@article {1299, title = {Fatty acids in the de novo lipogenesis pathway and risk of coronary heart disease: the Cardiovascular Health Study.}, journal = {Am J Clin Nutr}, volume = {94}, year = {2011}, month = {2011 Aug}, pages = {431-8}, abstract = {

BACKGROUND: De novo lipogenesis (DNL) is an endogenous pathway whereby carbohydrates and proteins are converted to fatty acids. DNL could affect coronary heart disease (CHD) or sudden cardiac arrest (SCA) via generation of specific fatty acids. Whether these fatty acids are prospectively associated with SCA or other CHD events is unknown.

OBJECTIVE: The objective was to investigate the relations of 4 fatty acids in the DNL pathway-palmitic acid (16:0), palmitoleic acid (16:1n-7), 7-hexadecenoic acid (16:1n-9), and cis-vaccenic acid (18:1n-7)-with incident CHD, including fatal CHD, nonfatal myocardial infarction (NFMI), and SCA.

DESIGN: A community-based prospective study was conducted in 2890 men and women aged >=65 y, who were free of known CHD at baseline and who were followed from 1992 to 2006. Cardiovascular disease risk factors and plasma phospholipid fatty acids were measured at baseline by using standardized methods. Incident CHD was ascertained prospectively and was centrally adjudicated by using medical records. Risk was assessed by using multivariable-adjusted Cox proportional hazards.

RESULTS: During 29,835 person-years of follow-up, 631 CHD and 71 SCA events occurred. Both 18:1n-7 and 16:1n-9 were associated with a higher risk of SCA [multivariable-adjusted hazard ratio (95\% CI) for the interquintile range: 7.63 (2.58, 22.6) for 18:1n-7 and 2.30 (1.16, 4.55) for 16:1n-9] but not of total CHD, fatal CHD, or NFMI. In secondary analyses censored to mid-follow-up (7 y) to minimize the effects of changes in concentrations over time, 16:1n-9 was also associated with a significantly higher risk of total CHD (2.11; 1.76, 2.54), including a higher risk of CHD death, NFMI, and SCA; 16:0 and 16:1n-7 were not associated with clinical CHD outcomes.

CONCLUSION: Higher plasma phospholipid 18:1n-7 and 16:1n-9 concentrations were prospectively associated with an elevated risk of SCA but not of other CHD events, except in secondary analyses.

}, keywords = {Aged, Aged, 80 and over, Cohort Studies, Coronary Disease, Death, Sudden, Cardiac, Diet, Fatty Acids, Female, Humans, Lipogenesis, Male, Phospholipids, Proportional Hazards Models, Prospective Studies, Risk Factors}, issn = {1938-3207}, doi = {10.3945/ajcn.111.012054}, author = {Wu, Jason H Y and Lemaitre, Rozenn N and Imamura, Fumiaki and King, Irena B and Song, Xiaoling and Spiegelman, Donna and Siscovick, David S and Mozaffarian, Dariush} } @article {6281, title = {Lipoprotein receptor-related protein 1 variants and dietary fatty acids: meta-analysis of European origin and African American studies.}, journal = {Int J Obes (Lond)}, volume = {37}, year = {2013}, month = {2013 Sep}, pages = {1211-20}, abstract = {

OBJECTIVE: Low-density lipoprotein-related receptor protein 1 (LRP1) is a multi-functional endocytic receptor and signaling molecule that is expressed in adipose and the hypothalamus. Evidence for a role of LRP1 in adiposity is accumulating from animal and in vitro models, but data from human studies are limited. The study objectives were to evaluate (i) relationships between LRP1 genotype and anthropometric traits, and (ii) whether these relationships were modified by dietary fatty acids.

DESIGN AND METHODS: We conducted race/ethnic-specific meta-analyses using data from 14 studies of US and European whites and 4 of African Americans to evaluate associations of dietary fatty acids and LRP1 genotypes with body mass index (BMI), waist circumference and hip circumference, as well as interactions between dietary fatty acids and LRP1 genotypes. Seven single-nucleotide polymorphisms (SNPs) of LRP1 were evaluated in whites (N up to 42 000) and twelve SNPs in African Americans (N up to 5800).

RESULTS: After adjustment for age, sex and population substructure if relevant, for each one unit greater intake of percentage of energy from saturated fat (SFA), BMI was 0.104 kg m(-2) greater, waist was 0.305 cm larger and hip was 0.168 cm larger (all P<0.0001). Other fatty acids were not associated with outcomes. The association of SFA with outcomes varied by genotype at rs2306692 (genotyped in four studies of whites), where the magnitude of the association of SFA intake with each outcome was greater per additional copy of the T allele: 0.107 kg m(-2) greater for BMI (interaction P=0.0001), 0.267 cm for waist (interaction P=0.001) and 0.21 cm for hip (interaction P=0.001). No other significant interactions were observed.

