.68), compared to those who never used hormone replacements. Future studies are needed to assess the underlying mechanisms, the relationships within these female reproductive factors, and the potential changes in smoking habits over time.

Association of female reproductive and hormonal factors with gallbladder cancer risk in Asia: A pooled analysis of the Asia Cohort Consortium.

The female predominance of gallbladder cancer (GBC) has led to a hypothesis regarding the hormone-related aetiology of GBC. We aimed to investigate the association between female reproductive factors and GBC risk, considering birth cohorts of Asian women. We conducted a pooled analysis of 331,323 women from 12 cohorts across 4 countries (China, Japan, Korea, and Singapore) in the Asia Cohort Consortium. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) to assess the association between reproductive factors (age at menarche, parity, age at first delivery, breastfeeding, and age at menopause) and GBC risk. We observed that a later age at menarche was associated with an increased risk of GBC (HR 1.4, 95% CI 1.16-1.70 for 17 years and older vs. 13-14 years), especially among the cohort born in 1940 and later (HR 2.5, 95% CI 1.50-4.35). Among the cohort born before 1940, women with a later age at first delivery showed an increased risk of GBC (HR 1.56, 95% CI 1.08-2.24 for 31 years of age and older vs. 20 years of age and younger). Other reproductive factors did not show a clear association with GBC risk. Later ages at menarche and at first delivery were associated with a higher risk of GBC, and these associations varied by birth cohort.

Diabetes is associated with increased liver cancer incidence and mortality in adults: A report from Asia Cohort Consortium.

There has been growing evidence suggesting that diabetes may be associated with increased liver cancer risk. However, studies conducted in Asian countries are limited. This project considered data of 968,738 adults pooled from 20 cohort studies of Asia Cohort Consortium to examine the association between baseline diabetes and liver cancer incidence and mortality. Cox proportional hazard model and competing risk approach was used for pooled data. Two-stage meta-analysis across studies was also done. There were 839,194 subjects with valid data regarding liver cancer incidence (5654 liver cancer cases [48.29/100,000 person-years]), follow-up time and baseline diabetes (44,781 with diabetes [5.3%]). There were 747,198 subjects with valid data regarding liver cancer mortality (5020 liver cancer deaths [44.03/100,000 person-years]), follow-up time and baseline diabetes (43,243 with diabetes [5.8%]). Hazard ratio (HR) (95% confidence interval [95%CI]) of liver cancer diagnosis in those with vs. without baseline diabetes was 1.97 (1.79, 2.16) (p < .0001) after adjusting for baseline age, gender, body mass index, tobacco smoking, alcohol use, and heterogeneity across studies (n = 586,072; events = 4620). Baseline diabetes was associated with increased cumulative incidence of death due to liver cancer (adjusted HR (95%CI) = 1.97 (1.79, 2.18); p < .0001) (n = 595,193; events = 4110). A two-stage meta-analytic approach showed similar results. This paper adds important population-based evidence to current literature regarding the increased incidence and mortality of liver cancer in adults with diabetes. The analysis of data pooled from 20 studies of different Asian countries and the meta-analysis across studies with large number of subjects makes the results robust.

Gut microbiome in association with chemotherapy-induced toxicities among patients with breast cancer.

BACKGROUND: Little research has focused on the relationship between gut microbiome and chemotherapy-induced toxicity. METHODS: This prospective study involves 301 patients with breast cancer who had prechemotherapy stool samples collected. Gut microbiome was sequenced by shotgun metagenomics; associations with chemotherapy-induced toxicities during first-line treatment by gut microbial diversity, composition, and metabolic pathways with severe (i.e., grade ≥3) hematological and gastrointestinal toxicities were evaluated via multivariable logistic regression. RESULTS: High prechemotherapy α-diversity was associated with a significantly reduced risk of both severe hematological toxicity (odds ratio [OR] = 0.94; 95% CI, 0.89-0.99; p = .048) and neutropenia (OR = 0.94; 95% CI, 0.89-0.99; p = .016). A high abundance of phylum Synergistota, class Synergistia, and order Synergistales were significantly associated with a reduced risk of severe neutropenia; conversely, enrichment of phylum Firmicutes C, class Negativicutes, phylum Firmicutes I, and class Bacilli A, order Paenibacillales were significantly associated with an increased risk of severe neutropenia (p range: 0.012-2.32 × 10-3; false discovery rate <0.1). Significant positive associations were also observed between severe nausea/vomiting and high Chao1 indexes, ß-diversity (p < .05), 20 species belonging to the family Lachnospiraceae, Oscillospiraceae, and Ruminococcaceae (p value range: 6.14 × 10-3 to 1.33 × 10-5; false discovery rate <0.1), and three metabolic pathways involved in reductive tricarboxylic acid cycle I and cycle II, and an incomplete reductive tricarboxylic acid cycle (p < .01). Conversely, a high abundance of species Odoribacter laneus and the pathway related to the L-proline biosynthesis II were inversely associated with severe nausea/vomiting. CONCLUSIONS: Our study suggests that gut microbiota may be a potential preventive target to reduce chemotherapy-induced toxicity.

