Diabetes risk reduction diet and risk of liver cancer and chronic liver disease mortality: A prospective cohort study.

BACKGROUND: We aimed to prospectively evaluate the association between a diabetes risk reduction diet (DRRD) score and the risk of liver cancer development and chronic liver disease-specific mortality. METHODS: We included 98,786 postmenopausal women from the Women's Health Initiative-Observational Study and the usual diet arm of the Diet Modification trial. The DRRD score was derived from eight factors: high intakes of dietary fiber, coffee, nuts, polyunsaturated fatty acids, low intakes of red and processed meat, foods with high glycemic index, sugar-sweetened beverages (SSBs), and trans fat based on a validated Food-Frequency Questionnaire administered at baseline (1993-1998). Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for liver cancer incidence and chronic liver disease mortality were estimated using Cox proportional hazards regression models. RESULTS AND CONCLUSION: After a median follow-up of 22.0 years, 216 incident liver cancer cases and 153 chronic liver disease deaths were confirmed. A higher DRRD score was significantly associated with a reduced risk of developing liver cancer (HRTertile 3 vs. Tertile 1 = 0.69; 95% CI: 0.49-0.97; Ptrend = 0.03) and chronic liver disease mortality (HRT3 vs. T1 = 0.54; 95% CI: 0.35-0.82; Ptrend = 0.003). We further found inverse associations with dietary fiber and coffee, and positive associations with dietary glycemic index, SSBs, and trans fat. A higher DRRD score was associated with reduced risk of developing liver cancer and chronic liver disease mortality among postmenopausal women.

An assessment of the clinical relevance of coracoid graft osteolysis following the Latarjet procedure: a clinical and radiological review.

Background: The Latarjet procedure was developed for the treatment of anterior shoulder instability in young, high-demand patients with attritional glenoid bone loss, whose risk of redislocation following primary dislocation may exceed 90%. Coracoid graft osteolysis and prominent screws are commonly observed in late computed tomography (CT) scans of patients who re-present following the procedure, but the clinical relevance of osteolysis in the overall Latarjet cohort is undetermined. We aimed to evaluate clinical and radiological outcomes in patients who underwent the Latarjet procedure, and to determine if severe coracoid graft osteolysis compromised clinical outcomes. Methods: This was a retrospective analysis of patients who underwent the open Latarjet procedure. Patients were invited via an e-questionnaire that contained a Western Ontario Shoulder Instability Index (WOSI), and queried about redislocation and reoperation since index surgery. Preoperative glenoid bone loss was calculated on CT using the best-fit circle method. Osteolysis was graded (0, screw head buried in graft; 1, screw head exposed; 2, threads exposed; 3, complete resorption/severe osteolysis) at the level of the proximal and distal screws respectively, on axial CT scans performed ≥ 12 months postoperatively. Results: Between 2011 and 2022, a single surgeon performed 442 Latarjet procedures. One hundred fifty eight patients responded to the questionnaire at median (interquartile range [IQR]) 44 (27-70) months postoperatively, among whom the median (IQR) WOSI score was 352 (142-666) points (0 = best, 2100 = worst). Recurrent anterior instability occurred in 3/158 (2%) patients. One patient required reoperation for this indication. Among patients who had CT scans ≥ 12 months postoperatively (median [IQR] 40 [29-69] months), 1 patient developed severe osteolysis around both screws (WOSI = 90), 17/62 (27%) patients developed severe osteolysis around 1 screw, all of which were proximal (median [IQR] WOSI = 235 [135-644]), and 44/62 (71%) patients did not develop severe osteolysis around either screw (median [IQR] WOSI = 487 [177-815]). There were no statistically significant differences in WOSI scores between groups based on the presence of severe osteolysis. Conclusion: The Latarjet is reliable procedure that has a low rate of redislocation and reoperation. Severe coracoid graft osteolysis occurs with time, and always affects the proximal graft first. The presence of severe osteolysis did not compromise clinical outcomes.

