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.

Soluble Glycoprotein VI Predicts Abdominal Aortic Aneurysm Growth Rate and is a Novel Therapeutic Target.

A common feature in patients with abdominal aortic aneurysms (AAA) is the formation of a nonocclusive intraluminal thrombus (ILT) in regions of aortic dilation. Platelets are known to maintain hemostasis and propagate thrombosis through several redundant activation mechanisms, yet the role of platelet activation in the pathogenesis of AAA associated ILT is still poorly understood. Thus, we sought to investigate how platelet activation impacts the pathogenesis of AAA. Using RNA-sequencing, we identify that the platelet-associated transcripts are significantly enriched in the ILT compared to the adjacent aneurysm wall and healthy control aortas. We found that the platelet specific receptor glycoprotein VI (GPVI) is among the top enriched genes in AAA ILT and is increased on the platelet surface of AAA patients. Examination of a specific indicator of platelet activity, soluble GPVI (sGPVI), in two independent AAA patient cohorts is highly predictive of a AAA diagnosis and associates more strongly with aneurysm growth rate when compared to D-dimer in humans. Finally, intervention with the anti-GPVI antibody (JAQ1) in mice with established aneurysms blunted the progression of AAA in two independent mouse models. In conclusion, we show that levels of sGPVI in humans can predict a diagnosis of AAA and AAA growth rate, which may be critical in the identification of high-risk patients. We also identify GPVI as a novel platelet-specific AAA therapeutic target, with minimal risk of adverse bleeding complications, where none currently exist.

Long-term trajectories of sleep duration are associated with incident diabetes in middle-to-older-aged Black and White Americans.

AIMS/HYPOTHESIS: Both short and long sleep durations have been linked to higher diabetes risk. However, sleep duration may vary over time, and there has been limited research focusing on individual sleep trajectories and diabetes risk. There are substantial racial disparities in both sleep health and diabetes risk in the USA. Thus, it is important to understand the role of suboptimal sleep patterns in diabetes risk in different racial groups. METHODS: We assessed long-term trajectories of sleep duration and incident diabetes in 22,285 Black adults (mean age ± SD, 51.1 ± 8.2 years; 64.8% women) and 13,737 White adults (mean age ± SD, 54.4 ± 9.0 years; 63.8% women) enrolled in the Southern Community Cohort Study. Nine sleep trajectories were derived based on self-reported sleep duration at baseline and after a mean of 5 years of follow-up: normal-normal (reference), short-normal, normal-short, short-short, long-normal, normal-long, long-long, long-short and short-long. Diabetes was reported using a validated questionnaire. Multivariable-adjusted logistic regression was used to determine relationships between sleep trajectories and incident diabetes. RESULTS: When compared with the normal-normal trajectory, suboptimal sleep trajectories were associated with higher likelihoods of developing diabetes (OR; 95% CI: short-normal 1.19; 1.09, 1.31; normal-short 1.14; 1.02, 1.27; short-short 1.17; 1.07, 1.28; long-normal 1.13; 0.98, 1.30; normal-long 1.16; 1.00, 1.34; long-long 1.23; 1.02, 1.48; long-short 1.45; 1.19, 1.77; short-long 1.51; 1.28, 1.77). Stratified analyses by race and socioeconomic status (i.e. education and household income) showed that most suboptimal sleep trajectories were consistently associated with incident diabetes in all sociodemographic subgroups. We also noted potential interaction with race and education for several sleep trajectories (i.e. short-long and normal-short with race; long-long and short-short with education). CONCLUSIONS/INTERPRETATION: Adults with suboptimal sleep duration trajectories are more likely to develop incident diabetes. Future research is needed to study how sociodemographic factors modulate this relationship.

Associations of neighborhood sociodemographic environment with mortality and circulating metabolites among low-income black and white adults living in the southeastern United States.

