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Rationale: Birth cohort studies have identified several temporal patterns of wheezing, only some of which are associated with asthma. Whether 17q12-21 genetic variants, which are closely associated...

Background: African ancestry is associated with a higher prevalence and greater severity of asthma than European ancestries, yet genetic studies of the most common locus associated with childhood-onset asthma, 17q12–21, in African Americans have been inconclusive. The aim of this study was to leverage both the phenotyping of the Children's Respiratory and Environmental Workgroup (CREW) birth cohort consortium, and the reduced linkage disequilibrium in African Americans, to fine map the 17q12–21 locus. Methods: We first did a genetic association study and meta-analysis using 17q12–21 tag single-nucleotide polymorphisms (SNPs) for childhood-onset asthma in 1613 European American and 870 African American children from the CREW consortium. Nine tag SNPs were selected based on linkage disequilibrium patterns at 17q12–21 and their association with asthma, considering the effect allele under an additive model (0, 1, or 2 effect alleles). Results were meta-analysed with publicly available summary data from the EVE consortium (on 4303 European American and 3034 African American individuals) for seven of the nine SNPs of interest. Subsequently, we tested for expression quantitative trait loci (eQTLs) among the SNPs associated with childhood-onset asthma and the expression of 17q12–21 genes in resting peripheral blood mononuclear cells (PBMCs) from 85 African American CREW children and in upper airway epithelial cells from 246 African American CREW children; and in lower airway epithelial cells from 44 European American and 72 African American adults from a case-control study of asthma genetic risk in Chicago (IL, USA). Findings: 17q12–21 SNPs were broadly associated with asthma in European Americans. Only two SNPs (rs2305480 in gasdermin-B [GSDMB] and rs8076131 in ORMDL sphingolipid biosynthesis regulator 3 [ORMDL3]) were associated with asthma in African Americans, at a Bonferroni-corrected threshold of p

Background Unexplained heterogeneity in clinical trials has resulted in questions regarding the effectiveness of ɣ-linolenic acid (GLA)-containing botanical oil supplements. This heterogeneity may be explained by genetic variation within the fatty acid desaturase (FADS) gene cluster that is associated with circulating and tissue concentrations of arachidonic acid (ARA) and dihomo-ɣ-linolenic acid (DGLA), both of which may be synthesized from GLA and result in proinflammatory and anti-inflammatory metabolites, respectively. Objectives The objective of this study was to prospectively compare the capacity of a non-Hispanic white cohort, stratified by FADS genotype at the key single-nucleotide polymorphism (SNP) rs174537, to metabolize 18-carbon omega-6 (n-6) PUFAs in borage oil (BO) and soybean oil (SO) to GLA, DGLA, and ARA. Methods Healthy adults (n = 64) participated in a randomized, double-blind, crossover intervention. Individuals received encapsulated BO (Borago officinalis L.; 37% LA and 23% GLA) or SO [Glycine max (L.) Merr.; 50% LA and 0% GLA] for 4 wk, followed by an 8-wk washout period, before consuming the opposite oil for 4 wk. Serum lipids and markers of inflammation (C-reactive protein) were assessed for both oil types at baseline and during weeks 2 and 4 of the intervention. Results SO supplementation failed to alter circulating concentrations of any n-6 long-chain PUFAs. In contrast, a modest daily dose of BO elevated serum concentrations of GLA and DGLA in an rs174537 genotype-dependent manner. In particular, DGLA increased by 57% (95% CI: 0.38, 0.79) in GG genotype individuals, but by 141% (95% CI: 1.03, 2.85) in TT individuals. For ARA, baseline concentrations varied substantially by genotype and increased modestly with BO supplementation, suggesting a key role for FADS variation in the balance of DGLA and ARA. Conclusions The results of this study clearly suggest that personalized and population-based approaches considering FADS genetic variation may be necessary to optimize the design of future clinical studies with GLA-containing oils. This trial was registered at clinicaltrials.gov as NCT02337231.