Estrogen Plus Progestin and Colorectal Cancer: Long-Term Findings From the Women's Health Initiative Randomized Clinical Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We report long-term colorectal cancer findings from the Women's Health Initiative trial where 16,608 postmenopausal women with a uterus were randomly assigned to daily conjugated equine estrogen (CEE) 0.625 mg, plus medroxyprogesterone acetate (MPA) 2.5 mg, or placebo. When intervention ended after 5.6 years, although there were 44% fewer colorectal cancers in the intervention group (43 v 72, P = .003), the cancers were more commonly lymph node-positive (59.0% v 29.4%, P = .003). Now after cumulative 24-year follow-up, with 431 colorectal cancers, CEE plus MPA no longer influenced colorectal cancer incidence (215 [0.15, annualized rate %] v 216 [0.15], hazard ratio [HR], 0.95 [95% CI, 0.79 to 1.15]). Although not statistically significant, there were more colorectal cancer deaths with CEE plus MPA (87 [0.049] v 69 [0.041] deaths, HR, 1.20 [95% CI, 0.87 to 1.65], P = .26). Vaginal bleeding (54.1% v 5.2% at 6 months) and breast changes were more frequent in the intervention group. After adjusting for postrandomization vaginal bleeding and breast changes, bowel examinations were significantly delayed in intervention group participants (P = .005), potentially contributing to diagnostic delay. Taken together, the findings suggest no clinically meaningful benefit for about 5 years of CEE plus MPA use on colorectal cancer outcome.

Novel DNA methylation-based epigenetic signatures in colorectal cancer from peripheral blood leukocytes.

Colorectal cancer (CRC) is a multifactorial disease characterized by accumulation of multiple genetic and epigenetic alterations, transforming colonic epithelial cells into adenocarcinomas. Alteration of DNA methylation (DNAm) is a promising biomarker for predicting cancer risk and prognosis, but its role in CRC tumorigenesis is inconclusive. Notably, few DNAm studies have used pre-diagnostic peripheral blood (PB) DNA, causing difficulty in postulating the underlying biologic mechanism of CRC initiation. We conducted epigenome-wide association (EWA) scans in postmenopausal women from Women's Health Initiative (WHI) with their pre-diagnostic DNAm in PB leukocytes (PBLs) to prospectively evaluate CRC development. Our site-specific DNAm analyses across the genome adjusted for DNAm-age, leukocyte heterogeneities, as well as body mass index, diabetes, and insulin resistance. We validated 20 top EWA-CpGs in 2 independent CRC tissue datasets. Also, we detected differentially methylated regions (DMRs) associated with CRC, further mapped to transcriptomic profile, and finally conducted a Gene Set Enrichment Analysis. We detected multiple novel CpGs validated across WHI and tissue datasets. In particular, 2 CpGs (B4GALNT4cg10321339, SV2Bcg18144285) had the strongest effect on CRC risk. Results from our DMR scans contained MIR663cg06007966, which was also validated in EWA analyses. Also, we detected 1 methylome region in PEG10 of Chr7 shared across datasets. Our findings reflect both novel and well-established epigenomic and transcriptomic sites in CRC, warranting further functional validations. Our study contributes to better understanding of the complex interrelated mechanisms on the methylome underlying CRC tumorigenesis and suggests novel preventive DNAm-targets in PBLs for detecting at-risk individuals for CRC development.

Prolonged intermittent theta burst stimulation targeting the left prefrontal cortex and cerebellum does not affect executive functions in healthy individuals.

Repetitive transcranial magnetic stimulation (rTMS) for alleviating negative symptoms and cognitive dysfunction in schizophrenia commonly targets the left dorsolateral prefrontal cortex (LDLPFC). However, the therapeutic effectiveness of rTMS at this site remains inconclusive and increasingly, studies are focusing on cerebellar rTMS. Recently, prolonged intermittent theta-burst stimulation (iTBS) has emerged as a rapid-acting form of rTMS with promising clinical benefits. This study explored the cognitive and neurophysiological effects of prolonged iTBS administered to the LDLPFC and cerebellum in a healthy cohort. 50 healthy participants took part in a cross-over study and received prolonged (1800 pulses) iTBS targeting the LDLPFC, cerebellar vermis, and sham iTBS. Mixed effects repeated measures models examined cognitive and event-related potentials (ERPs) from 2-back (P300, N200) and Stroop (N200, N450) tasks after stimulation. Exploratory non-parametric cluster-based permutation tests compared ERPs between conditions. There were no significant differences between conditions for behavioural and ERP outcomes on the 2-back and Stroop tasks. Exploratory cluster-based permutation tests of ERPs did not identify any significant differences between conditions. We did not find evidence that a single session of prolonged iTBS administered to either the LDLPFC or cerebellum could cause any cognitive or ERP changes compared to sham in a healthy sample.