BACKGROUND: Residing in a disadvantaged neighborhood has been linked to increased mortality. However, the impact of residential segregation and social vulnerability on cause-specific mortality is understudied. Additionally, the circulating metabolic correlates of neighborhood sociodemographic environment remain unexplored. Therefore, we examined multiple neighborhood sociodemographic metrics, i.e., neighborhood deprivation index (NDI), residential segregation index (RSI), and social vulnerability index (SVI), with all-cause and cardiovascular disease (CVD) and cancer-specific mortality and circulating metabolites in the Southern Community Cohort Study (SCCS). METHODS: The SCCS is a prospective cohort of primarily low-income adults aged 40-79, enrolled from the southeastern United States during 2002-2009. This analysis included self-reported Black/African American or non-Hispanic White participants and excluded those who died or were lost to follow-up ≤ 1 year. Untargeted metabolite profiling was performed using baseline plasma samples in a subset of SCCS participants. RESULTS: Among 79,631 participants, 23,356 deaths (7214 from CVD and 5394 from cancer) were documented over a median 15-year follow-up. Higher NDI, RSI, and SVI were associated with increased all-cause, CVD, and cancer mortality, independent of standard clinical and sociodemographic risk factors and consistent between racial groups (standardized HRs among all participants were 1.07 to 1.20 in age/sex/race-adjusted model and 1.04 to 1.08 after comprehensive adjustment; all P < 0.05/3 except for cancer mortality after comprehensive adjustment). The standard risk factors explained < 40% of the variations in NDI/RSI/SVI and mediated < 70% of their associations with mortality. Among 1110 circulating metabolites measured in 1688 participants, 134 and 27 metabolites were associated with NDI and RSI (all FDR < 0.05) and mediated 61.7% and 21.2% of the NDI/RSI-mortality association, respectively. Adding those metabolites to standard risk factors increased the mediation proportion from 38.4 to 87.9% and 25.8 to 42.6% for the NDI/RSI-mortality association, respectively. CONCLUSIONS: Among low-income Black/African American adults and non-Hispanic White adults living in the southeastern United States, a disadvantaged neighborhood sociodemographic environment was associated with increased all-cause and CVD and cancer-specific mortality beyond standard risk factors. Circulating metabolites may unveil biological pathways underlying the health effect of neighborhood sociodemographic environment. More public health efforts should be devoted to reducing neighborhood environment-related health disparities, especially for low-income individuals.

Associations of Long-term Sleep Duration Trajectories with Overall and Cause-Specific Mortality Among Middle-to-older Aged Black and White Adults.

Background: Both short and long sleep durations are adversely associated with numerous chronic conditions, including cardiovascular disease (CVD), diabetes, hypertension, and mortality. The American Academy of Sleep Medicine recommends adults in the United States sleep at least 7 hours and less than 9 hours per night to maintain optimal health. It remains unclear how sleep duration trajectories over time are associated with mortality. Methods: This observational cohort study includes 46,928 Black and White adults (mean age: 53 ± 9 years) who enrolled in the Southern Community Cohort Study between 2002-2009 and completed a follow-up survey in 2008-2013. Participants were categorized into nine sleep duration trajectory categories based on the reported average sleep duration between study enrollment and at follow-up. Participant vital status and date and cause of death were ascertained via linkage to the National Death Index through 2022. Cox regression analysis was performed to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between sleep duration trajectory and all-cause and cause-specific mortality (CVD, cancer, and neurodegenerative disease) after adjustment for sociodemographic characteristics, health behaviors, and clinical factors. Results: During a median 12.6 years of follow-up, we documented 13,579 deaths, including 4,135 from CVD, 3,067 from cancer, and 544 from neurodegenerative diseases. Compared to the optimal sleep duration trajectory (maintaining 7-9 hours), all sub-optimal trajectories were associated with significant 6 to 33% greater risk of all-cause mortality in fully adjusted models. Compared to the optimal sleep trajectory, three of the sub-optimal trajectories were associated with increased CVD mortality, with HRs ranging from 1.20 to 1.34. The short-long trajectory was associated with the greatest risk of all-cause mortality (HR:1.33; 95%CI: 1.21, 1.46) and the long-short trajectory was associated with the greatest CVD mortality risk (HR:1.34; 95%CI: 1.10, 1.65). The healthy-long trajectory was associated with the greatest risk of cancer mortality (HR: 1.19; 95%CI:1.00, 1.41). None of the sub-optimal trajectories was associated with neurodegenerative disease mortality. Conclusions: Suboptimal sleep duration trajectories were associated with increased risk of all-cause mortality as well as CVD mortality. Findings highlight the importance of maintaining healthy sleep duration throughout midlife to reduce mortality risk.

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.

