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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.

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).)

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.)

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).)

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.)

Background: Breast cancer incidence in the United States is lower in Hispanic/Latina (H/L) compared with African American/Black or Non-Hispanic White women. An Indigenous American breast cancer-protective germline variant (rs140068132) has been reported near the estrogen receptor 1 gene. This study tests the association of rs140068132 and other polymorphisms in the 6q25 region with subtype-specific breast cancer risk in H/Ls of high Indigenous American ancestry., Methods: Genotypes were obtained for 5,094 Peruvian women with (1,755) and without (3,337) breast cancer. Associations between genotype and overall and subtype-specific risk for the protective variant were tested using logistic regression models and conditional analyses, including other risk-associated polymorphisms in the region., Results: We replicated the reported association between rs140068132 and breast cancer risk overall [odds ratio (OR), 0.53; 95% confidence interval (CI), 0.47-0.59], as well as the lower odds of developing hormone receptor negative (HR-) versus HR+ disease (OR, 0.77; 95% CI, 0.61-0.97). Models, including HER2, showed further heterogeneity with reduced odds for HR+HER2+ (OR, 0.68; 95% CI, 0.51-0.92), HR-HER2+ (OR, 0.63; 95% CI, 0.44-0.90) and HR-HER2- (OR, 0.77; 95% CI, 0.56-1.05) compared with HR+HER2-. Inclusion of other risk-associated variants did not change these observations., Conclusions: The rs140068132 polymorphism is associated with decreased risk of breast cancer in Peruvians and is more protective against HR- and HER2+ diseases independently of other breast cancer-associated variants in the 6q25 region., Impact: These results could inform functional analyses to understand the mechanism by which rs140068132-G reduces risk of breast cancer development in a subtype-specific manner. They also illustrate the importance of including diverse individuals in genetic studies., (©2022 The Authors; Published by the American Association for Cancer Research.)

Differential mRNA expression between ancestry groups can be explained by both genetic and environmental factors. We outline a computational workflow to determine the extent to which germline genetic variation explains cancer-specific molecular differences across ancestry groups. Using multi-omics datasets from The Cancer Genome Atlas (TCGA), we enumerate ancestry-informative markers colocalized with cancer-type-specific expression quantitative trait loci (e-QTLs) at ancestry-associated genes. This approach is generalizable to other settings with paired germline genotyping and mRNA expression data for a multi-ethnic cohort. For complete details on the use and execution of this protocol, please refer to Carrot-Zhang et al. (2020), Robertson et al. (2021), and Sayaman et al. (2021)., Competing Interests: A.D.C. receives research funding from Bayer. R.B. owns equity in and consults for Scorpion Therapeutics and receives research funding from Novartis., (© 2022 The Author(s).)

Variability in response to short-acting β 2 -agonists (e.g., albuterol) among patients with asthma from diverse racial/ethnic groups may contribute to asthma disparities. We sought to identify genetic variants associated with bronchodilator response (BDR) to identify potential mechanisms of drug response and risk factors for worse asthma outcomes. Genome-wide association studies of bronchodilator response (BDR) were performed using TOPMed Whole Genome Sequencing data of the Asthma Translational Genomic Collaboration (ATGC), which corresponded to 1136 Puerto Rican, 656 Mexican and 4337 African American patients with asthma. With the population-specific GWAS results, a trans-ethnic meta-analysis was performed to identify BDR-associated variants shared across the three populations. Replication analysis was carried out in three pediatric asthma cohorts, including CAMP (Childhood Asthma Management Program; n = 560), GACRS (Genetics of Asthma in Costa Rica Study; n = 967) and HPR (Hartford-Puerto Rico; n = 417). A genome-wide significant locus (rs35661809; P = 3.61 × 10 -8 ) in LINC02220, a non-coding RNA gene, was identified in Puerto Ricans. While this region was devoid of protein-coding genes, capture Hi-C data showed a distal interaction with the promoter of the DNAH5 gene in lung tissue. In replication analysis, the GACRS cohort yielded a nominal association (1-tailed P < 0.05). No genetic variant was associated with BDR at the genome-wide significant threshold in Mexicans and African Americans. Our findings help inform genetic underpinnings of BDR for understudied minority patients with asthma, but the limited availability of genetic data for racial/ethnic minority children with asthma remains a paramount challenge., (© 2022. The Author(s).)

