Fang Fang

Testosterone is a key determinant of red blood cell (RBC) biology and susceptibility to hemolysis; however, its contribution to donor-dependent variation in RBC quality and transfusion effectiveness remains unclear. Using data from 2,357 male participants in the NHLBI REDS-III RBC-Omics study, we quantified plasma total testosterone, free testosterone (bioavailable form), and androstenedione and evaluated their associations with donor characteristics, RBC hemolysis, and recipient post-transfusion hemoglobin increments, a clinical measure of RBC transfusion effectiveness. Subphysiological testosterone concentrations were common (~35%) and independently associated with increased storage and osmotic hemolysis. Frequent blood donations were independently associated with lower circulating free testosterone concentrations, even after adjustment for demographic and hematologic factors. Genome-wide association analyses identified loci associated with circulating testosterone, including regions near SHBG , TNFSF12 , and the long noncoding RNA BALR6 . Several testosterone variants were associated with RBC transfusion effectiveness. Specifically, variants associated with lower testosterone (e.g., TNFSF12 ) corresponded to higher post-transfusion hemoglobin increments (+9%), whereas BALR6 variants associated with higher testosterone were linked to reduced hemoglobin increments (–40%). In contrast, androstenedione-associated variants were not related to hemolysis or transfusion outcomes. Together, these findings demonstrate that genetic and physiologic variation in testosterone contributes to inter-individual variability in RBC quality and transfusion effectiveness.

Combination antiretroviral therapy (ART) has changed the landscape of the HIV epidemic by providing an effective means for viral suppression to people living with HIV (PLWH). Understanding living with HIV as a chronic disease requires an improved understanding of how HIV and/or ART impacts susceptibility to and development of co-occurring conditions. Genome-wide gene expression (transcriptome) differences provide a key view into biological dysregulation associated with living with HIV. Here we present the first whole blood transcriptome-wide study comparing gene expression profiles between virally suppressed PLWH and HIV negative individuals (N=555). We identify 566 genes and 5 immune cell types with differential proportions by HIV status, which were significantly enriched for immune function and cancer pathways. Leveraging quantitative trait loci (QTL) for these HIV status-associated genes, partitioned heritability, and colocalization analyses, we observed limited genetic drivers of these relationships. Our findings suggest that gene dysregulation does not return to a pre-infection state for virally suppressed PLWH, and that persistent gene dysregulation is broadly associated with immune function and cancer pathways, highlighting potential biological drivers for these causes of excess mortality and targets for pharmacological preventative treatment among PLWH.

Background: Epigenetic clocks are promising tools for assessing biological age. We assessed the accuracy of pediatric epigenetic clocks in gestational and chronological age determination. Results: Our study used data from seven tissue types on three DNA methylation profiling microarrays and found that the Knight and Bohlin clocks performed similarly for blood cells, while the Lee clock was superior for placental samples. The pediatric-buccal-epigenetic clock performed the best for pediatric buccal samples, while the Horvath clock is recommended for children's blood cell samples. The NeoAge clock stands out for its unique ability to predict post-menstrual age with high correlation with the observed age in infant buccal cell samples. Conclusions: Our findings provide valuable guidance for future research and development of epigenetic clocks in pediatric samples, enabling more accurate assessments of biological age.

Summary: Ischaemic stroke is a common complication of sickle cell disease (SCD) and without intervention can affect 11% of children with SCD before the age of 20. Within the Trans‐Omics for Precision Medicine (TOPMed), a genome‐wide association study (GWAS) of ischaemic stroke was performed on 1333 individuals with SCD from Brazil (178 cases, 1155 controls). Via a novel Cox proportional‐hazards analysis, we searched for variants associated with ischaemic stroke occurring at younger ages. Variants at genome‐wide significance (p < 5 × 10⁻⁸) include two near genes previously linked to non‐SCD early‐onset stroke (ADAMTS2(rs147625068,p = 3.70 × 10⁻⁹) andCDK18(rs12144136,p = 2.38 × 10⁻⁹). Meta‐analysis, which included the independent SCD cohorts Walk‐PHaSST and PUSH, exhibited consistent association for variants rs1209987 near geneTBC1D32(p = 3.36 × 10⁻¹⁰), rs188599171 nearCUX1(p = 5.89 × 10⁻¹¹), rs77900855 nearBTG1(p = 4.66 × 10⁻⁸), and rs141674494 nearVPS13C(1.68 × 10⁻⁹). Findings from this study support a multivariant model of early ischaemic stroke risk and possibly a shared genetic architecture between SCD individuals and non‐SCD individuals younger than 65 years.