Metformin's role in lowering colorectal cancer risk among individuals with diabetes from the Southern Community Cohort Study.

BACKGROUND: Metformin, utilized to manage hyperglycemia, has been linked to a reduced risk of colorectal cancer (CRC) among individuals with diabetes. However, evidence is lacking for non-Hispanic Black individuals and those with lower socioeconomic status (SES), who face elevated risk for both diabetes and CRC. In this study, we investigated the association between metformin use and incident CRC risk within the Southern Community Cohort Study (SCCS), a racially- and SES-diverse prospective cohort. METHODS: Participants reported their diabetes diagnosis and medications, including metformin, upon enrollment (2002-2009) and during follow-up surveys approximately every five years. Incident cases of CRC were identified through state cancer registries and the National Death Index. Proportional hazards models were employed to explore the relationship between metformin use and CRC risk, adjusted for cancer risk factors. RESULTS: A total of 25,992 participants with diabetes were included in the analysis, among whom 10,095 were taking metformin. Of these participants, 76% identified as non-Hispanic Black, and 60% reported household incomes <$15,000/year. Metformin use was associated with a significantly lower CRC risk (HR [95% CI]: 0.71 [0.55-0.93]), with consistent results for both colon (0.80 [0.59-1.07]) and rectal cancers (0.49 [0.28-0.86]). The protective association appeared to be stronger among non-Hispanic White individuals (0.51 [0.31-0.85]) compared to non-Hispanic Black participants (0.80 [0.59-1.08], p-interaction =.13). Additionally, a protective association was observed among obese individuals (BMI ≥30 kg/m2, 0.59 [0.43-0.82] but not among non-obese participants (0.99 [0.65-1.51], p-interaction =.05) CONCLUSION: Our findings indicate that metformin use is associated with a reduced risk of CRC in individuals with diabetes, including among those from predominantly low SES backgrounds. These results support previous epidemiological findings, and demonstrate that the protective association for metformin in relation to incident CRC likely generalizes to populations with higher underlying risk.

Hypertension and Risk of Endometrial Cancer: A Pooled Analysis in the Epidemiology of Endometrial Cancer Consortium (E2C2).

BACKGROUND: The incidence rates of endometrial cancer are increasing, which may partly be explained by the rising prevalence of obesity, an established risk factor for endometrial cancer. Hypertension, another component of metabolic syndrome, is also increasing in prevalence, and emerging evidence suggests that it may be associated with the development of certain cancers. The role of hypertension independent of other components of metabolic syndrome in the etiology of endometrial cancer remains unclear. In this study, we evaluated hypertension as an independent risk factor for endometrial cancer and whether this association is modified by other established risk factors. METHODS: We included 15,631 endometrial cancer cases and 42,239 controls matched on age, race, and study-specific factors from 29 studies in the Epidemiology of Endometrial Cancer Consortium. We used multivariable unconditional logistic regression models to estimate ORs and 95% confidence intervals (CI) to evaluate the association between hypertension and endometrial cancer and whether this association differed by study design, race/ethnicity, body mass index, diabetes status, smoking status, or reproductive factors. RESULTS: Hypertension was associated with an increased risk of endometrial cancer (OR, 1.14; 95% CI, 1.09-1.19). There was significant heterogeneity by study design (Phet < 0.01), with a stronger magnitude of association observed among case-control versus cohort studies. Stronger associations were also noted for pre-/perimenopausal women and never users of postmenopausal hormone therapy. CONCLUSIONS: Hypertension is associated with endometrial cancer risk independently from known risk factors. Future research should focus on biologic mechanisms underlying this association. IMPACT: This study provides evidence that hypertension may be an independent risk factor for endometrial cancer.

Sodium Intake and Cause-Specific Mortality Among Predominantly Low-Income Black and White US Residents.