Age at lung cancer diagnosis in females versus males who never smoke by race and ethnicity.

BACKGROUND: We characterized age at diagnosis and estimated sex differences for lung cancer and its histological subtypes among individuals who never smoke. METHODS: We analyzed the distribution of age at lung cancer diagnosis in 33,793 individuals across 8 cohort studies and two national registries from East Asia, the United States (US) and the United Kingdom (UK). Student's t-tests were used to assess the study population differences (Δ years) in age at diagnosis comparing females and males who never smoke across subgroups defined by race/ethnicity, geographic location, and histological subtypes. RESULTS: We found that among Chinese individuals diagnosed with lung cancer who never smoke, females were diagnosed with lung cancer younger than males in the Taiwan Cancer Registry (n = 29,832) (Δ years = -2.2 (95% confidence interval (CI):-2.5, -1.9), in Shanghai (n = 1049) (Δ years = -1.6 (95% CI:-2.9, -0.3), and in Sutter Health and Kaiser Permanente Hawai'i in the US (n = 82) (Δ years = -11.3 (95% CI: -17.7, -4.9). While there was a suggestion of similar patterns in African American and non-Hispanic White individuals. the estimated differences were not consistent across studies and were not statistically significant. CONCLUSIONS: We found evidence of sex differences for age at lung cancer diagnosis among individuals who never smoke.

Epigenome-wide association study of lung cancer among never smokers in two prospective cohorts in Shanghai, China.

BACKGROUND: The aetiology of lung cancer among individuals who never smoked remains elusive, despite 15% of lung cancer cases in men and 53% in women worldwide being unrelated to smoking. Epigenetic alterations, particularly DNA methylation (DNAm) changes, have emerged as potential drivers. Yet, few prospective epigenome-wide association studies (EWAS), primarily focusing on peripheral blood DNAm with limited representation of never smokers, have been conducted. METHODS: We conducted a nested case-control study of 80 never-smoking incident lung cancer cases and 83 never-smoking controls within the Shanghai Women's Health Study and Shanghai Men's Health Study. DNAm was measured in prediagnostic oral rinse samples using Illumina MethylationEPIC array. Initially, we conducted an EWAS to identify differentially methylated positions (DMPs) associated with lung cancer in the discovery sample of 101 subjects. The top 50 DMPs were further evaluated in a replication sample of 62 subjects, and results were pooled using fixed-effect meta-analysis. RESULTS: Our study identified three DMPs significantly associated with lung cancer at the epigenome-wide significance level of p<8.22×10-8. These DMPs were identified as cg09198866 (MYH9; TXN2), cg01411366 (SLC9A10) and cg12787323. Furthermore, examination of the top 1000 DMPs indicated significant enrichment in epithelial regulatory regions and their involvement in small GTPase-mediated signal transduction pathways. Additionally, GrimAge acceleration was identified as a risk factor for lung cancer (OR=1.19 per year; 95% CI 1.06 to 1.34). CONCLUSIONS: While replication in a larger sample size is necessary, our findings suggest that DNAm patterns in prediagnostic oral rinse samples could provide novel insights into the underlying mechanisms of lung cancer in never smokers.

Drug-target Mendelian randomization revealed a significant association of genetically proxied metformin effects with increased prostate cancer risk.

