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BackgroundAsthma is one of the leading chronic illnesses among children in the United States. Asthma prevalence is higher among African Americans (11.2%) compared to European Americans (7.7%). Bronchodilator medications are part of the first-line therapy, and the rescue medication, for acute asthma symptoms. Bronchodilator drug response (BDR) varies substantially among different racial/ethnic groups. Asthma prevalence in African Americans is only 3.5% higher than that of European Americans, however, asthma mortality among African Americans is four times that of European Americans; variation in BDR may play an important role in explaining this health disparity. To improve our understanding of disparate health outcomes in complex phenotypes such as BDR, it is important to consider interactions between environmental and biological variables.ResultsWe evaluated the impact of pairwise and three-variable interactions between environmental, social, and biological variables on BDR in 233 African American youth with asthma using Visualization of Statistical Epistasis Networks (ViSEN). ViSEN is a non-parametric entropy-based approach able to quantify interaction effects using an information-theory metric known as Information Gain (IG). We performed analyses in the full dataset and in sex-stratified subsets. Our analyses identified several interaction models significantly, and suggestively, associated with BDR. The strongest interaction significantly associated with BDR was a pairwise interaction between pre-natal smoke exposure and socioeconomic status (full dataset IG: 2.78%, p = 0.001; female IG: 7.27%, p = 0.004)). Sex-stratified analyses yielded divergent results for females and males, indicating the presence of sex-specific effects.ConclusionsOur study identified novel interaction effects significantly, and suggestively, associated with BDR in African American children with asthma. Notably, we found that all of the interactions identified by ViSEN were "pure" interaction effects, in that they were not the result of strong main effects on BDR, highlighting the complexity of the network of biological and environmental factors impacting this phenotype. Several associations uncovered by ViSEN would not have been detected using regression-based methods, thus emphasizing the importance of employing statistical methods optimized to detect both additive and non-additive interaction effects when studying complex phenotypes such as BDR. The information gained in this study increases our understanding and appreciation of the complex nature of the interactions between environmental and health-related factors that influence BDR and will be invaluable to biomedical researchers designing future studies.

BackgroundPAI-1 gain-of-function variants promote airway fibrosis and are associated with asthma and with worse lung function in subjects with asthma.ObjectiveWe sought to determine whether the association of a gain-of-function polymorphism in plasminogen activator inhibitor-1 (PAI-1) with airway obstruction is modified by asthma status, and whether any genotype effect persists after accounting for common exposures that increase PAI-1 level.MethodsWe studied 2070 Latino children (8-21y) with genotypic and pulmonary function data from the GALA II cohort. We estimated the relationship of the PAI-1 risk allele with FEV1/FVC by multivariate linear regression, stratified by asthma status. We examined the association of the polymorphism with asthma and airway obstruction within asthmatics via multivariate logistic regression. We replicated associations in the SAPPHIRE cohort of African Americans (n=1056). Secondary analysis included the effect of the at-risk polymorphism on postbronchodilator lung function.ResultsThere was an interaction between asthma status and the PAI-1 polymorphism on FEV1 /FVC (P=.03). The gain-of-function variants, genotypes (AA/AG), were associated with lower FEV1 /FVC in subjects with asthma (β=-1.25, CI: -2.14,-0.35, P=.006), but not in controls. Subjects with asthma and the AA/AG genotypes had a 5% decrease in FEV1 /FVC (P

BackgroundYounger maternal age at birth is associated with increased risk of asthma in offspring in European descent populations, but has not been studied in Latino populations.ObjectivesWe sought to examine the relationship between maternal age at birth and prevalence of asthma in a nationwide study of Latino children.MethodsWe included 3473 Latino children aged 8-21 years (1696 subjects with physician-diagnosed asthma and 1777 healthy controls) from five US centres and Puerto Rico recruited from July 2008 through November 2011. We used multiple logistic regression models to examine the effect of maternal age at birth on asthma in offspring overall and in analyses stratified by ethnic subgroup (Mexican American, Puerto Rican and other Latino). Secondary analyses evaluated the effects of siblings, acculturation and income on this relationship.ResultsMaternal age < 20 years was significantly associated with decreased odds of asthma in offspring, independent of other risk factors (OR = 0.73, 95% CI: 0.57-0.93). In subgroup analyses, the protective effect of younger maternal age was observed only in Mexican Americans (OR = 0.53, 95% CI: 0.36, 0.79). In Puerto Ricans, older maternal age was associated with decreased odds of asthma (OR = 0.65, 95% CI: 0.44-0.97). In further stratified models, the protective effect of younger maternal age in Mexican Americans was seen only in children without older siblings (OR = 0.44, 95% CI: 0.23-0.81).Conclusion and clinical relevanceIn contrast to European descent populations, younger maternal age was associated with decreased odds of asthma in offspring in Mexican American women. Asthma is common in urban minority populations but the factors underlying the varying prevalence among different Latino ethnicities in the United States is not well understood. Maternal age represents one factor that may help to explain this variability.

