Very long-chain saturated fatty acids and diabetes and cardiovascular disease.

PURPOSE OF REVIEW: In contrast to other saturated fatty acids, very long-chain saturated fatty acids (VLSFAs) have received limited attention The purpose of this review is to summarize the associations of VLSFAs, including arachidic acid, behenic acid, and lignoceric acid, with cardiovascular disease outcomes and type 2 diabetes; to discuss the findings implications; and to call for future studies of the VLSFAs. RECENT FINDINGS: Increased levels of circulating VLSFAs have been found associated with lower risks of incident heart failure, atrial fibrillation, coronary heart disease, mortality, sudden cardiac arrest, type 2 diabetes, and with better aging. The VLSFA associations are paralleled by associations of plasma ceramide and sphingomyelin species carrying a VLSFA with lower risks of heart failure, atrial fibrillation, and mortality, suggesting VLSFAs affect the biological activity of ceramides and sphingomyelins thereby impacting health. For diabetes, there is no such parallel and the associations of VLSFAs with diabetes may be confounded or mediated by triglyceride and circulating palmitic acid, possible biomarkers of de novo lipogenesis. SUMMARY: In many ways, the epidemiology has preceded our knowledge of VLSFAs biology. We hope this review will spur interest from the research community in further studying these potentially beneficial fatty acids.

Circulating ceramides and sphingomyelins and the risk of incident cardiovascular disease among people with diabetes: the strong heart study.

BACKGROUND: Plasma ceramides and sphingomyelins have been independently linked to diabetes risk, glucose and insulin levels, and the risk of several cardiovascular (CVD) outcomes. However, whether individual ceramide and sphingomyelin species contribute to CVD risk among people with type 2 diabetes is uncertain. Our goal was to evaluate associations of 4 ceramide and 4 sphingomyelin species with incident CVD in a longitudinal population-based study among American Indians with diabetes. METHODS: This analysis included participants with prevalent type 2 diabetes from two cohorts: a prospective cohort of 597 participants in the Strong Heart Family Study (116 incident CVD cases; mean age: 49 years; average length of follow-up: 14 years), and a nested case-control sample of 267 participants in the Strong Heart Study (78 cases of CVD and 189 controls; mean age: 61 years; average time until incident CVD in cases: 3.8 years). The average onset of diabetes was 7 years prior to sphingolipid measurement. Sphingolipid species were measured using liquid chromatography and mass spectrometry. Cox regression and logistic regression were used to assess associations of sphingolipid species with incident CVD; results were combined across cohorts using inverse-variance weighted meta-analysis. RESULTS: There were 194 cases of incident CVD in the two cohorts. In meta-analysis of the 2 cohort results, higher plasma levels of Cer-16 (ceramide with acylated palmitic acid) were associated with higher CVD risk (HR per two-fold higher Cer-16: 1.85; 95% CI 1.05-3.25), and higher plasma levels of sphingomyelin species with a very long chain saturated fatty acid were associated with lower CVD risk (HR per two-fold higher SM-22: 0.48; 95% CI 0.26-0.87), although none of the associations met our pre-specified threshold for statistical significance of p = 0.006. CONCLUSIONS: While replication of the findings from the SHS in other populations is warranted, our findings add to a growing body of research suggesting that ceramides, in particular Cer-16, not only are associated with higher diabetes risk, but may also be associated with higher CVD risk after diabetes onset. We also find support for the hypothesis that sphingomyelins with a very long chain saturated fatty acid are associated with lower CVD risk among adults with type 2 diabetes.

Plasma ceramides containing saturated fatty acids are associated with risk of type 2 diabetes.

Recent studies suggest that the type of saturated fatty acid bound to sphingolipids influences the biological activity of those sphingolipids. However, it is unknown whether associations of sphingolipids with diabetes may differ by the identity of bound lipid species. Here, we investigated associations of 15 ceramide (Cer) and SM species (i.e., all sphingolipids, measured with coefficient of variation less than 20%) with incident type 2 diabetes in the Cardiovascular Health Study (n = 3,645), a large cohort study of cardiovascular disease among elderly adults who were followed from 1989 to 2015. Diabetes incidence was defined as fasting glucose ≥126 mg/dl or nonfasting glucose ≥200 mg/dl; reported use of insulin or oral hypoglycemic medication; or documentation of diabetes diagnosis through the Centers for Medicare and Medicaid Services records. Associations of each sphingolipid with incident diabetes were assessed using a Cox proportional hazards regression model. We found that higher circulating levels of Cer with acylated palmitic acid (Cer-16), stearic acid containing Cer (Cer-18), arachidic acid containing Cer (Cer-20), and behenic acid containing Cer (Cer-22) were each associated with a higher risk of diabetes. The hazard ratios for incident diabetes per 1 SD higher log levels of each Cer species were as follows: 1.21 (95% CI: 1.09-1.34) for Cer-16, 1.23 (95% CI: 1.10-1.37) for Cer-18, 1.14 (95% CI: 1.02-1.26) for Cer-20, and 1.18 (95% CI: 1.06-1.32) for Cer-22. In conclusion, higher levels of Cer-16, Cer-18, Cer-20, and Cer-22 were associated with a higher risk of diabetes.

