Temporal associations of plasma levels of the secreted phospholipase A2 family and mortality in severe COVID-19.

Previous research suggests that group IIA-secreted phospholipase A2 (sPLA2-IIA) plays a role in and predicts lethal COVID-19 disease. The current study reanalyzed a longitudinal proteomic data set to determine the temporal relationship between levels of several members of a family of sPLA2 isoforms and the severity of COVID-19 in 214 ICU patients. The levels of six secreted PLA2 isoforms, sPLA2-IIA, sPLA2-V, sPLA2-X, sPLA2-IB, sPLA2-IIC, and sPLA2-XVI, increased over the first 7 ICU days in those who succumbed to the disease but attenuated over the same time period in survivors. In contrast, a reversed pattern in sPLA2-IID and sPLA2-XIIB levels over 7 days suggests a protective role of these two isoforms. Furthermore, decision tree models demonstrated that sPLA2-IIA outperformed top-ranked cytokines and chemokines as a predictor of patient outcome. Taken together, proteomic analysis revealed temporal sPLA2 patterns that reflect the critical roles of sPLA2 isoforms in severe COVID-19 disease.

Genome-wide association studies and fine-mapping identify genomic loci for n-3 and n-6 polyunsaturated fatty acids in Hispanic American and African American cohorts.

Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) play critical roles in human health. Prior genome-wide association studies (GWAS) of n-3 and n-6 PUFAs in European Americans from the CHARGE Consortium have documented strong genetic signals in/near the FADS locus on chromosome 11. We performed a GWAS of four n-3 and four n-6 PUFAs in Hispanic American (n = 1454) and African American (n = 2278) participants from three CHARGE cohorts. Applying a genome-wide significance threshold of P < 5 × 10-8, we confirmed association of the FADS signal and found evidence of two additional signals (in DAGLA and BEST1) within 200 kb of the originally reported FADS signal. Outside of the FADS region, we identified novel signals for arachidonic acid (AA) in Hispanic Americans located in/near genes including TMX2, SLC29A2, ANKRD13D and POLD4, and spanning a > 9 Mb region on chromosome 11 (57.5 Mb ~ 67.1 Mb). Among these novel signals, we found associations unique to Hispanic Americans, including rs28364240, a POLD4 missense variant for AA that is common in CHARGE Hispanic Americans but absent in other race/ancestry groups. Our study sheds light on the genetics of PUFAs and the value of investigating complex trait genetics across diverse ancestry populations.

Genome-Wide Association Studies and fine-mapping of genomic loci for n-3 and n-6 Polyunsaturated Fatty Acids in Hispanic American and African American Cohorts.

Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) play critical roles in human health. Prior genome-wide association studies (GWAS) of n-3 and n-6 PUFAs in European Americans from the CHARGE Consortium have documented strong genetic signals in/near the FADS locus on chromosome 11. We performed a GWAS of four n-3 and four n-6 PUFAs in Hispanic American (n = 1454) and African American (n = 2278) participants from three CHARGE cohorts. Applying a genome-wide significance threshold of P < 5 x 10 - 8 , we confirmed association of the FADS signal and found evidence of two additional signals (in DAGLA and BEST1 ) within 200 kb of the originally reported FADS signal. Outside of the FADS region, we identified novel signals for arachidonic acid (AA) in Hispanic Americans located in/near genes including TMX2 , SLC29A2 , ANKRD13D and POLD4, and spanning a > 9 Mb region on chromosome 11 (57.5Mb ~ 67.1Mb). Among these novel signals, we found associations unique to Hispanic Americans, including rs28364240, a POLD4 missense variant for AA that is common in CHARGE Hispanic Americans but absent in other race/ancestry groups. Our study sheds light on the genetics of PUFAs and the value of investigating complex trait genetics across diverse ancestry populations.

Association between Dietary Fatty Acid Intake and Liver Steatosis and Fibrosis in a Sample of Mexican-Origin Hispanic Adults with Overweight or Obesity.

