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Overall, gastric adenocarcinoma (GC) incidence rates have declined in recent years, but racial and ethnic disparities persist. Individuals who identify as Hispanic/Spanish/Latino are diagnosed with GC at younger ages and have poorer outcomes than non-Hispanic individuals. However, our understanding of GC biology across racial/ethnic groups remains limited. We assessed tumor genomic patterns by race/ethnicity among 1019 patients with primary GC in the American Association for Cancer Research (AACR) Project GENIE Consortium. Hispanic individuals presented with significantly higher rates of ERBB2/HER2 amplification vs other racial/ethnic groups (Hispanic: 13.9% vs 9.8% non-Hispanic White, 8.1% non-Hispanic Asian, and 11.0% non-Hispanic Black; P < .001, FDR adjusted q < 0.001). Hispanic patients also had higher odds of an ERBB2 amplification vs non-Hispanic Whites in adjusted models (OR = 2.52, 95%CI = 1.20 to 5.33, P = .015). These findings underscore the important role of genomic factors in GC disparities. Ensuring equitable access to genomic profiling and targeted therapies, such as trastuzumab for HER2-overexpressing GC, is a promising avenue to mitigate GC disparities and improve outcomes., (© The Author(s) 2024. Published by Oxford University Press.)

Homo sapiens and Neanderthals underwent hybridization during the Middle/Upper Paleolithic age, culminating in retention of small amounts of Neanderthal-derived DNA in the modern human genome. In the current study, we address the potential roles Neanderthal single nucleotide polymorphisms (SNP) may be playing in autism susceptibility in samples of black non-Hispanic, white Hispanic, and white non-Hispanic people using data from the Simons Foundation Powering Autism Research (SPARK), Genotype-Tissue Expression (GTEx), and 1000 Genomes (1000G) databases. We have discovered that rare variants are significantly enriched in autistic probands compared to race-matched controls. In addition, we have identified 25 rare and common SNPs that are significantly enriched in autism on different ethnic backgrounds, some of which show significant clinical associations. We have also identified other SNPs that share more specific genotype-phenotype correlations but which are not necessarily enriched in autism and yet may nevertheless play roles in comorbid phenotype expression (e.g., intellectual disability, epilepsy, and language regression). These results strongly suggest Neanderthal-derived DNA is playing a significant role in autism susceptibility across major populations in the United States., (© 2024. The Author(s).)

Background: Breast cancer (BrCa) is the most common cancer for women globally. BrCa incidence varies by age and differs between racial groups, with Black women having an earlier age of onset and higher mortality compared to White women. The underlying biological mechanisms of this disparity remain uncertain. Here, we address this knowledge gap by examining the association between overall epigenetic age acceleration and BrCa initiation as well as the mediating role of race., Results: We measured whole-genome methylation (866,238 CpGs) using the Illumina EPIC array in blood DNA extracted from 209 women recruited from University Hospitals Cleveland Medical Center. Overall and intrinsic epigenetic age acceleration was calculated-accounting for the estimated white blood cell distribution-using the second-generation biological clock GrimAge. After quality control, 149 BrCa patients and 42 disease-free controls remained. The overall chronological mean age at BrCa diagnosis was 57.4 ± 11.4 years and nearly one-third of BrCa cases were self-reported Black women (29.5%). When comparing BrCa cases to disease-free controls, GrimAge acceleration was 2.48 years greater (p-value = 0.0056), while intrinsic epigenetic age acceleration was 1.72 years higher (p-value = 0.026) for cases compared to controls. After adjusting for known BrCa risk factors, we observed BrCa risk increased by 14% [odds ratio (OR) = 1.14; 95% CI: 1.05, 1.25] for a one-year increase in GrimAge acceleration. The stratified analysis by self-reported race revealed differing ORs for GrimAge acceleration: White women (OR = 1.17; 95% CI: 1.03, 1.36), and Black women (OR = 1.08; 95% CI: 0.96, 1.23). However, our limited sample size failed to detect a statistically significant interaction for self-reported race (p-value >0.05) when examining GrimAge acceleration with BrCa risk., Conclusions: Our study demonstrated that epigenetic age acceleration is associated with BrCa risk, and the association suggests variation by self-reported race. Although our sample size is limited, these results highlight a potential biological mechanism for BrCa risk and identifies a novel research area of BrCa health disparities requiring further inquiry., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Estimation of admixture proportions has become one of the most commonly used computational tools in population genomics. However, there is remarkably little population genetic theory on statistical properties of these variables. We develop theoretical results that can accurately predict means and variances of admixture proportions within a population using models with recombination and genetic drift. Based on established theory on measures of multilocus disequilibrium, we show that there is a set of recurrence relations that can be used to derive expectations for higher moments of the admixture proportions distribution. We obtain closed form solutions for some special cases. Using these results, we develop a method for estimating admixture parameters from estimated admixture proportions obtained from programs such as Structure or Admixture. We apply this method to HapMap 3 data and find that the population history of African Americans, as expected, is not best explained by a single admixture event between people of European and African ancestry. The model of constant gene flow starting at 8 generations and ending at 2 generations before present gives the best fit., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Multi-omics studies in Alzheimer's disease (AD) revealed many potential disease pathways and therapeutic targets. Despite their promise of precision medicine, these studies lacked Black Americans (BA) and Latin Americans (LA), who are disproportionately affected by AD., Methods: To bridge this gap, Accelerating Medicines Partnership in Alzheimer's Disease (AMP-AD) expanded brain multi-omics profiling to multi-ethnic donors., Results: We generated multi-omics data and curated and harmonized phenotypic data from BA (n = 306), LA (n = 326), or BA and LA (n = 4) brain donors plus non-Hispanic White (n = 252) and other (n = 20) ethnic groups, to establish a foundational dataset enriched for BA and LA participants. This study describes the data available to the research community, including transcriptome from three brain regions, whole genome sequence, and proteome measures., Discussion: The inclusion of traditionally underrepresented groups in multi-omics studies is essential to discovering the full spectrum of precision medicine targets that will be pertinent to all populations affected with AD., Highlights: Accelerating Medicines Partnership in Alzheimer's Disease Diversity Initiative led brain tissue profiling in multi-ethnic populations. Brain multi-omics data is generated from Black American, Latin American, and non-Hispanic White donors. RNA, whole genome sequencing and tandem mass tag proteomicsis completed and shared. Multiple brain regions including caudate, temporal and dorsolateral prefrontal cortex were profiled., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: Individuals with diabetes who carry genetic variants that lower hemoglobin A1c (HbA1c) independently of glycemia may have higher real, but undetected, hyperglycemia compared with those without these variants despite achieving similar HbA1c targets, potentially placing them at greater risk for diabetes-related complications. We sought to determine whether these genetic variants, aggregated in a polygenic score, and the large-effect African ancestry-specific missense variant in G6PD (rs1050828) that lower HbA1c were associated with higher retinopathy risk., Research Design and Methods: Using data from 29,828 type 2 diabetes cases of genetically inferred African American/African British and European ancestries, we calculated ancestry-specific nonglycemic HbA1c polygenic scores (ngA1cPS) composed of 122 variants associated with HbA1c at genome-wide significance, but not with glucose. We tested the association of the ngA1cPS and the G6PD variant with retinopathy, adjusting for measured HbA1c and retinopathy risk factors., Results: Participants in the bottom quintile of the ngA1cPS showed between 20% and 50% higher retinopathy prevalence, compared with those above this quintile, despite similar levels of measured HbA1c. The adjusted meta-analytic odds ratio for the bottom quintile was 1.31 (95% CI 1.0, 1.73; P = 0.05) in African ancestry and 1.31 (95% CI 1.15, 1.50; P = 6.5 × 10-5) in European ancestry. Among individuals of African ancestry with HbA1c below 7%, retinopathy prevalence was higher in individuals below, compared with above, the 50th percentile of the ngA1cPS regardless of sex or G6PD carrier status., Conclusions: Genetic effects need to be considered to personalize HbA1c targets and improve outcomes of people with diabetes from diverse ancestries., (© 2024 by the American Diabetes Association.)

There is an urgent need to pinpoint novel targets for drug discovery in the context of chronic kidney disease (CKD), and the proteome represents a significant pool of potential therapeutic targets. To address this, we performed proteome-wide analyses using Mendelian randomization (MR) and colocalization techniques to uncover potential targets for CKD. We extracted summary-level data from the ARIC study, focusing on 7213 European American (EA) individuals and 4657 plasma proteins. To broaden our analysis, we incorporated genetic association data from Icelandic cohorts, thereby enhancing our investigation into the correlations with chronic kidney disease (CKD), creatinine-based estimated glomerular filtration rate (eGFRcrea), and estimated glomerular filtration rate (eGFR). We utilized genetic association data from the GWAS Catalog, including CKD (765,348, 625,219 European ancestry and 140,129 non-European ancestry), eGFRcrea (1,004,040, European ancestry), and eGFR (567,460, European ancestry). Employing MR analysis, we estimated the associations between proteins and CKD risk. Additionally, we conducted colocalization analysis to evaluate the existence of shared causal variants between the identified proteins and CKD. We detected notable correlations between levels predicted based on genetics of three circulating proteins and CKD, eGFRcrea, and eGFR. Notably, our colocalization analysis provided robust evidence supporting these associations. Specifically, genetically predicted levels of Transcription elongation factor A protein 2 (TCEA2) and Neuregulin-4 (NRG4) exhibited an inverse relationship with CKD risk, while Glucokinase regulatory protein (GCKR) showed an increased risk of CKD. Furthermore, our colocalization analysis also supported the associations of TCEA2, NRG4, and GCKR with the risk of eGFRcrea and eGFR., (© 2024. The Author(s).)

