Association between circulating inflammatory markers and adult cancer risk: a Mendelian randomization analysis.

BACKGROUND: Tumour-promoting inflammation is a "hallmark" of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear. METHODS: We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,294 cancer cases and up to 1,238,345 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P < 5.0 × 10-8) cis-acting SNPs (i.e., in or ±250 kb from the gene encoding the relevant protein) in weak linkage disequilibrium (LD, r2 < 0.10). Effect estimates were generated using inverse-variance weighted random-effects models and standard errors were inflated to account for weak LD between variants with reference to the 1000 Genomes Phase 3 CEU panel. A false discovery rate (FDR)-corrected P-value ("q-value") <0.05 was used as a threshold to define "strong evidence" to support associations and 0.05 ≤ q-value < 0.20 to define "suggestive evidence". A colocalisation posterior probability (PPH4) >70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. Findings were replicated in the FinnGen study and then pooled using meta-analysis. FINDINGS: We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR: 1.19, 95% CI: 1.10-1.29, q-value = 0.033, PPH4 = 84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR: 1.42, 95% CI: 1.20-1.69, q-value = 0.055, PPH4 = 73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR: 0.66, 95% CI: 0.53-0.81, q-value = 0.067, PPH4 = 81.8%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR: 0.92, 95% CI: 0.88-0.97, q-value = 0.15, PPH4 = 85.6%). These findings were replicated in pooled analyses with the FinnGen study. Though suggestive evidence was found to support an association of macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR: 2.46, 95% CI: 1.48-4.10, q-value = 0.072, PPH4 = 76.1%), this finding was not replicated when pooled with the FinnGen study. For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk. INTERPRETATION: Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 4 circulating inflammatory markers in risk of 4 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated. FUNDING: Cancer Research UK (C68933/A28534, C18281/A29019, PPRCPJT∖100005), World Cancer Research Fund (IIG_FULL_2020_022), National Institute for Health Research (NIHR202411, BRC-1215-20011), Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4), Academy of Finland Project 326291, European Union's Horizon 2020 grant agreement no. 848158 (EarlyCause), French National Cancer Institute (INCa SHSESP20, 2020-076), Versus Arthritis (21173, 21754, 21755), National Institutes of Health (U19 CA203654), National Cancer Institute (U19CA203654).

High-dimensional quantile mediation analysis with application to a birth cohort study of mother-newborn pairs.

MOTIVATION: There has been substantial recent interest in developing methodology for high-dimensional mediation analysis. Yet, the majority of mediation statistical methods lean heavily on mean regression, which limits their ability to fully capture the complex mediating effects across the outcome distribution. To bridge this gap, we propose a novel approach for selecting and testing mediators throughout the full range of the outcome distribution spectrum. RESULTS: The proposed high-dimensional quantile mediation model provides a comprehensive insight into how potential mediators impact outcomes via their mediation pathways. This method's efficacy is demonstrated through extensive simulations. The study presents a real-world data application examining the mediating effects of DNA methylation on the relationship between maternal smoking and offspring birthweight. AVAILABILITY AND IMPLEMENTATION: Our method offers a publicly available and user-friendly function qHIMA(), which can be accessed through the R package HIMA at https://CRAN.R-project.org/package=HIMA.

Familial Hypercholesterolemia Variant and Cardiovascular Risk in Individuals With Elevated Cholesterol.