© The Author 2015. Published by Oxford University Press.Motivation: Approaches to identifying new risk loci, training risk prediction models, imputing untyped variants and fine-mapping causal variants from summary statistics of genome-wide association stud

Introduction: Percent mammographic density (PMD) adjusted for age and body mass index is one of the strongest risk factors for breast cancer and is known to be approximately 60% heritable. Here we report a finding of an association between genetic ancestry

Author(s): W. Sunda (corresponding author) [1]; D. J. Kieber [2]; R. P. Kiene [3]; S. Huntsman [1] The algal osmolyte dimethylsulphoniopropionate (DMSP) and its enzymatic cleavage product dimethylsulphide (DMS) contribute [...]

Matthew B Schabath,1,2 Tapashi B Dalvi,3 Hongyue A Dai,4 Alan L Crim,4 Anita Midha,5 Norah Shire,3 Nicholas T Gimbrone,1 Jill Walker,6 Danielle M Greenawalt,7 David Lawrence,8 James R Rigas,9 Robert Brody,9 Danielle Potter,9 Naveen S Kumar,4 Shane A Huntsman,4 Jhanelle E Gray2 1Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 2Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 3Oncology R&D, AstraZeneca, Gaithersburg, MD, USA; 4M2Gen, Tampa, FL, USA; 5Department of Personalised Healthcare and Biomarkers, AstraZeneca, Cambridge, UK; 6Department of Precision Medicine Oncology, AstraZeneca, Cambridge, UK; 7Department of iMED Oncology Informatics, AstraZeneca, Waltham, MA, USA; 8Department of Global Medicines Development, AstraZeneca, Cambridge, UK; 9Department of Global Medical Affairs Oncology, AstraZeneca, Gaithersburg, MD, USACorrespondence: Matthew B SchabathH. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USATel +1 813 745 4150Fax +1 813 745 6525Email matthew.schabath@moffitt.orgPurpose: To characterize programmed cell death ligand-1 (PD-L1) expression in relation to survival and gene mutation status in patients with advanced NSCLC. The study also explored the influence of tumor mutational burden (TMB) on PD-L1 expression and patient characteristics.Patients and methods: Adult patients with histologically or cytologically documented Stage IIIB/Stage IV/recurrent/progressive NSCLC, Eastern Cooperative Oncology Group performance status 0 to 3, and >2 lines of prior systemic treatment regimens were included in this retrospective analysis. Patients were treated from 1997 to 2015 at H. Lee Moffitt Cancer Center and Research Institute, Tampa, or at 7 community centers across the United States. PD-L1 expression level was determined using the VENTANA PD-L1 (SP263) Assay. EGFR and KRAS mutation status and ALK rearrangements were determined by targeted DNA sequencing; these were obtained from clinical records where targeted DNA sequencing was not performed. TMB was calculated as the total number of somatic mutations per sample.Results: From a total of 136 patients included in the study, 23.5% had tumors with high PD-L1 expression (≥25%). There were no significant differences in patient characteristics, overall survival (OS), and progression-free survival (PFS) between patients with high PD-L1 expression (median OS: 39.5 months; median PFS: 15.8 months) vs low PD-L1 expression (