CONCLUSION: Dietary SFA and LRP1 genotype may interactively influence anthropometric traits. Further exploration of this, and other diet x genotype interactions, may improve understanding of interindividual variability in the relationships of dietary factors with anthropometric traits.

}, keywords = {Adipose Tissue, Adult, African Continental Ancestry Group, Aged, Aged, 80 and over, Body Mass Index, Europe, European Continental Ancestry Group, Fatty Acids, Female, Gene Frequency, Gene-Environment Interaction, Genetic Predisposition to Disease, Genotype, Humans, Low Density Lipoprotein Receptor-Related Protein-1, Male, Middle Aged, Obesity, Phenotype, Polymorphism, Single Nucleotide, Prevalence, United States}, issn = {1476-5497}, doi = {10.1038/ijo.2012.215}, author = {Smith, C E and Ngwa, J and Tanaka, T and Qi, Q and Wojczynski, M K and Lemaitre, R N and Anderson, J S and Manichaikul, A and Mikkil{\"a}, V and van Rooij, F J A and Ye, Z and Bandinelli, S and Frazier-Wood, A C and Houston, D K and Hu, F and Langenberg, C and McKeown, N M and Mozaffarian, D and North, K E and Viikari, J and Zillikens, M C and Djouss{\'e}, L and Hofman, A and K{\"a}h{\"o}nen, M and Kabagambe, E K and Loos, R J F and Saylor, G B and Forouhi, N G and Liu, Y and Mukamal, K J and Chen, Y-D I and Tsai, M Y and Uitterlinden, A G and Raitakari, O and van Duijn, C M and Arnett, D K and Borecki, I B and Cupples, L A and Ferrucci, L and Kritchevsky, S B and Lehtim{\"a}ki, T and Qi, Lu and Rotter, J I and Siscovick, D S and Wareham, N J and Witteman, J C M and Ordov{\'a}s, J M and Nettleton, J A} } @article {6325, title = {Common variation in fatty acid metabolic genes and risk of incident sudden cardiac arrest.}, journal = {Heart Rhythm}, volume = {11}, year = {2014}, month = {2014 Mar}, pages = {471-7}, abstract = {

BACKGROUND: There is limited information on genetic factors associated with sudden cardiac arrest (SCA).

OBJECTIVE: To assess the association of common variation in genes in fatty acid pathways with SCA risk.

METHODS: We selected 85 candidate genes and 1155 single nucleotide polymorphisms (SNPs) tagging common variation in each gene. We investigated the SNP associations with SCA in a population-based case-control study. Cases (n = 2160) were from a repository of SCA in the greater Seattle area. Controls (n = 2615), frequency-matched on age and sex, were from the same area. We used linear logistic regression to examine SNP associations with SCA. We performed permutation-based p-min tests to account for multiple comparisons within each gene. The SNP associations with a corrected P value of <.05 were then examined in a meta-analysis of these SNP associations in 9 replication studies totaling 2129 SCA cases and 23,833 noncases.

RESULTS: Eight SNPs in or near 8 genes were associated with SCA risk in the discovery study, one of which was nominally significant in the replication phase (rs7737692, minor allele frequency 36\%, near the LPCAT1 gene). For each copy of the minor allele, rs7737692 was associated with 13\% lower SCA risk (95\% confidence interval -21\% to -5\%) in the discovery phase and 9\% lower SCA risk (95\% confidence interval -16\% to -1\%) in the replication phase.

CONCLUSIONS: While none of the associations reached significance with Bonferroni correction, a common genetic variant near LPCAT1, a gene involved in the remodeling of phospholipids, was nominally associated with incident SCA risk. Further study is needed to validate this observation.