Rates of non-alcoholic fatty liver disease (NAFLD) vary dramatically among Hispanic subpopulations, with Mexican-origin (MO) Hispanics experiencing a disproportionate burden. This study examined dietary fatty acid (FA) intake among overweight and obese MO Hispanic adults in the United States (US) and evaluated its association with liver steatosis and fibrosis. Participants (N = 285, MO Hispanic adults) completed 24-h dietary recalls to assess dietary FA exposure. Liver steatosis and fibrosis were estimated using transient elastography (FibroScan®). Multiple regression analysis tested relationships between FA intakes and liver steatosis or fibrosis, adjusting for age, sex, body mass index (BMI) and total energy. A total of 51% (n = 145) of participants were suspected to have NAFLD and 20% self-reported a type 2 diabetes diagnosis. No significant association was observed between Linoleic Acid and α-Linolenic Acid (LA:ALA) ratio, or omega-6 to omega-3 (n-6:n-3) ratio and liver steatosis. However, a one-point increase in the LA:ALA ratio resulted in a 1.01% increase in the liver fibrosis scores (95% CI: [1.00, 1.03]; p = 0.03), and a one-point increase in the n-6:n-3 ratio resulted in a 1.02% increase in liver fibrosis score (95% CI: [1.01, 1.03]; p = 0.01). Further research is needed to determine if modulation of FA intake could reduce NAFLD risk in this high-risk population.

Identification of an allele-specific transcription factor binding interaction that regulates PLA2G2A gene expression.

The secreted phospholipase A 2 (sPLA 2 ) isoform, sPLA 2 -IIA, has been implicated in a variety of diseases and conditions, including bacteremia, cardiovascular disease, COVID-19, sepsis, adult respiratory distress syndrome, and certain cancers. Given its significant role in these conditions, understanding the regulatory mechanisms impacting its levels is crucial. Genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs), including rs11573156, that are associated with circulating levels of sPLA 2 -IIA. Through Genotype-Tissue Expression (GTEx), 234 expression quantitative trait loci (eQTLs) were identified for the gene that encodes for sPLA 2 -IIA, PLA2G2A . SNP2TFBS ( https://ccg.epfl.ch/snp2tfbs/ ) was utilized to ascertain the binding affinities between transcription factors (TFs) to both the reference and alternative alleles of identified SNPs. Subsequently, ChIP-seq peaks highlighted the TF combinations that specifically bind to the SNP, rs11573156. SP1 emerged as a significant TF/SNP pair in liver cells, with rs11573156/SP1 interaction being most prominent in liver, prostate, ovary, and adipose tissues. Further analysis revealed that the upregulation of PLA2G2A transcript levels through the rs11573156 variant was affected by tissue SP1 protein levels. By leveraging an ordinary differential equation, structured upon Michaelis-Menten enzyme kinetics assumptions, we modeled the PLA2G2A transcription's dependence on SP1 protein levels, incorporating the SNP's influence. Collectively, these data strongly suggest that the binding affinity differences of SP1 for the different rs11573156 alleles can influence PLA2G2A expression. This, in turn, can modulate sPLA2-IIA levels, impacting a wide range of human diseases.

Temporal Associations of Plasma Levels of the Secreted Phospholipase A 2 Family and Mortality in Severe COVID-19.

Previous research suggests that group IIA secreted phospholipase A 2 (sPLA 2 -IIA) plays a role in and predicts severe COVID-19 disease. The current study reanalyzed a longitudinal proteomic data set to determine the temporal (days 0, 3 and 7) relationship between the levels of several members of a family of sPLA 2 isoforms and the severity of COVID-19 in 214 ICU patients. The levels of six secreted PLA 2 isoforms, sPLA 2 -IIA, sPLA 2 -V, sPLA 2 -X, sPLA 2 -IB, sPLA 2 -IIC, and sPLA 2 -XVI, increased over the first 7 ICU days in those who succumbed to the disease. sPLA 2 -IIA outperformed top ranked cytokines and chemokines as predictors of patient outcome. A decision tree corroborated these results with day 0 to day 3 kinetic changes of sPLA 2 -IIA that separated the death and severe categories from the mild category and increases from day 3 to day 7 significantly enriched the lethal category. In contrast, there was a time-dependent decrease in sPLA 2 -IID and sPLA 2 -XIIB in patients with severe or lethal disease, and these two isoforms were at higher levels in mild patients. Taken together, proteomic analysis revealed temporal sPLA 2 patterns that reflect the critical roles of sPLA 2 isoforms in severe COVID-19 disease.

The role of small airway dysfunction in asthma control and exacerbations: a longitudinal, observational analysis using data from the ATLANTIS study.