Circulating Ceramides and Sphingomyelins and Risk of Mortality: The Cardiovascular Health Study.

BACKGROUND: Recent studies suggest that associations of ceramides (Cer) and sphingomyelins (SM) with health outcomes differ according to the fatty acid acylated to the sphingoid backbone. The purpose of this study was to assess associations of Cer and SM species with mortality. METHODS: The study population included participants from the Cardiovascular Health Study (CHS), a community-based cohort of adults aged ≥65 years who were followed from 1992-2015 (n = 4612). Associations of plasma Cer and SM species carrying long-chain (i.e., 16:0) and very-long-chain (i.e., 20:0, 22:0, 24:0) saturated fatty acids with mortality were assessed using Cox proportional hazards models. RESULTS: During a median follow-up of 10.2 years, 4099 deaths occurred. High concentrations of Cer and SM carrying fatty acid 16:0 were each associated with an increased risk of mortality. Conversely, high concentrations of several ceramide and sphingomyelin species carrying longer fatty acids were each associated with a decreased risk of mortality. The hazard ratios for total mortality per 2-fold difference in each Cer and SM species were: 1.89 (95% CI), 1.65-2.17 for Cer-16, 0.79 (95% CI, 0.70-0.88) for Cer-22, 0.74 (95% CI, 0.65-0.84) for Cer-24, 2.51 (95% CI, 2.01-3.14) for SM-16, 0.68 (95% CI, 0.58-0.79) for SM-20, 0.57 (95% CI, 0.49-0.67) for SM-22, and 0.66 (0.57-0.75) for SM-24. We found no association of Cer-20 with risk of death. CONCLUSIONS: Associations of Cer and SM with the risk of death differ according to the length of their acylated saturated fatty acid. Future studies are needed to explore mechanisms underlying these relationships.

Plasma Ceramide Species Are Associated with Diabetes Risk in Participants of the Strong Heart Study.

BACKGROUND: Few studies have assessed the associations of ceramides and sphingomyelins (SMs) with diabetes in humans. OBJECTIVE: We assessed associations of 15 circulating ceramides and SM species with incident diabetes in 2 studies. METHODS: The analysis included 435 American-Indian participants from the Strong Heart Study (nested case-control design for analyses; mean age: 57 y; 34% male; median time until diabetes 4.3 y for cases) and 1902 participants from the Strong Heart Family Study (prospective design for analyses; mean age: 37 y; 39% male; median 12.5 y of follow-up). Sphingolipid species were measured using stored plasma samples by sequential LC and MS. Using logistic regression and parametric survival models within studies, and an inverse-variance-weighted meta-analysis across studies, we examined associations of 15 ceramides and SM species with incident diabetes. RESULTS: There were 446 cases of incident diabetes across the studies. Higher circulating concentrations of ceramides containing stearic acid (Cer-18), arachidic acid (Cer-20), and behenic acid (Cer-22) were each associated with a higher risk of diabetes. The RRs for incident diabetes per 1 SD of each log ceramide species (µM) were 1.22 (95% CI: 1.09, 1.37) for Cer-18, 1.18 (95% CI: 1.06, 1.31) for Cer-20, and 1.20 (95% CI: 1.08, 1.32) for Cer-22. Although the magnitude of the risk estimates for the association of ceramides containing lignoceric acid (Cer-24) with diabetes was similar to those for Cer-18, Cer-20, and Cer-22 (RR = 1.13; 95% CI: 1.01, 1.26), the association was not statistically significant after correction for multiple testing (P = 0.007). Ceramides carrying palmitic acid (Cer-16), SMs, glucosyl-ceramides, or a lactosyl-ceramide were not associated with diabetes risk. CONCLUSIONS: Higher concentrations of circulating Cer-18, Cer-20, and Cer-22 were associated with a higher risk of developing diabetes in 2 studies of American-Indian adults. This trial was registered at clinicaltrials.gov as NCT00005134.

Discovery and fine-mapping of loci associated with MUFAs through trans-ethnic meta-analysis in Chinese and European populations.