IMPORTANCE: Epidemiologic evidence regarding the outcomes of dietary sodium intake on mortality remains limited for low-income individuals, particularly Black people. OBJECTIVE: To investigate the associations of excessive dietary sodium with all-cause and cause-specific mortality among predominantly low-income Black and White Americans. DESIGN, SETTING, AND PARTICIPANTS: This cohort study included participants aged 40 to 79 years from the Southern Community Cohort Study who were recruited at Community Health Centers in 12 southeastern states from 2002 to 2009. Analyses were conducted between March 2022 and June 2023. EXPOSURES: Dietary sodium intake was assessed using a validated food frequency questionnaire at baseline. MAIN OUTCOMES AND MEASURES: Multivariable-adjusted Cox regression was used to estimate hazard ratios (HRs) and 95% CIs for mortality outcomes (all-cause, cardiovascular disease [CVD], coronary heart disease [CHD], stroke, heart failure, cancer, and other) associated with sodium intake. Nonlinear associations and population-attributable risk (PAR) of the mortality burden associated with excess sodium were further assessed. RESULTS: Among the 64 329 participants, 46 185 (71.8%) were Black, 18 144 (28.2%) were White, and 39 155 (60.9%) were female. The mean (SD) age at study enrollment was 51.3 (8.6) years for Black participants and 53.3 (9.3) years for White counterparts. Mean (SD) dietary sodium intake was 4512 (2632) mg/d in Black individuals and 4041 (2227) mg/d in White individuals; 37 482 Black individuals (81.2%) and 14 431 White individuals (79.5%) exceeded the current dietary recommendations of 2300 mg/d. During a median (IQR) follow-up of 13.8 (11.3-15.8) years, 17 811 deaths were documented, including 5701 from CVD. After adjustment for potential confounders, in Black individuals, HRs per 1000-mg increase in daily sodium intake were 1.07 (95% CI, 1.03-1.10) and 1.08 (95% CI, 1.02-1.14) for deaths from total CVD and CHD, respectively; while in White individuals, the corresponding HRs were 1.08 (95% CI, 1.02-1.14) and 1.13 (95% CI, 1.03-1.23). No significant associations were found for cancer mortality. PAR estimates suggest that sodium intake above the recommended threshold may account for 10% of total CVD, 13% of CHD, and 30% of heart failure deaths in this low-income southern population. CONCLUSIONS AND RELEVANCE: In this cohort study of 64 329 low-income Americans, nearly 80% of study participants consumed sodium exceeding the current recommended daily amount, which was associated with 10% to 30% of CVD mortality. Public health programs targeted to reduce sodium intake among this underserved population may be beneficial.

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.

Association of cardiometabolic comorbidities with mortality among low-income Black and White Americans.

METHODS: Investigated the association of multiple cardiometabolic comorbidities with total/major cause-specific mortality and evaluate if this association might be modified by race among predominantly low-income Black and White participants. METHODS: The Southern Community Cohort Study, prospective cohort study. Participants (40-79 years) recruited predominantly from community health centers across 12 states in southeastern United States. Enrollment began in 2002 and concluded in 2009, follow-up until 2020. Cardiometabolic comorbidities (diabetes, hypertension, myocardial infarction, stroke) ascertained at the baseline survey. Cox proportional hazard models used. RESULTS: Study included 76,721 participants; 16,197, 41,944, 5,247, and 4,919 participants with prior diagnosis of diabetes, hypertension, myocardial infarction, and stroke, respectively at baseline. Compared to individuals with no comorbidity, individuals with any single comorbidity experienced a significantly 30 to 90% increased rate of death due to any causes. The increase in mortality was elevated with an increasing number of comorbidities, with HR of 3.81 (95% CI: 3.26-4.46) and a cumulative risk of 62.5% at age 75 years for total mortality for those with four comorbidities. The risk was high for death due to cardiovascular diseases (HR: 6.18, 95% CI: 5.12-7.47). These associations were stronger among Blacks than Whites. Individuals with four comorbidities at age 40 years were estimated to have a 16-year loss in life expectancy compared with those without any comorbidity. CONCLUSION: Cardiometabolic comorbidities were associated with increases in all-cause and major cause-specific mortality, particularly Black Americans. This study calls for effective measures to prevent cardiometabolic comorbidities to reduce premature deaths in underserved Americans.

Interaction between Continuous Pack-Years Smoked and Polygenic Risk Score on Lung Cancer Risk: Prospective Results from the Framingham Heart Study.