Preeclampsia is a multi-organ complication of pregnancy characterized by sudden hypertension and proteinuria that is among the leading causes of preterm delivery and maternal morbidity and mortality worldwide. The heterogeneity of preeclampsia poses a challenge for understanding its etiology and molecular basis. Intriguingly, risk for the condition increases in high-altitude regions such as the Peruvian Andes. To investigate the genetic basis of preeclampsia in a population living at high altitude, we characterized genome-wide variation in a cohort of preeclamptic and healthy Andean families (n = 883) from Puno, Peru, a city located above 3,800 meters of altitude. Our study collected genomic DNA and medical records from case-control trios and duos in local hospital settings. We generated genotype data for 439,314 SNPs, determined global ancestry patterns, and mapped associations between genetic variants and preeclampsia phenotypes. A transmission disequilibrium test (TDT) revealed variants near genes of biological importance for placental and blood vessel function. The top candidate region was found on chromosome 13 of the fetal genome and contains clotting factor genes PROZ, F7, and F10. These findings provide supporting evidence that common genetic variants within coagulation genes play an important role in preeclampsia. A selection scan revealed a potential adaptive signal around the ADAM12 locus on chromosome 10, implicated in pregnancy disorders. Our discovery of an association in a functional pathway relevant to pregnancy physiology in an understudied population of Native American origin demonstrates the increased power of family-based study design and underscores the importance of conducting genetic research in diverse populations., Competing Interests: Declaration of interests J.W.C. is currently a full-time employee at Genentech, Inc. and hold stocks in Roche Holding AG., (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

To identify genetic determinants of airway dysfunction, we performed a transcriptome-wide association study for asthma by combining RNA-seq data from the nasal airway epithelium of 681 children, with UK Biobank genetic association data. Our airway analysis identified 95 asthma genes, 58 of which were not identified by transcriptome-wide association analyses using other asthma-relevant tissues. Among these genes were MUC5AC, an airway mucin, and FOXA3, a transcriptional driver of mucus metaplasia. Muco-ciliary epithelial cultures from genotyped donors revealed that the MUC5AC risk variant increases MUC5AC protein secretion and mucus secretory cell frequency. Airway transcriptome-wide association analyses for mucus production and chronic cough also identified MUC5AC. These cis-expression variants were associated with trans effects on expression; the MUC5AC variant was associated with upregulation of non-inflammatory mucus secretory network genes, while the FOXA3 variant was associated with upregulation of type-2 inflammation-induced mucus-metaplasia pathway genes. Our results reveal genetic mechanisms of airway mucus pathobiology., (© 2022. The Author(s).)

Introduction: DNA methylation studies have associated methylation levels at different CpG sites or genomic regions with lung function. Moreover, genetic ancestry has been associated with lung function in Latinos. However, no epigenome-wide association study (EWAS) of lung function has been performed in this population. Here, we aimed to identify DNA methylation patterns associated with lung function in pediatric asthma among Latinos., Results: We conducted an EWAS in whole blood from 250 Puerto Rican and 148 Mexican American children and young adults with asthma. A total of five CpGs exceeded the genome-wide significance threshold of p = 1.17 × 10 -7 in the combined analyses from Puerto Ricans and Mexican Americans: cg06035600 (MAP3K6, p = 6.13 × 10 -8 ) showed significant association with pre-bronchodilator Tiffeneau-Pinelli index, the probes cg00914963 (TBC1D16, p = 1.04 × 10 -7 ), cg16405908 (MRGPRE, p = 2.05 × 10 -8 ), and cg07428101 (MUC2, p = 5.02 × 10 -9 ) were associated with post-bronchodilator forced vital capacity (FVC), and cg20515679 (KCNJ6) with post-bronchodilator Tiffeneau-Pinelli index (p = 1.13 × 10 -8 ). However, these markers did not show significant associations in publicly available data from Europeans (p > 0.05). A methylation quantitative trait loci analysis revealed that methylation levels at these CpG sites were regulated by genetic variation in Latinos and the Biobank-based Integrative Omics Studies (BIOS) consortium. Additionally, two differentially methylated regions in REXOC and AURKC were associated with pre-bronchodilator Tiffeneau-Pinelli index (adjusted p < 0.05) in Puerto Ricans and Mexican Americans. Moreover, we replicated some of the previous differentially methylated signals associated with lung function in non-Latino populations., Conclusions: We replicated previous associations of epigenetic markers with lung function in whole blood and identified novel population-specific associations shared among Latino subgroups., (© 2022. The Author(s).)

