Gene-vegetarianism interactions in calcium, estimated glomerular filtration rate, and testosterone identified in genome-wide analysis across 30 biomarkers.

We examined the associations of vegetarianism with metabolic biomarkers using traditional and genetic epidemiology. First, we addressed inconsistencies in self-reported vegetarianism among UK Biobank participants by utilizing data from two dietary surveys to find a cohort of strict European vegetarians (N = 2,312). Vegetarians were matched 1:4 with nonvegetarians for non-genetic association analyses, revealing significant effects of vegetarianism in 15 of 30 biomarkers. Cholesterol measures plus vitamin D were significantly lower in vegetarians, while triglycerides were higher. A genome-wide association study revealed no genome-wide significant (GWS; 5×10-8) associations with vegetarian behavior. We performed genome-wide gene-vegetarianism interaction analyses for the biomarkers, and detected a GWS interaction impacting calcium at rs72952628 (P = 4.47×10-8). rs72952628 is in MMAA, a B12 metabolic pathway gene; B12 has major deficiency potential in vegetarians. Gene-based interaction tests revealed two significant genes, RNF168 in testosterone (P = 1.45×10-6) and DOCK4 in estimated glomerular filtration rate (eGFR) (P = 6.76×10-7), which have previously been associated with testicular and renal traits, respectively. These nutrigenetic findings indicate genotype can modify the associations between vegetarianism and health outcomes.

Correction: Genome-wide association study of fish oil supplementation on lipid traits in 81,246 individuals reveals new gene-diet interaction loci.

[This corrects the article DOI: 10.1371/journal.pgen.1009431.].

Accelerated expansion of pathogenic mitochondrial DNA heteroplasmies in Huntington's disease.

Mitochondrial dysfunction is found in the brain and peripheral tissues of patients diagnosed with Huntington's disease (HD), an irreversible neurodegenerative disease of which aging is a major risk factor. Mitochondrial function is encoded by not only nuclear DNA but also DNA within mitochondria (mtDNA). Expansion of mtDNA heteroplasmies (coexistence of mutated and wild-type mtDNA) can contribute to age-related decline of mitochondrial function but has not been systematically investigated in HD. Here, by using a sensitive mtDNA-targeted sequencing method, we studied mtDNA heteroplasmies in lymphoblasts and longitudinal blood samples of HD patients. We found a significant increase in the fraction of mtDNA heteroplasmies with predicted pathogenicity in lymphoblasts from 1,549 HD patients relative to lymphoblasts from 182 healthy individuals. The increased fraction of pathogenic mtDNA heteroplasmies in HD lymphoblasts also correlated with advancing HD stages and worsened disease severity measured by HD motor function, cognitive function, and functional capacity. Of note, elongated CAG repeats in HTT promoted age-dependent expansion of pathogenic mtDNA heteroplasmies in HD lymphoblasts. We then confirmed in longitudinal blood samples of 169 HD patients that expansion of pathogenic mtDNA heteroplasmies was correlated with decline in functional capacity and exacerbation of HD motor and cognitive functions during a median follow-up of 6 y. The results of our study indicate accelerated decline of mtDNA quality in HD, and highlight monitoring mtDNA heteroplasmies longitudinally as a way to investigate the progressive decline of mitochondrial function in aging and age-related diseases.

Genome-wide association study of fish oil supplementation on lipid traits in 81,246 individuals reveals new gene-diet interaction loci.

