Omega-3 Blood Levels and Stroke Risk: A Pooled and Harmonized Analysis of 183 291 Participants From 29 Prospective Studies.

BACKGROUND: The effect of marine omega-3 PUFAs on risk of stroke remains unclear. METHODS: We investigated the associations between circulating and tissue omega-3 PUFA levels and incident stroke (total, ischemic, and hemorrhagic) in 29 international prospective cohorts. Each site conducted a de novo individual-level analysis using a prespecified analytical protocol with defined exposures, covariates, analytical methods, and outcomes; the harmonized data from the studies were then centrally pooled. Multivariable-adjusted HRs and 95% CIs across omega-3 PUFA quintiles were computed for each stroke outcome. RESULTS: Among 183 291 study participants, there were 10 561 total strokes, 8220 ischemic strokes, and 1142 hemorrhagic strokes recorded over a median of 14.3 years follow-up. For eicosapentaenoic acid, comparing quintile 5 (Q5, highest) with quintile 1 (Q1, lowest), total stroke incidence was 17% lower (HR, 0.83 [CI, 0.76-0.91]; P<0.0001), and ischemic stroke was 18% lower (HR, 0.82 [CI, 0.74-0.91]; P<0.0001). For docosahexaenoic acid, comparing Q5 with Q1, there was a 12% lower incidence of total stroke (HR, 0.88 [CI, 0.81-0.96]; P=0.0001) and a 14% lower incidence of ischemic stroke (HR, 0.86 [CI, 0.78-0.95]; P=0.0001). Neither eicosapentaenoic acid nor docosahexaenoic acid was associated with a risk for hemorrhagic stroke. These associations were not modified by either baseline history of AF or prevalent CVD. CONCLUSIONS: Higher omega-3 PUFA levels are associated with lower risks of total and ischemic stroke but have no association with hemorrhagic stroke.

A Genome-Wide Interaction Study of Erythrocyte ω-3 Polyunsaturated Fatty Acid Species and Memory in the Framingham Heart Study Offspring Cohort.

BACKGROUND: Cognitive decline, and more specifically Alzheimer's disease, continues to increase in prevalence globally, with few, if any, adequate preventative approaches. Several tests of cognition are utilized in the diagnosis of cognitive decline that assess executive function, short- and long-term memory, cognitive flexibility, and speech and motor control. Recent studies have separately investigated the genetic component of both cognitive health, using these measures, and circulating fatty acids. OBJECTIVES: We aimed to examine the potential moderating effect of main species of ω-3 polyunsaturated fatty acids (PUFAs) on an individual's genetically conferred risk of cognitive decline. METHODS: The Offspring cohort from the Framingham Heart Study was cross-sectionally analyzed in this genome-wide interaction study (GWIS). Our sample included all individuals with red blood cell ω-3 PUFA, genetic, cognitive testing (via Trail Making Tests [TMTs]), and covariate data (N = 1620). We used linear mixed effects models to predict each of the 3 cognitive measures (TMT A, TMT B, and TMT D) by each ω-3 PUFA, single nucleotide polymorphism (SNP) (0, 1, or 2 minor alleles), ω-3 PUFA by SNP interaction term, and adjusting for sex, age, education, APOE ε4 genotype status, and kinship (relatedness). RESULTS: Our analysis identified 31 unique SNPs from 24 genes reaching an exploratory significance threshold of 1×10-5. Fourteen of the 24 genes have been previously associated with the brain/cognition, and 5 genes have been previously associated with circulating lipids. Importantly, 8 of the genes we identified, DAB1, SORCS2, SERINC5, OSBPL3, CPA6, DLG2, MUC19, and RGMA, have been associated with both cognition and circulating lipids. We identified 22 unique SNPs for which individuals with the minor alleles benefit substantially from increased ω-3 fatty acid concentrations and 9 unique SNPs for which the common homozygote benefits. CONCLUSIONS: In this GWIS of ω-3 PUFA species on cognitive outcomes, we identified 8 unique genes with plausible biology suggesting individuals with specific polymorphisms may have greater potential to benefit from increased ω-3 PUFA intake. Additional replication in prospective settings with more diverse samples is needed.