Cannabis is widely used worldwide, yet its links to health outcomes are not fully understood. DNA methylation can serve as a mediator to link environmental exposures to health outcomes. We conducted an epigenome-wide association study (EWAS) of peripheral blood-based DNA methylation and lifetime cannabis use (ever vs. never) in a meta-analysis including 9,436 participants (7,795 European and 1,641 African ancestry) from seven cohorts. Accounting for effects of cigarette smoking, our trans-ancestry EWAS meta-analysis revealed four CpG sites significantly associated with lifetime cannabis use at a false discovery rate of 0.05 ( p < 5.85 × 10 ⁻⁷ ): cg22572071 near gene ADGRF1 , cg15280358 in ADAM12 , cg00813162 in ACTN1 , and cg01101459 near LINC01132 . Additionally, our EWAS analysis in participants who never smoked cigarettes identified another epigenome-wide significant CpG site, cg14237301 annotated to APOBR . We used a leave-one-out approach to evaluate methylation scores constructed as a weighted sum of the significant CpGs. The best model can explain 3.79% of the variance in lifetime cannabis use. These findings unravel the DNA methylation changes associated with lifetime cannabis use that are independent of cigarette smoking and may serve as a starting point for further research on the mechanisms through which cannabis exposure impacts health outcomes.

Background: Air pollution exposure is associated with cardiovascular morbidity and mortality. Although exposure to air pollution early in life may represent a critical window for development of cardiovascular disease risk factors, few studies have examined associations of long-term air pollution exposure with markers of cardiovascular and cardiometabolic health in young adults. Objectives: By combining health data from the National Longitudinal Study of Adolescent to Adult Health (Add Health) with air pollution data from the Fused Air Quality Surface using Downscaling (FAQSD) archive, we: (1) calculated multi-year estimates of exposure to ozone (O ₃ ) and particulate matter with an aerodynamic diameter ≤2.5μm (PM _2.5 ) for Add Health participants; and (2) estimated associations between air pollution exposures and multiple markers of cardiometabolic health. Methods: Add Health is a nationally representative longitudinal cohort study of over 20,000 adolescents aged 12–19 in the United States (US) in 1994–95 (Wave I). Participants have been followed through adolescence and into adulthood with five in-home interviews. Estimated daily concentrations of O ₃ and PM _2.5 at census tracts were obtained from the FAQSD archive and used to generate tract-level annual averages of O ₃ and PM _2.5 concentrations. We estimated associations between average O ₃ and PM _2.5 exposures from 2002–07 and markers of cardiometabolic health measured at Wave IV (2008–09), including hypertension, hyperlipidemia, body mass index (BMI), diabetes, C-reactive protein, and metabolic syndrome. Results: The final sample size was 11,259 individual participants. The average age of participants at Wave IV was 28.4 years (range: 24–34 years). In models adjusting for age, race/ethnicity, and sex, long-term O ₃ exposure (2002–07) was associated with elevated odds of hypertension, with an odds ratio (OR) of 1.015 (95% confidence interval [CI]: 1.011, 1.029); obesity (1.022 [1.004, 1.040]); diabetes (1.032 [1.009,1.054]); and metabolic syndrome (1.028 [1.014, 1.041]); PM _2.5 exposure (2002–07) was associated with elevated odds of hypertension (1.022 [1.001, 1.045]). Conclusion: Findings suggest that long-term ambient air pollution exposure, particularly O ₃ exposure, is associated with cardiometabolic health in early adulthood.