Abstract Background CYYR1 is a recently identified gene located on human chromosome 21 whose product has no similarity to any known protein and is of unknown function. Analysis of expressed sequence tags (ESTs) have revealed high human CYYR1 expression in cells belonging to the diffuse neuroendocrine system (DNES). These cells may be the origin of neuroendocrine (NE) tumors. The aim of this study was to conduct an initial analysis of sequence, splicing and expression of the CYYR1 mRNA in human NE tumors. Methods The CYYR1 mRNA coding sequence (CDS) was studied in 32 NE tumors by RT-PCR and sequence analysis. A subtle alternative splicing was identified generating two isoforms of CYYR1 mRNA differing in terms of the absence (CAG- isoform, the first described mRNA for CYYR1 locus) or the presence (CAG+ isoform) of a CAG codon. When present, this specific codon determines the presence of an alanine residue, at the exon 3/exon 4 junction of the CYYR1 mRNA. The two mRNA isoform amounts were determined by quantitative relative RT-PCR in 29 NE tumors, 2 non-neuroendocrine tumors and 10 normal tissues. A bioinformatic analysis was performed to search for the existence of the two CYYR1 isoforms in other species. Results The CYYR1 CDS did not show differences compared to the reference sequence in any of the samples, with the exception of an NE tumor arising in the neck region. Sequence analysis of this tumor identified a change in the CDS 333 position (T instead of C), leading to the amino acid mutation P111S. NE tumor samples showed no significant difference in either CYYR1 CAG- or CAG+ isoform expression compared to control tissues. CYYR1 CAG- isoform was significantly more expressed than CAG+ isoform in NE tumors as well as in control samples investigated. Bioinformatic analysis revealed that only the genomic sequence of Pan troglodytes CYYR1 is consistent with the possible existence of the two described mRNA isoforms. Conclusion A new "subtle" splicing isoform (CAG+) of CYYR1 mRNA, the sequence and the expression of this gene were defined in a large series of NE tumors.

Identifying and refining clinically significant patient stratification is a critical step toward realizing the promise of precision medicine in asthma. Several peripheral blood hallmarks, including total peripheral blood eosinophil count (BEC) and immunoglobulin E (IgE) levels, are routinely used in asthma clinical practice for endotype classification and predicting response to state-of-the-art targeted biologic drugs. However, these biomarkers appear ineffective in predicting treatment outcomes in some patients, and they differ in distribution between racially and ethnically diverse populations, potentially compromising medical care and hindering health equity due to biases in drug eligibility. Here, we propose constructing an unbiased patient stratification score based on DNA methylation (DNAm) and utilizing it to refine the efficacy of hallmark biomarkers for predicting drug response. We developed Phenotype Aware Component Analysis (PACA), a novel contrastive machine-learning method for learning combinations of DNAm sites reflecting biomedically meaningful patient stratifications. Leveraging whole-blood DNAm from Latino (discovery; n=1,016) and African American (replication; n=756) pediatric asthma case-control cohorts, we applied PACA to refine the prediction of bronchodilator response (BDR) to the short-acting β2-agonist albuterol, the most used drug to treat acute bronchospasm worldwide. While BEC and IgE correlate with BDR in the general patient population, our PACA-derived DNAm score renders these biomarkers predictive of drug response only in patients with high DNAm scores. BEC correlates with BDR in patients with upper-quartile DNAm scores (OR 1.12; 95% CI [1.04, 1.22]; P=7.9 e-4) but not in patients with lower-quartile scores (OR 1.05; 95% CI [0.95, 1.17]; P=0.21); and IgE correlates with BDR in above-median (OR for response 1.42; 95% CI [1.24, 1.63]; P=3.9e-7) but not in below-median patients (OR 1.05; 95% CI [0.92, 1.2]; P=0.57). These results hold within the commonly recognized type 2 (T2)-high asthma endotype but not in T2-low patients, suggesting that our DNAm score primarily represents an unknown variation of T2 asthma. Among T2-high patients with high DNAm scores, elevated BEC or IgE also corresponds to baseline clinical presentation that is known to benefit more from biologic treatment, including higher exacerbation scores, higher allergen sensitization, lower BMI, more recent oral corticosteroids prescription, and lower lung function. Our findings suggest that BEC and IgE, the traditional asthma biomarkers of T2-high asthma, are poor biomarkers for millions worldwide. Revisiting existing drug eligibility criteria relying on these biomarkers in asthma medical care may enhance precision and equity in treatment.