Multimarker omnibus tests by leveraging individual marker summary statistics from large biobanks.

As biobanks become increasingly popular, access to genotypic and phenotypic data continues to increase in the form of precomputed summary statistics (PCSS). Widespread accessibility of PCSS alleviates many issues related to biobank data, including that of data privacy and confidentiality, as well as high computational costs. However, questions remain about how to maximally leverage PCSS for downstream statistical analyses. Here we present a novel method for testing the association of an arbitrary number of single nucleotide variants (SNVs) on a linear combination of phenotypes after adjusting for covariates for common multimarker tests (e.g., SKAT, SKAT-O) without access to individual patient-level data (IPD). We validate exact formulas for each method, and demonstrate their accuracy through simulation studies and an application to fatty acid phenotypic data from the Framingham Heart Study.

Reliability and Validity of the State-Trait Hopelessness Scale in a Primarily Rural Population of Adults With Ischemic Heart Disease in the US Great Plains.

PURPOSE: Hopelessness and rurality are each independently associated with increased mortality in adults with ischemic heart disease (IHD), yet there is no known research examining hopelessness in rural patients with IHD. The authors of this study evaluated the reliability and validity of the State-Trait Hopelessness Scale (STHS) in a primarily rural population of adults with IHD living in West North Central United States (US Great Plains). METHODS: Reliability, concurrent validity, and convergent validity were evaluated for 115 adults hospitalized for IHD. Rural-Urban Commuting Area codes were used to stratify participants by rurality level, with 66% categorized as rural. Principal component analysis was used to examine potential factor structure of the STHS. FINDINGS: Cronbach α for the State and Trait Hopelessness subscales were 0.884 and 0.903, respectively. Concurrent validity was supported for the State and Trait subscales using the Patient Health Questionnaire-8 (State: r = 0.50, P < .001; Trait: r = 0.35, P < .001). Convergent validity was supported for the State subscale using the Duke Activity Status Index ( r = -0.23, P = .013). Principal component analysis showed 2 factors (hopelessness present and hopelessness absent) for the State and Trait subscales, accounting for 63% and 58% of variance, respectively. CONCLUSIONS: Findings support the reliability and validity of the STHS for evaluation of hopelessness in rural adults with IHD in clinical and research settings. Results replicated the same factor structure found in testing of the STHS in a primarily urban sample. Because of the prevalence of hopelessness in rural adults with IHD and association with increased mortality, hopelessness should be assessed during hospitalization and in the recovery period.

Heart up! RCT protocol to increase physical activity in cardiac patients who report hopelessness: Amended for the COVID-19 pandemic.

Hopelessness is associated with decreased physical activity (PA) and increased adverse events and death in patients with ischemic heart disease (IHD). Rates of PA in patients with IHD continue to be low in both hospital-based cardiac rehabilitation and home settings. While researchers have investigated strategies to increase PA among patients with IHD, interventions to promote PA specifically in IHD patients who report hopelessness are lacking. We describe the protocol for a NIH-funded randomized controlled trial designed to establish the effectiveness of a 6-week intervention (Heart Up!) to promote increased PA in IHD patients who report hopelessness. Participants (n = 225) are randomized to one of three groups: (1) motivational social support (MSS) from a nurse, (2) MSS from a nurse plus significant other support (SOS), or (3) attention control. Aims are to: (1) test the effectiveness of 6 weeks of MSS and MSS with SOS on increasing mean minutes per day of moderate to vigorous PA; (2) determine the effects of change in moderate to vigorous PA on hopelessness; and (3) determine if perceived social support and motivation (exercise self-regulation) mediate the effects of the intervention on PA. A total of 69 participants have been enrolled to date. The protocol has been consistently and accurately used by research personnel. We address the protocol challenges presented by the COVID-19 pandemic and steps taken to maintain fidelity to the intervention. Findings from this study could transform care for IHD patients who report hopelessness by promoting self-management of important PA goals that can contribute to better health outcomes.