Importance: Familial hypercholesterolemia (FH) is a genetic disorder that often results in severely high low-density lipoprotein cholesterol (LDL-C) and high risk of premature coronary heart disease (CHD). However, the impact of FH variants on CHD risk among individuals with moderately elevated LDL-C is not well quantified. Objective: To assess CHD risk associated with FH variants among individuals with moderately (130-189 mg/dL) and severely (≥190 mg/dL) elevated LDL-C and to quantify excess CHD deaths attributable to FH variants in US adults. Design, Setting, and Participants: A total of 21 426 individuals without preexisting CHD from 6 US cohort studies (Atherosclerosis Risk in Communities study, Coronary Artery Risk Development in Young Adults study, Cardiovascular Health Study, Framingham Heart Study Offspring cohort, Jackson Heart Study, and Multi-Ethnic Study of Atherosclerosis) were included, 63 of whom had an FH variant. Data were collected from 1971 to 2018, and the median (IQR) follow-up was 18 (13-28) years. Data were analyzed from March to May 2023. Exposures: LDL-C, cumulative past LDL-C, FH variant status. Main Outcomes and Measures: Cox proportional hazards models estimated associations between FH variants and incident CHD. The Cardiovascular Disease Policy Model projected excess CHD deaths associated with FH variants in US adults. Results: Of the 21 426 individuals without preexisting CHD (mean [SD] age 52.1 [15.5] years; 12 041 [56.2%] female), an FH variant was found in 22 individuals with moderately elevated LDL-C (0.3%) and in 33 individuals with severely elevated LDL-C (2.5%). The adjusted hazard ratios for incident CHD comparing those with and without FH variants were 2.9 (95% CI, 1.4-6.0) and 2.6 (95% CI, 1.4-4.9) among individuals with moderately and severely elevated LDL-C, respectively. The association between FH variants and CHD was slightly attenuated when further adjusting for baseline LDL-C level, whereas the association was no longer statistically significant after adjusting for cumulative past LDL-C exposure. Among US adults 20 years and older with no history of CHD and LDL-C 130 mg/dL or higher, more than 417 000 carry an FH variant and were projected to experience more than 12 000 excess CHD deaths in those with moderately elevated LDL-C and 15 000 in those with severely elevated LDL-C compared with individuals without an FH variant. Conclusions and Relevance: In this pooled cohort study, the presence of FH variants was associated with a 2-fold higher CHD risk, even when LDL-C was only moderately elevated. The increased CHD risk appeared to be largely explained by the higher cumulative LDL-C exposure in individuals with an FH variant compared to those without. Further research is needed to assess the value of adding genetic testing to traditional phenotypic FH screening.

Community cervical cancer screening and precancer risk in women living with HIV in Jos Nigeria.

BACKGROUND: High HIV prevalence, and lack of organized screening for the indigent population receiving care and treatment within HIV clinics in low-resource settings increases cervical cancer incidence. We sought to determine predictors of cervical precancer in women living with HIV and receiving cervical cancer screening in Jos, Nigeria. METHODS: A cross-sectional study of women living with HIV and receiving care and treatment in adult HIV/AIDS clinics in Jos-Metropolis, Nigeria between June 2020 and April 2023. Ethical approvals were obtained from the ethics committee in Jos, Nigeria and Northwestern University IRB, USA. Informed consent was obtained from eligible participants, and data on socio-demographics, cancer risk factors, and cytology reports were collected. The outcome variables were cervical precancer lesions. The independent variables were prior Pap smear status, socio-demographics, income, educational, and other reproductive health factors. Descriptive statistics was done to obtain means ± sd, frequencies, and percentages for the variables. Univariate and bivariate analyses were done to determine predictors of cervical dysplasia. Analyses were performed using R software. RESULTS: Of 957 women screened, 570 were living with HIV and 566 women had cytology report and were included in the final analysis. The mean age was 45.08 ± 8.89 years and 81.6% had no prior evidence of Pap test (under-screened). Prevalence of cervical dysplasia was 24% (mild and severe dysplasia were 12.9% and 11.1%, respectively). Age above 45 years (aOR = 3.48, p = 0.009), postmenopausal status (aOR = 7.69, p = 0.000), and women with no history of prior IUCD use (aOR = 5.94, p = 0.0001), were predictors for severe dysplasia. Women who had history of STI (aOR = 0.17, p = 0.000), prior use of IUCD (aOR = 0.32, p = 0.004), prior use of condom (aOR = 2.50, p = 0.003) and had co-morbidities (aOR = 0.46, p = 0.009) were more likely to have had a Pap test in the past. CONCLUSIONS: The majority of indigent women receiving care at HIV clinics had their first Pap test screening, and lack of organized screening among older and post-menopausal women with HIV, puts women at a higher risk of developing severe cervical precancer lesions.