MUFAs are unsaturated FAs with one double bond and are derived from endogenous synthesis and dietary intake. Accumulating evidence has suggested that plasma and erythrocyte MUFA levels are associated with cardiometabolic disorders, including CVD, T2D, and metabolic syndrome (MS). Previous genome-wide association studies (GWASs) have identified seven loci for plasma and erythrocyte palmitoleic and oleic acid levels in populations of European origin. To identify additional MUFA-associated loci and the potential functional variant at each locus, we performed ethnic-specific GWAS meta-analyses and trans-ethnic meta-analyses in more than 15,000 participants of Chinese and European ancestry. We identified novel genome-wide significant associations for vaccenic acid at FADS1/2 and PKD2L1 [log10(Bayes factor) ≥ 8.07] and for gondoic acid at FADS1/2 and GCKR [log10(Bayes factor) ≥ 6.22], and also observed improved fine-mapping resolutions at FADS1/2 and GCKR loci. The greatest improvement was observed at GCKR, where the number of variants in the 99% credible set was reduced from 16 (covering 94.8 kb) to 5 (covering 19.6 kb, including a missense variant rs1260326) after trans-ethnic meta-analysis. We also confirmed the previously reported associations of PKD2L1, FADS1/2, GCKR, and HIF1AN with palmitoleic acid and of FADS1/2 and LPCAT3 with oleic acid in the Chinese-specific GWAS and the trans-ethnic meta-analyses. Pathway-based analyses suggested that the identified loci were in unsaturated FA metabolism and signaling pathways. Our findings provide novel insight into the genetic basis relevant to MUFA metabolism and biology.

Associations of Plasma Phospholipid SFAs with Total and Cause-Specific Mortality in Older Adults Differ According to SFA Chain Length.

BACKGROUND: Not much is known about the relations of circulating saturated fatty acids (SFAs), which are influenced by both metabolic and dietary determinants, with total and cause-specific mortality. OBJECTIVE: We examined the associations of plasma phospholipid SFAs with total and cause-specific mortality among 3941 older adults from the Cardiovascular Health Study, a population-based prospective study of adults aged ≥65 y who were followed from 1992 through 2011. METHODS: The relations of total and cause-specific mortality with plasma phospholipid palmitic acid (16:0), stearic acid (18:0), arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) were assessed using Cox proportional hazards models. RESULTS: During 45,450 person-years of follow-up, 3134 deaths occurred. Higher concentrations of the plasma phospholipid SFAs 18:0, 22:0, and 24:0 were associated with a lower risk of total mortality [multivariable-adjusted HRs (95% CIs)] for the top compared with the bottom quintile: 0.85 (0.75, 0.95) for 18:0; 0.85 (0.75, 0.95) for 22:0; and 0.80 (0.71, 0.90) for 24:0. In contrast, plasma 16:0 concentrations in the highest quintile were associated with a higher risk of total mortality compared with concentrations in the lowest quintile [1.25 (1.11, 1.41)]. We also found no association of plasma phospholipid 20:0 with total mortality. CONCLUSIONS: These findings suggest that the associations of plasma phospholipid SFAs with the risk of death differ according to SFA chain length and support future studies to better characterize the determinants of circulating SFAs and to explore the mechanisms underlying these relations.

Genetic loci associated with circulating levels of very long-chain saturated fatty acids.

Very long-chain saturated fatty acids (VLSFAs) are saturated fatty acids with 20 or more carbons. In contrast to the more abundant saturated fatty acids, such as palmitic acid, there is growing evidence that circulating VLSFAs may have beneficial biological properties. Whether genetic factors influence circulating levels of VLSFAs is not known. We investigated the association of common genetic variation with plasma phospholipid/erythrocyte levels of three VLSFAs by performing genome-wide association studies in seven population-based cohorts comprising 10,129 subjects of European ancestry. We observed associations of circulating VLSFA concentrations with common variants in two genes, serine palmitoyl-transferase long-chain base subunit 3 (SPTLC3), a gene involved in the rate-limiting step of de novo sphingolipid synthesis, and ceramide synthase 4 (CERS4). The SPTLC3 variant at rs680379 was associated with higher arachidic acid (20:0 , P = 5.81 × 10(-13)). The CERS4 variant at rs2100944 was associated with higher levels of 20:0 (P = 2.65 × 10(-40)) and in analyses that adjusted for 20:0, with lower levels of behenic acid (P = 4.22 × 10(-26)) and lignoceric acid (P = 3.20 × 10(-21)). These novel associations suggest an inter-relationship of circulating VLSFAs and sphingolipid synthesis.

Circulating omega-6 polyunsaturated fatty acids and total and cause-specific mortality: the Cardiovascular Health Study.