}, keywords = {1-Acylglycerophosphocholine O-Acyltransferase, Aged, Algorithms, Alleles, Case-Control Studies, Death, Sudden, Cardiac, Fatty Acids, Female, Genetic Predisposition to Disease, Genetic Variation, Genotype, Humans, Male, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1556-3871}, doi = {10.1016/j.hrthm.2014.01.008}, author = {Lemaitre, Rozenn N and Johnson, Catherine O and Hesselson, Stephanie and Sotoodehnia, Nona and Sotoodhenia, Nona and McKnight, Barbara and Sitlani, Colleen M and Rea, Thomas D and King, Irena B and Kwok, Pui-Yan and Mak, Angel and Li, Guo and Brody, Jennifer and Larson, Eric and Mozaffarian, Dariush and Psaty, Bruce M and Huertas-Vazquez, Adriana and Tardif, Jean-Claude and Albert, Christine M and Lyytik{\"a}inen, Leo-Pekka and Arking, Dan E and K{\"a}{\"a}b, Stefan and Huikuri, Heikki V and Krijthe, Bouwe P and Eijgelsheim, Mark and Wang, Ying A and Reinier, Kyndaron and Lehtim{\"a}ki, Terho and Pulit, Sara L and Brugada, Ramon and M{\"u}ller-Nurasyid, Martina and Newton-Cheh, Chris H and Karhunen, Pekka J and Stricker, Bruno H and Goyette, Philippe and Rotter, Jerome I and Chugh, Sumeet S and Chakravarti, Aravinda and Jouven, Xavier and Siscovick, David S} } @article {6397, title = {Plasma phospholipid saturated fatty acids and incident atrial fibrillation: the Cardiovascular Health Study.}, journal = {J Am Heart Assoc}, volume = {3}, year = {2014}, month = {2014 Jun 26}, pages = {e000889}, abstract = {

BACKGROUND: Prior studies suggest that circulating fatty acids may influence the risk of atrial fibrillation (AF), but little is known about the associations of circulating saturated fatty acids with risk of AF.

METHODS AND RESULTS: The study population included 2899 participants from the Cardiovascular Health Study, a community-based longitudinal cohort of adults aged 65 years or older in the United States who were free of prevalent coronary heart disease and AF in 1992. Cox regression was used to assess the association of all the long-chain saturated fatty acids-palmitic acid (16:0), stearic acid (18:0), arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0)-with incident AF. During a median of 11.2 years of follow-up, 707 cases of incident AF occurred. After adjustment for other AF risk factors, higher levels of circulating 16:0 were associated with a higher risk of AF (hazard ratio comparing highest and lowest quartiles: 1.48; 95\% CI: 1.18, 1.86). In contrast, higher levels of circulating 18:0, 20:0, 22:0, and 24:0 were each associated with a lower risk of AF. The hazard ratios (95\% CI) for AF in the top and bottom quartiles were 0.76 (95\% CI: 0.61, 0.95) for 18:0; 0.78 (95\% CI: 0.63, 0.97) for 20:0; 0.62 (95\% CI: 0.50, 0.78) for 22:0; and 0.68 (95\% CI: 0.55, 0.85) for 24:0.

CONCLUSIONS: Results from this prospective cohort study of older adults demonstrate divergent associations of circulating 16:0 versus longer-chain saturated fatty acids with incident AF, highlighting the need to investigate both determinants of these levels and potential pathways of the observed differential risk.

}, keywords = {Aged, Aged, 80 and over, Atrial Fibrillation, Eicosanoic Acids, Fatty Acids, Female, Humans, Longitudinal Studies, Male, Palmitic Acid, Phospholipids, Proportional Hazards Models, Prospective Studies, Risk Factors, Stearic Acids, United States}, issn = {2047-9980}, doi = {10.1161/JAHA.114.000889}, author = {Fretts, Amanda M and Mozaffarian, Dariush and Siscovick, David S and Djouss{\'e}, Luc and Heckbert, Susan R and King, Irena B and McKnight, Barbara and Sitlani, Colleen and Sacks, Frank M and Song, Xiaoling and Sotoodehnia, Nona and Spiegelman, Donna and Wallace, Erin R and Lemaitre, Rozenn N} } @article {6687, title = {Dietary fatty acids modulate associations between genetic variants and circulating fatty acids in plasma and erythrocyte membranes: Meta-analysis of nine studies in the CHARGE consortium.}, journal = {Mol Nutr Food Res}, volume = {59}, year = {2015}, month = {2015 Jul}, pages = {1373-83}, abstract = {

SCOPE: Tissue concentrations of omega-3 fatty acids may reduce cardiovascular disease risk, and genetic variants are associated with circulating fatty acids concentrations. Whether dietary fatty acids interact with genetic variants to modify circulating omega-3 fatty acids is unclear. We evaluated interactions between genetic variants and fatty acid intakes for circulating alpha-linoleic acid, eicosapentaenoic acid, docosahexaenoic acid, and docosapentaenoic acid.