Relationships of depression and antidepressant use with epigenetic age acceleration and all-cause mortality among postmenopausal women.

We investigated relations of depressive symptoms, antidepressant use, and epigenetic age acceleration with all-cause mortality risk among postmenopausal women. Data were analyzed from ≤1,900 participants in the Women's Health Initiative study testing four-way decomposition models. After a median 20.4y follow-up, 1,161 deaths occurred. Approximately 11% had elevated depressive symptoms (EDS+), 7% were taking antidepressant medication at baseline (ANTIDEP+), while 16.5% fell into either category (EDS_ANTIDEP+). Baseline ANTIDEP+, longitudinal transition into ANTIDEP+ and accelerated epigenetic aging directly predicted increased mortality risk. GrimAge DNA methylation age acceleration (AgeAccelGrim) partially mediated total effects of baseline ANTIDEP+ and EDS_ANTIDEP+ on all-cause mortality risk in socio-demographic factors-adjusted models (Pure Indirect Effect >0, P < 0.05; Total Effect >0, P < 0.05). Thus, higher AgeAccelGrim partially explained the relationship between antidepressant use and increased all-cause mortality risk, though only prior to controlling for lifestyle and health-related factors. Antidepressant use and epigenetic age acceleration independently predicted increased all-cause mortality risk. Further studies are needed in varying populations.

Individualised Transcranial Magnetic Stimulation Targeting of the Left Dorsolateral Prefrontal Cortex for Enhancing Cognition: A Randomised Controlled Trial.

Repetitive transcranial magnetic stimulation (rTMS) has been demonstrated to produce cognitive enhancing effects across different neuropsychiatric disorders; however, so far, these effects have been limited. This trial investigated the efficacy of using a novel individualised approach to target the left dorsolateral prefrontal cortex (L-DLPFC) for enhancing cognitive flexibility based on performance on a cognitive task. First, forty healthy participants had their single target site at the L-DLPFC determined based on each individual's performance on a random letter generation task. Participants then received, in a cross-over single-blinded experimental design, a single session of intermittent theta burst stimulation (iTBS) to their individualised DLPFC target site, an active control site and sham iTBS. Following each treatment condition, participants completed the Task Switching task and Colour-Word Stroop test. There was no significant main effect of treatment condition on the primary outcome measure of switch reaction times from the Task Switching task [F = 1.16 (2, 21.6), p = 0.33] or for any of the secondary cognitive outcome measures. The current results do not support the use of our novel individualised targeting methodology for enhancing cognitive flexibility in healthy participants. Research into alternative methodological targeting approaches is required to further improve rTMS's cognitive enhancing effects.

Low physical function following cancer diagnosis is associated with higher mortality risk in postmenopausal women.