BACKGROUND: Although omega-6 polyunsaturated fatty acids (n-6 PUFA) have been recommended to reduce coronary heart disease (CHD), controversy remains about benefits versus harms, including concerns over theorized proinflammatory effects of n-6 PUFA. We investigated associations of circulating n-6 PUFA including linoleic acid (the major dietary PUFA), γ-linolenic acid, dihomo-γ-linolenic acid, and arachidonic acid, with total and cause-specific mortality in the Cardiovascular Health Study, a community-based U.S. cohort. METHODS AND RESULTS: Among 2792 participants(aged ≥65 years) free of cardiovascular disease at baseline, plasma phospholipid n-6 PUFA were measured at baseline using standardized methods. All-cause and cause-specific mortality, and total incident CHD and stroke, were assessed and adjudicated centrally. Associations of PUFA with risk were assessed by Cox regression. During 34 291 person-years of follow-up (1992-2010), 1994 deaths occurred (678 cardiovascular deaths), with 427 fatal and 418 nonfatal CHD, and 154 fatal and 399 nonfatal strokes. In multivariable models, higher linoleic acid was associated with lower total mortality, with extreme-quintile hazard ratio =0.87 (P trend=0.005). Lower death was largely attributable to cardiovascular disease causes, especially nonarrhythmic CHD mortality (hazard ratio, 0.51; 95% confidence interval, 0.32-0.82; P trend=0.001). Circulating γ-linolenic acid, dihomo-γ-linolenic acid, and arachidonic acid were not significantly associated with total or cause-specific mortality (eg, for arachidonic acid and CHD death, the extreme-quintile hazard ratio was 0.97; 95% confidence interval, 0.70-1.34; P trend=0.87). Evaluated semiparametrically, linoleic acid showed graded inverse associations with total mortality (P=0.005). There was little evidence that associations of n-6 PUFA with total mortality varied by age, sex, race, or plasma n-3 PUFA. Evaluating both n-6 and n-3 PUFA, lowest risk was evident with highest levels of both. CONCLUSIONS: High circulating linoleic acid, but not other n-6 PUFA, was inversely associated with total and CHD mortality in older adults.

Plasma nutrient biomarkers are associated with waist-to-height ratio in youth with type 1 diabetes.

BACKGROUND: Plasma fatty acids (FAs) and micronutrients have been associated with central obesity in adults; however, previous studies of these associations in adults have yielded mixed results. In addition, no comparable research has been conducted among youth with type 1 diabetes (T1D). OBJECTIVE: We investigated the cross-sectional and longitudinal associations between plasma nutrient biomarkers and waist-to-height ratio (WHtR) in youth with T1D. METHODS: These analyses included 1324 youth aged 3-20 y at T1D diagnosis with a baseline visit in the SEARCH (Search for Diabetes in Youth) Study and a subset of 1178 of these youth with a follow-up visit an average of 23 mo (range: 16-40 mo) after their baseline visit. Plasma phospholipid FAs and vitamins were measured, and estimated desaturase activities were calculated at baseline. Anthropometric measurements and diabetes-related assessments were collected at each visit. Multiple linear regression was used to examine the association between plasma nutrient biomarkers and WHtR. RESULTS: In cross-sectional analysis, plasma palmitic acid (P = 0.004), dihomo-γ-linolenic acid (DGLA; P = 0.017) and Δ6 desaturase (D6D; P = 0.006) were positively correlated with WHtR after adjustment of confounders. Oleic acid (OA; P = 0.002), linoleic acid (LA; P = 0.015), Δ9 desaturase 18 (D9D-18; P = 0.027), and vitamin D (P < 0.0001) were negatively correlated with WHtR after adjustment. Weight status was an effect modifier (P < 0.05). In normal-weight youth, vitamin D (P = 0.003) was negatively associated with WHtR. In obese youth, stearic acid (P = 0.037), DGLA (P < 0.0001), and D6D (P < 0.0001) were positively associated and OA (P = 0.0008), D9D-18 (P = 0.0006), and vitamin D (P < 0.0001) were negatively associated with WHtR. In longitudinal analysis, baseline linoleic acid (P = 0.018), n-6:n-3 (ω-3:ω-6) FA ratio (P = 0.029), vitamin D (P = 0.003), and vitamin E (P < 0.0001) were negatively correlated with WHtR at follow-up only in obese participants. CONCLUSIONS: In T1D youth, plasma FAs and vitamins are associated with WHtR and are modified by weight status. These associations are particularly marked in obese youth.

Long-chain monounsaturated Fatty acids and incidence of congestive heart failure in 2 prospective cohorts.