Fish oil supplementation is widely used for reducing serum triglycerides (TAGs) but has mixed effects on other circulating cardiovascular biomarkers. Many genetic polymorphisms have been associated with blood lipids, including high- and low-density-lipoprotein cholesterol (HDL-C, LDL-C), total cholesterol, and TAGs. Here, the gene-diet interaction effects of fish oil supplementation on these lipids were analyzed in a discovery cohort of up to 73,962 UK Biobank participants, using a 1-degree-of-freedom (1df) test for interaction effects and a 2-degrees-of-freedom (2df) test to jointly analyze interaction and main effects. Associations with P < 1×10-6 in either test (26,157; 18,300 unique variants) were advanced to replication in up to 7,284 participants from the Atherosclerosis Risk in Communities (ARIC) Study. Replicated associations reaching 1df P < 0.05 (2,175; 1,763 unique variants) were used in meta-analyses. We found 13 replicated and 159 non-replicated (UK Biobank only) loci with significant 2df joint tests that were predominantly driven by main effects and have been previously reported. Four novel interaction loci were identified with 1df P < 5×10-8 in meta-analysis. The lead variant in the GJB6-GJB2-GJA3 gene cluster, rs112803755 (A>G; minor allele frequency = 0.041), shows exclusively interaction effects. The minor allele is significantly associated with decreased TAGs in individuals with fish oil supplementation, but with increased TAGs in those without supplementation. This locus is significantly associated with higher GJB2 expression of connexin 26 in adipose tissue; connexin activity is known to change upon exposure to omega-3 fatty acids. Significant interaction effects were also found in three other loci in the genes SLC12A3 (HDL-C), ABCA6 (LDL-C), and MLXIPL (LDL-C), but highly significant main effects are also present. Our study identifies novel gene-diet interaction effects for four genetic loci, whose effects on blood lipids are modified by fish oil supplementation. These findings highlight the need and possibility for personalized nutrition.

Recent advances in understanding the adaptive evolution of metabolic genes and traits.

PURPOSE OF REVIEW: This review summarizes the recent advances in understanding the adaptive evolution of metabolic genes and traits, providing insights into gene-diet interactions in human evolution and health. RECENT FINDINGS: The rapid accumulation of ancient DNA across time and geography illuminates unprecedented details of some well-established examples of genetic adaptation to diet, such as the LCT and FADS genes. Novel cases of thrifty genes were identified, especially a microRNA at the LCT locus that controls energy expenditure and glucose homeostasis, connecting the historical adaptation to present-day metabolic disorders. A new example of gene-diet-microbiota interactions was established among the AMY1 copy number, starchy diets, and resistant-starch-digesting Ruminococcus. The explosion of genome-wide association studies in large cohorts unravels the present-day health implications of historically adaptive genetic variants. It also enables studies into the polygenic adaptation of metabolic traits, revealing intriguing adaptive signals for increased bone mineral density, blood pressure, and risk of type 2 diabetes, but decreased body mass index and HbA1c. SUMMARY: The rapid accumulation of ancient and modern DNA has fueled the characterization of novel and existing cases of genetic adaptation. However, transferring these evolutionary insights into genome-informed precision nutrition requires extensive mechanistic studies and genotype-aware clinical trials.

Cognitive disorders associated with hospitalization of COVID-19: Results from an observational cohort study.

INTRODUCTION: Our understanding of risk factors for COVID­19, including pre-existing medical conditions and genetic variations, is limited. To what extent the pre-existing clinical condition and genetic background have implications for COVID-19 still needs to be explored. METHODS: Our study included 389,620 participants of European descent from the UK Biobank, of whom 3,884 received the COVID-19 test and 1,091 were tested positive for COVID-19. We examined the association of COVID-19 status with an extensive list of 974 medical conditions and 30 blood biomarkers. Additionally, we tested the association of genetic variants in two key genes related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2), with COVID-19 or any other phenotypes. RESULTS: The most significant risk factors for COVID-19 include Alzheimer's disease (OR = 2.29, 95% CI: 1.25-4.16), dementia (OR = 2.16, 95% CI: 1.36-3.42), and the overall category of delirium, dementia, amnestic and other cognitive disorders (OR = 1.90, 95% CI: 1.24-2.90). Evidence suggesting associations of genetic variants in SARS-CoV-2 infection-related genes with COVID-19 (rs7282236, OR = 1.33, 95% CI: 1.14-1.54, p = 2.31 × 10-4) and other phenotypes, such as an immune deficiency (p = 5.65 × 10-5) and prostate cancer (p = 1.1 × 10-5), was obtained. CONCLUSIONS: Our unbiased and extensive search identified pre-existing Alzheimer's disease and dementia as top risk factors for hospital admission due to COVID-19, highlighting the importance of providing special protective care for patients with cognitive disorders during this pandemic. We also obtained evidence suggesting a direct association of genetic variants with COVID-19.

Childhood adversity is linked to adult health among African Americans via adolescent weight gain and effects are genetically moderated.

