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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 − 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.

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.

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...

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 –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.

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.

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

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.

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., Yang et al. examine whether genetic ancestry is associated with genetic variation in fatty acid desaturases and plasma phospholipid levels of long chain polyunsaturated fatty acids (LC-PUFAs) in Hispanic Americans. They find strong associations between Amerind genetic ancestry and LC-PUFA levels; and report that the well-known FADS rs174537 variant was associated with several metabolic, inflammatory and anthropomorphic traits including circulating triglycerides.

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.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.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, p0·0001 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.Small airway disease, as measured by physiological tests, is longitudinally associated with clinically important asthma outcomes, such as asthma control and exacerbations.Chiesi Farmaceutici.

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.

Hispanic populations have higher rates of obesity, elevated triglycerides, and a greater prevalence of diabetes. Long chain polyunsaturated fatty acids (LC-PUFAs) and LC-PUFA metabolites have critical signaling roles that regulate dyslipidemia and inflammation. Genetic variation in the FADS cluster accounts for a large part of the 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 (AI) ancestry populations. In this study, we examined relationships between genetic ancestry and FADS variation, plasma phospholipid levels of LC-PUFAs, anthropometric measures, and circulating metabolic and inflammatory biomarkers in 1,102 Hispanic American participants, representing six distinct ancestry populations from the Multi-Ethnic Study of Atherosclerosis. We demonstrate strong negative associations between AI 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. We further replicated the association with circulating TGs in two additional Hispanic cohorts: the Hispanic Community Health Study/Study of Latinos and the Arizona Insulin Resistance Registry. 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.

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.

Background: Mexican-origin (MO) Hispanic adults have the highest rates of non-alcoholic fatty liver disease (NAFLD) in the United States (US), which places them at high risk of hepatocellular carcinoma (HCC). Diet plays a significant role in the development and treatment of NAFLD given the lack of pharmacological treatment. Nutritional components hypothesized to influence NAFLD risk include an imbalance in the consumption of omega-6 (n-6) relative to omega-3 (n-3) polyunsaturated fatty acids (PUFAs). However, data on the relationship between dietary intake of fatty acids (FA) and liver steatosis and fibrosis is limited for MO adults. Purpose: This study examined FA intake among overweight and obese Mexican-origin (MO) Hispanic adults and evaluated its association to liver steatosis and fibrosis. Methods: Overweight and obese participants (n=285, MO Hispanic adults) completed three 24-hour dietary recalls on two week days and one weekend day, to estimate dietary FA intake. Liver steatosis was defined by continuous attenuation parameter (CAP) scores that can range from 100 to 400 dB/m. Fibrosis was defined by kilopascals (kPa) and can range from 2 to 75 kPa. Liver steatosis and fibrosis were quantified using non-invasive transient elastography (Fibroscan®). Multiple regression analyses tested relationships between FA intakes and liver steatosis or fibrosis, adjusting for sex, BMI, and total energy intake. Results: Among MO Hispanic adults, mean CAP score was 289.5 ± 48.9 dB/m, equivalent to approximately 67% hepatic steatosis, and a mean fibrosis of 5.67± 2.83 kPa. The mean intake of n-6 and n-3 was 12.0 ± 6.5 g/day and 1.50 ± 1.01 g/day, respectively, with a ratio of 8.9 (range: 2.46 - 19.8). The most commonly consumed n-6 and n-3 FAs were linoleic acid (LA) (12 ± 6.5 g/day) and alpha-linoleic acid (ALA) (1.50 g/day ± 1.01), respectively. Overall, no associations were observed between the ratio of n-6 to n-3 and liver steatosis. However, LA-to-ALA ratio and the n-6 to n-3 ratio were positively associated with liver fibrosis such that a one point increase in the LA-to-ALA ratio resulted in a 1.01-point increase in fibrosis (95% CI: [1.00, 1.03]; p=0.029), and a one point increase in the n-6 to n-3 resulted in a 1.02-point increase in fibrosis (95% CI: [1.01, 1.03]; p=0.005). Conclusion: Intake and ratios of n-6 and n-3 PUFAs were comparable to what is observed in general US populations and were not associated with liver steatosis. However, n-6 and n-3 ratios were associated with liver fibrosis. These findings highlight the need for a more rigorous examination of the association between n-PUFAS and liver fibrosis and their potential as a therapeutic strategy for more severe liver disease such as non-alcoholic steatohepatitis (NASH) and cirrhosis in this high-risk population. Citation Format: Melissa Lopez-Pentecost, Brian Hallmark, Cynthia Thomson, Floyd Chilton, David Garcia. Relationship between fatty acid intake and liver steatosis and fibrosis among overweight and obese Mexican-origin adults [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5956.