Purpose: Genetic differences in immunity may contribute to toxicity and outcomes with immune checkpoint inhibitor (CPI) therapy, but these relationships are poorly understood. We examined the genetics of thyroid immune-related adverse events (irAE)., Experimental Design: In patients with non-small cell lung cancer (NSCLC) treated with CPIs at Memorial Sloan Kettering (MSK) and Vanderbilt University Medical Center (VUMC), we evaluated thyroid irAEs. We typed germline DNA using genome-wide single-nucleotide polymorphism (SNP) arrays and imputed genotypes. Germline SNP imputation was also performed in an independent Dana-Farber Cancer Institute (DFCI) cohort. We developed and validated polygenic risk scores (PRS) for hypothyroidism in noncancer patients using the UK and VUMC BioVU biobanks. These PRSs were applied to thyroid irAEs and CPI response in patients with NSCLC at MSK, VUMC, and DFCI., Results: Among 744 patients at MSK and VUMC, thyroid irAEs occurred in 13% and were associated with improved outcomes [progression-free survival adjusted HR (PFS aHR) = 0.68; 95% confidence interval (CI), 0.52-0.88]. The PRS for hypothyroidism developed from UK Biobank predicted hypothyroidism in the BioVU dataset in noncancer patients [OR per standard deviation (SD) = 1.33, 95% CI, 1.29-1.37; AUROC = 0.6]. The same PRS also predicted development of thyroid irAEs in both independent cohorts of patients treated with CPIs (HR per SD = 1.34; 95% CI, 1.08-1.66; AUROC = 0.6). The results were similar in the DFCI cohort. However, PRS for hypothyroidism did not predict CPI benefit., Conclusions: Thyroid irAEs were associated with response to anti-PD-1 therapy. Genetic risk for hypothyroidism was associated with risk of developing thyroid irAEs. Additional studies are needed to determine whether other irAEs also have shared genetic risk with known autoimmune disorders and the association with treatment response., (©2021 American Association for Cancer Research.)

Polynesia was settled in a series of extraordinary voyages across an ocean spanning one third of the Earth 1 , but the sequences of islands settled remain unknown and their timings disputed. Currently, several centuries separate the dates suggested by different archaeological surveys 2-4 . Here, using genome-wide data from merely 430 modern individuals from 21 key Pacific island populations and novel ancestry-specific computational analyses, we unravel the detailed genetic history of this vast, dispersed island network. Our reconstruction of the branching Polynesian migration sequence reveals a serial founder expansion, characterized by directional loss of variants, that originated in Samoa and spread first through the Cook Islands (Rarotonga), then to the Society (Tōtaiete mā) Islands (11th century), the western Austral (Tuha'a Pae) Islands and Tuāmotu Archipelago (12th century), and finally to the widely separated, but genetically connected, megalithic statue-building cultures of the Marquesas (Te Henua 'Enana) Islands in the north, Raivavae in the south, and Easter Island (Rapa Nui), the easternmost of the Polynesian islands, settled in approximately AD 1200 via Mangareva., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Latinos are heavily affected with childhood asthma. Little is known about epigenetic mechanisms of asthma in Latino youth. We conducted a meta-analysis of two epigenome-wide association studies (EWAS) of asthma, using DNA from white blood cells (WBCs) from 1,136 Latino children and youth aged 6 to 20 years. Genes near the top CpG sites in this EWAS were examined in a pathway enrichment analysis, and we then assessed whether our results replicated those from publicly available data from three independent EWAS conducted in non-Latino populations. We found that DNA methylation profiles differed between subjects with and without asthma. After adjustment for covariates and multiple testing, two CpGs were differentially methylated at a false discovery rate (FDR)-adjusted P < 0.1, and 193 CpG sites were differentially methylated at FDR-adjusted P < 0.2. The two top CpGs are near genes relevant to inflammatory signalling, including CAMK1D (Calcium/Calmodulin Dependent Protein Kinase ID) and TIGIT (T Cell Immunoreceptor With Ig And ITIM Domains). Moreover, 25 genomic regions were differentially methylated between subjects with and without asthma, at Šidák-corrected P < 0.10. An enrichment analysis then identified the TGF-beta pathway as most relevant to asthma in our analysis, and we replicated some of the top signals from publicly available EWAS datasets in non-Hispanic populations. In conclusion, we have identified novel epigenetic markers of asthma in WBCs from Latino children and youth, while also replicating previous results from studies conducted in non-Latinos.