Epigenetic Aging Is Associated With Measures of Midlife Muscle Volume and Attenuation in CARDIA Study.

BACKGROUND: GrimAge acceleration (GAA), an epigenetic marker that represents physiologic aging, is associated with age-related diseases including cancer and cardiovascular diseases. However, the associations between GAA and muscle mass and function are unknown. METHODS: We estimated measures of GAA in 1 118 Black and White participants from the Coronary Artery Risk Development in Young Adults (CARDIA) Study at exam years (Y) 15 (2000-2001) and 20 (2005-2006). Abdominal muscle composition was measured using CT scans at the Y25 (2010-2011) visit. We used multivariate regression models to examine associations of GAA estimates with muscle imaging measurements. RESULTS: In the CARDIA study, each 1-year higher GAA was associated with an average 1.1% (95% confidence interval [CI]: 0.6%, 1.5%) higher intermuscular adipose tissue (IMAT) volume for abdominal muscles. Each 1-year higher GAA was associated with an average -0.089 Hounsfield unit (HU; 95% CI: -0.146, -0.032) lower lean muscle attenuation and an average -0.049 HU (95% CI: -0.092, -0.007) lower IMAT attenuation for abdominal muscles. Stratified analyses showed that GAA was more strongly associated with higher abdominal muscle IMAT volume in females and significantly associated with lower lean muscle attenuation for White participants only. CONCLUSIONS: Higher GAA is associated with higher abdominal muscle IMAT volume and lower lean muscle attenuation in a midlife population.

Epidemiology and survival outcomes of HIV-associated cervical cancer in Nigeria.

INTRODUCTION: Invasive cervical cancer (ICC) is an HIV-associated cancer that is preventable and precancerous stages including early ICC stages could be detected through screening offering opportunities for treatment and cure. The high incidence in women living with HIV and late presentation often at advanced stages of ICC with limited treatment facilities often result in early mortality. We sought to compare the epidemiologic characteristics and survival differences in HIV status of ICC patients in Nigeria. METHODS: We conducted a cohort study at two federal academic hospital-based research sites in Jos University Teaching Hospital, and Lagos University Teaching Hospital Nigeria, between March 2018 and September 2022. We enrolled women with histologically confirmed ICC with known HIV status, and FIGO staging as part of the United States of America's National Institutes of Health/National Cancer Institute funded project titled 'Epigenomic Biomarkers of HIV-Associated Cancers in Nigeria'. The primary outcome was all-cause mortality with assessment of overall survival (OS) and time to death after ICC diagnosis. OS distribution was estimated using the method of Kaplan-Meier and compared between groups using the log-rank test. RESULTS: A total of 239 women with confirmed ICC were enrolled and included in this analysis, of whom 192 (80.3%) were HIV-negative (HIV-/ICC +), and 47 (19.7%) were HIV-positive (HIV +/ICC +). The HIV +/ICC + patients were younger with median age 46 (IQR: 40-51) years compared to 57 (IQR: 45-66) among HIV-/ICC + (P < 0.001). Squamous cell carcinoma was the commonest histopathologic variant in 80.4% of ICC diagnosis, moderately differentiated tumor grade in 68.1% in both groups. HIV +/ICC + diagnosis was at FIGO advanced stages in 64.9% compared to 47.9% in HIV-/ICC +. The HIV-/ICC + women had better OS compared to HIV +/ICC + participants (p = 0.018), with 12-month OS 84.1% (95%CI 75-90%) and 67.6% (95%CI 42-84%) respectively. CONCLUSION: ICC is diagnosed at a relatively young age in women living with HIV, with a significantly lower overall survival probability compared to women without HIV. The trend of presentation and diagnosis at advanced stages in women living with HIV could partly explain the differences in overall survival.

Incident Kaposi sarcoma during the expansion of antiretroviral therapy eligibility in Nigeria: a retrospective cohort study.