Importance: Racial disparities in prostate cancer are likely the result of complex relationships between both socioeconomic and environmental factors captured by the neighborhood environment and genetic factors, including West African genetic ancestry. However, few studies have examined the combined role of neighborhood environment and genetic ancestry in developing lethal prostate cancer., Objective: To examine the interactions between West African genetic ancestry and neighborhood deprivation in modifying prostate cancer risk and mortality., Design, Setting, and Participants: This case-control study was conducted in the Greater Baltimore area. Participants included men of African and European descent (617 cases with prostate cancer, 852 controls without prostate cancer) enrolled between January 2005 and January 2016. Follow-up was performed through December 31, 2020, using the National Death Index. Analysis was conducted from August 2023 to January 2024., Exposure: Included exposures were West African genetic ancestry, derived from large-scale genotyping, and neighborhood deprivation, defined using 2000 census-tract-level Neighborhood Deprivation Index (NDI) score., Main Outcomes and Measures: Outcomes of interest were prostate cancer and all-cause mortality., Results: Among a total of 1469 participants (mean [SD] age, 64.96 [7.95] years), there were 736 self-identified Black and 733 White men, and the mean (range) proportion of West African genetic ancestry was 0.27 (0.04-0.84) among participants residing in areas with low levels of deprivation and 0.48 (0.07-0.83) among participants residing in areas with high levels of deprivation. Multivariable logistic regression analysis revealed a significant multiplicative interaction of West African genetic ancestry and neighborhood deprivation with the odds of a prostate cancer diagnosis (P for interaction = .02). Among individuals living in neighborhoods with high NDI scores, West African genetic ancestry was associated with increased odds of a prostate cancer diagnosis (age-adjusted odds ratio [OR], 1.98; 95% CI, 1.23-3.19). In contrast, West African genetic ancestry was associated with reduced odds of this diagnosis among individuals residing in areas with medium to low levels of deprivation (age-adjusted OR, 0.22; 95% CI, 0.11-0.44). There was no significant multiplicative interaction between West African genetic ancestry and neighborhood deprivation for all-cause mortality (P for interaction = .44). The positive association of neighborhood deprivation with prostate cancer was independent of West African genetic ancestry (age- and West African ancestry-adjusted OR, 1,70; 95% CI, 1.50-1.94)., Conclusions and Relevance: This case-control study of men with West African and European ancestry found that West African genetic ancestry was associated with increased odds of prostate cancer among males who resided in neighborhoods with high deprivation but lower odds in more affluent neighborhoods. Thus, neighborhood environments may play a critical role in defining how genetic ancestry modulates prostate cancer risk.

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality, with large disparities in incidence rates between Black and White Americans. Polygenic risk scores (PRSs) limited to variants discovered in genome-wide association studies in European-ancestry samples can identify European-ancestry individuals at high risk of VTE. However, there is limited evidence on whether high-dimensional PRS constructed using more sophisticated methods and more diverse training data can enhance the predictive ability and their utility across diverse populations. We developed PRSs for VTE using summary statistics from the International Network against Venous Thrombosis (INVENT) consortium genome-wide association studies meta-analyses of European- (71 771 cases and 1 059 740 controls) and African-ancestry samples (7482 cases and 129 975 controls). We used LDpred2 and PRS-CSx to construct ancestry-specific and multi-ancestry PRSs and evaluated their performance in an independent European- (6781 cases and 103 016 controls) and African-ancestry sample (1385 cases and 12 569 controls). Multi-ancestry PRSs with weights tuned in European-ancestry samples slightly outperformed ancestry-specific PRSs in European-ancestry test samples (e.g. the area under the receiver operating curve [AUC] was 0.609 for PRS-CSx&#95;combinedEUR and 0.608 for PRS-CSxEUR [P = 0.00029]). Multi-ancestry PRSs with weights tuned in African-ancestry samples also outperformed ancestry-specific PRSs in African-ancestry test samples (PRS-CSxAFR: AUC = 0.58, PRS-CSx&#95;combined AFR: AUC = 0.59), although this difference was not statistically significant (P = 0.34). The highest fifth percentile of the best-performing PRS was associated with 1.9-fold and 1.68-fold increased risk for VTE among European- and African-ancestry subjects, respectively, relative to those in the middle stratum. These findings suggest that the multi-ancestry PRS might be used to improve performance across diverse populations to identify individuals at highest risk for VTE., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Ductal carcinoma in situ (DCIS) is a non-obligate precursor to invasive breast cancer (IBC). Studies have indicated differences in DCIS outcome based on race or ethnicity, but molecular differences have not been investigated., Methods: We examined the molecular profile of DCIS by self-reported race (SRR) and outcome groups in Black (n = 99) and White (n = 191) women in a large DCIS case-control cohort study with longitudinal follow up., Results: Gene expression and pathway analyses suggested that different genes and pathways are involved in diagnosis and ipsilateral breast outcome (DCIS or IBC) after DCIS treatment in White versus Black women. We identified differences in ER and HER2 expression, tumor microenvironment composition, and copy number variations by SRR and outcome groups., Conclusions: Our results suggest that different molecular mechanisms drive initiation and subsequent ipsilateral breast events in Black versus White women., (© 2024. The Author(s).)