Reliability and Validity of the State-Trait Hopelessness Scale in Patients With Heart Disease and Moderate to Severe Hopelessness.

OBJECTIVE: The aim of this study was to evaluate the reliability and validity of the State-Trait Hopelessness Scale (STHS) in patients with heart disease who report moderate to severe state hopelessness. METHODS: Reliability, concurrent validity, and convergent validity were evaluated for 20 patients. RESULTS: Cronbach's α for the State and Trait subscales were .81 and .79, respectively. Strong correlations between the State Hopelessness Subscale and Patient Health Questionnaire-9 (r = 0.77, P < .001), State Hope Scale (r = -0.75, P < .001), EQ-5D-5L (r = 0.59, P < .005), and PROMIS-29 domains of depression (P = .72, P < .001), fatigue (P = .61, P < .001), and social roles (P = .45, P = .047) were found. There were strong correlations between the Trait Hopelessness Subscale and Trait Hope Scale (r = -0.58, P < .005), State Hope Scale (r = -0.49, P = .03), and PROMIS-29 fatigue domain (r = 0.54, P = .015). CONCLUSIONS: Findings support the reliability and validity of the STHS for evaluation of hopelessness in patients with heart disease.

Lack of perceived social support in patients with ischemic heart disease is associated with hopelessness.

OBJECTIVE: To evaluate perceived social support (PSS) in ischemic heart disease (IHD) patients who report hopelessness. METHODS: Using a cross-sectional design, 156 patients were screened during their hospitalization for moderate to severe state hopelessness. Twenty patients who reported hopelessness during hospitalization and maintained hopelessness one week after hospital discharge were included. RESULTS: A moderately strong negative correlation was identified between PSS and state hopelessness (r = -0.54, p = .014). PSS was significantly higher in married/partnered patients (26.7 ± 4.85) compared to unmarried/unpartnered patients (18 ± 9.18; t = 2.45, p = .035). CONCLUSIONS: Social support may help reduce hopelessness in vulnerable cardiac patients, especially those who are unpartnered.

Common Pitfalls in Analysis of Tissue Scores.

Histopathology remains an important source of descriptive biological data in biomedical research. Recent petitions for enhanced reproducibility in scientific studies have elevated the role of tissue scoring (semiquantitative and quantitative) in research studies. Effective tissue scoring requires appropriate statistical analysis to help validate the group comparisons and give the pathologist confidence in interpreting the data. Each statistical test is typically founded on underlying assumptions regarding the data. If the underlying assumptions of a statistical test do not match the data, then these tests can lead to increased risk of erroneous interpretations of the data. The choice of appropriate statistical test is influenced by the study's experimental design and resultant data (eg, paired vs unpaired, normality, number of groups, etc). Here, we identify 3 common pitfalls in the analysis of tissue scores: shopping for significance, overuse of paired t-tests, and misguided analysis of multiple groups. Finally, we encourage pathologists to use the full breadth of resources available to them, such as using statistical software, reading key publications about statistical approaches, and identifying a statistician to serve as a collaborator on the multidisciplinary research team. These collective resources can be helpful in choosing the appropriate statistical test for tissue-scoring data to provide the most valid interpretation for the pathologist.

Ethnic minority members may be at risk for state hopelessness following hospitalization for ischemic heart disease.

OBJECTIVE: To examine differences in state and trait hopelessness between ethnic minority and White patients hospitalized with ischemic heart disease (IHD). METHODS: A descriptive cross-sectional design was used to enroll 517 patients at one Midwestern U.S. hospital. The State-Trait Hopelessness Scale measured hopelessness. RESULTS: State hopelessness was higher in ethnic minority patients compared to Whites. Ethnic minority patients who had never been married had higher state hopelessness than those who were married or separated/divorced. There were no differences in trait hopelessness. CONCLUSIONS: Ethnic minority patients with IHD, who have never been married, may be at higher risk for state hopelessness.