BACKGROUND: Postmenopausal women with cancer experience an accelerated physical dysfunction beyond what is expected through aging alone due to cancer and its treatments. The aim of this study was to determine whether declines in physical function after cancer diagnosis are associated with all-cause mortality and cancer-specific mortality. METHODS: This prospective cohort study included 8068 postmenopausal women enrolled in the Women's Health Initiative with a cancer diagnosis and who had physical function assessed within 1 year of that diagnosis. Self-reported physical function was measured using the 10-item physical function subscale of the 36-Item Short Form Health Survey. Cause of death was determined by medical record review, with central adjudication and linkage to the National Death Index. Death was adjudicated through February 2022. RESULTS: Over a median follow-up of 7.7 years from cancer diagnosis, 3316 (41.1%) women died. Our results showed that for every 10% difference in the physical function score after cancer diagnosis versus pre-diagnosis, all-cause mortality and cancer-specific mortality were reduced by 12% (hazard ratio [HR] = 0.88, 95% confidence interval [95% CI] = 0.87 to 0.89 and HR = 0.88, 95% CI = 0.86 to 0.91, respectively). Further categorical analyses showed a significant dose-response relationship between postdiagnosis physical function categories and mortality outcomes (P < .001 for trend), where the median survival time for women in the lowest physical function quartile was 9.1 years (Interquartile range [IQR] = 8.6-10.6 years) compared with 18.4 years (IQR = 15.8-22.0 years) for women in the highest physical function quartile. CONCLUSION: Postmenopausal women with low physical function after cancer diagnosis may be at higher risk of mortality from all causes and cancer-related mortality.

Efficacy of Repetitive Transcranial Magnetic Stimulation (rTMS) Combined with Psychological Interventions: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

(1) Background: Psychological interventions are effective in alleviating neuropsychiatric symptoms, though results can vary between patients. Repetitive transcranial magnetic stimulation (rTMS) has been proven to improve clinical symptoms and cognition. It remains unclear whether rTMS can augment the efficacy of psychological interventions. (2) Methods: We examined the effects of rTMS combined with psychological interventions on clinical, functional, and cognitive outcomes from randomized controlled trials conducted in healthy and clinical populations. We searched PubMed, EMBASE, Cochrane Library, and PsycINFO databases up to April 2023. (3) Results: Twenty-seven studies were ultimately included. Compared to sham rTMS combined with psychological interventions, active rTMS combined with psychological interventions significantly improved overall clinical symptoms (k = 16, SMD = 0.31, CIs 0.08 to 0.54, p < 0.01). We found that 10 or more sessions of rTMS combined with cognitive behavioural therapy significantly improved clinical outcomes overall (k = 3, SMD = 0.21, CIs 0.05 to 0.36, Z = 2.49, p < 0.01). RTMS combined with cognitive training (CT) significantly improved cognition overall compared to sham rTMS combined with CT (k = 13, SMD = 0.28, CIs 0.15 to 0.42, p < 0.01), with a significant effect on global cognition (k = 11, SMD = 0.45, CIs 0.21 to 0.68, p < 0.01), but not on the other cognitive domains. (4) Conclusion: The current results provide preliminary support for the augmentation effects of active rTMS on clinical and cognitive outcomes across diverse populations. Future clinical trials are required to confirm these augmentation effects for specific psychological interventions in specific clinical populations.

Estimating heritability explained by local ancestry and evaluating stratification bias in admixture mapping from summary statistics.

The heritability explained by local ancestry markers in an admixed population (hγ2) provides crucial insight into the genetic architecture of a complex disease or trait. Estimation of hγ2 can be susceptible to biases due to population structure in ancestral populations. Here, we present heritability estimation from admixture mapping summary statistics (HAMSTA), an approach that uses summary statistics from admixture mapping to infer heritability explained by local ancestry while adjusting for biases due to ancestral stratification. Through extensive simulations, we demonstrate that HAMSTA hγ2 estimates are approximately unbiased and are robust to ancestral stratification compared to existing approaches. In the presence of ancestral stratification, we show a HAMSTA-derived sampling scheme provides a calibrated family-wise error rate (FWER) of ∼5% for admixture mapping, unlike existing FWER estimation approaches. We apply HAMSTA to 20 quantitative phenotypes of up to 15,988 self-reported African American individuals in the Population Architecture using Genomics and Epidemiology (PAGE) study. We observe hˆγ2 in the 20 phenotypes range from 0.0025 to 0.033 (mean hˆγ2 = 0.012 ± 9.2 × 10-4), which translates to hˆ2 ranging from 0.062 to 0.85 (mean hˆ2 = 0.30 ± 0.023). Across these phenotypes we find little evidence of inflation due to ancestral population stratification in current admixture mapping studies (mean inflation factor of 0.99 ± 0.001). Overall, HAMSTA provides a fast and powerful approach to estimate genome-wide heritability and evaluate biases in test statistics of admixture mapping studies.