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.

Siberia is one of the coldest environments on Earth and has great seasonal temperature variation. Long-term settlement in northern Siberia undoubtedly required biological adaptation to severe cold stress, dramatic variation in photoperiod, and limited food resources. In addition, recent archeological studies show that humans first occupied Siberia at least 45,000 years ago; yet our understanding of the demographic history of modern indigenous Siberians remains incomplete. In this study, we use whole-exome sequencing data from the Nganasans and Yakuts to infer the evolutionary history of these two indigenous Siberian populations. Recognizing the complexity of the adaptive process, we designed a model-based test to systematically search for signatures of polygenic selection. Our approach accounts for stochasticity in the demographic process and the hitchhiking effect of classic selective sweeps, as well as potential biases resulting from recombination rate and mutation rate heterogeneity. Our demographic inference shows that the Nganasans and Yakuts diverged ∼12,000-13,000 years ago from East-Asian ancestors in a process involving continuous gene flow. Our polygenic selection scan identifies seven candidate gene sets with Siberian-specific signals. Three of these gene sets are related to diet, especially to fat metabolism, consistent with the hypothesis of adaptation to a fat-rich animal diet. Additional testing rejects the effect of hitchhiking and favors a model in which selection yields small allele frequency changes at multiple unlinked 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.

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.

OBJECTIVES We examined autosomal genome-wide SNPs and Y-chromosome data from 15 Siberian and 12 reference populations to study the affinities of Siberian populations, and to address hypotheses about the origin of the Samoyed peoples. METHODS Samples were genotyped for 567 096 autosomal SNPs and 147 Y-chromosome polymorphic sites. For several analyses, we used 281 093 SNPs from the intersection of our data with publicly available ancient Siberian samples. To examine genetic relatedness among populations, we applied PCA, FST , TreeMix, and ADMIXTURE analyses. To explore the potential effect of demography and evolutionary processes, the distribution of ROH and IBD sharing within population were studied. RESULTS Analyses of autosomal and Y-chromosome data reveal high differentiation of the Siberian groups. The Siberian populations have a large proportion of their genome in ROH and IBD segments. Several populations (ie, Nganasans, Evenks, Yukagirs, and Koryaks) do not appear to have experienced admixture with other Siberian populations (ie, producing only positive f3), while for the other tested populations the composition of mixing sources always included Nganasans or Evenks. The Nganasans from the Taymyr Peninsula demonstrate the greatest level of shared shorter ROH and IBD with nearly all other Siberian populations. CONCLUSIONS Autosomal SNP and Y-chromosome data demonstrate that Samoyedic populations differ significantly in their genetic composition. Genetic relationship is observed only between Forest and Tundra Nentsi. Selkups are affiliated with the Kets from the Yenisey River, while the Nganasans are separated from their linguistic neighbors, showing closer affinities with the Evenks and Yukagirs.