Application of novel and existing methods to identify genes with evidence of epigenetic association: results from GAW20.

BACKGROUND: The rise in popularity and accessibility of DNA methylation data to evaluate epigenetic associations with disease has led to numerous methodological questions. As part of GAW20, our working group of 8 research groups focused on gene searching methods. RESULTS: Although the methods were varied, we identified 3 main themes within our group. First, many groups tackled the question of how best to use pedigree information in downstream analyses, finding that (a) the use of kinship matrices is common practice, (b) ascertainment corrections may be necessary, and (c) pedigree information may be useful for identifying parent-of-origin effects. Second, many groups also considered multimarker versus single-marker tests. Multimarker tests had modestly improved power versus single-marker methods on simulated data, and on real data identified additional associations that were not identified with single-marker methods, including identification of a gene with a strong biological interpretation. Finally, some of the groups explored methods to combine single-nucleotide polymorphism (SNP) and DNA methylation into a single association analysis. CONCLUSIONS: A causal inference method showed promise at discovering new mechanisms of SNP activity; gene-based methods of summarizing SNP and DNA methylation data also showed promise. Even though numerous questions still remain in the analysis of DNA methylation data, our discussions at GAW20 suggest some emerging best practices.

Dog Ownership and Dog Walking: The Relationship With Exercise, Depression, and Hopelessness in Patients With Ischemic Heart Disease.

BACKGROUND: Dog ownership has been associated with increased physical activity in the general adult population. OBJECTIVE: The objective of this study was to examine dog ownership and dog walking and their relationship with home-based and phase II cardiac rehabilitation exercise, depression, and hopelessness in patients with ischemic heart disease. METHODS: A total of 122 patients with ischemic heart disease were included in this prospective observational study. Patients completed dog ownership/walking questions during their hospitalization. The Cardiac Rehabilitation Exercise Participation Tool, Patient Health Questionnaire-9, and State-Trait Hopelessness Scale were completed by mail at 3, 8, or 12 months later. Regression modeling was used to evaluate the significance of dog ownership/walking on exercise, depression and hopelessness. RESULTS: The sample was 34.4% female and had a mean age of 64.7 ± 9.1 years. Forty-two patients (34.4%) reported owning a dog. Patients who owned but did not walk their dog reported significantly lower levels of home exercise compared with patients who walked their dogs at least 1 day per week (36.8% for non-dog walkers vs 73.9% for dog walkers, P = .019). The odds of participating in home exercise were significantly higher for dog walkers compared with non-dog walkers (odds ratio, 8.1 [1.7, 38.5] vs 1.0). There were no differences in phase II cardiac rehabilitation exercise, depression, or hopelessness between dog owners and non-dog owners or between dog walkers and non-dog walkers. CONCLUSIONS: These findings show a beneficial effect on home-based exercise for those who dog-walk at least 1 day per week. Healthcare professionals should encourage dog walking to increase dog owners' physical activity levels.

Value of Mendelian laws of segregation in families: data quality control, imputation, and beyond.

When analyzing family data, we dream of perfectly informative data, even whole-genome sequences (WGSs) for all family members. Reality intervenes, and we find that next-generation sequencing (NGS) data have errors and are often too expensive or impossible to collect on everyone. The Genetic Analysis Workshop 18 working groups on quality control and dropping WGSs through families using a genome-wide association framework focused on finding, correcting, and using errors within the available sequence and family data, developing methods to infer and analyze missing sequence data among relatives, and testing for linkage and association with simulated blood pressure. We found that single-nucleotide polymorphisms, NGS data, and imputed data are generally concordant but that errors are particularly likely at rare variants, for homozygous genotypes, within regions with repeated sequences or structural variants, and within sequence data imputed from unrelated individuals. Admixture complicated identification of cryptic relatedness, but information from Mendelian transmission improved error detection and provided an estimate of the de novo mutation rate. Computationally, fast rule-based imputation was accurate but could not cover as many loci or subjects as more computationally demanding probability-based methods. Incorporating population-level data into pedigree-based imputation methods improved results. Observed data outperformed imputed data in association testing, but imputed data were also useful. We discuss the strengths and weaknesses of existing methods and suggest possible future directions, such as improving communication between data collectors and data analysts, establishing thresholds for and improving imputation quality, and incorporating error into imputation and analytical models.