BACKGROUND: Decades-old animal experiments suggested that dietary long-chain monounsaturated fatty acids (LCMUFAs) caused cardiotoxicity, leading, for example, development of Canola oil (Canadian oil low in erucic acid) from rapeseed. However, potential cardiotoxicity in humans and contemporary dietary sources of LCMUFAs are unknown. METHODS AND RESULTS: We prospectively investigated the associations of plasma phospholipid LCMUFAs (20:1, 22:1, and 24:1), assessed as objective biomarkers of exposure, with incidence congestive heart failure in 2 independent cohorts: 3694 older adults (mean age, 75.2±5.2 years) in the Cardiovascular Health Study (CHS; 1992-2006) and 3577 middle-aged adults (mean age, 54.1±5.8 years) in the Atherosclerosis Risk in Communities Study, Minnesota subcohort (ARIC; 1987-2008). We further examined dietary correlates of circulating LCMUFAs in CHS and ARIC and US dietary sources of LCMUFAs in the 2003-2010 National Health and Nutrition Examination Survey (NHANES). In CHS, 997 congestive heart failure events occurred during 39 238 person-years; in ARIC, 330 events congestive heart failure events occurred during 64 438 person-years. After multivariable adjustment, higher levels of 22:1 and 24:1 were positively associated with greater incident congestive heart failure in both CHS and ARIC; hazard ratios were 1.34 (95% confidence interval, 1.02-1.76) and 1.57 (95% confidence interval, 1.11-2.23) for highest versus lowest quintiles of 22:1, respectively, and 1.75 (95% confidence interval, 1.23-2.50) and 1.92 (95% confidence interval, 1.22-3.03) for 24:1, respectively (P for trend ≤0.03 each). A variety of foods were related to circulating LCMUFAs in CHS and ARIC, consistent with food sources of LCMUFAs in NHANES, including fish, poultry, meats, whole grains, and mustard. CONCLUSIONS: Higher circulating levels of 22:1 and 24:1, with apparently diverse dietary sources, were associated with incident congestive heart failure in 2 independent cohorts, suggesting possible cardiotoxicity of LCMUFAs in humans.

Plasma phospholipid and dietary α-linolenic acid, mortality, CHD and stroke: the Cardiovascular Health Study.

Previous studies have suggested that long-chain n-3 fatty acids derived from seafood are associated with a lower risk of mortality, CHD and stroke. Whether α-linolenic acid (ALA, 18 : 3n-3), a plant-derived long-chain essential n-3 fatty acid, is associated with a lower risk of these outcomes is unclear. The aim of the present study was to examine the associations of plasma phospholipid and dietary ALA with the risk of mortality, CHD and stroke among older adults who participated in the Cardiovascular Health Study, a cohort study of adults aged ≥ 65 years. A total of 2709 participants were included in the plasma phospholipid ALA analysis and 2583 participants were included in the dietary ALA analysis. Cox regression was used to assess the associations of plasma phospholipid and dietary ALA with the risk of mortality, incident CHD and stroke. In minimally and multivariable-adjusted models, plasma phospholipid ALA was found to be not associated with the risk of mortality, incident CHD or stroke. After adjustment for age, sex, race, enrolment site, education, smoking status, diabetes, BMI, alcohol consumption, treated hypertension and total energy intake, higher dietary ALA intake was found to be associated with a lower risk of total and non-cardiovascular mortality; on comparing the highest quintiles of dietary ALA with the lowest quintiles, the HR for total mortality and non-cardiovascular mortality were found to be 0·73 (95 % CI 0·61, 0·88) and 0·64 (95 % CI 0·52, 0·80), respectively. Dietary ALA was found to be not associated with the risk of cardiovascular mortality, incident CHD or stroke. In conclusion, the results of the present suggest study that dietary ALA, but not plasma phospholipid ALA, is associated with a lower risk of total and non-cardiovascular mortality in older adults.

Plasma phospholipid long-chain ω-3 fatty acids and total and cause-specific mortality in older adults: a cohort study.

BACKGROUND: Long-chain ω-3 polyunsaturated fatty acids (ω3-PUFAs), including eicosapentaenoic acid (EPA) (20:5ω-3), docosapentaenoic acid (DPA) (22:5ω-3), and docosahexaenoic acid (DHA) (22:6ω-3), have been shown to reduce cardiovascular risk, but effects on cause-specific and total mortality and potential dose-responses remain controversial. Most observational studies have assessed self-reported dietary intake and most randomized trials have tested effects of adding supplements to dietary intake and evaluated secondary prevention, thus limiting inference for dietary ω3-PUFAs or primary prevention. OBJECTIVE: To investigate associations of plasma phospholipid EPA, DPA, DHA, and total ω3-PUFA levels with total and cause-specific mortality among healthy older adults not receiving supplements. DESIGN: Prospective cohort study. SETTING: 4 U.S. communities. PARTICIPANTS: 2692 U.S. adults aged 74 years (±5 years) without prevalent coronary heart disease (CHD), stroke, or heart failure at baseline. MEASUREMENTS: Phospholipid fatty acid levels and cardiovascular risk factors were measured in 1992. Relationships with total and cause-specific mortality and incident fatal or nonfatal CHD and stroke through 2008 were assessed. RESULTS: During 30 829 person-years, 1625 deaths (including 570 cardiovascular deaths), 359 fatal and 371 nonfatal CHD events, and 130 fatal and 276 nonfatal strokes occurred. After adjustment, higher plasma levels of ω3-PUFA biomarkers were associated with lower total mortality, with extreme-quintile hazard ratios of 0.83 for EPA (95% CI, 0.71 to 0.98; P for trend = 0.005), 0.77 for DPA (CI, 0.66 to 0.90; P for trend = 0.008), 0.80 for DHA (CI, 0.67 to 0.94; P for trend = 0.006), and 0.73 for total ω3-PUFAs (CI, 0.61 to 0.86; P for trend < 0.001). Lower risk was largely attributable to fewer cardiovascular than noncardiovascular deaths. Individuals in the highest quintile of phospholipid ω3-PUFA level lived an average of 2.22 more years (CI, 0.75 to 3.13 years) after age 65 years than did those in the lowest quintile. LIMITATION: Temporal changes in fatty acid levels and misclassification of causes of death may have resulted in underestimated associations, and unmeasured or imperfectly measured covariates may have caused residual confounding. CONCLUSION: Higher circulating individual and total ω3-PUFA levels are associated with lower total mortality, especially CHD death, in older adults. PRIMARY FUNDING SOURCE: National Institutes of Health.