INTRODUCTION: The expansion of antiretroviral therapy (ART) eligibility could lead to earlier initiation of Human Immunodeficiency Virus (HIV) treatment and consequently reduce the risk of HIV-associated Kaposi Sarcoma (KS). We investigated the impact of changes in the Nigerian HIV treatment guidelines on KS incidence among adults enrolled in HIV care in Nigeria. METHODS: We analyzed data of adults who enrolled for HIV care from January 2006 to December 2016 at one of Nigeria's largest HIV treatment centers. Based on changes in HIV treatment guidelines, we classified 2006-2009 as the pre-expansion period and 2010-2016 as the post-expansion period. We used Kaplan Meier curves to compare the incidence of KS in the pre-expansion to the post-expansion period. We used Cox regression models to assess the hazard for incident KS between the two periods after adjusting for potential confounders. RESULTS: Among 14,479 patients with HIV, the overall KS incidence was 2.35; 95% CI 2.01-2.74/1,000 person-years. The incidence of KS decreased from 2.53 to 1.58 per 1,000 person-years from 2006 to 2009 to 2010-2016. In models adjusting for age, sex, CD4-T cell count, and ART use, the risk for KS remained lower in 2010-2016 compared to 2006-2009. In analyses restricted to time on ART, there was no significant difference in KS incidence between HIV patients who enrolled in 2006-2009 and 2010-2016 after adjusting for age, sex, and CD4 T-cell count. CONCLUSION: The expansion of ART eligibility was associated with a reduced incidence of HIV-associated KS among adults initiating HIV care in Jos, Nigeria. The reduction was likely driven by earlier enrollment for HIV care and ART initiation.

Epidemiology and Survival outcomes of HIV-associated cervical cancer in Nigeria.

Introduction: Invasive cervical cancer (ICC) is an HIV-associated cancer that is preventable and precancerous stages including early ICC stages could be detected through screening offering opportunities for treatment and cure. The high incidence in women living with HIV and late presentation often at advanced stages of ICC with limited treatment facilities often result in early mortality. We sought to compare the epidemiologic characteristics and survival differences in HIV status of ICC patients in Nigeria. Methods: We conducted a cohort study at two federal academic hospital-based research sites in Jos University Teaching Hospital, and Lagos University Teaching Hospital Nigeria, between March 2018 and September 2022. We enrolled women with histologically confirmed ICC with known HIV status, and FIGO staging as part of the United States of America's National Institutes of Health/National Cancer Institute funded project titled 'Epigenomic Biomarkers of HIV-Associated Cancers in Nigeria'. The primary outcome was all-cause mortality with assessment of overall survival (OS) and time to death after ICC diagnosis. OS distribution was estimated using the method of Kaplan-Meier and compared between groups using the log-rank test. Results: A total of 239 women with confirmed ICC were enrolled and included in this analysis, of whom 192 (80.3%) were HIV-negative (HIV-/ICC+), and 47 (19.7%) were HIV-positive (HIV+/ICC+). The HIV+/ICC) patients were younger with median age 46 (IQR: 40-51) years compared to 57 (IQR: 45-66) among HIV-/ICC+) (P<0.001. Squamous cell carcinoma was the commonest histopathologic variant in 80.4% of ICC diagnosis, moderately differentiated tumor grade in 68.1% in both groups. HIV+/ICC+ diagnosis was at FIGO advanced stages in 64.9% compared to 47.9% in HIV-/ICC+. The HIV-/ICC+ women had better OS compared to HIV+/ICC+ participants (p=0.018), with 12-month OS 84.1% (95%CI: 75% - 90%) and 67.6% (95%CI: 42%-84%) respectively. Conclusion: ICC is diagnosed at a relatively young age in women living with HIV, with a significantly lower overall survival probability compared to women without HIV. The trend of presentation and diagnosis at advanced stages in women living with HIV could partly explain the differences in overall survival.

Long-term exposure to ambient fine particulate components and leukocyte epigenome-wide DNA Methylation in older men: the Normative Aging Study.