A geometric framework for evaluating rare variant tests of association.

The wave of next-generation sequencing data has arrived. However, many questions still remain about how to best analyze sequence data, particularly the contribution of rare genetic variants to human disease. Numerous statistical methods have been proposed to aggregate association signals across multiple rare variant sites in an effort to increase statistical power; however, the precise relation between the tests is often not well understood. We present a geometric representation for rare variant data in which rare allele counts in case and control samples are treated as vectors in Euclidean space. The geometric framework facilitates a rigorous classification of existing rare variant tests into two broad categories: tests for a difference in the lengths of the case and control vectors, and joint tests for a difference in either the lengths or angles of the two vectors. We demonstrate that genetic architecture of a trait, including the number and frequency of risk alleles, directly relates to the behavior of the length and joint tests. Hence, the geometric framework allows prediction of which tests will perform best under different disease models. Furthermore, the structure of the geometric framework immediately suggests additional classes and types of rare variant tests. We consider two general classes of tests which show robustness to noncausal and protective variants. The geometric framework introduces a novel and unique method to assess current rare variant methodology and provides guidelines for both applied and theoretical researchers.

Plasma n6 polyunsaturated fatty acid levels and risk for total and cause-specific mortality: A prospective observational study from the UK Biobank.

BACKGROUND: The potential role of n-6 PUFAs in major health outcomes remains controversial. OBJECTIVES: To examine the relationship between the major plasma n6 PUFA, linoleic acid (LA), as well as the non-LA n6 PUFAs, and total and cause-specific mortality. METHODS: This was a prospective, observational, biomarker-based study in the UK Biobank. Individuals with complete information on baseline demographic, covariate and plasma PUFA levels (percent ot total fatty acids) and mortality outcomes were included (n=257,925). Multivariable-adjusted, Cox-proportional hazards models were used to predict risk of death from all-causes, and from cardiovascular disease (CVD), cancer, and other causes as a function of plasma LA and non-LA n6 levels, both continuously and by PUFA quintile (Q). RESULTS: Comparing LA Q5 to Q1, the hazard ratio (HR, 95% CI) for total mortality was 0.80 (0.76, 0.84; p<0.001), and this was similar for all three cause-specific death categories. On the other hand, mortality HR for non-LA n6 was 1.12 (1.08,1.17; p<0.001), and this was primarily due to increased risk for non-CVD, noncancer deaths [HR 1.29 (1.19,1.40; p<0.001)]. Exploratory analyses among the eight next most common other causes of death suggested that both the decreased risk associated with higher LA and the increased risk associated with non-LA n6 were confined to deaths from respiratory and digestive diseases. CONCLUSIONS: These findings highlight the profound differences in mortality risk related to LA and non-LA n6 PUFA levels and underscore the inappropriateness of treating n-6 PUFAs as a homogenous class with respect to health outcomes. They also support recommendations to maintain (if not increase) current LA intakes.

Higher docosahexaenoic acid proportions in blood are inversely associated with the prevalence of prediabetes: Evidence from the UK Biobank.