BACKGROUND: Although small airway disease is a feature of asthma, its association with relevant asthma outcomes remains unclear. The ATLANTIS study was designed to identify the combination of physiological and imaging variables that best measure the presence and extent of small airway disease in asthma, both cross-sectionally and longitudinally. In this longitudinal analysis, we evaluated which small airway parameters studied were most strongly associated with asthma control, exacerbations, and quality of life. METHODS: In this observational cohort study, participants with mild, moderate, or severe stable asthma were recruited between June 30, 2014, and March 3, 2017, via medical databases and advertisements in nine countries worldwide. Eligible participants were aged 18-65 years with a clinical asthma diagnosis for at least 6 months. Participants were followed up for 1 year, with visits at baseline, 6 months, and 12 months. Physiological tests included spirometry, lung volumes, impulse oscillometry, multiple breath nitrogen washout (MBNW), and percentage decrease in forced vital capacity during methacholine challenge. CT densitometry was performed to evaluate small airway disease. We examined the associations between these measurements and asthma exacerbations, asthma control, and quality of life using univariate and multivariate analyses. A composite ordinal score comprising percent predicted R5-20 (resistance of small-to-mid-sized airways), AX (area of reactance), and X5 (reactance of more central, conducting small airways at 5 Hz) was constructed. FINDINGS: 773 participants (median age 46 years [IQR 34-54]; 450 [58%] female) were included in this longitudinal study. Univariate analyses showed that components of impulse oscillometry, lung volumes, MBNW, and forced expiratory flow at 25-75% of FVC were significantly correlated with asthma control and exacerbations (Spearman correlations 0·20-0·25, p<0·0001 after Bonferroni correction). As a composite of impulse oscillometry, the ordinal score independently predicted asthma control and exacerbations in a multivariate analysis with known exacerbation predictors. CT parameters were not significantly correlated with asthma control, exacerbation, or quality of life. INTERPRETATION: Small airway disease, as measured by physiological tests, is longitudinally associated with clinically important asthma outcomes, such as asthma control and exacerbations. FUNDING: Chiesi Farmaceutici.

Group IIA secreted phospholipase A2 is associated with the pathobiology leading to COVID-19 mortality.

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 A2 (sPLA2) activity and mitochondrial dysfunction in patients with severe COVID-19. Deceased COVID-19 patients had higher levels of circulating, catalytically active sPLA2 group IIA (sPLA2-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 sPLA2-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 sPLA2-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 sPLA2-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 sPLA2-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 sPLA2-IIA as a therapeutic target to reduce COVID-19 mortality.

Omega-3 Supplementation and Heart Disease: A Population-Based Diet by Gene Analysis of Clinical Trial Outcomes.

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.

Impact of Amerind ancestry and FADS genetic variation on omega-3 deficiency and cardiometabolic traits in Hispanic populations.

Long chain polyunsaturated fatty acids (LC-PUFAs) have critical signaling roles that regulate dyslipidemia and inflammation. Genetic variation in the FADS gene cluster accounts for a large portion of interindividual differences in circulating and tissue levels of LC-PUFAs, with the genotypes most strongly predictive of low LC-PUFA levels at strikingly higher frequencies in Amerind ancestry populations. In this study, we examined relationships between genetic ancestry and FADS variation in 1102 Hispanic American participants from the Multi-Ethnic Study of Atherosclerosis. We demonstrate strong negative associations between Amerind genetic ancestry and LC-PUFA levels. The FADS rs174537 single nucleotide polymorphism (SNP) accounted for much of the AI ancestry effect on LC-PUFAs, especially for low levels of n-3 LC-PUFAs. Rs174537 was also strongly associated with several metabolic, inflammatory and anthropomorphic traits including circulating triglycerides (TGs) and E-selectin in MESA Hispanics. Our study demonstrates that Amerind ancestry provides a useful and readily available tool to identify individuals most likely to have FADS-related n-3 LC-PUFA deficiencies and associated cardiovascular risk.

Group IIA Secreted Phospholipase A 2 Plays a Central Role in the Pathobiology of COVID-19.

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 A 2 Group IIA (sPLA 2 -IIA) in severe and fatal COVID-19 disease compared with uninfected patients or mild illness. Machine learning demonstrated that sPLA 2 -IIA effectively stratifies severe from fatal COVID-19 disease. We further introduce a PLA-BUN index that combines sPLA 2 -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 sPLA 2 -IIA, our study opens the door to a precision intervention using indices discovered here to reduce COVID-19 mortality.

Chromosome 17q12-21 Variants Are Associated with Multiple Wheezing Phenotypes in Childhood.