BACKGROUND: Epigenome-wide association studies of ambient fine particulate matter (PM2.5) have been reported. However, few have examined PM2.5 components (PMCs) and sources or included repeated measures. The lack of high-resolution exposure measurements is the key limitation. We hypothesized that significant changes in DNA methylation might vary by PMCs and the sources. METHODS: We predicted the annual average of 14 PMCs using novel high-resolution exposure models across the contiguous U.S., between 2000-2018. The resolution was 50 m × 50 m in the Greater Boston Area. We also identified PM2.5 sources using positive matrix factorization. We repeatedly collected blood samples and measured leukocyte DNAm with the Illumina HumanMethylation450K BeadChip in the Normative Aging Study. We then used median regression with subject-specific intercepts to estimate the associations between long-term (one-year) exposure to PMCs / PM2.5 sources and DNA methylation at individual cytosine-phosphate-guanine CpG sites. Significant probes were identified by the number of independent degrees of freedom approach, using the number of principal components explaining > 95% of the variation of the DNA methylation data. We also performed regional and pathway analyses to identify significant regions and pathways. RESULTS: We included 669 men with 1,178 visits between 2000-2013. The subjects had a mean age of 75 years. The identified probes, regions, and pathways varied by PMCs and their sources. For example, iron was associated with 6 probes and 6 regions, whereas nitrate was associated with 15 probes and 3 regions. The identified pathways from biomass burning, coal burning, and heavy fuel oil combustion sources were associated with cancer, inflammation, and cardiovascular diseases, whereas there were no pathways associated with all traffic. CONCLUSIONS: Our findings showed that the effects of PM2.5 on DNAm varied by its PMCs and sources.

Vaginal microbiome community state types and high-risk human papillomaviruses in cervical precancer and cancer in North-central Nigeria.

BACKGROUND: High risk human papillomaviruses (HR-HPV) have a causal role in cervical oncogenesis, and HIV-mediated immune suppression allows HR-HPV to persist. We studied whether vaginal microbiome community state types (CSTs) are associated with high-grade precancer and/or invasive cervical cancer (HSIL/ICC). METHODS: This was a cross-sectional study of adult women with cervical cancer screening (CCS) at the Jos University Teaching Hospital (JUTH) in Jos, Nigeria, between January 2020 and February 2022. Cervical swabs underwent HPV genotyping (Anyplex™ II HPV28). Cervico-vaginal lavage (CVL) sample was collected for 16 S rRNA gene amplicon sequencing. We used multivariable logistic regression modelling to assess associations between CSTs and other factors associated with HSIL/ICC. RESULTS: We enrolled 155 eligible participants, 151 with microbiome data for this analysis. Women were median age 52 (IQR:43-58), 47.7% HIV positive, and 58.1% with HSIL/ICC. Of the 138 with HPV data, 40.6% were negative for HPV, 10.1% had low-risk HPV, 26.8% had single HR-HPV, and 22.5% had multiple HR-HPV types. The overall prevalence of any HR-HPV type (single and multiple) was 49.3%, with a higher proportion in women with HSIL/ICC (NILM 31.6%, LSIL 46.5%, HSIL 40.8%, and 81.5% ICC; p = 0.007). Women with HIV were more likely to have HSIL/ICC (70.3% vs. 29.7% among women without HIV). In crude and multivariable analysis CST was not associated with cervical pathology (CST-III aOR = 1.13, CST-IV aOR = 1.31). However, in the presence of HR-HPV CST-III (aOR = 6.7) and CST-IV (aOR = 3.6) showed positive association with HSIL/ICC. CONCLUSION: Vaginal microbiome CSTs were not significantly associated with HSIL/ICC. Our findings suggest however, that CST could be helpful in identifying women with HSIL/ICC and particularly those with HR-HPV. Characterization of CSTs using point-of-care molecular testing in women with HR-HPV should be studied as an approach to improve early detection and cervical cancer prevention. Future longitudinal research will improve our understanding of the temporal effect of non-optimal CST, HR-HPV, and other factors in cervical cancer development, prevention, and control.