Background: Black women are at an increased risk of developing uterine leiomyomas and experiencing worse disease prognosis than White women. Epidemiologic and molecular factors have been identified as underlying these disparities, but there remains a paucity of deep, multiomic analysis investigating molecular differences in uterine leiomyomas from Black and White patients., Objective: To identify molecular alterations within uterine leiomyoma tissues correlating with patient race by multiomic analyses of uterine leiomyomas collected from cohorts of Black and White women., Study Design: We performed multiomic analysis of uterine leiomyomas from Black (42) and White (47) women undergoing hysterectomy for symptomatic uterine leiomyomata. In addition, our analysis included the application of orthogonal methods to evaluate fibroid biomechanical properties, such as second harmonic generation microscopy, uniaxial compression testing, and shear-wave ultrasonography analyses., Results: We found a greater proportion of MED12 mutant uterine leiomyomas from Black women (>35% increase; Mann-Whitney U, P<.001). MED12 mutant tumors exhibited an elevated abundance of extracellular matrix proteins, including several collagen isoforms, involved in the regulation of the core matrisome. Histologic analysis of tissue fibrosis using trichrome staining and secondary harmonic generation microscopy confirmed that MED12 mutant tumors are more fibrotic than MED12 wild-type tumors. Using shear-wave ultrasonography in a prospectively collected cohort, Black patients had fibroids that were firmer than White patients, even when similar in size. In addition, these analyses uncovered ancestry-linked expression quantitative trait loci with altered allele frequencies in African and European populations correlating with differential abundance of several proteins in uterine leiomyomas independently of MED12 mutation status, including tetratricopeptide repeat protein 38., Conclusion: Our study shows that Black women have a higher prevalence of uterine leiomyomas harboring mutations in MED12 and that this mutational status correlates with increased tissue fibrosis compared with wild-type uterine leiomyomas. Our study provides insights into molecular alterations correlating with racial disparities in uterine leiomyomas and improves our understanding of the molecular etiology underlying uterine leiomyoma development within these populations., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Mitochondrial dysfunction manifests in neurodegenerative diseases and other age-associated disorders. In this study, we examined variation in inherited mitochondrial DNA (mtDNA) sequences in Black and White participants from 2 large aging studies to identify variants related to cognitive function., Methods: Participants included self-reported Black and White adults aged ≥70 years in the Lifestyle Interventions and Independence for Elders (LIFE; N = 1 319) and Health Aging and Body Composition (Health ABC; N = 788) studies. Cognitive function was measured by the Digit-Symbol Substitution Test (DSST), and the Modified Mini-Mental State Examination (3MSE) at baseline and over follow-up in LIFE (3.6 years) and Health ABC (10 years). We examined the joint effects of multiple variants across 16 functional mitochondrial regions with cognitive function using a sequence kernel association test. Based on these results, we prioritized meta-analysis of common variants in Black and White participants using mixed effects models. A Bonferroni-adjusted p value of <.05 was considered statistically significant., Results: Joint variation in subunits ND1, ND2, and ND5 of Complex I, 12S RNA, and hypervariable region (HVR) were significantly associated with DSST and 3MSE at baseline. In meta-analyses among Black participants, variant m.4216T>C, ND1 was associated with a faster decline in 3MSE, and variant m.462C>T in the HVR was associated with a slower decline in DSST. Variant m.5460G>C, ND2 was associated with slower and m.182C>T in the HVR was associated with faster decline in 3MSE in White participants., Conclusions: Among Black and White adults, oxidative phosphorylation Complex I variants were associated with cognitive function., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Black women experience a disproportionate impact of uterine fibroids compared to White women, including earlier diagnosis, higher frequency, and more severe symptoms. The etiology underlying this racial disparity remains elusive., Objective: The aim of this study was to evaluate the molecular differences in normal myometrium (fibroid-free uteri) and at-risk myometrium (fibroid-containing uteri) tissues in Black and White women., Study Design: We conducted whole-genome RNA-seq on normal and at-risk myometrium tissues obtained from both self-identified Black and White women (not Hispanic or Latino) to determine global gene expression profiles and to conduct enriched pathway analyses (n=3 per group). We initially assessed the differences within the same type of tissue (normal or at-risk myometrium) between races. Subsequently, we analyzed the transcriptome of normal myometrium compared to at-risk myometrium in each race and determined the differences between them. We validated our findings through real-time PCR (sample size range=5-12), western blot (sample size range=5-6), and immunohistochemistry techniques (sample size range=9-16)., Results: The transcriptomic analysis revealed distinct profiles between Black and White women in normal and at-risk myometrium tissues. Interestingly, genes and pathways related to extracellular matrix and mechanosensing were more enriched in normal myometrium from Black than White women. Transcription factor enrichment analysis detected greater activity of the serum response transcription factor positional motif in normal myometrium from Black compared to White women. Furthermore, we observed increased expression levels of myocardin-related transcription factor-serum response factor and the serum response factor in the same comparison. In addition, we noted increased expression of both mRNA and protein levels of vinculin, a target gene of the serum response factor, in normal myometrium tissues from Black women as compared to White women. Importantly, the transcriptomic profile of normal to at-risk myometrium conversion differs between Black and White women. Specifically, we observed that extracellular matrix-related pathways are involved in the transition from normal to at-risk myometrium and that these processes are exacerbated in Black women. We found increased levels of Tenascin C, type I collagen alpha 1 chain, fibronectin, and phospho-p38 MAPK (Thr180/Tyr182, active) protein levels in at-risk over normal myometrium tissues from Black women, whereas such differences were not observed in samples from White women., Conclusion: These findings indicate that the racial disparities in uterine fibroids may be attributed to heightened production of extracellular matrix in the myometrium in Black women, even before the tumors appear. Future research is needed to understand early life determinants of the observed racial differences., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Genetic variants and epigenetic features both contribute to the risk of Alzheimer's disease (AD). We studied the AD association of CpG-related single nucleotide polymorphisms (CGS), which act as a hub of both the genetic and epigenetic effects, in Caribbean Hispanics (CH) and generalized the findings to Non-Hispanic Whites (NHW). First, we conducted a genome-wide, sliding-window-based association with AD, in 7,155 CH and 1,283 NHW participants. Next, using data from the dorsolateral prefrontal cortex in 179 CH brains, we tested the cis- and trans-effects of AD-associated CGS on brain DNA methylation to mRNA expression. For the genes with significant cis- and trans-effects, we investigated their enriched pathways. We identified six genetic loci in CH with CGS dosage associated with AD at genome-wide significance levels: ADAM20 (Score = 55.19, P = 4.06 × 10 -8 ), the intergenic region between VRTN and SYNDIG1L (Score = - 37.67, P = 2.25 × 10 -9 ), SPG7 (16q24.3) (Score = 40.51, P = 2.23 × 10 -8 ), PVRL2 (Score = 125.86, P = 1.64 × 10 -9 ), TOMM40 (Score = - 18.58, P = 4.61 × 10 -8 ), and APOE (Score = 75.12, P = 7.26 × 10 -26 ). CGSes in PVRL2 and APOE were also significant in NHW. Except for ADAM20, CGSes in the other five loci were associated with CH brain methylation levels (mQTLs) and CGSes in SPG7, PVRL2, and APOE were also mQTLs in NHW. Except for SYNDIG1L (P = 0.08), brain methylation levels in the other five loci affected downstream mRNA expression in CH (P < 0.05), and methylation at VRTN and TOMM40 were also associated with mRNA expression in NHW. Gene expression in these six loci were also regulated by CpG sites in genes that were enriched in the neuron projection and glutamatergic synapse pathways (FDR < 0.05). DNA methylation at all six loci and mRNA expression of SYNDIG1 and TOMM40 were significantly associated with Braak Stage in CH. In summary, we identified six CpG-related genetic loci associated with AD in CH, harboring both genetic and epigenetic risks. However, their downstream effects on mRNA expression maybe ethnic specific and different from NHW., (© 2024. The Author(s).)

Introduction: Patients with the acquired immunodeficiency syndrome (AIDS) have an increased prevalence and incidence of intermediate-stage age-related macular degeneration (AMD). Several elevated plasma inflammatory biomarkers are associated with increased incidence of intermediate-stage AMD in this population. We evaluated the association between AMD risk alleles and plasma inflammatory biomarker levels in persons with AIDS., Materials and Methods: Cryopreserved plasma specimens of 229 non-Hispanic White and 252 non-Hispanic blacks from the Longitudinal Study of the Ocular Complications of AIDS cohort were assayed for plasma levels of soluble tumor necrosis factor receptor (sTNFR) 2, interleukin (IL)-18, C × 3motif chemokine ligand 1 (CX3CL1), C-reactive protein (CRP), and soluble CD14 (sCD14). Genotyping included AMD-associated variants rs10801553 and rs800292 for complement factor H (CFH) rs9332739 and rs547154 for complement factor 2 (C2), rs2230199 for C3, rs2285714 for CFI, and rs3732379 and rs3732378 for C × 3motif chemokine receptor 1 (CX3CR1)., Results: In Whites, AMD low-risk CX3CR1 variants (V249I and T280M) were associated with reduced plasma levels of IL-18. In Blacks, AMD low-risk C3 R102G and low-risk CX3CR1 T280M variants were associated with reduced CRP levels., Conclusions: Genetic variants in AMD-associated immune genes may influence AMD-associated systemic plasma inflammatory biomarker levels in patients with AIDS.