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 with asthma, are also associated with childhood wheezing phenotypes remains poorly explored.Objectives: To determine whether wheezing phenotypes, defined by latent class analysis (LCA), are associated with nine 17q12-21 SNPs and if so, whether these relationships differ by race/ancestry.Methods: Data from seven U.S. birth cohorts (n = 3,786) from the CREW (Children's Respiratory Research and Environment Workgroup) were harmonized to represent whether subjects wheezed in each year of life from birth until age 11 years. LCA was then performed to identify wheeze phenotypes. Genetic associations between SNPs and wheeze phenotypes were assessed separately in European American (EA) (n = 1,308) and, for the first time, in African American (AA) (n = 620) children.Measurements and Main Results: The LCA best supported four latent classes of wheeze: infrequent, transient, late-onset, and persistent. Odds of belonging to any of the three wheezing classes (vs. infrequent) increased with the risk alleles for multiple SNPs in EA children. Only one SNP, rs2305480, showed increased odds of belonging to any wheezing class in both AA and EA children.Conclusions: These results indicate that 17q12-21 is a "wheezing locus," and this association may reflect an early life susceptibility to respiratory viruses common to all wheezing children. Which children will have their symptoms remit or reoccur during childhood may be independent of the influence of rs2305480.

Interpreting Clinical Trials With Omega-3 Supplements in the Context of Ancestry and FADS Genetic Variation.

Human diets in developed countries such as the US have changed dramatically over the past 75 years, leading to increased obesity, inflammation, and cardiometabolic dysfunction. Evidence over the past decade indicates that the interaction of genetic variation with changes in the intake of 18-carbon essential dietary omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA), linoleic acid (LA) and α-linolenic acid (ALA), respectively, has impacted numerous molecular and clinical phenotypes. Interactions are particularly relevant with the FADS1 and FADS2 genes, which encode key fatty acid desaturases in the pathway that converts LA and ALA to their long chain (≥20 carbons), highly unsaturated fatty acid (HUFA) counterparts. These gene by nutrient interactions affect the levels and balance of n-6 and n-3 HUFA that in turn are converted to a wide array of lipids with signaling roles, including eicosanoids, docosanoids, other oxylipins and endocannabinoids. With few exceptions, n-6 HUFA are precursors of pro-inflammatory/pro-thrombotic signaling lipids, and n-3 HUFA are generally anti-inflammatory/anti-thrombotic. We and others have demonstrated that African ancestry populations have much higher frequencies (vs. European-, Asian- or indigenous Americas-ancestry populations) of a FADS "derived" haplotype that is associated with the efficient conversion of high levels of dietary n-6 PUFA to pro-inflammatory n-6 HUFA. By contrast, an "ancestral" haplotype, carrying alleles associated with a limited capacity to synthesize HUFA, which can lead to n-3 HUFA deficiency, is found at high frequency in certain Hispanic populations and is nearly fixed in several indigenous populations from the Americas. Based on these observations, a focused secondary subgroup analysis of the VITAL n-3 HUFA supplementation trial stratifying the data based on self-reported ancestry revealed that African Americans may benefit from n-3 HUFA supplementation, and both ancestry and FADS variability should be factored into future clinical trials design.

Identification of Plasma Glycosphingolipids as Potential Biomarkers for Prostate Cancer (PCa) Status.

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 naïve 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 >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.

Genomics in Personalized Nutrition: Can You "Eat for Your Genes"?

Genome-wide single nucleotide polymorphism (SNP) data are now quickly and inexpensively acquired, raising the prospect of creating personalized dietary recommendations based on an individual's genetic variability at multiple SNPs. However, relatively little is known about most specific gene-diet interactions, and many molecular and clinical phenotypes of interest (e.g., body mass index [BMI]) involve multiple genes. In this review, we discuss direct to consumer genetic testing (DTC-GT) and the current potential for precision nutrition based on an individual's genetic data. We review important issues such as dietary exposure and genetic architecture addressing the concepts of penetrance, pleiotropy, epistasis, polygenicity, and epigenetics. More specifically, we discuss how they complicate using genotypic data to predict phenotypes as well as response to dietary interventions. Then, several examples (including caffeine sensitivity, alcohol dependence, non-alcoholic fatty liver disease, obesity/appetite, cardiovascular, Alzheimer's disease, folate metabolism, long-chain fatty acid biosynthesis, and vitamin D metabolism) are provided illustrating how genotypic information could be used to inform nutritional recommendations. We conclude by examining ethical considerations and practical applications for using genetic information to inform dietary choices and the future role genetics may play in adopting changes beyond population-wide healthy eating guidelines.