METHODS AND RESULTS: We conducted meta-analyses (N = 11~668) evaluating interactions between dietary fatty acids and genetic variants (rs174538 and rs174548 in FADS1 (fatty acid desaturase 1), rs7435 in AGPAT3 (1-acyl-sn-glycerol-3-phosphate), rs4985167 in PDXDC1 (pyridoxal-dependent decarboxylase domain-containing 1), rs780094 in GCKR (glucokinase regulatory protein), and rs3734398 in ELOVL2 (fatty acid elongase 2)). Stratification by measurement compartment (plasma versus erthyrocyte) revealed compartment-specific interactions between FADS1 rs174538 and rs174548 and dietary alpha-linolenic acid and linoleic acid for docosahexaenoic acid and docosapentaenoic acid.

CONCLUSION: Our findings reinforce earlier reports that genetically based differences in circulating fatty acids may be partially due to differences in the conversion of fatty acid precursors. Further, fatty acids measurement compartment may modify gene-diet relationships, and considering compartment may improve the detection of gene-fatty acids interactions for circulating fatty acid outcomes.

}, keywords = {Acetyltransferases, Acyltransferases, Adaptor Proteins, Signal Transducing, Carboxy-Lyases, Diet, Docosahexaenoic Acids, Eicosapentaenoic Acid, Erythrocyte Membrane, Fatty Acid Desaturases, Fatty Acids, Fatty Acids, Omega-3, Female, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide}, issn = {1613-4133}, doi = {10.1002/mnfr.201400734}, author = {Smith, Caren E and Follis, Jack L and Nettleton, Jennifer A and Foy, Millennia and Wu, Jason H Y and Ma, Yiyi and Tanaka, Toshiko and Manichakul, Ani W and Wu, Hongyu and Chu, Audrey Y and Steffen, Lyn M and Fornage, Myriam and Mozaffarian, Dariush and Kabagambe, Edmond K and Ferruci, Luigi and Chen, Yii-Der Ida and Rich, Stephen S and Djouss{\'e}, Luc and Ridker, Paul M and Tang, Weihong and McKnight, Barbara and Tsai, Michael Y and Bandinelli, Stefania and Rotter, Jerome I and Hu, Frank B and Chasman, Daniel I and Psaty, Bruce M and Arnett, Donna K and King, Irena B and Sun, Qi and Wang, Lu and Lumley, Thomas and Chiuve, Stephanie E and Siscovick, David S and Ordovas, Jose M and Lemaitre, Rozenn N} } @article {6615, title = {Genetic loci associated with circulating levels of very long-chain saturated fatty acids.}, journal = {J Lipid Res}, volume = {56}, year = {2015}, month = {2015 Jan}, pages = {176-84}, abstract = {

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 {\texttimes} 10(-13)). The CERS4 variant at rs2100944 was associated with higher levels of 20:0 (P = 2.65 {\texttimes} 10(-40)) and in analyses that adjusted for 20:0, with lower levels of behenic acid (P = 4.22 {\texttimes} 10(-26)) and lignoceric acid (P = 3.20 {\texttimes} 10(-21)). These novel associations suggest an inter-relationship of circulating VLSFAs and sphingolipid synthesis.

}, keywords = {Cohort Studies, Fatty Acids, Genetic Loci, Genetic Variation, Genome-Wide Association Study, Humans}, issn = {1539-7262}, doi = {10.1194/jlr.M052456}, author = {Lemaitre, Rozenn N and King, Irena B and Kabagambe, Edmond K and Wu, Jason H Y and McKnight, Barbara and Manichaikul, Ani and Guan, Weihua and Sun, Qi and Chasman, Daniel I and Foy, Millennia and Wang, Lu and Zhu, Jingwen and Siscovick, David S and Tsai, Michael Y and Arnett, Donna K and Psaty, Bruce M and Djouss{\'e}, Luc and Chen, Yii-der I and Tang, Weihong and Weng, Lu-Chen and Wu, Hongyu and Jensen, Majken K and Chu, Audrey Y and Jacobs, David R and Rich, Stephen S and Mozaffarian, Dariush and Steffen, Lyn and Rimm, Eric B and Hu, Frank B and Ridker, Paul M and Fornage, Myriam and Friedlander, Yechiel} } @article {6663, title = {Plasma phospholipid very-long-chain saturated fatty acids and incident diabetes in older adults: the Cardiovascular Health Study.}, journal = {Am J Clin Nutr}, volume = {101}, year = {2015}, month = {2015 May}, pages = {1047-54}, abstract = {

BACKGROUND: Circulating saturated fatty acids (SFAs) are integrated biomarkers of diet and metabolism that may influence the pathogenesis of diabetes. In epidemiologic studies, circulating levels of palmitic acid (16:0) are associated with diabetes; however, very-long-chain SFAs (VLSFAs), with 20 or more carbons, differ from palmitic acid in their biological activities, and little is known of the association of circulating VLSFA with diabetes.