Predicting All-Cause Mortality in Women With and Without Breast Cancer Using the Schonberg Index: A Women's Health Initiative Study.

BACKGROUND: When treating older women with breast cancer, life expectancy is an important consideration. ASCO recommends calculating 10-year mortality probabilities to inform treatment decisions. One useful tool is the Schonberg index, which predicts risk-based all-cause 10-year mortality. We investigated the use of this index in women aged ≥65 years with breast cancer in the Women's Health Initiative (WHI). METHODS: We calculated 10-year mortality risk scores for 2,549 WHI participants with breast cancer ("cases") and 2,549 age-matched breast cancer-free participants ("controls") using Schonberg index risk scoring. Risk scores were grouped into quintiles for comparisons. Risk-stratified observed mortality rates and 95% confidence intervals were compared across cases and controls. Observed 10-year mortality rates in cases and controls were also compared with Schonberg index-based predicted 10-year mortality rates. RESULTS: Compared with controls, cases were more often white (P=.005), had higher income and education levels (P<.001 for both), more often lived with their husband/partner (P<.001), scored higher on subjective health/happiness (P<.001), and needed less assistance in activities of daily living (P<.001). Participants with breast cancer had similar risk-stratified 10-year mortality rates compared with controls (34% vs 33%, respectively). Stratified results showed that cases had slightly higher mortality rates than controls in the lowest risk quintile and lower mortality rates in the 2 highest risk quintiles. Observed mortality rates in cases and controls were similar to Schonberg index-predicted mortality, with model c-indexes of 0.71 and 0.76, respectively. CONCLUSIONS: Among women aged ≥65 years with incident breast cancer, the Schonberg index-based risk-stratified 10-year mortality rates were similar to those in women without breast cancer, demonstrating a similar performance of the index among both populations. Along with other health measures, prognostic indexes can help predict survival among older women with breast cancer and support geriatric oncology guidelines that promote using life expectancy calculation tools for shared decision-making.

Association between circulating inflammatory markers and adult cancer risk: a Mendelian randomization analysis.

Background: Tumour-promoting inflammation is a "hallmark" of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear. Methods: We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,162 cancer cases and up to 824,556 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P < 5.0 x 10-8) cis-acting SNPs (i.e. in or ±250 kb from the gene encoding the relevant protein) in weak linkage disequilibrium (LD, r2 < 0.10). Effect estimates were generated using inverse-variance weighted random-effects models and standard errors were inflated to account for weak LD between variants with reference to the 1000 Genomes Phase 3 CEU panel. A false discovery rate (FDR)-corrected P-value ("q-value") < 0.05 was used as a threshold to define "strong evidence" to support associations and 0.05 ≤ q-value < 0.20 to define "suggestive evidence". A colocalisation posterior probability (PPH4) > 70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. Results: We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR 1.19, 95% CI 1.10-1.29, q-value=0.033, PPH4=84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR 1.42, 95% CI 1.20-1.69, q-value=0.055, PPH4=73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR 0.66, 95% CI 0.53-0.81, q-value=0.067, PPH4=81.8%), macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR 1.14, 95% CI 1.05-1.23, q-value=0.072, PPH4=76.1%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR 0.92, 95% CI 0.88-0.97, q-value=0.15), PPH4=85.6%). For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥ 0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk. Conclusion: Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 5 circulating inflammatory markers in risk of 5 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated.

Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis.

Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis1. These lesions are precursors for blood cancers2-6, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.

Hepatocellular carcinoma presentation and prognosis among Nigerian adults with and without HIV.