Introduction: Immune checkpoint inhibitors (ICIs) can yield remarkable clinical responses in subsets of patients with solid tumors but can also often lead to immune-related adverse events (irAEs). Predictive features of clinically severe irAEs leading to cessation of ICIs have yet to be established. Using data from 1,327 patients with lung cancer treated with ICIs between 2009 and 2022 at four academic medical centers, we evaluated the association of a germline polygenic risk score for autoimmune disease and discontinuation of ICIs due to irAEs., Methods: Using Cox proportional hazards model, we assessed the association between a polygenic risk score for autoimmune disease (PRS AD ) and cessation of ICI therapy due to irAEs. All models were adjusted for age at diagnosis, sex, lung cancer histology, type of therapy, recruiting center, and the first 5 principal components. To further understand the differential effects of type of therapy and disease stage on the association between PRS AD and cessation of ICI due to irAEs, we conducted stratified logistic regression analysis by type of ICI therapy and disease stage., Results: We found an association between PRS AD and ICI cessation due to irAEs (HR per SD = 1.18, 95% CI = 1.02 - 1.37, P = 0.03). This association was particularly strong in patients who had ICI cessation due to irAEs within three months of therapy initiation (HR per SD = 1.38, 95% CI = 1.08 - 1.78, P = 0.01). Individuals in the top 20th percentile of PRS AD had 7.2% ICI discontinuation for irAEs by three months, compared to 3.9% discontinuation by three months among patients in the bottom 80th percentile (log-rank P = 0.02). In addition, among patients who received combination PD-1/PD-L1 and CTLA-4 inhibitor therapy, PRS AD had an OR per SD of 1.86 (95% CI = 1.08 - 3.51, P = 0.04)., Conclusions: We demonstrate an association between a polygenic risk score for autoimmune disease and early ICI discontinuation for irAEs, particularly among patients treated with combination ICI therapy. Our results suggest that germline genetics may be used as an adjunctive tool for risk stratification around ICI clinical decision-making in solid tumor oncology.

By incompletely understood mechanisms, type 2 (T2) inflammation present in the airways of severe asthmatics drives the formation of pathologic mucus which leads to airway mucus plugging. Here we investigate the molecular role and clinical significance of intelectin-1 (ITLN-1) in the development of pathologic airway mucus in asthma. Through analyses of human airway epithelial cells we find that ITLN1 gene expression is highly induced by interleukin-13 (IL-13) in a subset of metaplastic MUC5AC + mucus secretory cells, and that ITLN-1 protein is a secreted component of IL-13-induced mucus. Additionally, we find ITLN-1 protein binds the C-terminus of the MUC5AC mucin and that its deletion in airway epithelial cells partially reverses IL-13-induced mucostasis. Through analysis of nasal airway epithelial brushings, we find that ITLN1 is highly expressed in T2-high asthmatics, when compared to T2-low children. Furthermore, we demonstrate that both ITLN-1 gene expression and protein levels are significantly reduced by a common genetic variant that is associated with protection from the formation of mucus plugs in T2-high asthma. This work identifies an important biomarker and targetable pathways for the treatment of mucus obstruction in asthma., (© 2024. The Author(s).)

Immune checkpoint inhibitor-mediated colitis (IMC) is a common adverse event of treatment with immune checkpoint inhibitors (ICI). We hypothesize that genetic susceptibility to Crohn's disease (CD) and ulcerative colitis (UC) predisposes to IMC. In this study, we first develop a polygenic risk scores for CD (PRS CD ) and UC (PRS UC ) in cancer-free individuals and then test these PRSs on IMC in a cohort of 1316 patients with ICI-treated non-small cell lung cancer and perform a replication in 873 ICI-treated pan-cancer patients. In a meta-analysis, the PRS UC predicts all-grade IMC (OR meta =1.35 per standard deviation [SD], 95% CI = 1.12-1.64, P = 2×10 -03 ) and severe IMC (OR meta =1.49 per SD, 95% CI = 1.18-1.88, P = 9×10 -04 ). PRS CD is not associated with IMC. Furthermore, PRS UC predicts severe IMC among patients treated with combination ICIs (OR meta =2.20 per SD, 95% CI = 1.07-4.53, P = 0.03). Overall, PRS UC can identify patients receiving ICI at risk of developing IMC and may be useful to monitor patients and improve patient outcomes., (© 2024. The Author(s).)