Changes in physical function in older women with endometrial cancer with or without adjuvant therapy.

OBJECTIVE: To evaluate changes in physical function (PF) for older women with endometrial cancer (EC) + / - adjuvant therapy in the Women's Health Initiative Life and Longevity after Cancer cohort. MATERIALS AND METHODS: This study examined women ≥ 70 years of age with EC with available treatment records. Change in PF was measured using the RAND-36 and compared between groups using Wilcoxon rank-sum tests. Multivariable median regression was used to compare the changes in scores while adjusting for confounding variables. RESULTS: Included in the study were 287 women, 150 (52.3%) women who did not receive adjuvant therapy and 137 (47.7%) who received adjuvant therapy. When comparing PF scores, there was a statistically significant difference in the median percent change in functional decline, with a greater decline in those who received adjuvant therapy (- 5.9% [- 23.5 to 0%]) compared to those who did not (0 [- 18.8 to + 6.7%]), p = 0.02). Results were not statistically significant after multivariable adjustment, but women who underwent chemotherapy had a greater percent change (median ∆ - 13.8% [- 35.5 to 0%]) compared to those who received radiation alone (median ∆ - 5.9% [- 31.3 to 0%]) or chemotherapy and radiation (median ∆ - 6.5% [- 25.8 to + 5.7%]. CONCLUSIONS: Older women with EC who received adjuvant therapy experienced greater change in PF than those who did not receive adjuvant therapy, particularly women who received chemotherapy. These results were not statistically significant on multivariate analysis. IMPLICATIONS FOR CANCER SURVIVORS: EC survivors may experience changes in PF because of chemotherapy and/or radiation therapy. Additional supportive care may need to be provided to older women to mitigate functional decline.

Menopausal hormone therapy and change in physical activity in the Women's Health Initiative hormone therapy clinical trials.

OBJECTIVE: The menopausal transition results in a progressive decrease in circulating estrogen levels. Experimental evidence in rodents has indicated that estrogen depletion leads to a reduction of energy expenditure and physical activity. It is unclear whether treatment with estrogen therapy increases physical activity level in postmenopausal women. METHODS: A total of 27,327 postmenopausal women aged 50-79 years enrolled in the Women's Health Initiative randomized double-blind trials of menopausal hormone therapy. Self-reported leisure-time physical activity at baseline, and years 1, 3, and 6 was quantified as metabolic equivalents (MET)-h/wk. In each trial, comparison between intervention and placebo groups of changes in physical activity levels from baseline to follow-up assessment was examined using linear regression models. RESULTS: In the CEE-alone trial, the increase in MET-h/wk was greater in the placebo group compared with the intervention group at years 3 ( P = 0.002) and 6 ( P < 0.001). Similar results were observed when analyses were restricted to women who maintained an adherence rate ≥80% during the trial or who were physically active at baseline. In the CEE + MPA trial, the primary analyses did not show significant differences between groups, but the increase of MET-h/wk was greater in the placebo group compared with the intervention group at year 3 ( P = 0.004) among women with an adherence rate ≥80%. CONCLUSIONS: The results from this clinical trial do not support the hypothesis that estrogen treatment increases physical activity among postmenopausal women.

Bilateral Oophorectomy and Colorectal Cancer Incidence and Mortality in the Women's Health Initiative.

BACKGROUND: The few cohort studies examining oophorectomy and colorectal cancer risk provide mixed results. Therefore, we examined this issue in Women's Health Initiative Observational Study participants. METHODS: A total of 71,312 postmenopausal women were followed for 22.1 years (median). At enrollment, 55,643 (78%) had intact ovaries and 15,669 (22%) had undergone a bilateral oophorectomy. Colorectal cancers were verified by central medical record review with mortality findings enhanced by National Death Index queries. RESULTS: With 1,421 incident colorectal cancers, 450 colorectal cancer-specific mortalities, after controlling for covariates, bilateral oophorectomy was not associated with colorectal cancer incidence or colorectal cancer mortality. CONCLUSIONS: No significant associations between oophorectomy and colorectal cancer incidence and mortality were seen in a large cohort study with long follow-up. IMPACT: As the oophorectomy and colorectal cancer question remains open, further studies of high quality, even with null findings, should be encouraged.