Prediabetes and type 2 diabetes mellitus are growing global health concerns, predisposing individuals to various vascular complications. Lifestyle modifications, including dietary interventions, offer promising avenues for prevention and management. Using a multivariable-adjusted model, we analyzed the cross-sectional associations between plasma proportions (% of total fatty acids) of omega-3 polyunsaturated fatty acids (n3 PUFA, including total n3 PUFA, docosahexaenoic acid [DHA], non-DHA n3 PUFA), and glycated hemoglobin A1c (HbA1c) as well as the prevalence of prediabetes in a sample from the UK Biobank cohort. Our hypothesis was that proportions of n3 PUFA, especially DHA, would by inversely associated with the prediabetes prevalence. The sample (n = 92,762; 54.5% females) had an average age of 56 years and was overweight (mean body mass index = 27). The mean plasma DHA proportion in the sample was 2.03% (standard deviation [SD] = 0.67%), non-DHA n3 PUFA was 2.41% (SD = 1.02%) and total n3 PUFA was 4.43% (SD = 1.56%). Prediabetic individuals were identified by blood HbA1c proportions between 5.7% and 6.4% (39-46 mmol/mol) according to American Diabetes Association criteria. Each of the three n3 PUFA biomarkers was inversely associated with HbA1c proportions. In particular, DHA showed the strongest inverse association, with an OR of 0.62 (95% confidence intervals: 0.58, 0.67; P < .001) when comparing quintiles 5 to 1 in a fully adjusted model. These findings suggest a potential protective role of n3 PUFA, particularly DHA, in mitigating the risk of having prediabetes. Further prospective investigations are needed to clarify whether long-chain n3 PUFA could function as modifiable factors for prediabetes.

Circulating Docosahexaenoic Acid and Risk of All-Cause and Cause-Specific Mortality.

OBJECTIVE: To assess the associations of docosahexaenoic acid (DHA), a marine omega-3 fatty acid, with long-term all-cause mortality, cardiovascular (CV) mortality, and cancer mortality. PATIENTS AND METHODS: We analyzed data from UK Biobank, which included 117,702 subjects with baseline plasma DHA levels and 12.7 years of follow-up between April 2007 and December 2021. Associations with risk for mortality endpoints were analyzed categorically by quintile of DHA plasma levels. RESULTS: Comparing the lowest to highest quintiles of circulating levels of DHA, there was 21% lower risk of all-cause mortality (HR, 0.79; 95% CI, 0.74 to 0.85; P<.0001). In a secondary analysis, we merged the UK Biobank findings with those from a recent FORCE (Fatty Acid and Outcome Research Consortium) meta-analysis that included 17 prospective cohort studies and 42,702 individuals examining DHA and mortality associations. The cumulative sample population included 160,404 individuals and 24,342 deaths during a median of 14 years of follow-up. After multivariable adjustment for relevant risk factors comparing the lowest to the highest quintiles of DHA, there was 17% lower risk of all-cause mortality (95% CI, 0.79 to 0.87; P<.0001), 21% lower risk for CV disease mortality (95% CI, 0.73 to 0.87; P<.001), 17% lower risk for cancer mortality (95% CI, 0.77 to 0.89; P<.0001), and 15% lower risk for all other mortality (95% CI, 0.79 to 0.91; P<.001). CONCLUSION: Higher DHA levels were associated with significant risk reductions in all-cause mortality, as well as reduced risks for deaths due to CV disease, cancer, and all other causes. The findings strengthen the hypothesis that DHA, a marine-sourced omega-3, may support CV health and lifespan.

Omega-3 supplementation changes the physical properties of leukocytes but not erythrocytes in healthy individuals: An exploratory trial.