Background: The epigenetic mechanisms of asthma remain largely understudied in African Americans and Hispanics/Latinos, two populations disproportionately affected by asthma. We aimed to identify markers, regions and processes with differential patterns of DNA methylation (DNAm) in whole blood by asthma status in ethnically diverse children and youth, and to assess their functional consequences., Methods: DNAm levels were profiled with the Infinium MethylationEPIC or HumanMethylation450 BeadChip arrays among 1226 African Americans or Hispanics/Latinos and assessed for differential methylation per asthma status at the CpG and region (differentially methylated region (DMR)) level. Novel associations were validated in blood and/or nasal epithelium from ethnically diverse children and youth. The functional and biological implications of the markers identified were investigated by combining epigenomics with transcriptomics from study participants., Results: 128 CpGs and 196 DMRs were differentially methylated after multiple testing corrections, including 92.3% and 92.8% novel associations, respectively. 41 CpGs were replicated in other Hispanics/Latinos, prioritising cg17647904 ( NCOR2 ) and cg16412914 ( AXIN1 ) as asthma DNAm markers. Significant DNAm markers were enriched in previous associations for asthma, fractional exhaled nitric oxide, bacterial infections, immune regulation or eosinophilia. Functional annotation highlighted epigenetically regulated gene networks involved in corticosteroid response, host defence and immune regulation. Several implicated genes are targets for approved or experimental drugs, including TNNC1 and NDUFA12 . Many differentially methylated loci previously associated with asthma were validated in our study., Conclusions: We report novel whole-blood DNAm markers for asthma underlying key processes of the disease pathophysiology and confirm the transferability of previous asthma DNAm associations to ethnically diverse populations., Competing Interests: Conflict of interest: E. Herrera-Luis was supported by a fellowship awarded by MCIN/AEI/10.13039/501100011033 and by the European Social Fund (ESF) “Investing in your future” (PRE2018-083837). C. Rosa-Baez reports support for the present manuscript from the Ministry of Education and Vocational Training. M. Pino-Yanes was funded by the Ramón y Cajal Program (RYC-2015-17205) by MCIN/AEI/10.13039/501100011033 and by the ESF “Investing in your future”. She reports a grant from MCIN/AEI/10.13039/501100011033, and grant support from the EAACI Allergopharma Award 2021 and from GlaxoSmithKline, Spain, paid to Fundación Canaria Instituto de Investigación Sanitaria de Canarias for a project outside the submitted work. J. Villar and M. Pino-Yanes were also supported by CIBERES, Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia e Innovación and Unión Europea–European Regional Development Fund (CB06/06/1088). J. Villar also reports funding by ISCIII and the European Regional Development Fund “A way of making Europe”. E.G. Burchard reports grants from the National Institutes of Health, the Tobacco-Related Disease Research Program, the Sandler Family Foundation, the American Asthma Foundation, the Amos Medical Faculty Development Program from the Robert Wood Johnson Foundation, and from the Harry Wm. and Diana V. Hind Distinguished Professorship in Pharmaceutical Sciences II. C. Laprise is the director of the Centre Intersectoriel en Santé Durable, codirector of the Environment, Genetics and Cancer axis of the Respiratory Health Network, investigator of CHILD Study, member of the InFAC consortium, and chairholder of the Canada Research Chair in Asthma and Allergic Diseases Genomics. The remaining authors declare they have no competing interests or other interests that might be perceived to influence the interpretation of the article., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

Somatic mutational profiling is increasingly being used to identify potential targets for breast cancer. However, limited tumor-sequencing data from Hispanic/Latinas (H/L) are available to guide treatment. To address this gap, we performed whole-exome sequencing (WES) and RNA sequencing on 146 tumors and WES of matched germline DNA from 140 H/L women in California. Tumor intrinsic subtype, somatic mutations, copy-number alterations, and expression profiles of the tumors were characterized and compared with data from tumors of non-Hispanic White (White) women in The Cancer Genome Atlas (TCGA). Eight genes were significantly mutated in the H/L tumors including PIK3CA, TP53, GATA3, MAP3K1, CDH1, CBFB, PTEN, and RUNX1; the prevalence of mutations in these genes was similar to that observed in White women in TCGA. Four previously reported Catalogue of Somatic Mutations in Cancer (COSMIC) mutation signatures (1, 2, 3, 13) were found in the H/L dataset, along with signature 16 that has not been previously reported in other breast cancer datasets. Recurrent amplifications were observed in breast cancer drivers including MYC, FGFR1, CCND1, and ERBB2, as well as a recurrent amplification in 17q11.2 associated with high KIAA0100 gene expression that has been implicated in breast cancer aggressiveness. In conclusion, this study identified a higher prevalence of COSMIC signature 16 and a recurrent copy-number amplification affecting expression of KIAA0100 in breast tumors from H/L compared with White women. These results highlight the necessity of studying underrepresented populations., Significance: Comprehensive characterization of genomic and transcriptomic alterations in breast tumors from Hispanic/Latina patients reveals distinct genetic alterations and signatures, demonstrating the importance of inclusive studies to ensure equitable care for patients. See related commentary by Schmit et al., p. 2443., (©2023 The Authors; Published by the American Association for Cancer Research.)