Birth weight, adult body size, and risk of colorectal cancer.

BACKGROUND: Evidence suggests that birth weight may be associated with colorectal cancer (CRC) risk later in life. Whether the association is mediated by adult body size remains unexamined. METHOD: Cox proportional hazards models (Hazard Ratio (HR) and 95 % Confidence Intervals (CI)) were used to evaluate the association between self-reported birth weight (<6 lbs, 6-<8 lbs, ≥8 lbs) and CRC risk among 70,397 postmenopausal women from the Women's Health Initiative. Further, we assessed whether this association was mediated by adult body size using multiple mediation analyses. RESULTS: Compared with birth weights of 6-< 8 lbs, birth weight ≥ 8 lbs was associated with higher CRC risk in postmenopausal women (HR = 1.31, 95 % CI 1.16-1.48). This association was significantly mediated by adult height (proportion mediated =11.4 %), weight (11.2 %), waist circumference (10.9 %), and body mass index at baseline (4.0 %). The joint effect of adult height and weight explained 21.6 % of this positive association. CONCLUSION: Our data support the hypothesis that the intrauterine environment and fetal development may be related to the risk of developing CRC later in life. While adult body size partially explains this association, further investigation is required to identify other factors that mediate the link between birth weight and CRC.

Opium, phencyclidine, and crack cocaine smoking associations with lung and upper aerodigestive tract cancers: exploratory findings from a case-control study in Los Angeles County.

Background: Illicit drug use has become a global epidemic, yet it is unclear if drug smoking increases the risk of tobacco-related cancers.Objectives: We aimed to evaluate hypothesized associations between smoking three drugs - opium, phencyclidine (PCP) and crack cocaine and lung and upper aerodigestive tract (UADT) cancers.Methods: A population-based case-control study with 611 lung cancer cases (50% male), 601 UADT cancers cases (76% male), and 1,040 controls (60% male) was conducted in Los Angeles County (1999-2004). Epidemiologic data including drug smoking histories were collected in face-to-face interviews. Associations were estimated with logistic regressions.Results: Adjusting for potential confounders, ever vs. never crack smoking was positively associated with UADT cancers (aOR = 1.56, 95% CI: 1.05, 2.33), and a dose-response relationship was observed for lifetime smoking frequency (p for trend = .024). Heavy (> median) vs. never crack smoking was associated with UADT cancers (aOR = 1.81, 95% CI: 1.07, 3.08) and lung cancer (aOR = 1.58, 95% CI: 0.88, 2.83). A positive association was also observed between heavy PCP smoking and UADT cancers (aOR = 2.29, 95% CI: 0.91, 5.79). Little or no associations were found between opium smoking and lung cancer or UADT cancers.Conclusion: The positive associations between illicit drug use and lung and/or UADT cancers suggest that smoking these drugs may increase the risk of tobacco-related cancers. Despite the low frequency of drug smoking and possible residual confounding, our findings may provide additional insights on the development of lung and UADT cancers.

Biomarkers of glucose homeostasis as mediators of the relationship of body mass index and waist circumference with COVID-19 outcomes among postmenopausal women: The Women's Health Initiative.