BACKGROUND: Lung cancer risk attributable to smoking is dose dependent, yet few studies examining a polygenic risk score (PRS) by smoking interaction have included comprehensive lifetime pack-years smoked. METHODS: We analyzed data from participants of European ancestry in the Framingham Heart Study Original (n = 454) and Offspring (n = 2,470) cohorts enrolled in 1954 and 1971, respectively, and followed through 2018. We built a PRS for lung cancer using participant genotyping data and genome-wide association study summary statistics from a recent study in the OncoArray Consortium. We used Cox proportional hazards regression models to assess risk and the interaction between pack-years smoked and genetic risk for lung cancer adjusting for European ancestry, age, sex, and education. RESULTS: We observed a significant submultiplicative interaction between pack-years and PRS on lung cancer risk (P = 0.09). Thus, the relative risk associated with each additional 10 pack-years smoked decreased with increasing genetic risk (HR = 1.56 at one SD below mean PRS, HR = 1.48 at mean PRS, and HR = 1.40 at one SD above mean PRS). Similarly, lung cancer risk per SD increase in the PRS was highest among those who had never smoked (HR = 1.55) and decreased with heavier smoking (HR = 1.32 at 30 pack-years). CONCLUSIONS: These results suggest the presence of a submultiplicative interaction between pack-years and genetics on lung cancer risk, consistent with recent findings. Both smoking and genetics were significantly associated with lung cancer risk. IMPACT: These results underscore the contributions of genetics and smoking on lung cancer risk and highlight the negative impact of continued smoking regardless of genetic risk.

Race- and Gender-Specific Associations between Neighborhood-Level Socioeconomic Status and Body Mass Index: Evidence from the Southern Community Cohort Study.

Obesity and a low socioeconomic status (SES), measured at the neighborhood level, are more common among Americans of Black race and with a low individual-level SES. We examined the association between the neighborhood SES and body mass index (BMI) using data from 80,970 participants in the Southern Community Cohort Study, a cohort that oversamples Black and low-SES participants. BMI (kg/m2) was examined both continuously and categorically using cut points defined by the CDC. Neighborhood SES was measured using a neighborhood deprivation index composed of census-tract variables in the domains of education, employment, occupation, housing, and poverty. Generally, the participants in lower-SES neighborhoods were more likely to have a higher BMI and to be considered obese. We found effect modification by race and sex, where the neighborhood-BMI association was most apparent in White female participants in all the quintiles of the neighborhood SES (ORQ2 = 1.55, 95%CI = 1.34, 1.78; ORQ3 = 1.71, 95%CI = 1.48, 1.98; ORQ4 = 1.76, 95%CI = 1.52, 2.03; ORQ5 = 1.64, 95%SE = 1.39, 1.93). Conversely, the neighborhood-BMI association was mostly null in Black male participants (ORQ2 = 0.91, 95%CI = 0.72, 1.15; ORQ3 = 1.05, 95%CI = 0.84, 1.31; ßQ4 = 1.00, 95%CI = 0.81, 1.23; ORQ5 = 0.76, 95%CI = 0.63, 0.93). Within all the subgroups, the associations were attenuated or null in participants residing in the lowest-SES neighborhoods. These findings suggest that the associations between the neighborhood SES and BMI vary, and that other factors aside from the neighborhood SES may better predict the BMI in Black and low-SES groups.

Type 2 Diabetes and Colorectal Cancer Risk.