There is an urgent need to identify the cellular and molecular mechanisms responsible for severe COVID-19 that results in death. We initially performed both untargeted and targeted lipidomics as well as focused biochemical analyses of 127 plasma samples and found elevated metabolites associated with secreted phospholipase A(2) (sPLA(2)) activity and mitochondrial dysfunction in patients with severe COVID-19. Deceased COVID-19 patients had higher levels of circulating, catalytically active sPLA(2) group IIA (sPLA(2)-IIA), with a median value that was 9.6-fold higher than that for patients with mild disease and 5.0-fold higher than the median value for survivors of severe COVID-19. Elevated sPLA(2)-IIA levels paralleled several indices of COVID-19 disease severity (e.g., kidney dysfunction, hypoxia, multiple organ dysfunction). A decision tree generated by machine learning identified sPLA(2)-IIA levels as a central node in the stratification of patients who died from COVID-19. Random forest analysis and least absolute shrinkage and selection operator–based (LASSO-based) regression analysis additionally identified sPLA(2)-IIA and blood urea nitrogen (BUN) as the key variables among 80 clinical indices in predicting COVID-19 mortality. The combined PLA-BUN index performed significantly better than did either one alone. An independent cohort (n = 154) confirmed higher plasma sPLA(2)-IIA levels in deceased patients compared with levels in plasma from patients with severe or mild COVID-19, with the PLA-BUN index–based decision tree satisfactorily stratifying patients with mild, severe, or fatal COVID-19. With clinically tested inhibitors available, this study identifies sPLA(2)-IIA as a therapeutic target to reduce COVID-19 mortality.

Rationale: While small airways dysfunction (SAD) is a feature of asthma, the association of SAD with relevant asthma outcomes is not entirely clear. The ATLANTIS study was designed to identify which physiologic and imaging variables best measures the presence and extent of SAD in asthma and its association with exacerbations, asthma control and quality of life. Methods: 773 participants with mild, moderate and severe stable asthma were followed for one year with a six-month follow up. Physiologic tests included: spirometry, lung volumes, impulse oscillometry (IOS), multiple breath nitrogen washout (MBNW) and % fall in forced vital capacity during methacholine challenge. CT was performed to determine lung density ratio and lung volumes. We examined associations between these measurements and asthma control, exacerbations and quality of life using univariate and multivariate analyses. Results: IOS, lung volumes, MBNW and FEF25-75 significantly correlated with exacerbations and asthma control by univariate analysis (Spearman correlations: 0.20-0.25, p Conclusion: SAD measured by IOS is associated longitudinally with important asthma outcomes such as asthma control and exacerbations.

Omega-3 (n-3) polyunsaturated fatty acids (PUFA) and their metabolites have long been recognized to protect against inflammation-related diseases including heart disease. Recent reports present conflicting evidence on the effects of n-3 PUFAs on major cardiovascular events including death. While some studies document that n-3 PUFA supplementation reduces the risk for heart disease, others report no beneficial effects on heart disease composite primary outcomes. Much of this heterogeneity may be related to the genetic variation in different individuals/populations that alters their capacity to synthesize biologically active n-3 and omega 6 (n-6) PUFAs and metabolites from their 18 carbon dietary precursors, linoleic acid (LA, 18:2 n-6) and alpha-linolenic (ALA, 18:3, n-3). Here, we discuss the role of a FADS gene-by-dietary PUFA interaction model that takes into consideration dietary exposure, including the intake of LA and ALA, n-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in determining the efficacy of n-3 PUFA supplementation. We also review recent clinical trials with n-3 PUFA supplementation and coronary heart disease in the context of what is known about fatty acid desaturase (FADS) gene-by-dietary PUFA interactions. Given the dramatic differences in the frequencies of FADS variants that impact the efficiency of n-3 and n-6 PUFA biosynthesis, and their downstream signaling products among global and admixture populations, we conclude that large clinical trials utilizing “one size fits all” n-3 PUFA supplementation approaches are unlikely to show effectiveness. However, evidence discussed in this review suggests that n-3 PUFA supplementation may represent an important opportunity where precision interventions can be focused on those populations that will benefit the most from n-3 PUFA supplementation.

There is an urgent need to identify cellular and molecular mechanisms responsible for severe COVID-19 disease accompanied by multiple organ failure and high mortality rates. Here, we performed untargeted/targeted lipidomics and focused biochemistry on 127 patient plasma samples, and showed high levels of circulating, enzymatically active secreted phospholipase A2 Group IIA (sPLA2-IIA) in severe and fatal COVID-19 disease compared with uninfected patients or mild illness. Machine learning demonstrated that sPLA2-IIA effectively stratifies severe from fatal COVID-19 disease. We further introduce a PLA-BUN index that combines sPLA2-IIA and blood urea nitrogen (BUN) threshold levels as a critical risk factor for mitochondrial dysfunction, sustained inflammatory injury and lethal COVID-19. With the availability of clinically tested inhibitors of sPLA2-IIA, our study opens the door to a precision intervention using indices discovered here to reduce COVID-19 mortality.