We explored ancestry-related differences in the genetic architecture of whole-blood gene expression using whole-genome and RNA sequencing data from 2,733 African Americans, Puerto Ricans and Mexican Americans. We found that heritability of gene expression significantly increased with greater proportions of African genetic ancestry and decreased with higher proportions of Indigenous American ancestry, reflecting the relationship between heterozygosity and genetic variance. Among heritable protein-coding genes, the prevalence of ancestry-specific expression quantitative trait loci (anc-eQTLs) was 30% in African ancestry and 8% for Indigenous American ancestry segments. Most anc-eQTLs (89%) were driven by population differences in allele frequency. Transcriptome-wide association analyses of multi-ancestry summary statistics for 28 traits identified 79% more gene-trait associations using transcriptome prediction models trained in our admixed population than models trained using data from the Genotype-Tissue Expression project. Our study highlights the importance of measuring gene expression across large and ancestrally diverse populations for enabling new discoveries and reducing disparities., (© 2023. The Author(s).)

Background: Albuterol is the drug most widely used as asthma treatment among African Americans despite having a lower bronchodilator drug response (BDR) than other populations. Although BDR is affected by gene and environmental factors, the influence of DNA methylation is unknown., Objective: This study aimed to identify epigenetic markers in whole blood associated with BDR, study their functional consequences by multi-omic integration, and assess their clinical applicability in admixed populations with a high asthma burden., Methods: We studied 414 children and young adults (8-21 years old) with asthma in a discovery and replication design. We performed an epigenome-wide association study on 221 African Americans and replicated the results on 193 Latinos. Functional consequences were assessed by integrating epigenomics with genomics, transcriptomics, and environmental exposure data. Machine learning was used to develop a panel of epigenetic markers to classify treatment response., Results: We identified 5 differentially methylated regions and 2 CpGs genome-wide significantly associated with BDR in African Americans located in FGL2 (cg08241295, P = 6.8 × 10 -9 ) and DNASE2 (cg15341340, P = 7.8 × 10 -8 ), which were regulated by genetic variation and/or associated with gene expression of nearby genes (false discovery rate < 0.05). The CpG cg15341340 was replicated in Latinos (P = 3.5 × 10 -3 ). Moreover, a panel of 70 CpGs showed good classification for those with response and nonresponse to albuterol therapy in African American and Latino children (area under the receiver operating characteristic curve for training, 0.99; for validation, 0.70-0.71). The DNA methylation model showed similar discrimination as clinical predictors (P > .05)., Conclusions: We report novel associations of epigenetic markers with BDR in pediatric asthma and demonstrate for the first time the applicability of pharmacoepigenetics in precision medicine of respiratory diseases., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Aggressive breast cancers portend a poor prognosis, but current polygenic risk scores (PRSs) for breast cancer do not reliably predict aggressive cancers. Aggressiveness can be effectively recapitulated using tumor gene expression profiling. Thus, we sought to develop a PRS for the risk of recurrence score weighted on proliferation (ROR-P), an established prognostic signature. Using 2363 breast cancers with tumor gene expression data and single nucleotide polymorphism (SNP) genotypes, we examined the associations between ROR-P and known breast cancer susceptibility SNPs using linear regression models. We constructed PRSs based on varying p-value thresholds and selected the optimal PRS based on model r 2 in 5-fold cross-validation. We then used Cox proportional hazards regression to test the ROR-P PRS's association with breast cancer-specific survival in two independent cohorts totaling 10,196 breast cancers and 785 events. In meta-analysis of these cohorts, higher ROR-P PRS was associated with worse survival, HR per SD = 1.13 (95% CI 1.06-1.21, p = 4.0 × 10 -4 ). The ROR-P PRS had a similar magnitude of effect on survival as a comparator PRS for estrogen receptor (ER)-negative versus positive cancer risk (PRS ER-/ER+ ) . Furthermore, its effect was minimally attenuated when adjusted for PRS ER-/ER+ , suggesting that the ROR-P PRS provides additional prognostic information beyond ER status. In summary, we used integrated analysis of germline SNP and tumor gene expression data to construct a PRS associated with aggressive tumor biology and worse survival. These findings could potentially enhance risk stratification for breast cancer screening and prevention., (© 2023. The Author(s).)