Importance: Type 2 diabetes and colorectal cancer (CRC) disproportionately burden indviduals of low socioeconomic status and African American race. Although diabetes is an emerging CRC risk factor, associations between diabetes and CRC in these populations are understudied. Objective: To determine if diabetes is associated with CRC risk in a cohort representing understudied populations. Design, Setting, and Participants: This cohort study uses data from the prospective Southern Community Cohort Study in the US, which recruited from 2002 to 2009 and completed 3 follow-up surveys by 2018. Of about 85 000 participants, 86% enrolled at community health centers, while 14% were enrolled via mail or telephone from the same 12 recruitment states. Participants with less than 2 years of follow-up, previous cancer diagnosis (excluding nonmelanoma skin cancer) at enrollment, missing enrollment diabetes status, diabetes diagnosis before age 30, and without diabetes at enrollment with no follow-up participation were excluded. Data were analyzed from January to September 2023. Exposures: Physician-diagnosed diabetes and age at diabetes diagnosis were self-reported via survey at enrollment and 3 follow-ups. Main Outcomes and Measures: Diabetes diagnosis was hypothesized to be positively associated with CRC risk before analysis. Incident CRC was assessed via state cancer registry and National Death Index linkage. Hazard ratios and 95% CIs were obtained via Cox proportional hazard models, using time-varying diabetes exposure. Results: Among 54 597 participants, the median (IQR) enrollment age was 51 (46-58) years, 34 786 (64%) were female, 36 170 (66%) were African American, and 28 792 (53%) had income less than $15 000 per year. In total, 289 of 25 992 participants with diabetes developed CRC, vs 197 of 28 605 participants without diabetes. Diabetes was associated with increased CRC risk (hazard ratio [HR], 1.47; 95% CI, 1.21-1.79). Greater associations were observed among participants without colonoscopy screening (HR, 2.07; 95% CI, 1.16-3.67) and with smoking history (HR, 1.62; 95% CI, 1.14-2.31), potentially due to cancer screening differences. Greater associations were also observed for participants with recent diabetes diagnoses (diabetes duration <5 years compared with 5-10 years; HR, 2.55; 95% CI, 1.77-3.67), possibly due to recent screening. Conclusions and Relevance: In this study where the majority of participants were African American with low socioeconomic status, diabetes was associated with elevated CRC risk, suggesting that diabetes prevention and control may reduce CRC disparities. The association was attenuated for those who completed colonoscopies, highlighting how adverse effects of diabetes-related metabolic dysregulation may be disrupted by preventative screening.

Metabolite Signature of Life's Essential 8 and Risk of Coronary Heart Disease Among Low-Income Black and White Americans.

BACKGROUND: Life's essential 8 (LE8) is a comprehensive construct of cardiovascular health. Yet, little is known about the LE8 score, its metabolic correlates, and their predictive implications among Black Americans and low-income individuals. METHODS: In a nested case-control study of coronary heart disease (CHD) among 299 pairs of Black and 298 pairs of White low-income Americans from the Southern Community Cohort Study, we estimated LE8 score and applied untargeted plasma metabolomics and elastic net with leave-one-out cross-validation to identify metabolite signature (MetaSig) of LE8. Associations of LE8 score and MetaSig with incident CHD were examined using conditional logistic regression. The mediation effect of MetaSig on the LE8-CHD association was also examined. The external validity of MetaSig was evaluated in another nested CHD case-control study among 299 pairs of Chinese adults. RESULTS: Higher LE8 score was associated with lower CHD risk (standardized odds ratio, 0.61 [95% CI, 0.53-0.69]). The MetaSig, consisting of 133 metabolites, showed significant correlation with LE8 score (r=0.61) and inverse association with CHD (odds ratio, 0.57 [0.49-0.65]), robust to adjustment for LE8 score and across participants with different sociodemographic and health status ([odds ratios, 0.42-0.69]; all P<0.05). MetaSig mediated a large portion of the LE8-CHD association: 53% (32%-80%). Significant associations of MetaSig with LE8 score and CHD risk were found in validation cohort (r=0.49; odds ratio, 0.57 [0.46-0.69]). CONCLUSIONS: Higher LE8 score and its MetaSig were associated with lower CHD risk among low-income Black and White Americans. Metabolomics may offer an objective measure of LE8 and its metabolic phenotype relevant to CHD prevention among diverse populations.

Night shift work, sleep duration and endometrial cancer risk: A pooled analysis from the Epidemiology of Endometrial Cancer Consortium (E2C2).

Data on the role of circadian related factors in the etiology of endometrial cancer are scarce. We collected individual data on night shift work or daily sleep duration from 7,207 cases and 22,027 controls participating in 11 studies from the Epidemiology of Endometrial Cancer Consortium (E2C2). Main analyses were performed among postmenopausal women: 6,335 endometrial cancer cases and 18,453 controls. Using individual data, study-specific odd ratios (ORs) and their corresponding 95% confidence intervals (CIs) were estimated with logistic regression and pooled analyses were conducted using random-effects meta-analyses. A non-significant inverse association was observed between endometrial cancer and night shift work (OR=0.89, 95%CI=0.72-1.09; I2=0.0%, Pheterogeneity=0.676). Associations did not vary by shift type (permanent or rotating), or duration of night work. Categorizations of short (<7h) or long (≥9h) sleep duration were not associated with endometrial cancer risk (ORshort=1.02, 95%CI=0.95-1.10; I2=55.3%, Pheterogeneity=0.022; ORlong=0.93, 95%CI=0.81-1.06; I2=11.5%, Pheterogeneity=0.339). No associations were observed per 1-h increment of sleep (OR=0.98, 95%CI=0.95-1.01; I2=46.1%, Pheterogeneity=0.063), but an inverse association was identified among obese women (OR=0.93, 95%CI=0.89-0.98 per 1-h increment; I2=12.7%, Pheterogeneity=0.329). Overall, these pooled analyses provide evidence that night shift work and sleep duration are not strong risk factors for endometrial cancer in postmenopausal women.