Identifying the mechanisms linking early experiences, genetic risk factors, and their interaction with later health consequences is central to the development of preventive interventions and identifying potential boundary conditions for their efficacy. In the current investigation of 412 African American adolescents followed across a 20-year period, we examined change in body mass index (BMI) across adolescence as one possible mechanism linking childhood adversity and adult health. We found associations of childhood adversity with objective indicators of young adult health, including a cardiometabolic risk index, a methylomic aging index, and a count of chronic health conditions. Childhood adversities were associated with objective indicators indirectly through their association with gains in BMI across adolescence and early adulthood. We also found evidence of an association of genetic risk with weight gain across adolescence and young adult health, as well as genetic moderation of childhood adversity's effect on gains in BMI, resulting in moderated mediation. These patterns indicated that genetic risk moderated the indirect pathways from childhood adversity to young adult health outcomes and childhood adversity moderated the indirect pathways from genetic risk to young adult health outcomes through effects on weight gain during adolescence and early adulthood.

Actinomycin X2, an Antimicrobial Depsipeptide from Marine-Derived Streptomyces cyaneofuscatus Applied as a Good Natural Dye for Silk Fabric.

Actinomycins as clinical medicine have been extensively studied, while few investigations were conducted to discover the feasibility of actinomycins as antimicrobial natural dye contributing to the medical value of the functional fabrics. This study was focused on the application of actinomycin X2 (Ac.X2), a peptide pigment cultured from marine-derived Streptomyces cyaneofuscatus, in the dyeing and finishing of silk fabric. The dyeing potential of Ac.X2 with silk vs. cotton fabrics was assessed. As a result, the silk fabric exhibited greater uptake and color fastness with Ac.X2. Through Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), and X-ray diffraction (XRD) analyses, some changes of chemical property for the dyed fabric and Ac.X2 were studied. The silk fabric dyed with Ac.X2 exhibited good UV protection ability. The antibacterial properties of dyed and finished silk were also evaluated, which exhibited over 90% antibacterial activity even after 20 washing cycles. In addition, the brine shrimp assay was conducted to evaluate the general toxicity of the tested fabric, and the results indicated that the dyed silk fabrics had a good biological safety property.

Comparative Genomic Insights into Secondary Metabolism Biosynthetic Gene Cluster Distributions of Marine Streptomyces.

Bacterial secondary metabolites have huge application potential in multiple industries. Biosynthesis of bacterial secondary metabolites are commonly encoded in a set of genes that are organized in the secondary metabolism biosynthetic gene clusters (SMBGCs). The development of genome sequencing technology facilitates mining bacterial SMBGCs. Marine Streptomyces is a valuable resource of bacterial secondary metabolites. In this study, 87 marine Streptomyces genomes were obtained and carried out into comparative genomic analysis, which revealed their high genetic diversity due to pan-genomes owning 123,302 orthologous clusters. Phylogenomic analysis indicated that the majority of Marine Streptomyces were classified into three clades named Clade I, II, and III, containing 23, 38, and 22 strains, respectively. Genomic annotations revealed that SMBGCs in the genomes of marine Streptomyces ranged from 16 to 84. Statistical analysis pointed out that phylotypes and ecotypes were both associated with SMBGCs distribution patterns. The Clade I and marine sediment-derived Streptomyces harbored more specific SMBGCs, which consisted of several common ones; whereas the Clade II and marine invertebrate-derived Streptomyces have more SMBGCs, acting as more plentiful resources for mining secondary metabolites. This study is beneficial for broadening our knowledge about SMBGC distribution patterns in marine Streptomyces and developing their secondary metabolites in the future.

Independent impacts of aging on mitochondrial DNA quantity and quality in humans.