BACKGROUND & AIMS: Systematic reviews, meta-analyses and Mendelian randomization studies suggest that cardiometabolic diseases may be associated with COVID-19 risk and prognosis, with evidence implicating insulin resistance (IR) as a common biological mechanism. As driving factors for IR, we examined body mass index (BMI) and waist circumference (WC) among postmenopausal women in association with COVID-19 outcomes (positivity and hospitalization), and the role of glucose homeostasis as a mediator of this relationship. METHODS: Associations of BMI and WC at baseline (1993-1998) with COVID-19 outcomes collected at Survey 1 (June-December, 2020) and/or Survey 2 (September-December, 2021) were evaluated among 42,770 Women's Health Initiative (WHI) participants (baseline age: 59.36 years) of whom 16,526 self-reported having taken ≥1 COVID-19 test, with 1242 reporting ≥1 positive COVID-19 test and 362 reporting ≥1 COVID-19 hospitalization. We applied logistic regression and causal mediation analyses to sub-samples with available fasting biomarkers of glucose homeostasis (glucose, insulin, Homeostatic Model Assessment for Insulin Resistance, Homeostasis Model Assessment for ß-cell function, Quantitative Insulin-sensitivity Check Index, Triglyceride-Glucose index (TyG)) at baseline, whereby 57 of 759 reported COVID-19 test positivity and 23 of 1896 reported COVID-19 hospitalization. RESULTS: In fully adjusted models, higher BMI, WC and TyG were associated with COVID-19 test positivity and hospitalization. Glucose concentrations mediated associations of BMI and WC with COVID-19 positivity, whereas TyG mediated BMI and WC's associations with COVID-19 hospitalization. CONCLUSIONS: Obesity and central obesity markers collected an average of 24 years prior were associated with COVID-19 outcomes among postmenopausal women. Glucose concentration and TyG partly mediated these associations.

Estimating heritability explained by local ancestry and evaluating stratification bias in admixture mapping from summary statistics.

The heritability explained by local ancestry markers in an admixed population hγ2 provides crucial insight into the genetic architecture of a complex disease or trait. Estimation of hγ2 can be susceptible to biases due to population structure in ancestral populations. Here, we present a novel approach, Heritability estimation from Admixture Mapping Summary STAtistics (HAMSTA), which uses summary statistics from admixture mapping to infer heritability explained by local ancestry while adjusting for biases due to ancestral stratification. Through extensive simulations, we demonstrate that HAMSTA hγ2 estimates are approximately unbiased and are robust to ancestral stratification compared to existing approaches. In the presence of ancestral stratification, we show a HAMSTA-derived sampling scheme provides a calibrated family-wise error rate (FWER) of ~5% for admixture mapping, unlike existing FWER estimation approaches. We apply HAMSTA to 20 quantitative phenotypes of up to 15,988 self-reported African American individuals in the Population Architecture using Genomics and Epidemiology (PAGE) study. We observe hˆγ2 in the 20 phenotypes range from 0.0025 to 0.033 (mean hˆγ2=0.012+/-9.2×10-4), which translates to hˆ2 ranging from 0.062 to 0.85 (mean hˆ2=0.30+/-0.023). Across these phenotypes we find little evidence of inflation due to ancestral population stratification in current admixture mapping studies (mean inflation factor of 0.99 +/- 0.001). Overall, HAMSTA provides a fast and powerful approach to estimate genome-wide heritability and evaluate biases in test statistics of admixture mapping studies.

DNA methylation patterns associated with breast cancer prognosis that are specific to tumor subtype and menopausal status.

Tumor subtype and menopausal status are strong predictors of breast cancer (BC) prognosis. We aimed to find and validate subtype- or menopausal-status-specific changes in tumor DNA methylation (DNAm) associated with all-cause mortality or BC progression. Associations between site-specific tumor DNAm and BC prognosis were estimated among The Cancer Genome Atlas participants (n = 692) with Illumina Infinium HumanMethylation450 BeadChip array data. All-cause mortality and BC progression were modeled using Cox proportional hazards models stratified by tumor subtypes, adjusting for age, race, stage, menopausal status, tumor purity, and cell type proportion. Effect measure modification by subtype and menopausal status were evaluated by incorporating a product term with DNAm. Site-specific inference was used to identify subtype- or menopausal-status-specific differentially methylated regions (DMRs) and functional pathways. The validation of the results was carried out on an independent dataset (GSE72308; n = 180). We identified a total of fifteen unique CpG probes that were significantly associated ( P ≤ 1 × 10 - 7 with survival outcomes in subtype- or menopausal-status-specific manner. Seven probes were associated with overall survival (OS) or progression-free interval (PFI) for women with luminal A subtype, and four probes were associated with PFI for women with luminal B subtype. Five probes were associated with PFI for post-menopausal women. A majority of significant probes showed a lower risk of OS or BC progression with higher DNAm. We identified subtype- or menopausal-status-specific DMRs and functional pathways of which top associated pathways differed across subtypes or menopausal status. None of significant probes from site-specific analyses met genome-wide significant level in validation analyses while directions and magnitudes of coefficients showed consistent pattern. We have identified subtype- or menopausal-status-specific DNAm biomarkers, DMRs and functional pathways associated with all-cause mortality or BC progression, albeit with limited validation. Future studies with larger independent cohort of non-post-menopausal women with non-luminal A subtypes are warranted for identifying subtype- and menopausal-status-specific DNAm biomarkers for BC prognosis.