Background: Although molecular biomarkers have significantly advanced precision oncology in glioblastoma, the prevalence of these biomarkers by race remains underexplored. This study aims to characterize the genomic alterations in glioblastoma across Asian, Black, and White patients, offering insights into racial disparities that may influence treatment outcomes and disease progression., Methods: Analyzing data from the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange database V13.0, this study examined 2390 primary glioblastoma samples from unique patients. Genomic alterations in 566 cancer-related genes were assessed using targeted next-generation sequencing panels from 3 large cancer institutes. The patient cohort included 112 Asians, 67 Blacks, and 2211 Whites. Statistical significance of associations between genomic alterations and race was evaluated using the chi-squared test, with the Benjamini-Hochberg method applied to control for multiple testing adjustments., Results: Significant racial differences were observed in the frequency of genomic alterations. Asians exhibited a higher frequency of TP53 alterations (52.68%, P < 0.001), Blacks showed more frequent alterations in NRAS (7.46%, P < 0.001), MTOR (10.45%, P = 0.039), and TET2 (8.96%, P = 0.039), and Whites had a higher occurrence of PTEN alterations (48.67%, P = 0.045). Additionally, Black patients had an elevated rate of RET deletions (14.29%, P < 0.001)., Conclusions: This study identifies significant racial disparities in the alteration frequencies of 6 key glioblastoma genes: NRAS, TP53, MTOR, TET2, PTEN, and RET. These findings underscore the need for racial considerations in glioblastoma treatment strategies and highlight potential avenues for targeted therapeutic interventions. Further research is needed to explore the clinical implications of these genomic disparities., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Black men are at a higher risk of prostate cancer (PC) diagnosis and present with more high-grade PC than White men in an equal access setting. This study aimed to identify differential transcriptional regulation between Black and White men with PC., Methods: We performed microarray of radical prostatectomy tissue blocks from 305 Black and 238 White men treated at the Durham Veterans Affairs Medical Center. Differential expression, gene set enrichment analysis, master regulator analysis, and network modeling were conducted to compare gene expression by race. Findings were validated using external datasets that are available in the Gene Expression Omnibus (GEO) database. The first was a multi-institutional cohort of 1152 prostate cancer patients (596 Black, 556 White) with microarray data (GEO ID: GSE169038). The second was an Emory cohort of 106 patients (22 Black, 48 White, 36 men of unknown race) with RNA-seq data (GEO ID: GSE54460). Additionally, we analyzed androgen receptor (AR) chromatin binding profiles using paired AR ChIP-Seq datasets from Black and White men (GEO IDs: GSE18440 and GSE18441)., Results: We identified 871 differentially expressed genes between Black and White men. White men had higher activity of MYC-related pathways, while Black men showed increased activity of inflammation, steroid hormone responses, and cancer progression-related pathways. We further identified the top 10 transcription factors (TFs) in Black patients, which formed a transcriptional regulatory network centered on the AR. The activities of this network and the pathways were significantly different in Black vs. White men across multiple cohorts and PC molecular subtypes., Conclusions: These findings suggest PC in Black and White men have distinct tumor transcriptional profiles. Furthermore, a highly interactive TF network centered on AR drives differential gene expression in Black men. Additional study is needed to understand the degree to which these differences in transcriptional regulatory elements contribute to PC health disparities., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Blacks/African American (BAA) patients diagnosed with head and neck squamous cell carcinoma (HNSCC) have worse survival outcomes than White patients. However, the mechanisms underlying racial disparities in HNSCC have not been thoroughly characterized., Methods: Data on gene expression, copy number variants (CNVs), gene mutations, and methylation were obtained from 6 head and neck cancer datasets. Comparative bioinformatics analysis of the above genomic features was performed between BAAs and Whites. The expression pattern of GSTM1 was validated by immunohistochemistry using tumor tissue microarray (TMA). Effect of GSTM1 knockdown were assessed by cell proliferation, colony formation, and tumor development in an orthotopic mouse model. The changes in protein kinases were determined using the Proteome Profiler Human Phospho-Kinase Array Kit in HNSCC cells with or without GSTM1 knockdown., Results: We identified ancestry-related differential genomic profiles in HNSCC. Specifically, in BAA HNSCC, FAT1 mutations were associated with its gene expression, SALL3 gene expression correlated with its gene CNVs, and RTP4 gene expression showed an inverse correlation with its methylation. Notably, GSTM1 emerged as a prognostic risk factor for BAA HNSCC, with high gene CNVs and expression levels correlating with poor overall survival in BAA patients. Immunohistochemistry results from newly developed in-house TMA validated the expression pattern of GSTM1 between BAA HNSCC and White HNSCC. In an orthotopic mouse model, GSTM1 knockdown significantly inhibited malignant progression in tumors derived from BAAs. In contrast, loss of GSTM1 did not affect the development of HNSCC originating in Whites. Mechanistically, GSTM1 knockdown suppressed HSP27 phosphorylation and β-catenin in BAA HNSCC cells, but not in White HNSCC cells. This differential effect at least partially contributes to tumor development in BAA patients., Conclusion: This study identifies GSTM1 as a novel molecular determinant of survival in HNSCC patients of African descent. It also provides a molecular basis for future research focused on identifying molecular determinants and developing therapeutic interventions to improve outcomes for BAA patients with HNSCC., (© 2024. The Author(s).)

There is increasing evidence of the clinical utility of genetic and genomic testing (GT); however, factors influencing personal utility of GT, especially in diverse, multilingual populations, remain unclear. We explored these factors in a diverse cohort of parents/guardians (participants) whose children received clinical GT through the NYCKidSeq program. A total of 847 participants completed surveys at baseline, post-results disclosure, and 6 months (6m) post-results. The largest population groups were Hispanic/Latino(a) (48%), White/European American (24%), and Black/African American (16%). Personal utility was assessed using the Personal Utility (PrU) scale, adapted for pediatric populations and included on the surveys. Three PrU subscales were identified using factor analysis: practical, educational, and parental psychological utility. Overall personal utility summary score and the three subscales significantly decreased after receiving results and over time. Hispanic/Latino(a) participants identified greater overall personal utility than European American and African American participants at all time points (p < 0.001) as did participants whose children received positive/likely positive results compared with those with negative and uncertain results (post-results: p < 0.001 and p < 0.001; 6m post-results: p = 0.002 and p < 0.001, respectively). Post-results, higher subscale scores were associated with lower education levels (practical, parental psychological: p ≤ 0.02) and higher levels of trust in the healthcare system (practical, parental psychological: p ≤ 0.04). These findings help to understand the perspectives of diverse parents/guardians, which is critical to tailoring pre- and post-test counseling across a variety of populations and clinical settings., Competing Interests: Declaration of interests N.S.A.-H. is currently employed by 23andMe, was previously employed by Regeneron Pharmaceuticals, received personal fees from Genentech, Allelica, and 23andMe, received research funding from Akcea, and serves as a scientific advisory board member for Allelica. E.E.K. received personal fees from Illumina, 23andMe, Allelica, and Regeneron Pharmaceuticals, received research funding from Allelica, and serves as a scientific advisory board member for Encompass, Bio, Overtone, and Galateo Bio., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Head and neck squamous cell carcinoma (HNSCC) is the 6 th leading cause of cancer-related mortality, with racial disparities amplifying the challenges in treatment. Although the relationship between hybrid epithelial/mesenchymal (E/M) states and tumor progression is of interest, no studies have characterized the clinical relevance of hybrid E/M states in head and neck cancer outcomes among self-reported racial cohorts., Methods: Given the overlap in gene expression between hybrid E/M malignant cells and cancer-associated fibroblasts, we utilized deconvolution of bulk RNA sequencing data from oral cavity and laryngeal squamous cell carcinoma tumors from The Cancer Genome Atlas. We utilized our previously collected single-cell profiles to generate inferred malignant profiles and then scored these for hybrid E/M. We then conducted a survival analysis on overall and disease-free survival among self-reported Black and White Americans., Findings: The hybrid E/M state was differentially associated with head and neck cancer survival by self-reported race and ethnicity, with a stronger association in non-Hispanic Black patients. Black patients with a high hybrid E/M score had a higher risk of death or recurrence (hazard ratio [HR]: 4.18 [95% confidence interval (CI): 2.06, 8.49]) than White patients with a high hybrid E/M score (HR: 1.58 [95% CI: 1.11, 2.26])., Conclusion: Our results suggest a complex interplay of social structure, racism, and genetic diversity. We implore researchers to consider the social and biological context contributing to disparities., Funding: A.L.M. received support from the National Institute of Minority Health and Health Disparities (K01MD013897 [principal investigator (PI), A.L.M.]). S.V.P. received support from the National Institute of Dental and Craniofacial Research (R01DE032865 [PI, S.V.P.] and R01DE032371 [PI, S.V.P.])., Competing Interests: Declaration of interests J.P.Z. is a founder and equity shareholder in Droplet Biosciences, an equity shareholder in Summit Biolabs, a consultant for Merck, and receives clinical trial funding from Merck. S.V.P., I.T., and A.S.P. are co-inventors on a patent related to partial EMT., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

This study investigates the genetic factors contributing to the disparity in prostate cancer incidence and progression among African American men (AAM) compared to European American men (EAM). The research focuses on employing Weighted Gene Co-expression Network Analysis (WGCNA) on public microarray data obtained from prostate cancer patients. The study employed WGCNA to identify clusters of genes with correlated expression patterns, which were then analyzed for their connection to population backgrounds. Additionally, pathway enrichment analysis was conducted to understand the significance of the identified gene modules in prostate cancer pathways. The Least Absolute Shrinkage and Selection Operator (LASSO) and Correlation-based Feature Selection (CFS) methods were utilized for selection of biomarker genes. The results revealed 353 differentially expressed genes (DEGs) between AAM and EAM. Six significant gene expression modules were identified through WGCNA, showing varying degrees of correlation with prostate cancer. LASSO and CFS methods pinpointed critical genes, as well as six common genes between both approaches, which are indicative of their vital role in the disease. The XGBoost classifier validated these findings, achieving satisfactory prediction accuracy. Genes such as APRT, CCL2, BEX2, MGC26963, and PLAU were identified as key genes significantly associated with cancer progression. In conclusion, the research underlines the importance of incorporating AAM and EAM population diversity in genomic studies, particularly in cancer research. In addition, the study highlights the effectiveness of integrating machine learning techniques with gene expression analysis as a robust methodology for identifying critical genes in cancer research., (© 2024. The Author(s).)

Purpose: African American/Black (AA/B) individuals are under-represented in genomic databases and thus less likely to receive definitive information from germline genetic testing (GGT) than non-Hispanic White (NHW) individuals. With nearly 500,000 AA/B and NHW individuals having undergone multigene panel testing (MGPT) for hereditary cancer risk at a single commercial laboratory, to our knowledge, we present the largest study to date investigating cancer GGT results in AA/B and NHW individuals., Methods: MGPT results from a retrospective cohort of AA/B (n = 48,684) and NHW (n = 444,831) patients were evaluated. Frequencies of pathogenic germline variants (PGVs) and variants of uncertain significance (VUS) were compared between AA/B and NHW individuals. Changes in frequency of VUS over time were determined. Pearson's chi-squared test was used to compare categorical variables among groups. All significance tests were two-tailed, and P < .05 was considered statistically significant., Results: Between 2015 and 2022, rates of VUS decreased 2.3-fold in AA/B and 1.8-fold in NHW individuals; however, frequencies of VUS and PGV remained significantly higher (46% v 32%; P < .0001) and lower (9% v 13%; P < .0001) in AA/B compared with NHW individuals. Rates of VUS in ATM , BRCA1 , BRCA2 , PALB2 , and PMS2 were significantly higher in AA/B compared with NHW individuals, whereas rates of PGV in BRCA1 , BRCA2 , and PALB2 were higher in AA/B compared with NHW individuals ( P < .001)., Conclusion: Despite reductions in VUS frequencies over time, disparities in definitive GGT results persist. Increasing inclusion of AA/B populations in both testing and research will further increase knowledge of genetic variants across these racial groups.