Severe asthma exacerbations are a major cause of school absences and healthcare costs in children, particularly those in high-risk racial/ethnic groups.To identify susceptibility genes for severe asthma exacerbations in Latino children and adolescents, we conducted a meta-analysis of genome-wide association studies (GWAS) in 4010 Latino youth with asthma in four independent cohorts, including 1693 Puerto Ricans, 1019 Costa Ricans, 640 Mexicans, 256 Brazilians and 402 members of other Latino subgroups. We then conducted methylation quantitative trait locus, expression quantitative trait locus and expression quantitative trait methylation analyses to assess whether the top single nucleotide polymorphism (SNP) in the meta-analysis is linked to DNA methylation and gene expression in nasal (airway) epithelium in separate cohorts of Puerto Rican and Dutch children and adolescents.In the meta-analysis of GWAS, an SNP in FLJ22447 (rs2253681) was significantly associated with 1.55 increased odds of severe asthma exacerbation (95% CI 1.34-1.79, p=6.3×10 -9 ). This SNP was significantly associated with DNA methylation of a CpG site (cg25024579) at the FLJ22447 locus, which was in turn associated with increased expression of KCNJ2-AS1 in nasal airway epithelium from Puerto Rican children and adolescents (β=0.10, p=2.18×10 -7 ).SNP rs2253681 was significantly associated with both DNA methylation of a cis-CpG in FLJ22447 and severe asthma exacerbations in Latino youth. This may be partly explained by changes in airway epithelial expression of a gene recently implicated in atopic asthma in Puerto Rican children and adolescents ( KCNJ2-AS1 )., Competing Interests: Conflict of interest: Q. Yan reports grants from National Institutes of Health (K01HL138098), during the conduct of the study. Conflict of interest: E. Forno has nothing to disclose. Conflict of interest: E. Herrera-Luis reports grants from the Spanish Ministry of Science, Innovation and Universities (PRE2018-083837), during the conduct of the study. Conflict of interest: M. Pino-Yanes reports grants from Spanish Ministry of Economy, Industry and Competitiveness, the State Research Agency and the European Regional Development Funds from the European Union (MINECO/AEI/FEDER, UE, SAF2017-83417R), and grants from Spanish Ministry of Economy, Industry and Competitiveness (Ramón y Cajal grant RYC-2015-17205), during the conduct of the study. Conflict of interest: C. Qi has nothing to disclose. Conflict of interest: R. Rios has nothing to disclose. Conflict of interest: Y-Y. Han has nothing to disclose. Conflict of interest: S. Kim has nothing to disclose. Conflict of interest: S. Oh has nothing to disclose. Conflict of interest: E. Acosta-Pérez has nothing to disclose. Conflict of interest: R. Zhang has nothing to disclose. Conflict of interest: D. Hu has nothing to disclose. Conflict of interest: C. Eng has nothing to disclose. Conflict of interest: S. Huntsman has nothing to disclose. Conflict of interest: L. Avila has nothing to disclose. Conflict of interest: N. Boutaoui has nothing to disclose. Conflict of interest: M.M. Cloutier has nothing to disclose. Conflict of interest: M.E. Soto-Quiros has nothing to disclose. Conflict of interest: C-J. Xu has nothing to disclose. Conflict of interest: S.T. Weiss has nothing to disclose. Conflict of interest: J. Lasky-Su has nothing to disclose. Conflict of interest: M.R. Kiedrowski has nothing to disclose. Conflict of interest: C. Figueiredo has nothing to disclose. Conflict of interest: J. Bomberger has nothing to disclose. Conflict of interest: M.L. Barreto has nothing to disclose. Conflict of interest: G. Canino has nothing to disclose. Conflict of interest: W. Chen has nothing to disclose. Conflict of interest: G.H. Koppelman reports grants from the Lung Foundation of the Netherlands, during the conduct of the study; grants from Ubbo Emmius Foundation, TETRI Foundation, GSK, Vertex, TEVA, the Lung Foundation of the Netherlands and the European Union H2020 Program, outside the submitted work; and has served on advisory boards to GSK and PURE IMS (fees paid to institution). Conflict of interest: E.G. Burchard reports grants from National Heart, Lung, and Blood Institute, National Institute of Health, General Medical Sciences, National Institute on Minority Health and Health Disparities, Tobacco-Related Disease Research Program, Food and Drug Administration, and the Sandler Family Foundation, during the conduct of the study. Conflict of interest: J.C. Celedón has received research materials from GSK and Merck (inhaled steroids) and Pharmavite (vitamin D and placebo capsules), in order to provide medications free of cost to participants in NIH-funded studies, unrelated to the current work., (Copyright ©ERS 2021.)