BACKGROUND: The accumulation of mitochondrial DNA (mtDNA) mutations, and the reduction of mtDNA copy number, both disrupt mitochondrial energetics, and may contribute to aging and age-associated phenotypes. However, there are few genetic and epidemiological studies on the spectra of blood mtDNA heteroplasmies, and the distribution of mtDNA copy numbers in different age groups and their impact on age-related phenotypes. In this work, we used whole-genome sequencing data of isolated peripheral blood mononuclear cells (PBMCs) from the UK10K project to investigate in parallel mtDNA heteroplasmy and copy number in 1511 women, between 17 and 85 years old, recruited in the TwinsUK cohorts. RESULTS: We report a high prevalence of pathogenic mtDNA heteroplasmies in this population. We also find an increase in mtDNA heteroplasmies with age (ß = 0.011, P = 5.77e-6), and showed that, on average, individuals aged 70-years or older had 58.5% more mtDNA heteroplasmies than those under 40-years old. Conversely, mtDNA copy number decreased by an average of 0.4 copies per year (ß = -0.395, P = 0.0097). Multiple regression analyses also showed that age had independent effects on mtDNA copy number decrease and heteroplasmy accumulation. Finally, mtDNA copy number was positively associated with serum bicarbonate level (P = 4.46e-5), and inversely correlated with white blood cell count (P = 0.0006). Moreover, the aggregated heteroplasmy load was associated with blood apolipoprotein B level (P = 1.33e-5), linking the accumulation of mtDNA mutations to age-related physiological markers. CONCLUSIONS: Our population-based study indicates that both mtDNA quality and quantity are influenced by age. An open question for the future is whether interventions that would contribute to maintain optimal mtDNA copy number and prevent the expansion of heteroplasmy could promote healthy aging.

Positive Selection on a Regulatory Insertion-Deletion Polymorphism in FADS2 Influences Apparent Endogenous Synthesis of Arachidonic Acid.

Long chain polyunsaturated fatty acids (LCPUFA) are bioactive components of membrane phospholipids and serve as substrates for signaling molecules. LCPUFA can be obtained directly from animal foods or synthesized endogenously from 18 carbon precursors via the FADS2 coded enzyme. Vegans rely almost exclusively on endogenous synthesis to generate LCPUFA and we hypothesized that an adaptive genetic polymorphism would confer advantage. The rs66698963 polymorphism, a 22-bp insertion-deletion within FADS2, is associated with basal FADS1 expression, and coordinated induction of FADS1 and FADS2 in vitro. Here, we determined rs66698963 genotype frequencies from 234 individuals of a primarily vegetarian Indian population and 311 individuals from the US. A much higher I/I genotype frequency was found in Indians (68%) than in the US (18%). Analysis using 1000 Genomes Project data confirmed our observation, revealing a global I/I genotype of 70% in South Asians, 53% in Africans, 29% in East Asians, and 17% in Europeans. Tests based on population divergence, site frequency spectrum, and long-range haplotype consistently point to positive selection encompassing rs66698963 in South Asian, African, and some East Asian populations. Basal plasma phospholipid arachidonic acid (ARA) status was 8% greater in I/I compared with D/D individuals. The biochemical pathway product-precursor difference, ARA minus linoleic acid, was 31% and 13% greater for I/I and I/D compared with D/D, respectively. This study is consistent with previous in vitro data suggesting that the insertion allele enhances n-6 LCPUFA synthesis and may confer an adaptive advantage in South Asians because of the traditional plant-based diet practice.

Extensive pathogenicity of mitochondrial heteroplasmy in healthy human individuals.

A majority of mitochondrial DNA (mtDNA) mutations reported to be implicated in diseases are heteroplasmic, a status with coexisting mtDNA variants in a single cell. Quantifying the prevalence of mitochondrial heteroplasmy and its pathogenic effect in healthy individuals could further our understanding of its possible roles in various diseases. A total of 1,085 human individuals from 14 global populations have been sequenced by the 1000 Genomes Project to a mean coverage of ∼2,000× on mtDNA. Using a combination of stringent thresholds and a maximum-likelihood method to define heteroplasmy, we demonstrated that ∼90% of the individuals carry at least one heteroplasmy. At least 20% of individuals harbor heteroplasmies reported to be implicated in disease. Mitochondrial heteroplasmy tend to show high pathogenicity, and is significantly overrepresented in disease-associated loci. Consistent with their deleterious effect, heteroplasmies with derived allele frequency larger than 60% within an individual show a significant reduction in pathogenicity, indicating the action of purifying selection. Purifying selection on heteroplasmies can also be inferred from nonsynonymous and synonymous heteroplasmy comparison and the unfolded site frequency spectra for different functional sites in mtDNA. Nevertheless, in comparison with population polymorphic mtDNA mutations, the purifying selection is much less efficient in removing heteroplasmic mutations. The prevalence of mitochondrial heteroplasmy with high pathogenic potential in healthy individuals, along with the possibility of these mutations drifting to high frequency inside a subpopulation of cells across lifespan, emphasizes the importance of managing mitochondrial heteroplasmy to prevent disease progression.