n3-PUFA impact health in several ways, including cardiovascular protection and anti-inflammatory effects, but the underlying mechanisms are not fully understood. In this exploratory study involving 31 healthy subjects, we aimed to investigate the effects of 12 weeks of fish-oil supplementation (1500 mg EPA+DHA/day) on the physical properties of multiple blood cell types. We used deformability cytometry (DC) for all cell types and Laser-assisted Optical Rotational Red Cell Analysis (Lorrca) to assess red blood cell (RBC) deformability. We also investigated the correlation between changes in the physical properties of blood cells and changes in the Omega-3 Index (O3I), defined as the relative content of EPA+DHA in RBCs. Following supplementation, the mean±SD O3I increased from 5.3 %±1.5 % to 8.3 %±1.4 % (p < 0.001). No significant changes in RBC properties were found by both techniques. However, by DC we observed a consistent pattern of physical changes in lymphocytes, neutrophils and monocytes. Among these were significant increases in metrics correlated with the cells' deformability resulting in less stiff cells. The results suggest that leukocytes become softer and have an increased ability to deform under induced short-term physical stress such as hydrodynamic force in the circulation. These changes could impact immune function since softer leukocytes can potentially circulate more easily and could facilitate a more rapid response to systemic inflammation or infection. In conclusion, fish-oil supplementation modulates some physical properties of leukocyte-subfractions, potentially enhancing their biological function. Further studies are warranted to explore the impact of n3-PUFA on blood cell biology, particularly in disease states associated with leukocyte dysregulation.

Lower omega-3 status associated with higher erythrocyte distribution width and neutrophil-lymphocyte ratio in UK Biobank cohort.

High red blood distribution width (RDW) is associated with decreased red blood cell deformability, and high neutrophil-lymphocyte ratio (NLR) is a biomarker of systemic inflammation and innate-adaptive immune system imbalance. Both RDW and NLR are predictors of chronic disease risk and mortality. Omega-3 index (O3I) values have previously been shown to be inversely associated with RDW and NLR levels. Our objective was to determine if total plasma long chain omega-3 fatty acids (Omega3%) measured in the UK Biobank cohort were associated with RDW and NLR values. RDW- and NLR- relationships with Omega3% were characterized in 109,191 adults (58.4% female). RDW- and NLR-Omega3% relationships were inversely associated with Omega3% (both p < 0.0001). These cross-sectional associations confirm previous findings that increasing RDW and NLR values are associated with low O3I. The hypothesis that RDW and/or NLR values can be reduced in individuals with less-than optimal long chain omega 3 values need to be tested in randomized controlled intervention trials using EPA and/or DHA.

Association between blood N-3 fatty acid levels and the risk of coronavirus disease 2019 in the UK Biobank.

BACKGROUND: The role of nutritional status and the risk of contracting and/or experiencing adverse outcomes from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are unclear. Preliminary studies suggest that higher n-3 PUFA intakes are protective. OBJECTIVES: This study aimed to compare the risk of 3 coronavirus disease 2019 (COVID-19) outcomes (testing positive for SARS-CoV-2, hospitalization, and death) as a function of the baseline plasma DHA levels. METHODS: The DHA levels (% of total fatty acids [FAs]) were measured by nuclear magnetic resonance. The 3 outcomes and relevant covariates were available for 110,584 subjects (hospitalization and death) and for 26,595 ever-tested subjects (positive for SARS-CoV-2) in the UK Biobank prospective cohort study. Outcome data between 1 January, 2020, and 23 March, 2021, were included. The Omega-3 Index (O3I) (RBC EPA + DHA%) values across DHA% quintiles were estimated. The multivariable Cox proportional hazards models were constructed, and linear (per 1 SD) relations with the risk of each outcome were computed as HRs. RESULTS: In the fully adjusted models, comparing the fifth to the first DHA% quintiles, the HRs (95% confidence intervals) for testing positive, being hospitalized, and dying with COVID-19 were 0.79 (0.71, 0.89, P < 0.001), 0.74 (0.58, 0.94, P < 0.05), and 1.04 (0.69-1.57, not significant), respectively. On a per 1-SD increase in DHA% basis, the HRs for testing positive, hospitalization, and death, were 0.92 (0.89, 0.96, P < 0.001), 0.89 (0.83, 0.97, P < 0.01), and 0.95 (0.83, 1.09), respectively. The estimated O3I values across DHA quintiles ranged from 3.5% (quintile 1) to 8% (quintile 5). CONCLUSIONS: These findings suggest that nutritional strategies to increase the circulating n-3 PUFA levels, such as increased consumption of oily fish and/or use of n-3 FA supplements, may reduce the risk of adverse COVID-19 outcomes.

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.