Understanding the contribution of the host's genetic background to cancer immunity may lead to improved stratification for immunotherapy and to the identification of novel therapeutic targets. We investigated the effect of common and rare germline variants on 139 well-defined immune traits in ∼9000 cancer patients enrolled in TCGA. High heritability was observed for estimates of NK cell and T cell subset infiltration and for interferon signaling. Common variants of IFIH1, TMEM173 (STING1), and TMEM108 were associated with differential interferon signaling and variants mapping to RBL1 correlated with T cell subset abundance. Pathogenic or likely pathogenic variants in BRCA1 and in genes involved in telomere stabilization and Wnt-β-catenin also acted as immune modulators. Our findings provide evidence for the impact of germline genetics on the composition and functional orientation of the tumor immune microenvironment. The curated datasets, variants, and genes identified provide a resource toward further understanding of tumor-immune interactions., Competing Interests: Declarations of interests R.F.S. has received consulting honoraria from Aduro, Astellas, AstraZeneca, BMS, EMD Serono, Exelixis, Eisai, Janssen, Mirati, Pfizer, Puma, and Seattle Genetics. R.F.S. has received research support (to institution) from Abbvie, Aduro, Bayer, BMS, CytomX, Eisai, Eli Lilly, Genentech/Roche, Immunocore, Novartis, Merck, Mirati, Moderna, and QED therapeutics. F.M.M. is an employee of Refuge Biotechnologies. J.G. has patents associated with ‘‘in vitro method for the prognosis of progression of a cancer’’ (PCT/IB2006/003168, PCT/EP2013/062405)” and received royalties from INSERM. J.G. is Co-founder and chairman of the scientific advisory board of HalioDx. J.G. has Collaborative Research Agreement grants with Akoya, IObiotech, MedImmune, AstraZeneca, Janssen, and Imcheck Therapeutics. J.G. participated to Scientific Advisory Boards and is consultant for BMS, Novartis, Merck Serono, IObiotech, Nanostring, Illumina, Northwest Biotherapeutics, Actelion, Amgen, Merck MSD, Lunaphore, Catalym, and Sanofi., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Asthma is the most common chronic disease in children. Short-acting bronchodilator medications are the most commonly prescribed asthma treatment worldwide, regardless of disease severity. Puerto Rican children display the highest asthma morbidity and mortality of any US population. Alarmingly, Puerto Rican children with asthma display poor bronchodilator drug response (BDR). Reduced BDR may explain, in part, the increased asthma morbidity and mortality observed in Puerto Rican children with asthma. Gene-environment interactions may explain a portion of the heritability of BDR. We aimed to identify gene-environment interactions associated with BDR in Puerto Rican children with asthma., Setting: Genetic, environmental, and psycho-social data from the Genes-environments and Admixture in Latino Americans (GALA II) case-control study., Participants: Our discovery dataset consisted of 658 Puerto Rican children with asthma; our replication dataset consisted of 514 Mexican American children with asthma., Main Outcome Measures: We assessed the association of pairwise interaction models with BDR using ViSEN (Visualization of Statistical Epistasis Networks)., Results: We identified a non-linear interaction between Native American genetic ancestry and air pollution significantly associated with BDR in Puerto Rican children with asthma. This interaction was robust to adjustment for age and sex but was not significantly associated with BDR in our replication population., Conclusions: Decreased Native American ancestry coupled with increased air pollution exposure was associated with increased BDR in Puerto Rican children with asthma. Our study acknowledges BDR's phenotypic complexity, and emphasizes the importance of integrating social, environmental, and biological data to further our understanding of complex disease., Competing Interests: Competing Interests: None declared., (Copyright © 2021, Ethnicity & Disease, Inc.)

Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2, an emerging virus that utilizes host proteins ACE2 and TMPRSS2 as entry factors. Understanding the factors affecting the pattern and levels of expression of these genes is important for deeper understanding of SARS-CoV-2 tropism and pathogenesis. Here we explore the role of genetics and co-expression networks in regulating these genes in the airway, through the analysis of nasal airway transcriptome data from 695 children. We identify expression quantitative trait loci for both ACE2 and TMPRSS2, that vary in frequency across world populations. We find TMPRSS2 is part of a mucus secretory network, highly upregulated by type 2 (T2) inflammation through the action of interleukin-13, and that the interferon response to respiratory viruses highly upregulates ACE2 expression. IL-13 and virus infection mediated effects on ACE2 expression were also observed at the protein level in the airway epithelium. Finally, we define airway responses to common coronavirus infections in children, finding that these infections generate host responses similar to other viral species, including upregulation of IL6 and ACE2. Our results reveal possible mechanisms influencing SARS-CoV-2 infectivity and COVID-19 clinical outcomes.

The genetic control of gene expression is a core component of human physiology. For the past several years, transcriptome-wide association studies have leveraged large datasets of linked genotype and RNA sequencing information to create a powerful gene-based test of association that has been used in dozens of studies. While numerous discoveries have been made, the populations in the training data are overwhelmingly of European descent, and little is known about the generalizability of these models to other populations. Here, we test for cross-population generalizability of gene expression prediction models using a dataset of African American individuals with RNA-Seq data in whole blood. We find that the default models trained in large datasets such as GTEx and DGN fare poorly in African Americans, with a notable reduction in prediction accuracy when compared to European Americans. We replicate these limitations in cross-population generalizability using the five populations in the GEUVADIS dataset. Via realistic simulations of both populations and gene expression, we show that accurate cross-population generalizability of transcriptome prediction only arises when eQTL architecture is substantially shared across populations. In contrast, models with non-identical eQTLs showed patterns similar to real-world data. Therefore, generating RNA-Seq data in diverse populations is a critical step towards multi-ethnic utility of gene expression prediction., Competing Interests: We have read the journal's policy and one author of this manuscript (Chris Gignoux) has the following competing interests: ownership of stock in 23andMe. The remaining authors have declared that no competing interests exist.