Dravet syndrome (DS) is a rare, devastating form of childhood epilepsy that is often associated with mutations in the voltage-gated sodium channel gene, SCN1A. There is considerable variability in expressivity within families, as well as among individuals carrying the same primary mutation, suggesting that clinical outcome is modulated by variants at other genes. To identify modifier gene variants that contribute to clinical outcome, we sequenced the exomes of 22 individuals at both ends of a phenotype distribution (i.e., mild and severe cognitive condition). We controlled for variation associated with different mutation types by limiting inclusion to individuals with a de novo truncation mutation resulting in SCN1A haploinsufficiency. We performed tests aimed at identifying 1) single common variants that are enriched in either phenotypic group, 2) sets of common or rare variants aggregated in and around genes associated with clinical outcome, and 3) rare variants in 237 candidate genes associated with neuronal excitability. While our power to identify enrichment of a common variant in either phenotypic group is limited as a result of the rarity of mild phenotypes in individuals with SCN1A truncation variants, our top candidates did not map to functional regions of genes, or in genes that are known to be associated with neurological pathways. In contrast, we found a statistically-significant excess of rare variants predicted to be damaging and of small effect size in genes associated with neuronal excitability in severely affected individuals. A KCNQ2 variant previously associated with benign neonatal seizures is present in 3 of 12 individuals in the severe category. To compare our results with the healthy population, we performed a similar analysis on whole exome sequencing data from 70 Japanese individuals in the 1000 genomes project. Interestingly, the frequency of rare damaging variants in the same set of neuronal excitability genes in healthy individuals is nearly as high as in severely affected individuals. Rather than a single common gene/variant modifying clinical outcome in SCN1A-related epilepsies, our results point to the cumulative effect of rare variants with little to no measurable phenotypic effect (i.e., typical genetic background) unless present in combination with a disease-causing truncation mutation in SCN1A.

In the second half of the 20th century, investigations of indigenous environmental knowledge have been the subject of broader anthropological debates over how knowledge and experience are formed. Many such approaches have focused on environmental nomenclature and taxonomy, or what Roy Ellen has called “formal lexical knowledge” (1999). Such knowledge is readily available to an ethnographer and also more easily transmitted through language between subjects. These characteristics of formal lexical knowledge have led to considerable attention given to differences in environmental knowledge between cultures and have possibly resulted in the inflation of the efficacy of language in forming knowledge. However, if a different form of environmental knowledge is examined are there differences that emerge within communities and other processes beyond symbolic systems that shape knowledge? To address these questions, individuals in two Balinese agricultural communities were asked to construct food webs by linking photos of plant and animal species according to ecological interaction. The results showed significant variation in subjects’ knowledge by gender, which corresponds to labor experience in Balinese wet rice agricultural systems. By shifting attention toward emic models of ecological interactions, this article attempts to demonstrate (1) that environmental knowledge differs within a single community; and, (2) the role of labor experience or praxis has in forming environmental knowledge.

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.

The early history of island Southeast Asia is often characterized as the story of two major population dispersals: the initial Paleolithic colonization of Sahul approximately 45 ka ago and the much later Neolithic expansion of Austronesian-speaking farmers approximately 4 ka ago. Here, in the largest survey of Indonesian Y chromosomes to date, we present evidence for multiple genetic strata that likely arose through a series of distinct migratory processes. We genotype an extensive battery of Y chromosome markers, including 85 single-nucleotide polymorphisms/indels and 12 short tandem repeats, in a sample of 1,917 men from 32 communities located across Indonesia. We find that the paternal gene pool is sharply subdivided between western and eastern locations, with a boundary running between the islands of Bali and Flores. Analysis of molecular variance reveals one of the highest levels of between-group variance yet reported for human Y chromosome data (e.g., Phi(ST) = 0.47). Eastern Y chromosome haplogroups are closely related to Melanesian lineages (i.e., within the C, M, and S subclades) and likely reflect the initial wave of colonization of the region, whereas the majority of western Y chromosomes (i.e., O-M119*, O-P203, and O-M95*) are related to haplogroups that may have entered Indonesia during the Paleolithic from mainland Asia. In addition, two novel markers (P201 and P203) provide significantly enhanced phylogenetic resolution of two key haplogroups (O-M122 and O-M119) that are often associated with the Austronesian expansion. This more refined picture leads us to put forward a four-phase colonization model in which Paleolithic migrations of hunter-gatherers shape the primary structure of current Indonesian Y chromosome diversity, and Neolithic incursions make only a minor impact on the paternal gene pool, despite the large cultural impact of the Austronesian expansion.