The association between metformin use and risk of prostate cancer remains controversial, while data from randomized trials is lacking. We aim to evaluate the association of genetically proxied metformin effects with prostate cancer risk using a drug-target Mendelian randomization (MR) approach. Summary statistics for prostate cancer were obtained from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome Consortium (79,148 cases and 61,106 controls). Cis-expression quantitative trait loci (cis-eQTL) variants in the gene targets of metformin were identified in the GTEx project and eQTLGen consortium. We also obtained male-specific genome-wide association study data for type 2 diabetes, body mass index (BMI), total testosterone, bioavailable testosterone, estradiol, and sex hormone binding globulin for mediation analysis. Inverse-variance weighted (IVW) regression, weighted median, MR-Egger regression, and MR-PRESSO were performed in the main MR analysis. Multivariable MR was used to identify potential mediators and genetic colocalization analysis was performed to assess any shared genetic basis between two traits of interest. We found that genetically proxied metformin effects (1-SD HbA1c reduction, equivalent to 6.75 mmol/mol) were associated with higher risk of prostate cancer (odds ratioIVW [ORIVW]: 1.55, 95% confidence interval, CI: 1.23-1.96, p = 3.0 × 10-3). Two metformin targets, mitochondrial complex I (ORIVW: 1.48, 95% CI: 1.07-2.03, p = 0.016) and gamma-secretase complex (ORIVW: 2.58, 95%CI :1.47-4.55, p = 0.001), showed robust associations with prostate cancer risk, and their effects were partly mediated through BMI (16.4%) and total testosterone levels (34.3%), respectively. These results were further supported by colocalization analysis that expressions of NDUFA13 and BMI, APH1A, and total testosterone may be influenced by shared genetic factors, respectively. In summary, our study indicated that genetically proxied metformin effects may be associated with an increased risk of prostate cancer. Repurposing metformin for prostate cancer prevention in general populations is not supported by our findings.

Genetic correlation and causal associations between circulating C-reactive protein levels and lung cancer risk.

PURPOSE: We aimed to characterize genetic correlations and causal associations between circulating C-reactive protein (CRP) levels and the risk of lung cancer (LC). METHODS: Leveraging summary statistics from genome-wide association studies of circulating CRP levels among 575,531 individuals of European ancestry, and LC risk among 29,266 cases and 56,450 controls, we investigated genetic associations of circulating CRP levels with the risk of overall lung cancer and its histological subtypes, by using linkage disequilibrium score (LDSC) regression and Mendelian randomization (MR) analyses. RESULTS: Significant positive genetic correlations between circulating CRP levels and the risk of LC and its histological subtypes were identified from LDSC regression, with correlation coefficients ranging from 0.12 to 0.26, and all false discovery adjusted p < 0.05. Univariable MR demonstrated a nominal association between CRP levels and an increased risk of lung squamous cell carcinoma (SCC) (inverse variance-weighted OR = 1.15, 95% CI 1.01-1.30). However, this association disappeared when multivariable MR included cigarettes per day and/or body mass index. By using our recently developed constrained maximum likelihood-based MR method, we identified significant associations of CRP levels with the risk of overall LC (OR 1.06, 95% CI 1.03-1.09), SCC (OR 1.06, 95% CI 1.02-1.09), and small cell lung cancer (SCLC, OR 1.09, 95% CI 1.03-1.15). Moreover, most univariable and multivariable MR analyses also revealed consistent CRP-SCLC associations. CONCLUSION: There may be a genetic and causal association between circulating CRP levels and the risk of SCLC, which is in line with previous population-based observational studies.

Lifestyle factors, genetic susceptibility to obesity and their interactions on coronary artery disease risk: A cohort study in the UK Biobank.