Importance: African American men experience greater prostate cancer incidence and mortality than White men. Growing literature supports associations of neighborhood disadvantage, which disproportionately affects African American men, with aggressive prostate cancer; chronic stress and downstream biological impacts (eg, increased inflammation) may contribute to these associations., Objective: To examine whether several neighborhood disadvantage metrics are associated with prostate tumor RNA expression of stress-related genes., Design, Setting, and Participants: This cross-sectional study leveraged prostate tumor transcriptomic data for African American and White men with prostate cancer who received radical prostatectomy at the University of Maryland Medical Center between August 1992 and January 2021. Data were analyzed from May 2023 to April 2024., Exposures: Using addresses at diagnosis, 2 neighborhood deprivation metrics (Area Deprivation Index [ADI] and validated bayesian Neighborhood Deprivation Index) as well as the Racial Isolation Index (RI) and historical redlining were applied to participants' addresses. Self-reported race was determined using electronic medical records., Main Outcomes and Measures: A total of 105 stress-related genes were evaluated with each neighborhood metric using linear regression, adjusting for race, age, and year of surgery. Genes in the Conserved Transcriptional Response to Adversity (CTRA) and stress-related signaling genes were included., Results: A total of 218 men (168 [77%] African American, 50 [23%] White) with a median (IQR) age of 58 (53-63) years were included. African American participants experienced greater neighborhood disadvantage than White participants (median [IQR] ADI, 115 [100-130] vs 92 [83-104]; median [IQR] RI, 0.68 [0.34-0.87] vs 0.11 [0.06-0.14]). ADI was positively associated with expression for 11 genes; HTR6 (serotonin pathway) remained significant after multiple-comparison adjustment (β = 0.003; SE, 0.001; P < .001; Benjamini-Hochberg q value = .01). Several genes, including HTR6, were associated with multiple metrics. We observed higher expression of 5 proinflammatory genes in the CTRA with greater neighborhood disadvantage (eg, CXCL8 and ADI, β = 0.008; SE, 0.003; P = .01; q value = .21)., Conclusions and Relevance: In this cross-sectional study, the expression of several stress-related genes in prostate tumors was higher among men residing in disadvantaged neighborhoods. This study is one of the first to suggest associations of neighborhood disadvantage with prostate tumor RNA expression. Additional research is needed in larger studies to replicate findings and further investigate interrelationships of neighborhood factors, tumor biology, and aggressive prostate cancer to inform interventions to reduce disparities.

African American (AA) women are twice as likely to develop triple-negative breast cancer (TNBC) as women of European descent. Additionally, AA women with TNBC present a much more aggressive disease course than their European American (EA) counterparts. Thus, there is an unmet clinical need to identify race-specific biomarkers and improve survival outcomes in AA patients with TNBC. The minus-end directed microtubule motor protein kinesin family member C1 (KIFC1) promotes centrosome clustering and chromosomal instability and is often overexpressed in TNBC. Previous findings suggest that KIFC1 plays a role in cell proliferation and migration in TNBC cells from AAs and that the levels of nuclear KIFC1 (nKIFC1) are particularly high in AA patients with TNBC. The nuclear localization of KIFC1 in interphase may underlie its previously unrecognized race-specific association. In this study, we found that in TNBC cells derived from AAs, nKIFC1 interacted with the tumor suppressor myosin heavy chain 9 (MYH9) over EA cells. Treatment of AA TNBC cells with commercial inhibitors of KIFC1 and MYH9 disrupted the interaction between KIFC1 and MYH9. To characterize the racial differences in the KIFC1-MYH9-MYC axis in TNBC, we established homozygous KIFC1 knockout (KO) TNBC cell lines. KIFC1 KO significantly inhibited proliferation, migration, and invasion in AA TNBC cells but not in EA TNBC cells. RNA sequencing analysis showed significant downregulation of genes involved in cell migration, invasion, and metastasis upon KIFC1 KO in TNBC cell lines from AAs compared to those from EAs. These data indicate that mechanistically, the role of nKIFC1 in driving TNBC progression and metastasis is stronger in AA patients than in EA patients, and that KIFC1 may be a critical therapeutic target for AA patients with TNBC., (© 2024. The Author(s).)

Background: For patients with weak or discrepant RhD RBC phenotypes, RHD genotyping is employed to determine need for RhD-negative management. However, many RHD variants are type D-negative or D-positive. Serological recognition rates (RRs) of weak and partial RHD variants are poorly characterized., Study Design and Methods: Four US studies employing RHD genotyping for weak or discrepant RhD phenotypes provided data for race/ethnicity-specific serological recognition. Three studies used microplate, and 1 used gel and tube; 2 had anti-D data. We obtained White and Hispanic/Latino allele frequencies (AFs) of weak D types 1, 2, and 3 single-nucleotide variants (SNVs) from the Genome Aggregation Database (gnomAD, v4.0.0) and devised Hardy-Weinberg-based formulas to correct for gnomAD's overcount of hemizygous RHD SNVs as homozygous. We compiled common partial RHD AF from genotyped cohorts of US Black or sickle cell disease subjects. From variant AF, we calculated hemizygous-plus-homozygous genetic prevalences. Serological prevalence: genetic prevalence ratios yielded serological RRs., Results: Overall RRs of weak D types 1-3 were 17% (95% confidence interval 12%-24%) in Whites and 12% (5%-27%) in Hispanics/Latinos. For eight partial RHD variants in Blacks, overall RR was 11% (8%-14%). However, DAR RR was 80% (38%-156%). Compared to microplate, gel-tube recognition was higher for type 2 and DAU5 and lower for type 4.0. Anti-D was present in 6% of recognized partial RHD cases, but only in 0.7% of estimated total genetic cases., Discussion: Based on AF, >80% of patients with weak or partial RHD variants were unrecognized serologically. Although overall anti-D rates were low, better detection of partial RHD variants is desirable., (© 2024 The Authors. Transfusion published by Wiley Periodicals LLC on behalf of AABB.)

Alzheimer's disease (AD) prevalence is twice as high in non-Hispanic Blacks (NHBs) as in non-Hispanic Whites (NHWs). The objective of this study was to determine whether aberrant methylation at imprint control regions (ICRs) is associated with AD. Differentially methylated regions (DMRs) were bioinformatically identified from whole-genome bisulfite sequenced DNA derived from brain tissue of 9 AD (5 NHBs and 4 NHWs) and 8 controls (4 NHBs and 4 NHWs). We identified DMRs located within 120 regions defined as candidate ICRs in the human imprintome ( https://genome.ucsc.edu/s/imprintome/hg38.AD.Brain&#95;track ). Eighty-one ICRs were differentially methylated in NHB-AD, and 27 ICRs were differentially methylated in NHW-AD, with two regions common to both populations that are proximal to the inflammasome gene, NLRP1, and a known imprinted gene, MEST/MESTIT1. These findings indicate that early developmental alterations in DNA methylation of regions regulating genomic imprinting may contribute to AD risk and that this epigenetic risk differs between NHBs and NHWs., (© 2024. The Author(s).)