INTRODUCTION: Hepatocellular carcinoma (HCC) is an increasing cause of mortality in Nigeria among persons with HIV (PLH), as access to antiretroviral therapy (ART) improves. In this study we describe clinical, radiological, and laboratory characteristics in Nigerian adults with HCC, with and without HIV, and examine how HIV impacts survival. METHODS: This prospective observational study was conducted between August 2018 and November 2021 at two Nigerian hospitals [Jos University Teaching Hospital (JUTH) and Lagos University Teaching Hospital (LUTH)]. Subjects ≥18 years with HCC diagnosed according to American Association for the Study of Liver Diseases (AASLD) criteria were included. Baseline characteristics were compared, and Kaplan-Meier curves were generated to estimate survival. RESULTS: 213 subjects [177 (83%) without HIV and 36 (17%) with HIV (PLH)] were enrolled. Median age was 52 years (IQR 42,60) and most subjects were male (71%). 83% PLH were on antiretroviral therapy (ART). Hepatitis B surface antigen (HBsAg) positivity was similar between the two groups [91/177 (51%) without HIV vs. 18/36 (50%) with HIV; p = 0.86]. 46/213 (22%) subjects had active hepatitis C (anti-HCV+/HCV RNA>10 IU/mL). Cirrhosis was more common in PLH but there were no other significant differences in clinical and tumor characteristics between the groups. Overall, 99% subjects were symptomatic and 78% in late-stage HCC. Median overall survival was significantly shorter in PLH vs. without HIV (0.98 months vs 3.02 months, HR = 1.55, 95%CI 1.02, 2.37, p = 0.04). This association was not significant after adjusting for known risk factors including gender, current alcohol use, alpha-fetoprotein (AFP), albumin, and total bilirubin (HR = 1.38, 95%CI 0.84, 2.29, p = 0.21). CONCLUSION: HCC presented late with an extremely poor overall prognosis, highlighting the urgent need for more intensive surveillance in Nigeria to diagnose HCC at earlier stages. Early diagnosis and management of viral hepatitis, and access to HCC therapies, could prevent early mortality among persons with HCC, especially among PLH.

Social Determinants, Cardiovascular Disease, and Health Care Cost: A Nationwide Study in the United States Using Machine Learning.

Background Existing studies on cardiovascular diseases (CVDs) often focus on individual-level behavioral risk factors, but research examining social determinants is limited. This study applies a novel machine learning approach to identify the key predictors of county-level care costs and prevalence of CVDs (including atrial fibrillation, acute myocardial infarction, congestive heart failure, and ischemic heart disease). Methods and Results We applied the extreme gradient boosting machine learning approach to a total of 3137 counties. Data are from the Interactive Atlas of Heart Disease and Stroke and a variety of national data sets. We found that although demographic composition (eg, percentages of Black people and older adults) and risk factors (eg, smoking and physical inactivity) are among the most important predictors for inpatient care costs and CVD prevalence, contextual factors such as social vulnerability and racial and ethnic segregation are particularly important for the total and outpatient care costs. Poverty and income inequality are the major contributors to the total care costs for counties that are in nonmetro areas or have high segregation or social vulnerability levels. Racial and ethnic segregation is particularly important in shaping the total care costs for counties with low poverty rates or social vulnerability level. Demographic composition, education, and social vulnerability are consistently important across different scenarios. Conclusions The findings highlight the differences in predictors for different types of CVD cost outcomes and the importance of social determinants. Interventions directed toward areas that have been economically and socially marginalized may aid in reducing the impact of CVDs.

Lack of Association of C677T Methylenetetrahydrofolate Reductase Polymorphism with Breast Cancer Risk in Mali.

Methylenetetrahydrofolate reductase (MTHFR) plays a major role in the metabolism of folates and homocysteine, which in turn can affect gene expression and ultimately promote the development of breast cancer. Thus, mutations in the MTHFR gene could influence homocysteine, methionine, and S-adenosylmethionine levels and, indirectly, nucleotide levels. Imbalance in methionine and S-adenosylmethionine synthesis affects protein synthesis and methylation. These changes, which affect gene expression, may ultimately promote the development of breast cancer. We therefore hypothesized that such mutations could also play an important role in the occurrence and pathogenesis of breast cancer in a Malian population. In this study, we used the PCR-RFLP technique to identify the different genotypic profiles of the C677T MTHFR polymorphism in 127 breast cancer women and 160 healthy controls. The genotypic distribution of the C677T polymorphism in breast cancer cases was 88.2% for CC, 11.0% for CT, and 0.8% for TT. Healthy controls showed a similar distribution with 90.6% for CC, 8.8% for CT, and 0.6% for TT. We found no statistical association between the C677T polymorphism and breast cancer risk for the codominant models CT and TT (p > 0.05). The same trend was observed when the analysis was extended to other genetic models, including dominant (p = 0.50), recessive (p = 0.87), and additive (p = 0.50) models. The C677T polymorphism of MTHFR gene did not influence the risk of breast cancer in the Malian samples.