OBJECTIVE: We aimed to evaluate potential modifying effects of genetic susceptibility to obesity on the association of lifestyle factors with coronary artery disease (CAD) risk. METHODS: A total of 328,606 participants (54% women) were included using data from the UK Biobank. We evaluated the risk of developing CAD associated with obesity-related polygenic scores (PGSs) and healthy lifestyle scores (HLSs). HLSs were constructed using six lifestyle factors. Obesity PGSs were created using genetic variants identified by genome-wide association studies, including 941 variants for body mass index (BMI) and 457 for waist-to-hip ratio (WHR). Both HLSs and PGSs were categorized into three groups. RESULTS: During a 9-year median follow-up, 14,541 participants developed CAD. An unhealthy lifestyle was significantly associated with an increased CAD risk (hazard ratio [HR] = 2.24, 95% confidence interval [CI] = 2.09-2.40). High BMI and WHR PGSs were each significantly associated with an increased CAD risk (HRBMI = 1.23, 1.17-1.29; HRWHR = 1.15, 1.09-1.21). Lifestyle factors explained 41% (95% CI = 38%-45%) of CAD, while genetic variants for BMI explained only 10% (7%-14%). Risks of CAD were increased with poorer HLS independent of obesity-related PGSs. Individuals with the most unhealthy lifestyle and highest BMI PGS had the highest risk of CAD risk (HR = 2.59, 95% CI = 2.26-2.97), compared with participants with the healthiest lifestyle and lowest BMI PGS. CONCLUSIONS: While the observational nature of the study precludes the establishment of causality, our study provides supports for a causal association between obesity and CAD risk and the importance of lifestyle modification in the prevention of CAD.

Family history and gastric cancer incidence and mortality in Asia: a pooled analysis of more than half a million participants.

BACKGROUND: The family history of gastric cancer holds important implications for cancer surveillance and prevention, yet existing evidence predominantly comes from case-control studies. We aimed to investigate the association between family history of gastric cancer and gastric cancer risk overall and by various subtypes in Asians in a prospective study. METHODS: We included 12 prospective cohorts with 550,508 participants in the Asia Cohort Consortium. Cox proportional hazard regression was used to estimate study-specific adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between family history of gastric cancer and gastric cancer incidence and mortality, then pooled using random-effects meta-analyses. Stratified analyses were performed for the anatomical subsites and histological subtypes. RESULTS: During the mean follow-up of 15.6 years, 2258 incident gastric cancers and 5194 gastric cancer deaths occurred. The risk of incident gastric cancer was higher in individuals with a family history of gastric cancer (HR 1.44, 95% CI 1.32-1.58), similarly in males (1.44, 1.31-1.59) and females (1.45, 1.23-1.70). Family history of gastric cancer was associated with both cardia (HR 1.26, 95% CI 1.00-1.60) and non-cardia subsites (1.49, 1.35-1.65), and with intestinal- (1.48, 1.30-1.70) and diffuse-type (1.59, 1.35-1.87) gastric cancer incidence. Positive associations were also found for gastric cancer mortality (HR 1.30, 95% CI 1.19-1.41). CONCLUSIONS: In this largest prospective study to date on family history and gastric cancer, a familial background of gastric cancer increased the risk of gastric cancer in the Asian population. Targeted education, screening, and intervention in these high-risk groups may reduce the burden of gastric cancer.

Occupational benzene exposure and cancer risk among Chinese men: A report from the Shanghai Men's Health Study.

BACKGROUND: Benzene exposure has been associated with increased leukemia and other cancer risk; however, epidemiological evidence is inconsistent for the latter and confounding from smoking and alcohol was rarely adjusted. METHODS: We investigated associations of occupational benzene exposure and risk of leukemia, lymphoma, myeloma, lung, stomach, liver, and kidney cancers in a population-based cohort of 61,377 men ages 40-74. A job-exposure matrix, constructed by industrial hygienists specifically for the study population, was used to derive cumulative benzene exposure from all jobs held. Cox regressions were performed to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for benzene-cancer risk associations with adjustment for potential confounders. RESULTS: Over 15-years of follow-up, 1,145 lung, 656 stomach, 445 liver, 243 kidney cancer cases, 100 leukemia, 124 lymphoma, and 46 myeloma cases were identified. Benzene exposure >550mg/m3 was associated with increased leukemia (aHR=2.3, 95%CI=1.1-4.5), lung (aHR=1.2, 95%CI=1.0-1.6), and stomach (aHR=1.4, 95%CI=1.0-1.9) cancer risk; benzene-exposure was associated with early cancer diagnosis age. The benzene-leukemia and -stomach cancer associations followed a linear dose-response pattern (Plinear=0.016 and 0.023), whereas benzene-lung cancer association was evident at higher exposure levels (Pnon-linear=0.027). Alcohol consumption modified the benzene-leukemia association (HR=3.0, 95%CI=1.1-8.3 for drinkers, aHR=0.9, 95%CI=0.4-2.0 for non-drinkers, Pinteraction=0.047). CONCLUSIONS: Benzene exposure was associated with increased leukemia, stomach, and lung cancer risk. Alcohol consumption may modify the benzene-leukemia association, although estimates are imprecise. IMPACT: Our study provides additional evidence that benzene exposure increases cancer risk beyond leukemia, information important for policymakers to develop programs to mitigate cancer risk among benzene-exposed workers.