The possibility of voyaging contact between prehistoric Polynesian and Native American populations has long intrigued researchers. Proponents have pointed to the existence of New World crops, such as the sweet potato and bottle gourd, in the Polynesian archaeological record, but nowhere else outside the pre-Columbian Americas 1-6 , while critics have argued that these botanical dispersals need not have been human mediated 7 . The Norwegian explorer Thor Heyerdahl controversially suggested that prehistoric South American populations had an important role in the settlement of east Polynesia and particularly of Easter Island (Rapa Nui) 2 . Several limited molecular genetic studies have reached opposing conclusions, and the possibility continues to be as hotly contested today as it was when first suggested 8-12 . Here we analyse genome-wide variation in individuals from islands across Polynesia for signs of Native American admixture, analysing 807 individuals from 17 island populations and 15 Pacific coast Native American groups. We find conclusive evidence for prehistoric contact of Polynesian individuals with Native American individuals (around AD 1200) contemporaneous with the settlement of remote Oceania 13-15 . Our analyses suggest strongly that a single contact event occurred in eastern Polynesia, before the settlement of Rapa Nui, between Polynesian individuals and a Native American group most closely related to the indigenous inhabitants of present-day Colombia.

Baseline lung function, quantified as forced expiratory volume in the first second of exhalation (FEV 1 ), is a standard diagnostic criterion used by clinicians to identify and classify lung diseases. Using whole-genome sequencing data from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine project, we identified a novel genetic association with FEV 1 on chromosome 12 in 867 African American children with asthma ( P = 1.26 × 10 -8 , β = 0.302). Conditional analysis within 1 Mb of the tag signal (rs73429450) yielded one major and two other weaker independent signals within this peak. We explored statistical and functional evidence for all variants in linkage disequilibrium with the three independent signals and yielded nine variants as the most likely candidates responsible for the association with FEV 1 Hi-C data and expression QTL analysis demonstrated that these variants physically interacted with KITLG (KIT ligand, also known as SCF ), and their minor alleles were associated with increased expression of the KITLG gene in nasal epithelial cells. Gene-by-air-pollution interaction analysis found that the candidate variant rs58475486 interacted with past-year ambient sulfur dioxide exposure ( P = 0.003, β = 0.32). This study identified a novel protective genetic association with FEV 1 , possibly mediated through KITLG , in African American children with asthma. This is the first study that has identified a genetic association between lung function and KITLG , which has established a role in orchestrating allergic inflammation in asthma., (Copyright © 2020 by the Genetics Society of America.)

Background: More than 180 single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility have been identified; these SNPs can be combined into polygenic risk scores (PRS) to predict breast cancer risk. Because most SNPs were identified in predominantly European populations, little is known about the performance of PRS in non-Europeans. We tested the performance of a 180-SNP PRS in Latinas, a large ethnic group with variable levels of Indigenous American, European, and African ancestry., Methods: We conducted a pooled case-control analysis of US Latinas and Latin American women (4658 cases and 7622 controls). We constructed a 180-SNP PRS consisting of SNPs associated with breast cancer risk (P < 5 × 10-8). We evaluated the association between the PRS and breast cancer risk using multivariable logistic regression, and assessed discrimination using an area under the receiver operating characteristic curve. We also assessed PRS performance across quartiles of Indigenous American genetic ancestry. All statistical tests were two-sided., Results: Of 180 SNPs tested, 142 showed directionally consistent associations compared with European populations, and 39 were nominally statistically significant (P < .05). The PRS was associated with breast cancer risk, with an odds ratio per SD increment of 1.58 (95% confidence interval [CI = 1.52 to 1.64) and an area under the receiver operating characteristic curve of 0.63 (95% CI = 0.62 to 0.64). The discrimination of the PRS was similar between the top and bottom quartiles of Indigenous American ancestry., Conclusions: The 180-SNP PRS predicts breast cancer risk in Latinas, with similar performance as reported for Europeans. The performance of the PRS did not vary substantially according to Indigenous American ancestry., (© The Author(s) 2019. Published by Oxford University Press.)