OBJECTIVE: By using data from the Cardiovascular Health Study, we examined the associations of plasma phospholipid VLSFA levels measured at baseline with subsequent incident diabetes.

DESIGN: A total of 3179 older adults, with a mean age of 75 y at study baseline (1992-1993), were followed through 2011. We used multiple proportional hazards regression to examine the associations of arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) with diabetes.

RESULTS: Baseline levels of each VLSFA were cross-sectionally associated with lower triglyceride levels and lower circulating palmitic acid. We identified 284 incident diabetes cases during follow-up. Compared with the lowest quartile, levels of arachidic acid in the highest quartile of the fatty acid distribution were associated with a 47\% lower risk of diabetes (95\% CI: 23\%, 63\%; P-trend: <0.001), after adjustment for demographics, lifestyle factors, and clinical conditions. In analogous comparisons, levels of behenic and lignoceric acid were similarly associated with 33\% (95\% CI: 6\%, 53\%; P-trend: 0.02) and 37\% (95\% CI: 11\%, 55\%; P-trend: 0.01) lower diabetes risk, respectively. Adjustment for triglycerides and palmitic acid attenuated the associations toward the null, and only the association of arachidic acid remained statistically significant (32\% lower risk for fourth vs. first quartile; P-trend: 0.04).

CONCLUSIONS: These results suggest that circulating VLSFAs are associated with a lower risk of diabetes, and these associations may be mediated by lower triglycerides and palmitic acid. The study highlights the need to distinguish the effects of different SFAs and to explore determinants of circulating VLSFAs. This trial was registered at clinicaltrials.gov as NCT00005133.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Cross-Sectional Studies, Diabetes Mellitus, Diet, Eicosanoic Acids, Fatty Acids, Fatty Acids, Nonesterified, Female, Follow-Up Studies, Humans, Incidence, Male, Observational Studies as Topic, Palmitic Acid, Phospholipids, Prospective Studies, Risk Factors, Triglycerides}, issn = {1938-3207}, doi = {10.3945/ajcn.114.101857}, author = {Lemaitre, Rozenn N and Fretts, Amanda M and Sitlani, Colleen M and Biggs, Mary L and Mukamal, Kenneth and King, Irena B and Song, Xiaoling and Djouss{\'e}, Luc and Siscovick, David S and McKnight, Barbara and Sotoodehnia, Nona and Kizer, Jorge R and Mozaffarian, Dariush} } @article {6929, title = {Associations of Plasma Phospholipid SFAs with Total and Cause-Specific Mortality in Older Adults Differ According to SFA Chain Length.}, journal = {J Nutr}, volume = {146}, year = {2016}, month = {2016 Feb}, pages = {298-305}, abstract = {

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.

}, keywords = {Aged, Aged, 80 and over, Cause of Death, Diet, Dietary Fats, Eicosanoic Acids, Fatty Acids, Female, Humans, Male, Mortality, Palmitic Acid, Phospholipids, Prospective Studies, Risk Factors, Stearic Acids}, issn = {1541-6100}, doi = {10.3945/jn.115.222117}, author = {Fretts, Amanda M and Mozaffarian, Dariush and Siscovick, David S and King, Irena B and McKnight, Barbara and Psaty, Bruce M and Rimm, Eric B and Sitlani, Colleen and Sacks, Frank M and Song, Xiaoling and Sotoodehnia, Nona and Spiegelman, Donna and Lemaitre, Rozenn N} } @article {6951, title = {Interaction of methylation-related genetic variants with circulating fatty acids on plasma lipids: a meta-analysis of 7 studies and methylation analysis of 3 studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.}, journal = {Am J Clin Nutr}, volume = {103}, year = {2016}, month = {2016 Feb}, pages = {567-78}, abstract = {

BACKGROUND: DNA methylation is influenced by diet and single nucleotide polymorphisms (SNPs), and methylation modulates gene expression.

OBJECTIVE: We aimed to explore whether the gene-by-diet interactions on blood lipids act through DNA methylation.

DESIGN: We selected 7 SNPs on the basis of predicted relations in fatty acids, methylation, and lipids. We conducted a meta-analysis and a methylation and mediation analysis with the use of data from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium and the ENCODE (Encyclopedia of DNA Elements) consortium.