Rationale: Although small airway disease (SAD) is a feature of asthma, the association between SAD and relevant asthma outcomes remains unclear. The Assessment of Small Airways Involvement in Asthma (ATLANTIS) study was designed to identify the combination of physiological and imaging variables that best measure the presence and extent of SAD in asthma cross-sectionally and longitudinally. In this longitudinal analysis, we determined which small airway parameters studied were most strongly associated with asthma control, exacerbations, and quality of life. Methods: Total 773 participants with mild, moderate, or severe stable asthma were followed up for one year with a six-month clinic follow-up. Physiological tests included spirometry, lung volumes, impulse oscillometry (IOS), multiple breath nitrogen washout (MBNW), and percentage fall in forced vital capacity during methacholine challenge. Computed tomography was performed to determine CT densitometry of small airways disease. We examined the associations between these measurements and asthma exacerbations, control, and quality of life using univariate and multivariate analyses. Findings: Univariate analyses revealed that components of IOS, lung volumes, MBNW, and FEF25-75 were significantly correlated with asthma control and exacerbations (Spearman correlations: 0·20–0·25, p < 0·0001 Bonferroni correction). As a composite of IOS s, the ordinal score independently predicted asthma control and exacerbation in a multivariate analysis with known exacerbation predictors. CT parameters were not significantly correlated with asthma control, exacerbation, or quality of life. Interpretation: The results confirm that SAD, as measured by physiological tests, is longitudinally associated with clinically important asthma outcomes, such as asthma control and exacerbations. Funding: Chiesi Farmaceutici Declaration of Interest: MK reports grants paid to their institution for their research from National Institutes of Health, American Lung Association, Chiesi Farmaceutici (for support of this study), AstraZeneca and Sanofi-Regeneron; reports personal fees for consultancies from Chiesi Farmaceutici, Genentech (Roche), GSK, Sanofi Regeneron, and Astra-Zeneca, Speaker fees from Chiesi Farmaceutici; personal fees from participation in a data safety and monitoring board for Astra-Zeneca and ALung and leadership in the American Thoracic Society; MR has nothing to report; BH has nothing to report; DB has nothing to report; MVB receives grants paid to their institution from Chiesi Farmaceutici (for this study), Sanofi, Genentech, GSK and Roche; LMF reported personal fees for consultancies from Chiesi Farmaceutici; Speaker fees from participation in advisory boards for Chiesi Farmaceutici, Astra-Zeneca, GSK, Alfasigma, Novartis and Verona Pharma; Travel expense reimbursement from Chiesi Farmaceutici, Novartis and Menarini; personal fees from participation in a data safety and monitoring board for Novartis; GN reports being employed by Chiesi Farmaceutici; AP reports funding by Chiesi Farmaceutici (for this and other studies), AstraZeneca, GSK, Boehringer Ingelheim, Pfizer, Teva and Sanofi paid to their institution; reports personal fees for consulting from Chiesi Farmaceutici, AstraZeneca, GSK, Novartis, Sanofi, Iqvia, Avillion, Elpen Pharmaceutic, ALS; reports personal fees for lectures and presentations from Chiesi Farmaceutici, AstraZeneca, GSK, Boehringer Ingelheim, Menarini, Novartis, Zambon, Mundipharma, Teva, Sanofi, Edmond Pharma, Iqvia, MSD, Avillion, Elpen Pharmaceutic, ALS. KFR reported support from Chiesi Farmaceutici paid to their institution for this study; reports speaker fees from Astra-Zeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Novartis, Sanofi & Regeneron, GlaxoSmithKline, Berlin Chemie and Roche Pharma; personal fees from participation in a data safety and monitoring board for Astra- Zeneca, Boehringer Ingelheim and Sanofi & Regeneron; reports leadership or fiduciary role for German Center for Lung Research, German Chest Society and American Thoracic Society; DS reports personal fees for consulting from Aerogen, Astra-Zeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Cipla, CSL Behring, Epiendo, Genentech, GlaxoSmithKline, Glenmark, Gossamerbio, Kinaset, Menarini, Novartis, Pulmatrix, Sanofi, Teva, Theravance, Verona; CB reports paid to their institution from Chiesi Farmaceutici for this study, NIHR Biomedical Research Centre, grants paid to their institution GSK, AZ, BI, Novartis, Chiesi Farmaceutici, Sanofi, Genetech, Merck, Mologic, 4DPharma, Gossamer, personal fees for consulting from GSK, AZ, BI, Novartis, Chiesi Farmaceutici, Sanofi, Genentech, Merck, Mologic, 4DPharma, Gossamer, TEVA, Regeneron, Roche, CSL Behring; SS reports funding paid to their institution from Chiesi Farmaceutici for support of this study, personal fees from GSK, Novartis, ERT Medical, Astra Zeneca, Knopp Biotech, Owlstone Medical, Mundipharma, CSL Behring, Boehringer Ingelheim; reports personal fees for lectures from Chiesi Farmaceutici. Ethical Approval: The Medical Ethics Committee of each centre approved the protocol.