High-proportion spliced-in titin truncating variants (hiPSI TTNtvs) have been associated with an increased risk of atrial fibrillation, dilated cardiomyopathy (DCM) and heart failure in individuals of European ancestry 1 . However, similar data in individuals of African ancestry are lacking. Here we examined the association of hiPSI TTNtvs with atrial fibrillation, DCM and heart failure in individuals of African ancestry using data from the All of Us Research Program. Among 38,154 individuals of African ancestry, 169 (0.4%) individuals carried a hiPSI TTNtv. hiPSI TTNtv carriers were at a higher risk of developing atrial fibrillation (adjusted hazard ratio (HR adj ) 2.42, 95% confidence interval (CI) 1.52-3.85), DCM (HR adj 2.82, 95% CI 1.81-4.39) and heart failure (HR adj 2.07, 95% CI 1.43-3.00) compared with noncarriers. The association of hiPSI TTNtvs with atrial fibrillation, DCM and heart failure was similar in individuals of African ancestry and those of European ancestry. Therefore, genetic testing for hiPSI TTNtvs may permit early identification of carriers and support preventive measures to reduce the likelihood of heart failure development both in individuals of European ancestry and in individuals of African ancestry., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: We previously showed the 21-gene breast recurrence score (RS) has lower prognostic accuracy for non-Hispanic Black (NHB) compared with non-Hispanic White (NHW) women with estrogen receptor (ER)-positive/HER2-negative breast cancer. The purpose of this study was to determine the clinical validity of the RS for predicting chemotherapy benefit as recommended in the current NCCN Guidelines for Breast Cancer among women from diverse racial/ethnic groups., Methods: Using the SEER Oncotype database, we estimated propensity score-weighted hazard ratios (HRs) and 95% confidence intervals for breast cancer death with chemotherapy for women with ER-positive/HER2-negative, AJCC stages I-II, axillary node-negative, invasive breast cancer according to race/ethnicity., Results: We included 6,033 (8.2%) Asian/Pacific Islander (API), 5,697 (7.8%) NHB, 6,688 (9.1%) Hispanic, and 54,945 (74.9%) NHW women. Breast cancer death was reduced with chemotherapy for NHB (HR, 0.48, 95% CI, 0.28-0.81), Hispanic (HR, 0.48; 95% CI, 0.25-0.94), and NHW (HR, 0.80; 95% CI, 0.65-0.99) women with an RS of 26 to 100. There was a nonsignificant reduction for API women (HR, 0.59; 95% CI, 0.28-1.24). For women with an RS of 11 to 25, there was no reduction in death for any racial/ethnic group. Among women aged ≤50 years, the reduction in breast cancer death with chemotherapy differed according to race (NHB: HR, 0.37 [95% CI, 0.20-0.67]; NHW: HR, 0.56 [95% CI, 0.44-0.74]; Pinteraction for chemotherapy * race <.0499). An exploratory subgroup analysis found that young NHB women may benefit from chemotherapy at a lower RS cutoff than other women., Conclusions: The RS was clinically validated as a predictive biomarker for NHB, Hispanic, and NHW women with ER-positive, axillary node-negative breast cancer, but it may underestimate the benefit of chemotherapy for young NHB women. If this finding is confirmed, the RS cutoff for recommending adjuvant chemotherapy for young NHB women with ER-positive, axillary node-negative breast cancer may need to be lower than for other women.

Background: We analyzed the genetic causes of sensorineural hearing loss in racial and ethnic minorities of South Florida by reviewing demographic, phenotypic, and genetic data on 136 patients presenting to the Hereditary Hearing Loss Clinic at the University of Miami. In our retrospective chart review, of these patients, half self-identified as Hispanic, and the self-identified racial distribution was 115 (86%) White, 15 (11%) Black, and 6 (4%) Asian. Our analysis helps to reduce the gap in understanding the prevalence, impact, and genetic factors related to hearing loss among diverse populations., Results: The causative gene variant or variants were identified in 54 (40%) patients, with no significant difference in the molecular diagnostic rate between Hispanics and Non-Hispanics. However, the total solve rate based on race was 40%, 47%, and 17% in Whites, Blacks, and Asians, respectively. In Non-Hispanic Whites, 16 different variants were identified in 13 genes, with GJB2 (32%), MYO7A (11%), and SLC26A4 (11%) being the most frequently implicated genes. In White Hispanics, 34 variants were identified in 20 genes, with GJB2 (22%), MYO7A (7%), and STRC-CATSPER2 (7%) being the most common. In the Non-Hispanic Black cohort, the gene distribution was evenly dispersed, with 11 variants occurring in 7 genes, and no variant was identified in 3 Hispanic Black probands. For the Asian cohort, only one gene variant was found out of 6 patients., Conclusion: This study demonstrates that the diagnostic rate of genetic studies in hearing loss varies according to race in South Florida, with more heterogeneity in racial and ethnic minorities. Further studies to delineate deafness gene variants in underrepresented populations, such as African Americans/Blacks from Hispanic groups, are much needed to reduce racial and ethnic disparities in genetic diagnoses., (© 2023. The Author(s).)

Women of African descent have the highest breast cancer mortality in the United States and are more likely than women from other population groups to develop an aggressive disease. It remains uncertain to what extent breast cancer in Africa is reminiscent of breast cancer in African American or European American patients. Here, we performed whole-exome sequencing of genomic DNA from 191 breast tumor and non-cancerous adjacent tissue pairs obtained from 97 African American, 69 European American, 2 Asian American, and 23 Kenyan patients. Our analysis of the sequencing data revealed an elevated tumor mutational burden in both Kenyan and African American patients, when compared with European American patients. TP53 mutations were most prevalent, particularly in African American patients, followed by PIK3CA mutations, which showed similar frequencies in European American, African American, and the Kenyan patients. Mutations targeting TBX3 were confined to European Americans and those targeting the FBXW7 tumor suppressor to African American patients whereas mutations in the ARID1A gene that are known to confer resistance to endocrine therapy were distinctively enriched among Kenyan patients. A Kyoto Encyclopedia of Genes and Genomes pathway analysis could link FBXW7 mutations to an increased mitochondrial oxidative phosphorylation capacity in tumors carrying these mutations. Finally, Catalogue of Somatic Mutations in Cancer (COSMIC) mutational signatures in tumors correlated with the occurrence of driver mutations, immune cell profiles, and neighborhood deprivation with associations ranging from being mostly modest to occasionally robust. To conclude, we found mutational profiles that were different between these patient groups. The differences concentrated among genes with low mutation frequencies in breast cancer., Significance: The study describes differences in tumor mutational profiles between African American, European American, and Kenyan breast cancer patients. It also investigates how these profiles may relate to the tumor immune environment and the neighborhood environment in which the patients had residence. Finally, it describes an overrepresentation of ARID1A gene mutations in breast tumors of the Kenyan patients., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Importance: Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and appears to have disproportionately higher incidence and worse outcomes among younger African American females., Objective: To investigate whether epigenetic differences exist in TNBCs of younger African American females that may explain clinical disparities seen in this patient group., Design, Setting, and Participants: This cross-sectional study used clinical, demographic, DNA methylation (HumanMethylation450; Illumina), and gene expression (RNA sequencing) data for US patient populations from publicly available data repositories (The Cancer Genome Atlas [TCGA], 2006-2012, and Gene Expression Omnibus [GEO], 2004-2013) accessed on April 13, 2021. White and African American females with TNBC identified in TCGA (69 patients) and a validation cohort of 210 African American patients from GEO (GSE142102) were included. Patients without available race or age data were excluded. Data were analyzed from September 2022 through April 2023., Main Outcomes and Measures: DNA methylation and gene expression profiles of TNBC tumors by race (self-reported) and age were assessed. Age was considered a dichotomous variable using age 50 years as the cutoff (younger [<50 years] vs older [≥50 years])., Results: A total of 69 female patients (34 African American [49.3%] and 35 White [50.7%]; mean [SD; range] age, 55.7 [11.6; 29-82] years) with TNBC were included in the DNA methylation analysis; these patients and 210 patients in the validation cohort were included in the gene expression analysis (279 patients). There were 1115 differentially methylated sites among younger African American females. The DNA methylation landscape on TNBC tumors in this population had increased odds of enrichment of hormone (odds ratio [OR], 1.82; 95% CI, 1.21 to 2.67; P = .003), muscle (OR, 1.85; 95% CI, 1.44 to 2.36; P < .001), and proliferation (OR, 3.14; 95% CI, 2.71 to 3.64; P < .001) pathways vs other groups (older African American females and all White females). Alterations in regulators of these molecular features in TNBCs of younger African American females were identified involving hormone modulation (downregulation of androgen receptor: fold change [FC] = -2.93; 95% CI, -4.76 to -2.11; P < .001) and upregulation of estrogen-related receptor α (FC = 0.86; 95% CI, 0.34 to 1.38; P = .002), muscle metabolism (upregulation of FOXC1: FC = 1.33; 95% CI, 0.62 to 2.03; P < .001), and proliferation mediators (upregulation of NOTCH1: FC = 0.71; 95% CI, 0.23 to 1.19; P = .004 and MYC (FC = 0.81; 95% CI, 0.18 to 1.45; P = .01)., Conclusions and Relevance: These findings suggest that TNBC of younger African American females may represent a distinct epigenetic entity and offer novel insight into molecular alterations associated with TNBCs of this population. Understanding these epigenetic differences may lead to the development of more effective therapies for younger African American females, who have the highest incidence and worst outcomes from TNBC of any patient group.

Race-related variation in breast cancer incidence and mortality are well-documented in the United States. The effect of genetic ancestry on disparities in tumor genomics, risk factors, treatment, and outcomes of breast cancer is less understood. The Cancer Genome Atlas (TCGA) is a publicly available resource that has allowed for the recent emergence of genome analysis research seeking to characterize tumor DNA and protein expression by ancestry as well as the social construction of race and ethnicity. Results from TCGA based studies support previous clinical evidence that demonstrates that American women with African ancestry are more likely to be afflicted with breast cancers featuring aggressive biology and poorer outcomes compared with women with other backgrounds. Data from TCGA based studies suggest that Asian women have tumors with favorable immune microenvironments and may experience better disease-free survival compared with white Americans. TCGA contains limited data on Hispanic/Latinx patients due to small sample size. Overall, TCGA provides important opportunities to define the molecular, biologic, and germline genetic factors that contribute to breast cancer disparities., (© 2023. Society of Surgical Oncology.)