RESULTS: On the basis of the meta-analysis of 7 cohorts in the CHARGE consortium, higher plasma HDL cholesterol was associated with fewer C alleles at ATP-binding cassette subfamily A member 1 (ABCA1) rs2246293 (β = -0.6 mg/dL, P = 0.015) and higher circulating eicosapentaenoic acid (EPA) (β = 3.87 mg/dL, P = 5.62 {\texttimes} 10(21)). The difference in HDL cholesterol associated with higher circulating EPA was dependent on genotypes at rs2246293, and it was greater for each additional C allele (β = 1.69 mg/dL, P = 0.006). In the GOLDN (Genetics of Lipid Lowering Drugs and Diet Network) study, higher ABCA1 promoter cg14019050 methylation was associated with more C alleles at rs2246293 (β = 8.84\%, P = 3.51 {\texttimes} 10(18)) and lower circulating EPA (β = -1.46\%, P = 0.009), and the mean difference in methylation of cg14019050 that was associated with higher EPA was smaller with each additional C allele of rs2246293 (β = -2.83\%, P = 0.007). Higher ABCA1 cg14019050 methylation was correlated with lower ABCA1 expression (r = -0.61, P = 0.009) in the ENCODE consortium and lower plasma HDL cholesterol in the GOLDN study (r = -0.12, P = 0.0002). An additional mediation analysis was meta-analyzed across the GOLDN study, Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis. Compared with the model without the adjustment of cg14019050 methylation, the model with such adjustment provided smaller estimates of the mean plasma HDL cholesterol concentration in association with both the rs2246293 C allele and EPA and a smaller difference by rs2246293 genotypes in the EPA-associated HDL cholesterol. However, the differences between 2 nested models were NS (P > 0.05).

CONCLUSION: We obtained little evidence that the gene-by-fatty acid interactions on blood lipids act through DNA methylation.

}, keywords = {Apolipoproteins E, ATP Binding Cassette Transporter 1, Cholesterol, HDL, Cohort Studies, Diet, DNA Methylation, Eicosapentaenoic Acid, Epigenesis, Genetic, Fatty Acids, Gene Expression Regulation, Humans, Lipids, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Triglycerides}, issn = {1938-3207}, doi = {10.3945/ajcn.115.112987}, author = {Ma, Yiyi and Follis, Jack L and Smith, Caren E and Tanaka, Toshiko and Manichaikul, Ani W and Chu, Audrey Y and Samieri, Cecilia and Zhou, Xia and Guan, Weihua and Wang, Lu and Biggs, Mary L and Chen, Yii-der I and Hernandez, Dena G and Borecki, Ingrid and Chasman, Daniel I and Rich, Stephen S and Ferrucci, Luigi and Irvin, Marguerite Ryan and Aslibekyan, Stella and Zhi, Degui and Tiwari, Hemant K and Claas, Steven A and Sha, Jin and Kabagambe, Edmond K and Lai, Chao-Qiang and Parnell, Laurence D and Lee, Yu-Chi and Amouyel, Philippe and Lambert, Jean-Charles and Psaty, Bruce M and King, Irena B and Mozaffarian, Dariush and McKnight, Barbara and Bandinelli, Stefania and Tsai, Michael Y and Ridker, Paul M and Ding, Jingzhong and Mstat, Kurt Lohmant and Liu, Yongmei and Sotoodehnia, Nona and Barberger-Gateau, Pascale and Steffen, Lyn M and Siscovick, David S and Absher, Devin and Arnett, Donna K and Ordovas, Jose M and Lemaitre, Rozenn N} } @article {8041, title = {Fatty acid biomarkers of dairy fat consumption and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies.}, journal = {PLoS Med}, volume = {15}, year = {2018}, month = {2018 10}, pages = {e1002670}, abstract = {

BACKGROUND: We aimed to investigate prospective associations of circulating or adipose tissue odd-chain fatty acids 15:0 and 17:0 and trans-palmitoleic acid, t16:1n-7, as potential biomarkers of dairy fat intake, with incident type 2 diabetes (T2D).