Genome-Wide Association Study of CKD Progression.

SIGNIFICANCE STATEMENT: Rapid progression of CKD is associated with poor clinical outcomes. Most previous studies looking for genetic factors associated with low eGFR have used cross-sectional data. The authors conducted a meta-analysis of genome-wide association studies of eGFR decline among 116,870 participants with CKD, focusing on longitudinal data. They identified three loci (two of them novel) associated with longitudinal eGFR decline. In addition to the known UMOD/PDILT locus, variants within BICC1 were associated with significant differences in longitudinal eGFR slope. Variants within HEATR4 also were associated with differences in eGFR decline, but only among Black/African American individuals without diabetes. These findings help characterize molecular mechanisms of eGFR decline in CKD and may inform new therapeutic approaches for progressive kidney disease. BACKGROUND: Rapid progression of CKD is associated with poor clinical outcomes. Despite extensive study of the genetics of cross-sectional eGFR, only a few loci associated with eGFR decline over time have been identified. METHODS: We performed a meta-analysis of genome-wide association studies of eGFR decline among 116,870 participants with CKD-defined by two outpatient eGFR measurements of <60 ml/min per 1.73 m 2 , obtained 90-365 days apart-from the Million Veteran Program and Vanderbilt University Medical Center's DNA biobank. The primary outcome was the annualized relative slope in outpatient eGFR. Analyses were stratified by ethnicity and diabetes status and meta-analyzed thereafter. RESULTS: In cross-ancestry meta-analysis, the strongest association was rs77924615, near UMOD / PDILT ; each copy of the G allele was associated with a 0.30%/yr faster eGFR decline ( P = 4.9×10 -27 ). We also observed an association within BICC1 (rs11592748), where every additional minor allele was associated with a 0.13%/yr slower eGFR decline ( P = 5.6×10 -9 ). Among participants without diabetes, the strongest association was the UMOD/PDILT variant rs36060036, associated with a 0.27%/yr faster eGFR decline per copy of the C allele ( P = 1.9×10 -17 ). Among Black participants, a significantly faster eGFR decline was associated with variant rs16996674 near APOL1 (R 2 =0.29 with the G1 high-risk genotype); among Black participants with diabetes, lead variant rs11624911 near HEATR4 also was associated with a significantly faster eGFR decline. We also nominally replicated loci with known associations with eGFR decline, near PRKAG2, FGF5, and C15ORF54. CONCLUSIONS: Three loci were significantly associated with longitudinal eGFR change at genome-wide significance. These findings help characterize molecular mechanisms of eGFR decline and may contribute to the development of new therapeutic approaches for progressive CKD.

Metabolite Signature of Life's Essential 8 and Risk of Coronary Heart Disease among Low-Income Black and White Americans.

Background and Aims: Life's Essential 8 (LE8) is a comprehensive construct of cardiovascular health. Yet, little is known about LE8 score, its metabolic correlates, and their predictive implications among Black Americans and low-income individuals. Methods: In a nested case-control study of coronary heart disease (CHD) among 598 Black and 596 White low-income Americans, we estimated LE8 score, conducted untargeted plasma metabolites profiling, and used elastic net with leave-one-out cross-validation to identify metabolite signature (MetaSig) of LE8. Associations of LE8 score and MetaSig with incident CHD were examined using conditional logistic regression. Mediation effect of MetaSig on the LE8-CHD association was also examined. The external validity of MetaSig was evaluated in another nested CHD case-control study among 598 Chinese adults. Results: Higher LE8 score was associated with lower CHD risk [standardized OR (95% CI)=0.61 (0.53-0.69)]. The identified MetaSig, consisting of 133 metabolites, showed strong correlation with LE8 score ( r =0.61) and inverse association with CHD risk [OR (95% CI)=0.57 (0.49-0.65)], robust to adjustment for LE8 score and across participants with different sociodemographic and health status (ORs: 0.42-0.69; all P <0.05). MetaSig mediated a large portion of the LE8-CHD association: 53% (32%-80%) ( P <0.001). Significant associations of MetaSig with LE8 score and CHD risk were found in validation cohort [ r =0.49; OR (95% CI)=0.57 (0.46-0.69)]. Conclusions: Higher LE8 score and its MetaSig were associated with lower CHD risk among low-income Black and White Americans. Metabolomics may offer an objective and comprehensive measure of LE8 score and its metabolic phenotype relevant to CHD prevention among diverse populations.