Alzheimer's Disease (AD) continues to be a leading cause of death in the US. As the US aging population (ages 65 +) expands, the impact will disproportionately affect vulnerable populations, e.g., Hispanic/Latino population, due to their AD-related health disparities. Age-related regression in mitochondrial activity and ethnic-specific differences in metabolic burden could potentially explain in part the racial/ethnic distinctions in etiology that exist for AD. Oxidation of guanine (G) to 8-oxo-guanine (8oxoG) is a prevalent lesion and an indicator of oxidative stress and mitochondrial dysfunction. Damaged mtDNA (8oxoG) can serve as an important marker of age-related systemic metabolic dysfunction and upon release into peripheral circulation may exacerbate pathophysiology contributing to AD development and/or progression. Analyzing blood samples from Mexican American (MA) and non-Hispanic White (NHW) participants enrolled in the Texas Alzheimer's Research & Care Consortium, we used blood-based measurements of 8oxoG from both buffy coat PBMCs and plasma to determine associations with population, sex, type-2 diabetes, and AD risk. Our results show that 8oxoG levels in both buffy coat and plasma were significantly associated with population, sex, years of education, and reveal a potential association with AD. Furthermore, MAs are significantly burdened by mtDNA oxidative damage in both blood fractions, which may contribute to their metabolic vulnerability to developing AD., (© 2023. Springer Nature Limited.)

Background: African American men are much more likely than Caucasian men to be diagnosed with and to die of prostate cancer. Genetic differences likely play a role. The cBioPortal database reveals that African American men with prostate cancer have higher rates of CDK12 somatic mutations compared to Caucasian men. However, this does not account for prior prostate cancer treatments, which are particularly important in the castrate-resistant setting. We aimed to compare somatic mutations based on circulating tumor DNA (ctDNA) in metastatic castration-resistant prostate cancer (mCRPC) between African American and Caucasian men after exposure to abiraterone and/or enzalutamide., Methods: This single-institution retrospective study characterizes the somatic mutations detected on ctDNA for African American and Caucasian men with mCRPC who had progressed after abiraterone and/or enzalutamide from 2015 through 2022. We evaluated the gene mutations and types of mutations in this mCRPC cohort., Results: There were 50 African American and 200 Caucasian men with CRPC with available ctDNA data. African American men were younger at the time of diagnosis (p = 0.008) and development of castration resistance (p = 0.006). African American men were more likely than Caucasian men to have pathogenic/likely pathogenic (P/LP) mutations in CDK12 (12% vs. 1.5%; p = 0.003) and copy number amplifications and P/LP mutations in KIT (8.0% vs. 1.5%; p = 0.031). African American men were also significantly more likely to have frameshift mutations (28% vs. 14%; p = 0.035)., Conclusions: Compared to Caucasian men, African American men with mCRPC after exposure to abiraterone and/or enzalutamide had a higher incidence of somatic CDK12 P/LP mutations and KIT amplifications and P/LP mutations based on ctDNA. African American men also had more frameshift mutations. We hypothesize that these findings have potential implications for tumor immunogenicity., (© 2023 The Authors. The Prostate published by Wiley Periodicals LLC.)

Racial disparities in many aging-related health outcomes are persistent and pervasive among older Americans, reflecting accelerated biological aging for Black Americans compared to White, known as weathering. Environmental determinants that contribute to weathering are poorly understood. Having a higher biological age, measured by DNA methylation (DNAm), than chronological age is robustly associated with worse age-related outcomes and higher social adversity. We hypothesize that individual socioeconomic status (SES), neighborhood social environment, and air pollution exposures contribute to racial disparities in DNAm aging according to GrimAge and Dunedin Pace of Aging methylation (DPoAm). We perform retrospective cross-sectional analyses among 2,960 non-Hispanic participants (82% White, 18% Black) in the Health and Retirement Study whose 2016 DNAm age is linked to survey responses and geographic data. DNAm aging is defined as the residual after regressing DNAm age on chronological age. We observe Black individuals have significantly accelerated DNAm aging on average compared to White individuals according to GrimAge (239%) and DPoAm (238%). We implement multivariable linear regression models and threefold decomposition to identify exposures that contribute to this disparity. Exposure measures include individual-level SES, census-tract-level socioeconomic deprivation and air pollution (fine particulate matter, nitrogen dioxide, and ozone), and perceived neighborhood social and physical disorder. Race and gender are included as covariates. Regression and decomposition results show that individual-level SES is strongly associated with and accounts for a large portion of the disparity in both GrimAge and DPoAm aging. Higher neighborhood deprivation for Black participants significantly contributes to the disparity in GrimAge aging. Black participants are more vulnerable to fine particulate matter exposure for DPoAm, perhaps due to individual- and neighborhood-level SES, which may contribute to the disparity in DPoAm aging. DNAm aging may play a role in the environment "getting under the skin", contributing to age-related health disparities between older Black and White Americans., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Yannatos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Sarcoidosis is a systemic granulomatous disease with predominant pulmonary involvement and vast heterogeneity of clinical manifestations and disease outcomes. African American (AA) patients suffer greater morbidity and mortality. Using Multiple Correspondence Analysis, we identified seven clusters of organ involvement in European American (EA; n = 385) patients which were similar to those previously described in a Pan-European (GenPhenReSa) and a Spanish cohort (SARCOGEAS). In contrast, AA (n = 987) had six, less well-defined and overlapping clusters with little similarity to the cluster identified in the EA cohort evaluated at the same U.S. institutions. Association of cluster membership with two-digit HLA-DRB1 alleles demonstrated ancestry-specific patterns of association and replicated known HLA effects.These results further support the notion that genetically influenced immune risk profiles, which differ based on ancestry, play a role in phenotypic heterogeneity. Dissecting such risk profiles will move us closer to personalized medicine for this complex disease., (© 2023. The Author(s).)

With the properties of aggressive cancer and heterogeneous tumor biology, triple-negative breast cancer (TNBC) is a type of breast cancer known for its poor clinical outcome. The lack of estrogen, progesterone, and human epidermal growth factor receptor in the tumors of TNBC leads to fewer treatment options in clinics. The incidence of TNBC is higher in African American (AA) women compared with European American (EA) women with worse clinical outcomes. The significant factors responsible for the racial disparity in TNBC are socioeconomic lifestyle and tumor biology. The current study considered the open-source gene expression data of triple-negative breast cancer samples' racial information. We implemented a state-of-the-art classification Support Vector Machine (SVM) method with a recurrent feature elimination approach to the gene expression data to identify significant biomarkers deregulated in AA women and EA women. We also included Spearman's rho and Ward's linkage method in our feature selection workflow. Our proposed method generates 24 features/genes that can classify the AA and EA samples 98% accurately. We also performed the Kaplan-Meier analysis and log-rank test on the 24 features/genes. We only discussed the correlation between deregulated expression and cancer progression with a poor survival rate of 2 genes, KLK10 and LRRC37A2 , out of 24 genes. We believe that further improvement of our method with a higher number of RNA-seq gene expression data will more accurately provide insight into racial disparity in TNBC.

Classic and clinical variant galactosemia (CG/CVG) are allelic, autosomal recessive disorders that result from deficiency of galactose-1-P uridylyltransferase (GALT). CG/CVG has been reported globally among patients of diverse ancestries, but most large studies of outcomes have included, almost exclusively, patients categorized as White or Caucasian. As a first step to explore whether the cohorts studied are representative of the CG/CVG population at large, we sought to define the racial and ethnic makeup of CG/CVG newborns in a diverse population with essentially universal newborn screening (NBS) for galactosemia: the United States (US). First, we estimated the predicted racial and ethnic distribution of CG/CVG by combining the reported demographics of US newborns from 2016 to 2018 with predicted homozygosity or compound heterozygosity of pathogenic, or likely pathogenic, GALT alleles from the relevant ancestral groups. Incorporating some simplifying assumptions, we predicted that of US newborns diagnosed with CG/CVG, 65% should be White (non-Hispanic), 23% should be Black (non-Hispanic), 10% should be Hispanic, and 2% should be Asian (non-Hispanic). Next, we calculated the observed racial and ethnic distribution of US newborns diagnosed with CG/CVG using available de-identified data from state NBS programs from 2016 to 2018. Of the 235 newborns in this cohort, 41 were categorized as other or unknown. Of the remaining 194, 66% were White (non-Hispanic or ethnicity unknown), 16% were Black (non-Hispanic or ethnicity unknown),15% were Hispanic, and 2% were Asian (non-Hispanic or ethnicity unknown). This observed distribution was statistically indistinguishable from the predicted distribution. To the limits of our study, these data confirm the racial and ethnic diversity of newborns with CG/CVG in the US, demonstrate an approach for estimating CG/CVG racial and ethnic diversity in other populations, and raise the troubling possibility that current understanding of long-term outcomes in CG/CVG may be skewed by ascertainment bias of the cohorts studied., Competing Interests: Declaration of Competing Interest Nichole Stettner, David Cutler, and Judith Fridovich-Keil all declare that they have no conflict of interest with this work., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: To estimate the risk of contralateral breast cancer (CBC) among women with germline pathogenic variants (PVs) in ATM , BRCA1 , BRCA2 , CHEK2 , and PALB2 ., Methods: The study population included 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer. The risk of CBC was estimated for PV carriers in each gene compared with women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor (ER) status., Results: Germline BRCA1 , BRCA2 , and CHEK2 PV carriers with breast cancer were at significantly elevated risk (hazard ratio > 1.9) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks (hazard ratio, 2.9). By contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 10-year cumulative incidence of CBC was estimated to be 33% for BRCA1 , 27% for BRCA2 , and 13% for CHEK2 PV carriers with breast cancer and 35% for PALB2 PV carriers with ER-negative breast cancer. The 10-year cumulative incidence of CBC among postmenopausal PV carriers was 12% for BRCA1 , 9% for BRCA2 , and 4% for CHEK2 ., Conclusion: Women diagnosed with breast cancer and known to carry germline PVs in BRCA1 , BRCA2 , CHEK2 , or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk reduction strategies.