Blood Lipids, Lipoproteins, and Apolipoproteins With Risk of Coronary Heart Disease: A Prospective Study Among Racially Diverse Populations.

BACKGROUND: Comprehensive blood lipoprotein profiles and their association with incident coronary heart disease (CHD) among racially and geographically diverse populations remain understudied. METHODS AND RESULTS: We conducted nested case-control studies of CHD among 3438 individuals (1719 pairs), including 1084 White Americans (542 pairs), 1244 Black Americans (622 pairs), and 1110 Chinese adults (555 pairs). We examined 36 plasma lipids, lipoproteins, and apolipoproteins, measured by nuclear magnetic resonance spectroscopy, with incident CHD among all participants and subgroups by demographics, lifestyle, and metabolic health status using conditional or unconditional logistic regression adjusted for potential confounders. Conventionally measured blood lipids, that is, total cholesterol, triglycerides, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol, were each associated with incident CHD, with odds ratios (ORs) being 1.33, 1.32, 1.24, and 0.79 per 1-SD increase among all participants. Seventeen lipoprotein biomarkers showed numerically stronger associations than conventional lipids, with ORs per 1-SD among all participants ranging from 1.35 to 1.57 and a negative OR of 0.78 (all false discovery rate <0.05), including apolipoprotein B100 to apolipoprotein A1 ratio (OR, 1.57 [95% CI, 1.45-1.7]), low-density lipoprotein-triglycerides (OR, 1.55 [95% CI, 1.43-1.69]), and apolipoprotein B (OR, 1.49 [95% CI, 1.37-1.62]). All these associations were significant and consistent across racial groups and other subgroups defined by age, sex, smoking, obesity, and metabolic health status, including individuals with normal levels of conventionally measured lipids. CONCLUSIONS: Our study highlighted several lipoprotein biomarkers, including apolipoprotein B/ apolipoprotein A1 ratio, apolipoprotein B, and low-density lipoprotein-triglycerides, strongly and consistently associated with incident CHD. Our results suggest that comprehensive lipoprotein measures may complement the standard lipid panel to inform CHD risk among diverse populations.

Circulating Metabolite Profiles and Risk of Coronary Heart Disease Among Racially and Geographically Diverse Populations.

BACKGROUND: Metabolomics may reveal novel biomarkers for coronary heart disease (CHD). We aimed to identify circulating metabolites and construct a metabolite risk score (MRS) associated with incident CHD among racially and geographically diverse populations. METHODS: Untargeted metabolomics was conducted using baseline plasma samples from 900 incident CHD cases and 900 age-/sex-/race-matched controls (300 pairs of Black Americans, White Americans, and Chinese adults, respectively), which detected 927 metabolites with known identities among ≥80% of samples. After quality control, 896 case-control pairs remained and were randomly divided into discovery (70%) and validation (30%) sets within each race. In the discovery set, conditional logistic regression and least absolute shrinkage and selection operator over 100 subsamples were applied to identify metabolites robustly associated with CHD risk and construct the MRS. The MRS-CHD association was evaluated using conditional logistic regression and the C-index. Mediation analysis was performed to examine if MRS mediated associations between conventional risk factors and incident CHD. The results from the validation set were presented as the main findings. RESULTS: Twenty-four metabolites selected in ≥90% of subsamples comprised the MRS, which was significantly associated with incident CHD (odds ratio per 1 SD, 2.21 [95% CI, 1.62-3.00] after adjusting for sociodemographics, lifestyles, family history, and metabolic health status). MRS could distinguish incident CHD cases from matched controls (C-index, 0.69 [95% CI, 0.63-0.74]) and improve CHD risk prediction when adding to conventional risk factors (C-index, 0.71 [95% CI, 0.65-0.76] versus 0.67 [95% CI, 0.61-0.73]; P<0.001). The odds ratios and C-index were similar across subgroups defined by race, sex, socioeconomic status, lifestyles, metabolic health, family history, and follow-up duration. The MRS mediated large portions (46.0%-74.2%) of the associations for body mass index, smoking, diabetes, hypertension, and dyslipidemia with incident CHD. CONCLUSIONS: In a diverse study sample, we identified 24 circulating metabolites that, when combined into an MRS, were robustly associated with incident CHD and modestly improved CHD risk prediction beyond conventional risk factors.