METHODS AND FINDINGS: Sixteen prospective cohorts from 12 countries (7 from the United States, 7 from Europe, 1 from Australia, 1 from Taiwan) performed new harmonised individual-level analysis for the prospective associations according to a standardised plan. In total, 63,682 participants with a broad range of baseline ages and BMIs and 15,180 incident cases of T2D over the average of 9 years of follow-up were evaluated. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Prespecified interactions by age, sex, BMI, and race/ethnicity were explored in each cohort and were meta-analysed. Potential heterogeneity by cohort-specific characteristics (regions, lipid compartments used for fatty acid assays) was assessed with metaregression. After adjustment for potential confounders, including measures of adiposity (BMI, waist circumference) and lipogenesis (levels of palmitate, triglycerides), higher levels of 15:0, 17:0, and t16:1n-7 were associated with lower incidence of T2D. In the most adjusted model, the hazard ratio (95\% CI) for incident T2D per cohort-specific 10th to 90th percentile range of 15:0 was 0.80 (0.73-0.87); of 17:0, 0.65 (0.59-0.72); of t16:1n7, 0.82 (0.70-0.96); and of their sum, 0.71 (0.63-0.79). In exploratory analyses, similar associations for 15:0, 17:0, and the sum of all three fatty acids were present in both genders but stronger in women than in men (pinteraction < 0.001). Whereas studying associations with biomarkers has several advantages, as limitations, the biomarkers do not distinguish between different food sources of dairy fat (e.g., cheese, yogurt, milk), and residual confounding by unmeasured or imprecisely measured confounders may exist.

CONCLUSIONS: In a large meta-analysis that pooled the findings from 16 prospective cohort studies, higher levels of 15:0, 17:0, and t16:1n-7 were associated with a lower risk of T2D.

}, keywords = {Aged, Australia, Biomarkers, Dairy Products, Diabetes Mellitus, Type 2, Dietary Fats, Europe, Fatty Acids, Fatty Acids, Monounsaturated, Female, Humans, Incidence, Male, Middle Aged, Prospective Studies, Sex Factors, Taiwan, United States}, issn = {1549-1676}, doi = {10.1371/journal.pmed.1002670}, author = {Imamura, Fumiaki and Fretts, Amanda and Marklund, Matti and Ardisson Korat, Andres V and Yang, Wei-Sin and Lankinen, Maria and Qureshi, Waqas and Helmer, Catherine and Chen, Tzu-An and Wong, Kerry and Bassett, Julie K and Murphy, Rachel and Tintle, Nathan and Yu, Chaoyu Ian and Brouwer, Ingeborg A and Chien, Kuo-Liong and Frazier-Wood, Alexis C and Del Gobbo, Liana C and Djouss{\'e}, Luc and Geleijnse, Johanna M and Giles, Graham G and de Goede, Janette and Gudnason, Vilmundur and Harris, William S and Hodge, Allison and Hu, Frank and Koulman, Albert and Laakso, Markku and Lind, Lars and Lin, Hung-Ju and McKnight, Barbara and Rajaobelina, Kalina and Riserus, Ulf and Robinson, Jennifer G and Samieri, Cecilia and Siscovick, David S and Soedamah-Muthu, Sabita S and Sotoodehnia, Nona and Sun, Qi and Tsai, Michael Y and Uusitupa, Matti and Wagenknecht, Lynne E and Wareham, Nick J and Wu, Jason HY and Micha, Renata and Forouhi, Nita G and Lemaitre, Rozenn N and Mozaffarian, Dariush} } @article {7791, title = {Genome-wide association meta-analysis of circulating odd-numbered chain saturated fatty acids: Results from the CHARGE Consortium.}, journal = {PLoS One}, volume = {13}, year = {2018}, month = {2018}, pages = {e0196951}, abstract = {

BACKGROUND: Odd-numbered chain saturated fatty acids (OCSFA) have been associated with potential health benefits. Although some OCSFA (e.g., C15:0 and C17:0) are found in meats and dairy products, sources and metabolism of C19:0 and C23:0 are relatively unknown, and the influence of non-dietary determinants, including genetic factors, on circulating levels of OCSFA is not established.

OBJECTIVE: To elucidate the biological processes that influence circulating levels of OCSFA by investigating associations between genetic variation and OCSFA.

DESIGN: We performed a meta-analysis of genome-wide association studies (GWAS) of plasma phospholipid/erythrocyte levels of C15:0, C17:0, C19:0, and C23:0 among 11,494 individuals of European descent. We also investigated relationships between specific single nucleotide polymorphisms (SNPs) in the lactase (LCT) gene, associated with adult-onset lactase intolerance, with circulating levels of dairy-derived OCSFA, and evaluated associations of candidate sphingolipid genes with C23:0 levels.