Genetic loci associated with plasma phospholipid n-3 fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium.

Long-chain n-3 polyunsaturated fatty acids (PUFAs) can derive from diet or from α-linolenic acid (ALA) by elongation and desaturation. We investigated the association of common genetic variation with plasma phospholipid levels of the four major n-3 PUFAs by performing genome-wide association studies in five population-based cohorts comprising 8,866 subjects of European ancestry. Minor alleles of SNPs in FADS1 and FADS2 (desaturases) were associated with higher levels of ALA (p = 3 x 10⁻64) and lower levels of eicosapentaenoic acid (EPA, p = 5 x 10⁻58) and docosapentaenoic acid (DPA, p = 4 x 10⁻¹54). Minor alleles of SNPs in ELOVL2 (elongase) were associated with higher EPA (p = 2 x 10⁻¹²) and DPA (p = 1 x 10⁻4³) and lower docosahexaenoic acid (DHA, p = 1 x 10⁻¹5). In addition to genes in the n-3 pathway, we identified a novel association of DPA with several SNPs in GCKR (glucokinase regulator, p = 1 x 10⁻8). We observed a weaker association between ALA and EPA among carriers of the minor allele of a representative SNP in FADS2 (rs1535), suggesting a lower rate of ALA-to-EPA conversion in these subjects. In samples of African, Chinese, and Hispanic ancestry, associations of n-3 PUFAs were similar with a representative SNP in FADS1 but less consistent with a representative SNP in ELOVL2. Our findings show that common variation in n-3 metabolic pathway genes and in GCKR influences plasma phospholipid levels of n-3 PUFAs in populations of European ancestry and, for FADS1, in other ancestries.

Circulating Sphingolipids and All-Cause Mortality: The Strong Heart Family Study.

BACKGROUND: A growing body of research indicates that associations of ceramides and sphingomyelins with mortality depend on the chain length of the fatty acid acylated to the backbone sphingoid base. We examined associations of 8 ceramide and sphingomyelin species with mortality among an American Indian population. METHODS AND RESULTS: The analysis comprised 2688 participants from the SHFS (Strong Heart Family Study). Plasma ceramide and sphingomyelin species carrying long-chain (ie, 16:0) and very-long-chain (ie, 20:0, 22:0, 24:0) saturated fatty acids were measured by sequential liquid chromatography and mass spectroscopy using samples from 2001 to 2003. Participants were followed for 18.8 years (2001-2020). Associations of ceramides and sphingomyelins with mortality were assessed using Cox models. The mean age of participants was 40.8 years. There were 574 deaths during a median 17.4-year follow-up. Ceramides and sphingomyelins carrying fatty acid 16:0 were positively associated with mortality. Ceramides and sphingomyelins carrying longer fatty acids were inversely associated with mortality. Per SD difference in each ceramide and sphingomyelin species, hazard ratios for death were: 1.68 (95% CI, 1.44-1.96) for ceramide-16 (Cer-16), 0.82 (95% CI, 0.71-0.95) for Cer-20, 0.60 (95% CI, 0.51-0.70) for Cer-22, 0.67 (95% CI, 0.56-0.79) for Cer-24, 1.80 (95% CI-1.57, 2.05) for sphingomyelin-16 (SM-16), 0.54 (95% CI, 0.47-0.62) for SM-20, 0.50 (95% CI, 0.44-0.57) for SM-22, and 0.59 (95% CI, 0.52-0.67) for SM-24. CONCLUSIONS: The direction/magnitude of associations of ceramides and sphingomyelins with mortality differs according to the length of the fatty acid acylated to the backbone sphingoid base. REGISTRATION: URL: https://www.clinicatrials.gov; Unique identifier: NCT00005134.

Association of plasma phospholipid long-chain ω-3 fatty acids with incident atrial fibrillation in older adults: the cardiovascular health study.