COVID-19 is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The severity of COVID-19 is highly variable and related to known (e.g., age, obesity, immune deficiency) and unknown risk factors. The widespread clinical symptoms encompass a large group of asymptomatic COVID-19 patients, raising a crucial question regarding genetic susceptibility, e.g., whether individual differences in immunity play a role in patient symptomatology and how much human leukocyte antigen (HLA) contributes to this. To reveal genetic determinants of susceptibility to COVID-19 severity in the population and further explore potential immune-related factors, we performed a genome-wide association study on 284 confirmed COVID-19 patients (cases) and 95 healthy individuals (controls). We compared cases and controls of European (EUR) ancestry and African American (AFR) ancestry separately. We identified two loci on chromosomes 5q32 and 11p12, which reach the significance threshold of suggestive association (p<1x10-5 threshold adjusted for multiple trait testing) and are associated with the COVID-19 susceptibility in the European ancestry (index rs17448496: odds ratio[OR]  = 0.173; 95% confidence interval[CI], 0.08-0.36 for G allele; p = 5.15× 10-5 and index rs768632395: OR  =  0.166; 95% CI, 0.07-0.35 for A allele; p =  4.25×10-6, respectively), which were associated with two genes, PPP2R2B at 5q32, and LRRC4C at 11p12, respectively. To explore the linkage between HLA and COVID-19 severity, we applied fine-mapping analysis to dissect the HLA association with mild and severe cases. Using In-silico binding predictions to map the binding of risk/protective HLA to the viral structural proteins, we found the differential presentation of viral peptides in both ancestries. Lastly, extrapolation of the identified HLA from the cohort to the worldwide population revealed notable correlations. The study uncovers possible differences in susceptibility to COVID-19 in different ancestral origins in the genetic background, which may provide new insights into the pathogenesis and clinical treatment of the disease., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Shen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The aging Mexican American (MA) population is the fastest growing ethnic minority group in the US. MAs have a unique metabolic-related risk for Alzheimer's disease (AD) and mild cognitive impairment (MCI), compared to non-Hispanic whites (NHW). This risk for cognitive impairment (CI) is multifactorial involving genetics, environmental, and lifestyle factors. Changes in environment and lifestyle can alter patterns and even possibly reverse derangement of DNA methylation (a form of epigenetic regulation)., Objective: We sought to identify ethnicity-specific DNA methylation profiles that may be associated with CI in MAs and NHWs., Methods: DNA obtained from peripheral blood of 551 participants from the Texas Alzheimer's Research and Care Consortium was typed on the Illumina Infinium® MethylationEPIC chip array, which assesses over 850K CpG genomic sites. Within each ethnic group (N = 299 MAs, N = 252 NHWs), participants were stratified by cognitive status (control versus CI). Beta values, representing relative degree of methylation, were normalized using the Beta MIxture Quantile dilation method and assessed for differential methylation using the Chip Analysis Methylation Pipeline (ChAMP), limma and cate packages in R., Results: Two differentially methylated sites were significant: cg13135255 (MAs) and cg27002303 (NHWs) based on an FDR p < 0.05. Three suggestive sites obtained were cg01887506 (MAs) and cg10607142 and cg13529380 (NHWs). Most methylation sites were hypermethylated in CI compared to controls, except cg13529380 which was hypomethylated., Conclusion: The strongest association with CI was at cg13135255 (FDR-adjusted p = 0.029 in MAs), within the CREBBP gene. Moving forward, identifying additional ethnicity-specific methylation sites may be useful to discern CI risk in MAs.

Background: Associations have been observed among genetic variants, dietary patterns, and metabolic syndrome (MetS). A gap in knowledge is whether a genetic risk score (GRS) and dietary patterns interact to increase MetS risk among African Americans. We investigated whether MetS risk was influenced by interaction between a GRS and dietary patterns among Whites and African Americans. A secondary aim examined if molecular genetic clusterings differed by racial ancestry., Methods: We used longitudinal data over 4-visits (1987-1998) that included 10,681 participants aged 45-64y at baseline from the Atherosclerosis Risk in Communities study (8451 Whites and 2230 African Americans). We constructed a simple-count GRS as the linear weighted sum of high-risk alleles (0, 1, 2) from cardiovascular disease polymorphisms from the genome-wide association studies catalog associated with MetS risk. Three dietary patterns were determined by factor analysis of food frequency questionnaire data: Western, healthy, and high-fat dairy. MetS was defined according to the 2016 National Cholesterol Education Program Adult Treatment Panel III criteria but used 2017 American Heart Association/American College of Cardiology criteria for elevated blood pressure. Analyses included generalized linear model risk ratios (RR), 95% confidence intervals (CI), and Bonferroni correction for multiple testing., Results: The Western dietary pattern was associated with higher risk for MetS across increasing GRS tertiles among Whites (p < 0.017). The high-fat dairy pattern was protective against MetS, but its impact was most effective in the lowest GRS tertile in Whites (RR = 0.62; CI: 0.52-0.74) and African Americans (RR = 0.67; CI: 0.49-0.91). Among each racial group within GRS tertiles, the Western dietary pattern was associated with development and cycling of MetS status between visits, and the high-fat dairy pattern with being free from MetS (p < 0.017). The healthy dietary pattern was associated with higher risk of MetS among African Americans which may be explained by higher sucrose intake (p < 0.0001). Fewer genes, but more metabolic pathways for obesity, body fat distribution, and lipid and carbohydrate metabolism were identified in African Americans than Whites. Some polymorphisms were linked to the Western and high-fat dairy patterns., Conclusion: The influence of dietary patterns on MetS risk appears to differ by genetic predisposition and racial ancestry.

Aggressive high-grade, estrogen receptor negative (ER-) breast cancer is more common among American women of African ancestry (AA) than those of European ancestry (EA). Epigenetic mechanisms, particularly DNA methylation and altered microRNA (miRNA) expression, may contribute to racial differences in breast cancer. However, few studies have specifically characterized genome-wide DNA methylation-based modifications at the miRNA level in relation to ER+ and ER- subtype, and their functional role in the regulation of miRNA expression, especially among high risk AA women. In this study, we evaluated DNA methylation patterns of miRNA encoding genes and their effect on expression in breast tumors from both AA and EA women. The genome-wide methylation screen identified a total of 7,191 unique CpGs mapped to 1,292 miRNA genes, corresponding to 2,035 unique mature miRNAs. We identified differentially methylated loci (DMLs: (|delta β|)>0.10, FDR<0.05) between ER- and ER+ tumor subtypes, including 290 DMLs shared in both races, 317 and 136 were specific to AA and EA women, respectively. Integrated analysis identified certain DMLs whose methylation levels were significantly correlated with the expression of relevant miRNAs, such as multiple CpGs within miR-190b and miR-135b highly negatively correlated with their expression. These results were then validated in the TCGA dataset. Target prediction and pathway analysis showed that these DNA methylation-dysregulated miRNAs are involved in multiple cancer-related pathways, including cell cycle G1-S growth factor regulation, cytoskeleton remodeling, angiogenesis, EMT, and ESR1-mediated signaling pathways. In summary, our results suggest that DNA methylation changes within miRNA genes are associated with altered miRNA expression, which may contribute to the network of subtype- and race-related tumor biological differences in breast cancer. These findings support the involvement of epigenetic regulation of miRNA expression and provide insights into the relations of clinical-relevant miRNAs to their target genes, which may serve as potential preventative and therapeutic targets., Competing Interests: The authors have declared that no competing interests exist.