Association of mitochondrial DNA variants with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) symptoms.

Earlier this year, we described an analysis of mitochondrial DNA (mtDNA) variants in myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) patients and healthy controls. We reported that there was no significant association of haplogroups or singe nucleotide polymorphisms (SNPs) with disease status. Nevertheless, a commentary about our paper appeared (Finsterer and Zarrouk-Mahjoub. J Transl Med14:182, 2016) that criticized the association of mtDNA haplogroups with ME/CFS, a conclusion that was absent from our paper. The aforementioned commentary also demanded experiments that were outside of the scope of our study, ones that we had suggested as follow-up studies. Because they failed to consult a published and cited report describing the cohorts we studied, the authors also cast aspersions on the method of selection of cases for inclusion. We reiterate that we observed statistically significant association of mtDNA variants with particular symptoms and their severity, though we observed no association with disease status.

Mitochondrial DNA variants correlate with symptoms in myalgic encephalomyelitis/chronic fatigue syndrome.

BACKGROUND: Mitochondrial dysfunction has been hypothesized to occur in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a disease characterized by fatigue, cognitive difficulties, pain, malaise, and exercise intolerance. We investigated whether haplogroup, single nucleotide polymorphisms (SNPs), or heteroplasmy of mitochondrial DNA (mtDNA) were associated with health status and/or symptoms. METHODS: Illumina sequencing of PCR-amplified mtDNA was performed to analyze sequence and extent of heteroplasmy of mtDNAs of 193 cases and 196 age- and gender-matched controls from DNA samples collected by the Chronic Fatigue Initiative. Association testing was carried out to examine possible correlations of mitochondrial sequences with case/control status and symptom constellation and severity as reported by subjects on Short Form-36 and DePaul Symptom Questionnaires. RESULTS: No ME/CFS subject exhibited known disease-causing mtDNA mutations. Extent of heteroplasmy was low in all subjects. Although no association between mtDNA SNPs and ME/CFS vs. healthy status was observed, haplogroups J, U and H as well as eight SNPs in ME/CFS cases were significantly associated with individual symptoms, symptom clusters, or symptom severity. CONCLUSIONS: Analysis of mitochondrial genomes in ME/CFS cases indicates that individuals of a certain haplogroup or carrying specific SNPs are more likely to exhibit certain neurological, inflammatory, and/or gastrointestinal symptoms. No increase in susceptibility to ME/CFS of individuals carrying particular mitochondrial genomes or SNPs was observed.

Natural selection on HFE in Asian populations contributes to enhanced non-heme iron absorption.

BACKGROUND: HFE, a major regulator of iron (Fe) homeostasis, has been suggested to be under positive selection in both European and Asian populations. While the genetic variant under selection in Europeans (a non-synonymous mutation, C282Y) has been relatively well-studied, the adaptive variant in Asians and its functional consequences are still unknown. Identifying the adaptive HFE variants in Asians will not only elucidate the evolutionary history and the genetic basis of population difference in Fe status, but also assist the future practice of genome-informed dietary recommendation. RESULTS: Using data from the International HapMap Project, we confirmed the signatures of positive selection on HFE in Asian populations and identified a candidate adaptive haplotype that is common in Asians (52.35-54.71%) but rare in Europeans (5.98%) and Africans (4.35%). The T allele at tag SNP rs9366637 (C/T) captured 95.8% of this Asian-common haplotype. A significantly reduced HFE expression was observed in individuals carrying T/T at rs9366637 compared to C/C and C/T, indicating a possible role of gene regulation in adaptation. We recruited 57 women of Asian descent and measured Fe absorption using stable isotopes in those homozygous at rs9366637. We observed a 22% higher absorption in women homozygous for the Asian-common haplotype (T/T) compared to the control genotype (C/C). Additionally, compared with a group of age-matched Caucasian women, Asian women exhibited significantly elevated Fe absorption. CONCLUSIONS: Our results indicate parallel adaptation of HFE gene in Europeans and Asians with different genetic variants. Moreover, natural selection on HFE may have contributed to elevated Fe absorption in Asians. This study regarding population differences in Fe homeostasis has significant medical impact as high Fe level has been linked to an increased disease risk of metabolic syndromes.

Higher ratio of plasma omega-6/omega-3 fatty acids is associated with greater risk of all-cause, cancer, and cardiovascular mortality: a population-based cohort study in UK Biobank.