Impacts of Poverty and Lifestyles on Mortality: A Cohort Study in Predominantly Low-Income Americans.

INTRODUCTION: Low socioeconomic status has been linked to increased mortality. However, the impacts of poverty, alone or combined with health behaviors, on mortality and life expectancy have not been adequately investigated. METHODS: Data from the Southern Community Cohort Study was used, including nearly 86,000 participants recruited during 2002-2009 across 12 US southeastern states. Analysis was conducted from February 2022 to January 2023. RESULTS: During a median follow-up of 12.1 years, 19,749 deaths were identified. A strong dose-response relationship was found between household incomes and mortality, with a 3.3-fold (95%CI=3.1-3.6) increased all-cause mortality observed for individuals in the lowest income group (<$15,000/year) compared with those in the highest group (≥$50,000/year). Within each income group, mortality monotonically increased with declining healthy lifestyle score. Risk was significantly lower among those in the lowest income but healthiest lifestyle group, compared to those with the highest income but unhealthiest lifestyle (HR=0.82, 95%CI=0.69-0.97). Poor White participants appeared to experience higher all-cause mortality than poor Black participants. Life expectancy was more than 10.0 years shorter for those in the lowest income group compared with those in the highest income group. CONCLUSIONS: Poverty is strongly associated with increased risk of death, but the risks could be modestly abated by a healthier lifestyle. These findings call for a comprehensive strategy for enhancing a healthy lifestyle and improving income equality to reduce death risks, particularly among those experiencing health disparities due to poverty.

Cardiometabolic Improvements After Metabolic Surgery and Related Presurgery Factors.

Context: Metabolic surgery remains the most effective and durable treatment for severe obesity and related metabolic diseases. Objective: We examined cardiometabolic improvements after metabolic surgery and associated presurgery demographic and clinical factors in a large multiracial cohort. Methods: Included were 7804 patients (20-79 years) undergoing first-time metabolic surgery at Vanderbilt University Medical Center from 1999 to 2022. Pre- and 1-year postsurgery cardiometabolic profiles were extracted from medical records, including body mass index (BMI), blood pressure, blood lipids, glucose, and hemoglobin A1c. The 10-year atherosclerotic cardiovascular disease (ASCVD) risk was estimated per American College of Cardiology/American Heart Association equations. Pre- to postsurgery cardiometabolic profiles were compared by paired t-test, and associated factors were identified by multivariable linear and logistic regression. Results: Among 7804 patients, most were women and White, while 1618 were men and 1271 were Black; median age and BMI were 45 years [interquartile range (IQR): 37-53] and 46.4 kg/m2 (IQR: 42.1-52.4). At 1-year postsurgery, patients showed significant decreases in systolic blood pressure (10.5 [95% confidence interval: 10.1, 10.9] mmHg), total cholesterol (13.5 [10.3, 16.7] mg/dL), glucose (13.6 [12.9, 14.4] mg/dL), hemoglobin A1c (1.13% [1.06, 1.20]), and 10-year ASCVD risk (absolute reduction: 1.58% [1.22, 1.94]; relative reduction: 34.4% [29.4, 39.3]); all P < .0001. Older, male, or Black patients showed less reduction in 10-year ASCVD risk and lower odds of diabetes/hypertension/dyslipidemia remission than younger, female, or White patients. Patients with a history of diabetes, hypertension, dyslipidemia, or cardiovascular disease showed less cardiometabolic improvements than those without. Results were similar with or without further adjusting for weight loss and largely sustained at 2-year postsurgery. Conclusion: Metabolic surgery results in significant cardiometabolic improvements, particularly among younger, female, or White patients and those without comorbidities.