Background: In the USA, genetically admixed populations have the highest asthma prevalence and severe asthma exacerbations rates. This could be explained not only by environmental factors but also by genetic variants that exert ethnic-specific effects. However, no admixture mapping has been performed for severe asthma exacerbations., Objective: We sought to identify genetic variants associated with severe asthma exacerbations in Hispanic/Latino subgroups by means of admixture mapping analyses and fine mapping, and to assess their transferability to other populations and potential functional roles., Methods: We performed an admixture mapping in 1124 Puerto Rican and 625 Mexican American children with asthma. Fine-mapping of the significant peaks was performed via allelic testing of common and rare variants. We performed replication across Hispanic/Latino subgroups, and the transferability to non-Hispanic/Latino populations was assessed in 1001 African Americans, 1250 Singaporeans and 941 Europeans with asthma. The effects of the variants on gene expression and DNA methylation from whole blood were also evaluated in participants with asthma and in silico with data obtained through public databases., Results: Genomewide significant associations of Indigenous American ancestry with severe asthma exacerbations were found at 5q32 in Mexican Americans as well as at 13q13-q13.2 and 3p13 in Puerto Ricans. The single nucleotide polymorphism (SNP) rs1144986 ( C5orf46 ) showed consistent effects for severe asthma exacerbations across Hispanic/Latino subgroups, but it was not validated in non-Hispanics/Latinos. This SNP was associated with DPYSL3 DNA methylation and SCGB3A2 gene expression levels., Conclusions: Admixture mapping study of asthma exacerbations revealed a novel locus that exhibited Hispanic/Latino-specific effects and regulated DPYSL3 and SCGB3A2 ., Competing Interests: Competing interests: EH-L, and M.P.-Y. report funding from the Spanish Ministry of Science and Innovation (MCIN/AEI/10.13039/501100011033) and by “ESF Investing in your future” by the European Union. JP-G reports funding from the Spanish Ministry of Universities. M.P.-Y. and F.L.D. report grants from MCIN/AEI/10.13039/501100011033 and the European Regional Development Fund “ERDF A way of making Europe” by the European Union. MP-Y reports grant support from GlaxoSmithKline, Spain paid to Fundación Canaria Instituto de Investigación Sanitaria de Canarias (FIISC) for a project outside the submitted work. MP-Y and JV reports grants from Instituto de Salud Carlos III, Madrid, Spain. JV also reports funding by ISCIII and the European Regional Development Fund “ERDF A way of making Europe”. JMH-P has received fees from CSL Behring, GSK, Astra-Zeneca, Laboratorios Menarini, Boehringer Ingelheim, FAES, Laboratorios Esteve, Laboratorios Ferrer, Mundipharma, Laboratorios Rovi, Roche, Novartis, GRIFOLS, Pfizer, Acthelion-Jansen, Chiesi y Laboratorios Bial for the realization of courses, talks, consultancies, and other activities related to his professional activity. FTC has received research support from the Singapore Ministry of Education Academic Research Fund, Singapore Immunology Network (SIgN), National Medical Research Council (NMRC) (Singapore), Biomedical Research Council (BMRC) (Singapore), and the Agency for Science Technology and Research (A*STAR) (Singapore). F.T.C. has received consulting fees from Sime Darby Technology Centre; First Resources Ltd; Genting Plantation, and Olam International, outside the submitted work. YYS has received research support from the NUS Resilience & Growth Postdoctoral Fellowships. The other authors declare no conflict of interest., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Germline genetic variants modulate human immune response. We present analytical pipelines for assessing the contribution of hosts' genetic background to the immune landscape of solid tumors using harmonized data from more than 9,000 patients in The Cancer Genome Atlas (TCGA). These include protocols for heritability, genome-wide association studies (GWAS), colocalization, and rare variant analyses. These workflows are developed around the structure of TCGA but can be adapted to explore other repositories or in the context of cancer immunotherapy. For complete details on the use and execution of this protocol, please refer to Sayaman et al. (2021)., Competing Interests: Declaration of interests Authors have no conflict or competing interests to declare., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)