Background: Circulating omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) have been associated with various chronic diseases and mortality, but results are conflicting. Few studies examined the role of omega-6/omega-3 ratio in mortality. Methods: We investigated plasma omega-3 and omega-6 PUFAs and their ratio in relation to all-cause and cause-specific mortality in a large prospective cohort, the UK Biobank. Of 85,425 participants who had complete information on circulating PUFAs, 6,461 died during follow-up, including 2,794 from cancer and 1,668 from cardiovascular disease (CVD). Associations were estimated by multivariable Cox proportional hazards regression with adjustment for relevant risk factors. Results: Risk for all three mortality outcomes increased as the ratio of omega-6/omega-3 PUFAs increased (all Ptrend < 0.05). Comparing the highest to the lowest quintiles, individuals had 26% (95% CI, 15-38%) higher total mortality, 14% (95% CI, 0-31%) higher cancer mortality, and 31% (95% CI, 10-55%) higher CVD mortality. Moreover, omega-3 and omega-6 PUFAs in plasma were all inversely associated with all-cause, cancer, and CVD mortality, with omega-3 showing stronger effects. Conclusions: Using a population-based cohort in UK Biobank, our study revealed a strong association between the ratio of circulating omega-6/omega-3 PUFAs and the risk of all-cause, cancer, and CVD mortality.

Fish oil supplementation modifies the associations between genetically predicted and observed concentrations of blood lipids: a cross-sectional gene-diet interaction study in UK Biobank.

BACKGROUND: Dyslipidemia is a well-known risk factor for cardiovascular disease, the leading cause of mortality worldwide. Although habitual intake of fish oil is associated with cardioprotective effects through triglyceride reduction, the interactions of fish oil with the genetic predisposition to dysregulated lipids remain elusive. OBJECTIVES: We examined whether fish oil supplementation modifies the association between genetically predicted and observed concentrations of total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. METHODS: A total of 441,985 participants with complete genetic and phenotypic data from the UK Biobank were included. Polygenic scores (PGS) of the 4 lipids were calculated in participants of diverse ancestries. For each lipid, multivariable linear regression models were used to assess if fish oil supplementation modified the association between PGS and the observed circulating concentration, with adjustment for relevant covariates. RESULTS: Fish oil supplementation attenuates the associations between genetically predicted and observed circulating concentrations of total cholesterol, LDL cholesterol, and triglycerides while accentuating the corresponding association for HDL cholesterol among 424,090 participants of European ancestry. Consistent significant findings were obtained using PGS calculated based on multiple genome-wide association studies or alternative PGS methods. For triglycerides, each standard deviation (SD) increment in PGS is associated with 0.254 [95% confidence interval (CI): 0.248, 0.259] SD increase in the observed concentration among European-ancestry participants who reported fish oil usage. In contrast, a stronger association was observed in nonusers (0.267; 95% CI: 0.263, 0.270). Consistently, we showed that fish oil significantly attenuates the association between genetically predicted and observed concentrations of triglycerides in African-ancestry participants. CONCLUSIONS: Fish oil supplementation attenuates the association between genetically predicted and observed circulating concentrations of total cholesterol, LDL cholesterol, and triglycerides while accentuating the corresponding association for HDL cholesterol in individuals of European ancestry. Further research is needed to understand the clinical implications of these findings.

Associations of plasma omega-6 and omega-3 fatty acids with overall and 19 site-specific cancers: a population-based cohort study in UK Biobank.

Background: Previous epidemiological studies of the associations between polyunsaturated fatty acids (PUFAs) and cancer incidence have been inconsistent. We investigated the associations of plasma omega-3 and omega-6 PUFAs with the incidence of overall and 19 site-specific cancers in a large prospective cohort. Methods: 253,138 eligible UK Biobank participants were included in our study. With a mean follow-up of 12.9 years, 29,838 participants were diagnosed with cancer. The plasma levels of omega-3 and omega-6 PUFAs were expressed as percentages of total fatty acids (omega-3% and omega-6%). Results: In our main models, both omega-6% and omega-3% were inversely associated with overall cancer incidence (HR per SD = 0.98, 95% CI = 0.96-0.99; HR per SD = 0.99, 95% CI = 0.97-1.00; respectively). Of the 19 site-specific cancers available, 14 were associated with omega-6% and five with omega-3%, all indicating inverse associations, with the exception that prostate cancer was positively associated with omega-3% (HR per SD = 1.03, 95% CI = 1.01 - 1.05). Conclusions: Our population-based cohort study in UK Biobank indicates small inverse associations of plasma omega-6 and omega-3 PUFAs with the incidence of overall and most site-specific cancers, although there are notable exceptions, such as prostate cancer.