Hispanic populations in the US have increased risk of obesity, elevated circulating triglycerides, nonalcoholic fatty liver disease, and diabetes. Our previous studies suggest that ancestry-related differences in the frequency of variants in the fatty acid desaturase ( FADS) gene cluster in the context of the modern Western diet can lead to inadequate circulating and tissues levels of n-3 long-chain (LC-; ≥ 20 carbons) polyunsaturated fatty acids (PUFA); these deficiencies in turn have the capacity to increase metabolic disease risk. Specifically, we and others have demonstrated Amerindian (AI)-Ancestry populations have high frequencies of FADS gene variants that may lead to less efficient n-3 LC-PUFA biosynthesis. To test this hypothesis, concentrations of fatty acids, including LC-PUFAs in plasma phospholipids were analyzed in 1,102 Hispanic American participants from Multi-Ethnic Study of Atherosclerosis (MESA) cohort, which represent six Hispanic subgroups based on self-reported region of origin: Central America, South America, Mexico, Cuba, Dominican Republic, and Puerto Rico. These data revealed a striking inverse relationship between genome-wide AI-ancestry and levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Additional analyses revealed that the genotype at FADS SNP rs174537, for which the frequency of the T allele increases with AI-ancestry, could primarily explain the associations. There also was a strong association between the number of T alleles (additive model) at rs174537 and circulating triglycerides (18.5 mg/dL per T allele; P =2.0 x 10 -5 ) as well as an important marker of vascular inflammation sICAM-1 (β=12.7 ng/mL, P =0.02). We also genotyped the FADS SNP, rs174537, in a separate adult Arizona Hispanic cohort (Arizona Insulin Resistance [AIR] registry) and compared the FADS genotypic frequencies with other racial/ethnic groups. Importantly, the TT genotype associated with limited LC-PUFA biosynthesis ranges from FADS gene*dietary PUFA interactions give rise to n-3 LC-PUFA deficiencies and may enhance metabolic and inflammatory diseases in a large proportion of individuals in AI-Ancestry Hispanic populations.

Prostate cancer (PCa) is the most common male cancer and the second leading cause of cancer death in United States men. Controversy continues over the effectiveness of prostate-specific antigen (PSA) for distinguishing aggressive from indolent PCa. There is a critical need for more specific and sensitive biomarkers to detect and distinguish low- versus high-risk PCa cases. Discovery metabolomics were performed utilizing ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) on plasma samples from 159 men with treatment na&iuml, ve prostate cancer participating in the North Carolina-Louisiana PCa Project to determine if there were metabolites associated with aggressive PCa. Thirty-five identifiable plasma small molecules were associated with PCa aggressiveness, 15 of which were sphingolipids, nine common molecules were present in both African-American and European-American men. The molecules most associated with PCa aggressiveness were glycosphingolipids, levels of trihexosylceramide and tetrahexosylceramide were most closely associated with high-aggressive PCa. The Cancer Genome Atlas was queried to determine gene alterations within glycosphingolipid metabolism that are associated with PCa and other cancers. Genes that encode enzymes associated with the metabolism of glycosphingolipids were altered in 12% of PCa and &gt, 30% of lung, uterine, and ovarian cancers. These data suggest that the identified plasma (glyco)sphingolipids should be further validated for their association with aggressive PCa, suggesting that specific sphingolipids may be included in a diagnostic signature for PCa.

The Austronesian expansion into Island Southeast Asia and the Pacific was the last and most far-reaching prehistoric human migration. Austronesian languages replaced indigenous languages over nearly half the globe, yet the absolute number of Austronesian colonists was small. Recently, geneticists have identified large geographic disparities in the relative proportions of Asian ancestry across different genetic systems (NRY, mitochondrial DNA, autosomes and X chromosomes) in Austronesian-speaking societies of Island Southeast Asia and the Pacific. Surprisingly, a substantial genetic discontinuity occurs in the middle of a continuous chain of islands that form the southern arc of the Indonesian archipelago, near the geographic center of the Austronesian world. In the absence of geographic barriers to migration, this genetic boundary and swathe of Austronesian language replacement must have emerged from social behavior. Drawing on decades of comparative ethnological research inspired by F.A.E. van Wouden's structural model of Austronesian social organization, later codified by Claude Levi-Strauss as "House societies" ("societes a maison"), we propose a two-stage ethnographic model in which the appearance of matrilocal "House societies" during the initial phase of the Austronesian expansion, and the subsequent disappearance of "House societies" in lowland rice-growing regions, accounts for the observed linguistic, genetic and cultural patterns.