BACKGROUND: Experimental studies suggest that long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) may reduce the risk of atrial fibrillation (AF). Prior studies evaluating fish or n-3 PUFA consumption from dietary questionnaires and incident AF have been conflicting. Circulating levels of n-3 PUFAs provide an objective measurement of exposure. METHODS AND RESULTS: Among 3326 US men and women ≥65 years of age and free of AF or heart failure at baseline, plasma phospholipid levels of eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid were measured at baseline by use of standardized methods. Incident AF (789 cases) was identified prospectively from hospital discharge records and study visit ECGs during 31 169 person-years of follow-up (1992-2006). In multivariable Cox models adjusted for other risk factors, the relative risk in the top versus lowest quartile of total n-3 PUFAs (eicosapentaenoic acid+docosapentaenoic acid+docosahexaenoic acid) levels was 0.71 (95% confidence interval, 0.57-0.89; P for trend=0.004) and of DHA levels was 0.77 (95% confidence interval, 0.62-0.96; P for trend=0.01). Eicosapentaenoic acid and docosapentaenoic acid levels were not significantly associated with incident AF. Evaluated nonparametrically, both total n-3 PUFAs and docosahexaenoic acid showed graded and linear inverse associations with incidence of AF. Adjustment for intervening events such as heart failure or myocardial infarction during follow-up did not appreciably alter results. CONCLUSIONS: In older adults, higher circulating total long-chain n-3 PUFA and docosahexaenoic acid levels were associated with lower risk of incident AF. These results highlight the need to evaluate whether increased dietary intake of these fatty acids could be effective for the primary prevention of AF.

Serum phospholipid fatty acids, genetic variation in myeloperoxidase, and prostate cancer risk in heavy smokers: a gene-nutrient interaction in the carotene and retinol efficacy trial.

The authors investigated associations of serum phospholipid n-3 and n-6 polyunsaturated fatty acids (PUFAs) and trans-fatty acids with prostate cancer risk, and whether myeloperoxidase G-463A (rs2333227) modified the associations in the Carotene and Retinol Efficacy Trial (CARET) (Seattle, Washington; Irvine, California; New Haven, Connecticut; San Francisco, California; Baltimore, Maryland; and Portland, Oregon, 1985-2003). Prerandomization sera were assayed for fatty acids among 641 men with incident prostate cancer (368 nonaggressive and 273 aggressive (stage III/IV or Gleason score ≥7)) and 1,398 controls. Overall, dihomo-γ-linolenic (quartiles 4 vs. 1: odds ratio (OR) = 0.66, 95% confidence interval (CI): 0.49, 0.95; P(trend) = 0.024) and docosatetraenoic (OR = 0.69, 95% CI: 0.46, 1.02; P(trend) = 0.011) acids were inversely associated with nonaggressive and aggressive prostate cancer risks, respectively. Among men with MPO GG, the genotype upregulating oxidative stress, quartiles 4 versus 1 eicosapentaenoic plus docosahexaenoic acids were suggestively associated with an increased risk of aggressive prostate cancer (OR = 1.66, 95% CI: 0.95, 2.92; P(trend) = 0.07). However, the association was the inverse among men with MPO GA/AA genotypes (P(interaction) = 0.011). Interactions were also observed for docosapentaenoic acid, total n-3 PUFAs, and arachidonic acid. MPO GA/AA vs. GG was associated with a 2-fold increase in aggressive prostate cancer risk among men with low (quartile 1) n-3 PUFAs. This study adds important evidence linking oxidative stress with prostate carcinogenesis.

The 2011-2016 Transdisciplinary Research on Energetics and Cancer (TREC) initiative: rationale and design.

PURPOSE: Recognition of the complex, multidimensional relationship between excess adiposity and cancer control outcomes has motivated the scientific community to seek new research models and paradigms. METHODS: The National Cancer Institute developed an innovative concept to establish a center grant mechanism in nutrition, energetics, and physical activity, referred to as the Transdisciplinary Research on Energetics and Cancer (TREC) Initiative. This paper gives an overview of the 2011-2016 TREC Collaborative Network and the 15 research projects being conducted at the centers. RESULTS: Four academic institutions were awarded TREC center grants in 2011: Harvard University, University of California San Diego, University of Pennsylvania, and Washington University in St. Louis. The Fred Hutchinson Cancer Research Center is the Coordination Center. The TREC research portfolio includes three animal studies, three cohort studies, four randomized clinical trials, one cross-sectional study, and two modeling studies. Disciplines represented by TREC investigators include basic science, endocrinology, epidemiology, biostatistics, behavior, medicine, nutrition, physical activity, genetics, engineering, health economics, and computer science. Approximately 41,000 participants will be involved in these studies, including children, healthy adults, and breast and prostate cancer survivors. Outcomes include biomarkers of cancer risk, changes in weight and physical activity, persistent adverse treatment effects (e.g., lymphedema, urinary and sexual function), and breast and prostate cancer mortality. CONCLUSION: The NIH Science of Team Science group will evaluate the value added by this collaborative science. However, the most important outcome will be whether this transdisciplinary initiative improves the health of Americans at risk of cancer as well as cancer survivors.