Higher ratio of plasma omega-6/omega-3 fatty acids is associated with greater risk of all-cause, cancer, and cardiovascular mortality: A population-based cohort study in UK Biobank.

Background: Circulating omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) have been associated with various chronic diseases and mortality, but results are conflicting. Few studies examined the role of omega-6/omega-3 ratio in mortality. Methods: We investigated plasma omega-3 and omega-6 PUFAs and their ratio in relation to all-cause and cause-specific mortality in a large prospective cohort, the UK Biobank. Of 85,425 participants who had complete information on circulating PUFAs, 6461 died during follow-up, including 2794 from cancer and 1668 from cardiovascular disease (CVD). Associations were estimated by multivariable Cox proportional hazards regression with adjustment for relevant risk factors. Results: Risk for all three mortality outcomes increased as the ratio of omega-6/omega-3 PUFAs increased (all Ptrend <0.05). Comparing the highest to the lowest quintiles, individuals had 26% (95% CI, 15-38%) higher total mortality, 14% (95% CI, 0-31%) higher cancer mortality, and 31% (95% CI, 10-55%) higher CVD mortality. Moreover, omega-3 and omega-6 PUFAs in plasma were all inversely associated with all-cause, cancer, and CVD mortality, with omega-3 showing stronger effects. Conclusions: Using a population-based cohort in UK Biobank, our study revealed a strong association between the ratio of circulating omega-6/omega-3 PUFAs and the risk of all-cause, cancer, and CVD mortality. Funding: Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institute of Health under the award number R35GM143060 (KY). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Fatty acids play an essential role in health. Studies have shown that diets high in omega-3 fatty acids found in foods like fish, fish oil, flaxseed and walnuts may be beneficial. Yet some studies have raised concern that too many omega-6 fatty acids in Western diets rich in vegetable oils may be harmful. Some scientists have proposed that the balance of omega-3 and omega-6 in diets is vital to health. They hypothesize that a higher omega-6 to omega-3 fatty acids ratio is detrimental. But, proving that a higher ratio of omega-6 to omega-3 fatty acids is harmful has been difficult. Many studies have found conflicting results. Scientists have struggled to accurately measure fatty acid intake as tracking an individual's dietary intake is challenging and self-reported dietary intake may be incorrect. Additionally, scientists must follow individuals for many years to determine if a high ratio of omega-6 to omega-3 is linked with cancer, heart disease, or death. But, measuring circulating fatty acids in an individual's blood may offer an easier and more reliable approach to studying the health impacts of these vital nutrients. Zhang et al. show that people with higher ratios of omega-6 to omega-3 fatty acids in their blood are at greater risk of dying from cancer, heart disease, or any cause than those with lower ratios. The experiments measured omega-6 and omega-3 fatty acid levels in more than 85,000 participants in the UK Biobank who scientists followed for an average of about 13 years. Participants with the highest ratios of omega-6 to omega-3 fatty acids were 26% more likely to die of any cause, 14% more likely to die of cancer, and 31% more likely to die of heart disease than individuals with the lowest ratios. Individually, high levels of omega-6 fatty acids and high levels of omega-3 fatty acids were both associated with a lower risk of dying. But the protective effects of omega-3 were greater. For example, individuals with the highest levels of omega-6 fatty acids were 23% less likely to die of any cause. By comparison, those with the highest levels of omega-3s were 31% less likely to die. The stronger protection offered by high levels of omega-3s likely explains why having a high ratio of omega-6s to omega-3s was linked to harm. Both are protective. But the protection provided by omega-3s is more robust. The experiments support dietary interventions to raise omega-3 fatty acid levels and maintain a low omega-6 to omega-3 fatty acid ratio to prevent early deaths from cancer, heart disease or other causes. More research is needed to understand the impact of dietary fatty acid intake on other diseases and how genetics may influence the health impact of fatty acids.