It has been known for over a decade that a majority of men who self report as members of the Jewish priesthood (Cohanim) carry a characteristic Y chromosome haplotype termed the Cohen Modal Haplotype (CMH). The CMH has since been used to trace putative Jewish ancestral origins of various populations. However, the limited number of binary and STR Y chromosome markers used previously did not provide the phylogenetic resolution needed to infer the number of independent paternal lineages that are encompassed within the Cohanim or their coalescence times. Accordingly, we have genotyped 75 binary markers and 12 Y-STRs in a sample of 215 Cohanim from diverse Jewish communities, 1,575 Jewish men from across the range of the Jewish Diaspora, and 2,099 non-Jewish men from the Near East, Europe, Central Asia, and India. While Cohanim from diverse backgrounds carry a total of 21 Y chromosome haplogroups, 5 haplogroups account for 79.5% of Cohanim Y chromosomes. The most frequent Cohanim lineage (46.1%) is marked by the recently reported P58 T->C mutation, which is prevalent in the Near East. Based on genotypes at 12 Y-STRs, we identify an extended CMH on the J-P58* background that predominates in both Ashkenazi and non-Ashkenazi Cohanim and is remarkably absent in non-Jews. The estimated divergence time of this lineage based on 17 STRs is 3,190 ± 1,090 years. Notably, the second most frequent Cohanim lineage (J-M410*, 14.4%) contains an extended modal haplotype that is also limited to Ashkenazi and non-Ashkenazi Cohanim and is estimated to be 4.2 ± 1.3 ky old. These results support the hypothesis of a common origin of the CMH in the Near East well before the dispersion of the Jewish people into separate communities, and indicate that the majority of contemporary Jewish priests descend from a limited number of paternal lineages. Electronic supplementary material The online version of this article (doi:10.1007/s00439-009-0727-5) contains supplementary material, which is available to authorized users.

A central tenet of evolutionary social science holds that behaviors, such as those associated with social dominance, produce fitness effects that are subject to cultural selection. However, evidence for such selection is inconclusive because it is based on short-term statistical associations between behavior and fertility. Here, we show that the evolutionary effects of dominance at the population level can be detected using noncoding regions of DNA. Highly variable polymorphisms on the nonrecombining portion of the Y chromosome can be used to trace lines of descent from a common male ancestor. Thus, it is possible to test for the persistence of differential fertility among patrilines. We examine haplotype distributions defined by 12 short tandem repeats in a sample of 1269 men from 41 Indonesian communities and test for departures from neutral mutation-drift equilibrium based on the Ewens sampling formula. Our tests reject the neutral model in only 5 communities. Analysis and simulations show that we have sufficient power to detect such departures under varying demographic conditions, including founder effects, bottlenecks, and migration, and at varying levels of social dominance. We conclude that patrilines seldom are dominant for more than a few generations, and thus traits or behaviors that are strictly paternally inherited are unlikely to be under strong cultural selection.

Numerous studies indicate strong associations between languages and genes among human populations at the global scale, but all broader scale genetic and linguistic patterns must arise from processes originating at the community level. We examine linguistic and genetic variation in a contact zone on the eastern Indonesian island of Sumba, where Neolithic Austronesian farming communities settled and began interacting with aboriginal foraging societies ≈3,500 years ago. Phylogenetic reconstruction based on a 200-word Swadesh list sampled from 29 localities supports the hypothesis that Sumbanese languages derive from a single ancestral Austronesian language. However, the proportion of cognates (words with a common origin) traceable to Proto-Austronesian (PAn) varies among language subgroups distributed across the island. Interestingly, a positive correlation was found between the percentage of Y chromosome lineages that derive from Austronesian (as opposed to aboriginal) ancestors and the retention of PAn cognates. We also find a striking correlation between the percentage of PAn cognates and geographic distance from the site where many Sumbanese believe their ancestors arrived on the island. These language–gene–geography correlations, unprecedented at such a fine scale, imply that historical patterns of social interaction between expanding farmers and resident hunter-gatherers largely explain community-level language evolution on Sumba. We propose a model to explain linguistic and demographic coevolution at fine spatial and temporal scales.