Women of Latin American origin in the United States are more likely to be diagnosed with advanced breast cancer and have a higher risk of mortality than non-Hispanic White women. Studies in U.S. Latinas and Latin American women have reported a high incidence of HER2 positive (+) tumors; however, the factors contributing to this observation are unknown. Genome-wide genotype data for 1,312 patients from the Peruvian Genetics and Genomics of Breast Cancer Study (PEGEN-BC) were used to estimate genetic ancestry. We tested the association between HER2 status and genetic ancestry using logistic and multinomial logistic regression models. Findings were replicated in 616 samples from Mexico and Colombia. Average Indigenous American (IA) ancestry differed by subtype. In multivariate models, the odds of having an HER2 + tumor increased by a factor of 1.20 with every 10% increase in IA ancestry proportion (95% CI, 1.07-1.35; P = 0.001). The association between HER2 status and IA ancestry was independently replicated in samples from Mexico and Colombia. Results suggest that the high prevalence of HER2 + tumors in Latinas could be due in part to the presence of population-specific genetic variant(s) affecting HER2 expression in breast cancer. SIGNIFICANCE: The positive association between Indigenous American genetic ancestry and HER2 + breast cancer suggests that the high incidence of HER2 + subtypes in Latinas might be due to population and subtype-specific genetic risk variants., (©2020 American Association for Cancer Research.)

Background: Current South American populations trace their origins mainly to three continental ancestries, i.e. European, Amerindian and African. Individual variation in relative proportions of each of these ancestries may be confounded with socio-economic factors due to population stratification. Therefore, ancestry is a potential confounder variable that should be considered in epidemiologic studies and in public health plans. However, there are few studies that have assessed the ancestry of the current admixed Chilean population. This is partly due to the high cost of genome-scale technologies commonly used to estimate ancestry. In this study we have designed a small panel of SNPs to accurately assess ancestry in the largest sampling to date of the Chilean mestizo population (n = 3349) from eight cities. Our panel is also able to distinguish between the two main Amerindian components of Chileans: Aymara from the north and Mapuche from the south., Results: A panel of 150 ancestry-informative markers (AIMs) of SNP type was selected to maximize ancestry informativeness and genome coverage. Of these, 147 were successfully genotyped by KASPar assays in 2843 samples, with an average missing rate of 0.012, and a 0.95 concordance with microarray data. The ancestries estimated with the panel of AIMs had relative high correlations (0.88 for European, 0.91 for Amerindian, 0.70 for Aymara, and 0.68 for Mapuche components) with those obtained with AXIOM LAT1 array. The country's average ancestry was 0.53 ± 0.14 European, 0.04 ± 0.04 African, and 0.42 ± 0.14 Amerindian, disaggregated into 0.18 ± 0.15 Aymara and 0.25 ± 0.13 Mapuche. However, Mapuche ancestry was highest in the south (40.03%) and Aymara in the north (35.61%) as expected from the historical location of these ethnic groups. We make our results available through an online app and demonstrate how it can be used to adjust for ancestry when testing association between incidence of a disease and nongenetic risk factors., Conclusions: We have conducted the most extensive sampling, across many different cities, of current Chilean population. Ancestry varied significantly by latitude and human development. The panel of AIMs is available to the community for estimating ancestry at low cost in Chileans and other populations with similar ancestry.

Native American genetic variation remains underrepresented in most catalogs of human genome sequencing data. Previous genotyping efforts have revealed that Mexico's Indigenous population is highly differentiated and substructured, thus potentially harboring higher proportions of private genetic variants of functional and biomedical relevance. Here we have targeted the coding fraction of the genome and characterized its full site frequency spectrum by sequencing 76 exomes from five Indigenous populations across Mexico. Using diffusion approximations, we modeled the demographic history of Indigenous populations from Mexico with northern and southern ethnic groups splitting 7.2 KYA and subsequently diverging locally 6.5 and 5.7 KYA, respectively. Selection scans for positive selection revealed BCL2L13 and KBTBD8 genes as potential candidates for adaptive evolution in Rarámuris and Triquis, respectively. BCL2L13 is highly expressed in skeletal muscle and could be related to physical endurance, a well-known phenotype of the northern Mexico Rarámuri. The KBTBD8 gene has been associated with idiopathic short stature and we found it to be highly differentiated in Triqui, a southern Indigenous group from Oaxaca whose height is extremely low compared to other Native populations., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)