The association between hepatic steatosis and incident cardiovascular disease, cancer, and all-cause mortality in a US multicohort study.

BACKGROUND AND AIMS: NAFLD strongly associates with cardiovascular disease (CVD) risk factors; however, the association between NAFLD and incident CVD, CVD-related mortality, incident cancer, and all-cause mortality is unclear. APPROACH AND RESULTS: We included 10,040 participants from the Framingham Heart Study, the Coronary Artery Risk Development in Young Adults Study, and the Multi-ethnic Study of Atherosclerosis to assess the longitudinal association between liver fat (defined on CT) and incident CVD, CVD-related mortality, incident cancer, and all-cause mortality. We performed multivariable-adjusted Cox regression models including age, sex, diabetes, systolic blood pressure, alcohol use, smoking, HDL, triglycerides, and body mass index at baseline or time-varying covariates. The average age was 51.3±3.3 years and 50.6% were women. Hepatic steatosis was associated with all-cause mortality after 12.7 years of mean follow-up when adjusting for baseline CVD risk factors, including body mass index (HR: 1.21, 1.04-1.40); however, the results were attenuated when utilizing time-varying covariates. The association between hepatic steatosis and incident CVD was not statistically significant after we accounted for body mass index in models considering baseline covariates or time-varying covariates. We observed no association between hepatic steatosis and CVD-related mortality or incident cancer. CONCLUSIONS: In this large, multicohort study of participants with CT-defined hepatic steatosis, accounting for change in CVD risk factors over time attenuated associations between liver fat and overall mortality or incident CVD. Our work highlights the need to consider concurrent cardiometabolic disease when determining associations between NAFLD and CVD and mortality outcomes.

Epigenome-wide DNA methylation in leukocytes and toenail metals: The normative aging study.

BACKGROUND: Environmental metal exposures have been associated with multiple deleterious health endpoints. DNA methylation (DNAm) may provide insight into the mechanisms underlying these relationships. Toenail metals are non-invasive biomarkers, reflecting a medium-term time exposure window. OBJECTIVES: This study examined variation in leukocyte DNAm and toenail arsenic (As), cadmium (Cd), lead (Pb), manganese (Mn), and mercury (Hg) among elderly men in the Normative Aging Study, a longitudinal cohort. METHODS: We repeatedly collected samples of blood and toenail clippings. We measured DNAm in leukocytes with the Illumina HumanMethylation450 K BeadChip. We first performed median regression to evaluate the effects of each individual toenail metal on DNAm at three levels: individual cytosine-phosphate-guanine (CpG) sites, regions, and pathways. Then, we applied a Bayesian kernel machine regression (BKMR) to assess the joint and individual effects of metal mixtures on DNAm. Significant CpGs were identified using a multiple testing correction based on the independent degrees of freedom approach for correlated outcomes. The approach considers the effective degrees of freedom in the DNAm data using the principal components that explain >95% variation of the data. RESULTS: We included 564 subjects (754 visits) between 1999 and 2013. The numbers of significantly differentially methylated CpG sites, regions, and pathways varied by metals. For example, we found six significant pathways for As, three for Cd, and one for Mn. The As-associated pathways were associated with cancer (e.g., skin cancer) and cardiovascular disease, whereas the Cd-associated pathways were related to lung cancer. Metal mixtures were also associated with 47 significant CpG sites, as well as pathways, mainly related to cancer and cardiovascular disease. CONCLUSIONS: This study provides an approach to understanding the potential epigenetic mechanisms underlying observed relations between toenail metals and adverse health endpoints.