FADS genetic and metabolomic analyses identify the ∆5 desaturase (FADS1) step as a critical control point in the formation of biologically important lipids.

Humans have undergone intense evolutionary selection to optimize their capacity to generate necessary quantities of long chain (LC-) polyunsaturated fatty acid (PUFA)-containing lipids. To better understand the impact of genetic variation within a locus of three FADS genes (FADS1, FADS2, and FADS3) on a diverse family of lipids, we examined the associations of 247 lipid metabolites (including four major classes of LC-PUFA-containing molecules and signaling molecules) with common and low-frequency genetic variants located within the FADS locus. Genetic variation in the FADS locus was strongly associated (p < 1.2 × 10-8) with 52 LC-PUFA-containing lipids and signaling molecules, including free fatty acids, phospholipids, lyso-phospholipids, and an endocannabinoid. Notably, the majority (80%) of FADS-associated lipids were not significantly associated with genetic variants outside of this FADS locus. These findings highlight the central role genetic variation at the FADS locus plays in regulating levels of physiologically critical LC-PUFA-containing lipids that participate in innate immunity, energy homeostasis, and brain development/function.

Expression quantitative trait locus fine mapping of the 17q12-21 asthma locus in African American children: a genetic association and gene expression study.

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<0·0055 (for rs2305480_G, odds ratio [OR] 1·36 [95% CI 1·12-1·65], p=0·0014; and for rs8076131_A, OR 1·37 [1·13-1·67], p=0·0010). In upper airway epithelial cells from African American children, genotype at rs2305480 was the most significant eQTL for GSDMB (eQTL effect size [ß] 1·35 [95% CI 1·25-1·46], p<0·0001), and to a lesser extent showed an eQTL effect for post-GPI attachment to proteins phospholipase 3 (ß 1·15 [1·08-1·22], p<0·0001). No SNPs were eQTLs for ORMDL3. By contrast, in PBMCs, the five core SNPs were associated only with expression of GSDMB and ORMDL3. Genotype at rs12936231 (in zona pellucida binding protein 2) showed the strongest associations across both genes (for GSDMB, eQTLß 1·24 [1·15-1·32], p<0·0001; and for ORMDL3 (ß 1·19 [1·12-1·24], p<0·0001). The eQTL effects of rs2305480 on GSDMB expression were replicated in lower airway cells from African American adults (ß 1·29 [1·15-1·44], p<0·0001). INTERPRETATION: Our study suggests that SNPs regulating GSDMB expression in airway epithelial cells have a major role in childhood-onset asthma, whereas SNPs regulating the expression levels of 17q12-21 genes in resting blood cells are not central to asthma risk. Our genetic and gene expression data in African Americans and European Americans indicated GSDMB to be the leading candidate gene at this important asthma locus. FUNDING: National Institutes of Health, Office of the Director.

Prospective clinical trial examining the impact of genetic variation in FADS1 on the metabolism of linoleic acid- and ɣ-linolenic acid-containing botanical oils.

BACKGROUND: Unexplained heterogeneity in clinical trials has resulted in questions regarding the effectiveness of É£-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-É£-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.

Genomic Evidence of Local Adaptation to Climate and Diet in Indigenous Siberians.

The indigenous inhabitants of Siberia live in some of the harshest environments on earth, experiencing extended periods of severe cold temperatures, dramatic variation in photoperiod, and limited and highly variable food resources. While the successful long-term settlement of this area by humans required multiple behavioral and cultural innovations, the nature of the underlying genetic changes has generally remained elusive. In this study, we used a three-part approach to identify putative targets of positive natural selection in Siberians. We first performed selection scans on whole exome and genome-wide single nucleotide polymorphism array data from multiple Siberian populations. We then annotated candidates in the tails of the empirical distributions, focusing on candidates with evidence linking them to biological processes and phenotypes previously identified as relevant to adaptation in circumpolar groups. The top candidates were then genotyped in additional populations to determine their spatial allele frequency distributions and associations with climate variables. Our analysis reveals missense mutations in three genes involved in lipid metabolism (PLA2G2A, PLIN1, and ANGPTL8) that exhibit genomic and spatial patterns consistent with selection for cold climate and/or diet. These variants are unified by their connection to brown adipose tissue and may help to explain previously observed physiological differences in Siberians such as low serum lipid levels and increased basal metabolic rate. These results support the hypothesis that indigenous Siberians have genetically adapted to their local environment by selection on multiple genes.