DNA methylation in peripheral blood leukocytes for the association with glucose metabolism and invasive breast cancer.

BACKGROUND: Insulin resistance (IR) is a well-established factor for breast cancer (BC) risk in postmenopausal women, but the interrelated molecular pathways on the methylome are not explicitly described. We conducted a population-level epigenome-wide association (EWA) study for DNA methylation (DNAm) probes that are associated with IR and prospectively correlated with BC development, both overall and in BC subtypes among postmenopausal women. METHODS: We used data from Women's Health Initiative (WHI) ancillary studies for our EWA analyses and evaluated the associations of site-specific DNAm across the genome with IR phenotypes by multiple regressions adjusting for age and leukocyte heterogeneities. For our analysis of the top 20 IR-CpGs with BC risk, we used the WHI and the Cancer Genomic Atlas (TCGA), using multiple Cox proportional hazards and logit regressions, respectively, accounting for age, diabetes, obesity, leukocyte heterogeneities, and tumor purity (for TCGA). We further conducted a Gene Set Enrichment Analysis. RESULTS: We detected several EWA-CpGs in TXNIP, CPT1A, PHGDH, and ABCG1. In particular, cg19693031 in TXNIP was replicated in all IR phenotypes, measured by fasting levels of glucose, insulin, and homeostatic model assessment-IR. Of those replicated IR-genes, 3 genes (CPT1A, PHGDH, and ABCG1) were further correlated with BC risk; and 1 individual CpG (cg01676795 in POR) was commonly detected across the 2 cohorts. CONCLUSIONS: Our study contributes to better understanding of the interconnected molecular pathways on the methylome between IR and BC carcinogenesis and suggests potential use of DNAm markers in the peripheral blood cells as preventive targets to detect an at-risk group for IR and BC in postmenopausal women.

Genetic variants of glucose metabolism and exposure to smoking in African American breast cancer.

Insulin resistance (IR) is a well-established risk factor for breast cancer (BC) development in African American (AA) postmenopausal women. While obesity and IR are more prevalent in AA than in white women, they are under-represented in genome-wide studies for systemic regulation of IR. By examining 780 genome-wide IR single-nucleotide polymorphisms (SNPs) available in our data, we tested 4689 AA women in a Random Survival Forest framework. With 37 BC-associated lifestyle factors, we conducted a gene-environment interaction analysis to estimate risk prediction for BC with the most influential genetic and behavioral factors and evaluated their combined and joint effects on BC risk. By accounting for variations of individual SNPs in BC in the prediction model, we detected four fasting glucose-associated SNPs in PCSK1, SPC25, ADCY5, and MTNR1B and three lifestyle factors (smoking, oral contraceptive use, and age at menopause) as the most predictive markers for BC risk. Our joint analysis of risk genotypes and lifestyle with smoking revealed a synergistic effect on the increased risk of BC, particularly estrogen/progesterone positive (ER/PR+) BC, in a gene-lifestyle dose-dependent manner. The joint effect of smoking was more substantial in women with prolonged exposure to cigarette smoking and female hormones. The top genome-wide association-SNPs associated with metabolic biomarkers in combination with lifestyles synergistically increase the predictability of invasive ER/PR+ BC risk among AA women. Our findings highlight generically targeted preventive interventions for women who carry particular risk genotypes and lifestyles.