Associations of life course obesity with endometrial cancer in the Epidemiology of Endometrial Cancer Consortium (E2C2).

BACKGROUND: Adult obesity is a strong risk factor for endometrial cancer (EC); however, associations of early life obesity with EC are inconclusive. We evaluated associations of young adulthood (18-21 years) and adulthood (at enrolment) body mass index (BMI) and weight change with EC risk in the Epidemiology of Endometrial Cancer Consortium (E2C2). METHODS: We pooled data from nine case-control and 11 cohort studies in E2C2. We performed multivariable logistic regression analyses to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for BMI (kg/m2) in young adulthood and adulthood, with adjustment for BMI in adulthood and young adulthood, respectively. We evaluated categorical changes in weight (5-kg increments) and BMI from young adulthood to adulthood, and stratified analyses by histology, menopausal status, race and ethnicity, hormone replacement therapy (HRT) use and diabetes. RESULTS: We included 14 859 cases and 40 859 controls. Obesity in adulthood (OR = 2.85, 95% CI = 2.47-3.29) and young adulthood (OR = 1.26, 95% CI = 1.06-1.50) were positively associated with EC risk. Weight gain and BMI gain were positively associated with EC; weight loss was inversely associated with EC. Young adulthood obesity was more strongly associated with EC among cases diagnosed with endometrioid histology, those who were pre/perimenopausal, non-Hispanic White and non-Hispanic Black, among never HRT users and non-diabetics. CONCLUSIONS: Young adulthood obesity is associated with EC risk, even after accounting for BMI in adulthood. Weight gain is also associated with EC risk, whereas weight loss is inversely associated. Achieving and maintaining a healthy weight over the life course is important for EC prevention efforts.

Dietary omega-3 fatty acids and endometrial cancer risk in the Epidemiology of Endometrial Cancer Consortium: An individual-participant meta-analysis.

BACKGROUND: Limited data from prospective studies suggest that higher dietary intake of long-chain omega-3 polyunsaturated fatty acids (LCn3PUFA), which hold anti-inflammatory properties, may reduce endometrial cancer risk; particularly among certain subgroups characterized by body mass and tumor pathology. MATERIALS AND METHODS: Data from 12 prospective cohort studies participating in the Epidemiology of Endometrial Cancer Consortium were harmonized as nested case-control studies, including 7268 endometrial cancer cases and 26,133 controls. Habitual diet was assessed by food frequency questionnaire, from which fatty acid intakes were estimated. Two-stage individual-participant data mixed effects meta-analysis estimated adjusted odds ratios (OR) and 95% confidence intervals (CI) through logistic regression for associations between study-specific energy-adjusted quartiles of LCn3PUFA and endometrial cancer risk. RESULTS: Women with the highest versus lowest estimated dietary intakes of docosahexaenoic acid, the most abundant LCn3PUFA in diet, had a 9% increased endometrial cancer risk (Quartile 4 vs. Quartile 1: OR 1.09, 95% CI: 1.01-1.19; P trend = 0.04). Similar elevated risks were observed for the summary measure of total LCn3PUFA (OR 1.07, 95% CI: 0.99-1.16; P trend = 0.06). Stratified by body mass index, higher intakes of LCn3PUFA were associated with 12-19% increased endometrial cancer risk among overweight/obese women and no increased risk among normal-weight women. Higher associations appeared restricted to White women. The results did not differ by cancer grade. CONCLUSION: Higher dietary intakes of LCn3PUFA are unlikely to reduce endometrial cancer incidence; rather, they may be associated with small to moderate increases in risk in some subgroups of women, particularly overweight/obese women.