Circulating Omega-3 and Omega-6 Fatty Acids, Cognitive Decline, and Dementia in Older Adults.

BACKGROUND: Comprising nearly 35% of brain lipids, polyunsaturated fatty acids (PUFA) are essential for optimal brain function. However, the role of PUFA on cognitive health outcomes later in life is largely unknown. OBJECTIVE: We investigated prospective associations of plasma phospholipid omega-3 (ALA [18 : 3], EPA [20 : 5], DPA [22 : 5], DHA [22 : 6]) and omega-6 (LA [18 : 2], AA [20 : 4]) PUFA with cognitive decline, risk of cognitive impairment and dementia among adults aged≥65 years in the Cardiovascular Health Study. METHODS: Circulating fatty acid concentrations were measured serially at baseline (1992/1993), 6 years, and 13 years later. Cognitive decline and impairment were assessed using the 100-point Modified Mini-Mental State Examination (3MSE) up to 7 times. Clinical dementia was identified using adjudicated neuropsychological tests, and ICD-9 codes. RESULTS: Among 3,564 older adults free of stroke and dementia at baseline, cognitive function declined annually by approximately -0.5 3MSE points; 507 participants developed cognitive impairment and 499 dementia over up to 23 years of follow-up. In multivariable models, higher circulating arachidonic acid (AA) concentrations were associated with slower cognitive decline and lower dementia risk, with associations growing stronger with greater length of follow-up (hazard ratio [HR,95% CI] of dementia per interquintile range, 0.74 [0.56-0.97] at 5 years, and 0.53 [0.37-0.77] at 15 years). Circulating docosapentaenoic (DPA) concentrations were associated with slower cognitive decline and lower risk of cognitive impairment (extreme-quintile HR, 0.72 [95% CI: 0.55, 0.95]). Findings were generally null or inconsistent for other omega-3 or omega-6 PUFA. CONCLUSION: Circulating AA and DPA, but not other PUFA, are associated with slower rate of cognitive decline and lower risk of dementia or cognitive impairment later in life.

Plasma Ceramides and Sphingomyelins and Sudden Cardiac Death in the Cardiovascular Health Study.

Importance: Sphingolipids, including ceramides and sphingomyelins, may influence the pathophysiology and risk of sudden cardiac death (SCD) through multiple biological activities. Whether the length of the fatty acid acylated to plasma sphingolipid species is associated with SCD risk is not known. Objective: To determine whether the saturated fatty acid length of plasma ceramides and sphingomyelins influences the association with SCD risk. Design, Setting, and Participants: In this cohort study, multivariable Cox proportional hazards regression models were used to examine the association of sphingolipid species with SCD risk. The study population included 4612 participants in the Cardiovascular Health Study followed up prospectively for a median of 10.2 (IQR, 5.5-11.6) years. Baseline data were collected from January 1992 to December 1995 during annual examinations. Data were analyzed from February 11, 2020, to September 9, 2023. Exposures: Eight plasma sphingolipid species (4 ceramides and 4 sphingomyelins) with saturated fatty acids of 16, 20, 22, and 24 carbons. Main Outcome and Measure: Association of plasma ceramides and sphingomyelins with saturated fatty acids of different lengths with SCD risk. Results: Among the 4612 CHS participants included in the analysis (mean [SD] age, 77 [5] years; 2724 [59.1%] women; 6 [0.1%] American Indian; 4 [0.1%] Asian; 718 [15.6%] Black; 3869 [83.9%] White, and 15 [0.3%] Other), 215 SCD cases were identified. In adjusted Cox proportional hazards regression analyses, plasma ceramides and sphingomyelins with palmitic acid (Cer-16 and SM-16) were associated with higher SCD risk per higher SD of log sphingolipid levels (hazard ratio [HR] for Cer-16, 1.34 [95% CI, 1.12-1.59]; HR for SM-16, 1.37 [95% CI, 1.12-1.67]). Associations did not differ by baseline age, sex, race, or body mass index. No significant association of SCD with sphingolipids with very-long-chain saturated fatty acids was observed after correction for multiple testing (HR for ceramide with arachidic acid, 1.06 [95% CI, 0.90-1.24]; HR for ceramide with behenic acid, 0.92 [95% CI, 0.77-1.10]; HR for ceramide with lignoceric acid, 0.92 [95% CI, 0.77-1.09]; HR for sphingomyelin with arachidic acid, 0.83 [95% CI, 0.71-0.98]; HR for sphingomyelin with behenic acid, 0.84 [95% CI, 0.70-1.00]; HR for sphingomyelin with lignoceric acid, 0.86 [95% CI, 0.72-1.03]). Conclusions and Relevance: The findings of this large, population-based cohort study of SCD identified that higher plasma levels of Cer-16 and SM-16 were associated with higher risk of SCD. Future studies are needed to examine the underlying mechanism of these associations.