RESULTS: We found no genome-wide significant evidence that common genetic variation is associated with circulating levels of C15:0 or C23:0. In two cohorts with available data, we identified one intronic SNP (rs13361131) in myosin X gene (MYO10) associated with C17:0 level (P = 1.37{\texttimes}10-8), and two intronic SNP (rs12874278 and rs17363566) in deleted in lymphocytic leukemia 1 (DLEU1) region associated with C19:0 level (P = 7.07{\texttimes}10-9). In contrast, when using a candidate-gene approach, we found evidence that three SNPs in LCT (rs11884924, rs16832067, and rs3816088) are associated with circulating C17:0 level (adjusted P = 4{\texttimes}10-2). In addition, nine SNPs in the ceramide synthase 4 (CERS4) region were associated with circulating C23:0 levels (adjusted P<5{\texttimes}10-2).

CONCLUSIONS: Our findings suggest that circulating levels of OCSFA may be predominantly influenced by non-genetic factors. SNPs associated with C17:0 level in the LCT gene may reflect genetic influence in dairy consumption or in metabolism of dairy foods. SNPs associated with C23:0 may reflect a role of genetic factors in the synthesis of sphingomyelin.

}, keywords = {Fatty Acids, Genome-Wide Association Study, Humans, Introns, Lactase, Myosins, Polymorphism, Single Nucleotide, Sphingomyelins, Sphingosine N-Acyltransferase, Tumor Suppressor Proteins}, issn = {1932-6203}, doi = {10.1371/journal.pone.0196951}, author = {de Oliveira Otto, Marcia C and Lemaitre, Rozenn N and Sun, Qi and King, Irena B and Wu, Jason H Y and Manichaikul, Ani and Rich, Stephen S and Tsai, Michael Y and Chen, Y D and Fornage, Myriam and Weihua, Guan and Aslibekyan, Stella and Irvin, Marguerite R and Kabagambe, Edmond K and Arnett, Donna K and Jensen, Majken K and McKnight, Barbara and Psaty, Bruce M and Steffen, Lyn M and Smith, Caren E and Riserus, Ulf and Lind, Lars and Hu, Frank B and Rimm, Eric B and Siscovick, David S and Mozaffarian, Dariush} } @article {9455, title = {PUFA ω-3 and ω-6 biomarkers and sleep: a pooled analysis of cohort studies on behalf of the Fatty Acids and Outcomes Research Consortium (FORCE).}, journal = {Am J Clin Nutr}, volume = {115}, year = {2022}, month = {2022 Mar 04}, pages = {864-876}, abstract = {

BACKGROUND: n-3 and n-6 PUFAs have physiologic roles in sleep processes, but little is known regarding circulating n-3 and n-6 PUFA and sleep parameters.

OBJECTIVES: We sought to assess associations between biomarkers of n-3 and n-6 PUFA intake with self-reported sleep duration and difficulty falling sleeping in the Fatty Acids and Outcome Research Consortium.

METHODS: Harmonized, de novo, individual-level analyses were performed and pooled across 12 cohorts. Participants were 35-96 y old and from 5 nations. Circulating measures included α-linolenic acid (ALA), EPA, docosapentaenoic acid (DPA), DHA, EPA~+~DPA~+~DHA, linoleic acid, and arachidonic acid. Sleep duration (10 cohorts, n~=~18,791) was categorized as short (<=6 h), 7-8 h (reference), or long (>=9 h). Difficulty falling asleep (8 cohorts, n~=~12,500) was categorized as yes or no. Associations between PUFAs, sleep duration, and difficulty falling sleeping were assessed by cross-sectional multinomial logistic regression using standardized protocols and covariates. Cohort-specific multivariable-adjusted ORs per quintile of PUFAs were pooled with inverse-variance weighted meta-analysis.

RESULTS: In pooled analysis adjusted for sociodemographic characteristics and health status, participants with higher very long-chain n-3 PUFAs were less likely to have long sleep duration. In the top compared with the bottom quintiles, the multivariable-adjusted ORs (95\% CIs) for long sleep were 0.78 (95\% CI: 0.65, 0.95) for DHA and 0.76 (95\% CI: 0.63, 0.93) for EPA~+~DPA~+~DHA. Significant associations for ALA and n-6 PUFA with short sleep duration or difficulty falling sleeping were not identified.

CONCLUSIONS: Participants with higher concentrations of very long-chain n-3 PUFAs were less likely to have long sleep duration. While objective biomarkers reduce recall bias and misclassification, the cross-sectional design limits assessment of the temporal nature of this relation. These novel findings across 12 cohorts highlight the need for experimental and biological assessments of very long-chain n-3 PUFAs and sleep duration.

}, keywords = {Biomarkers, Cohort Studies, Cross-Sectional Studies, Fatty Acids, Fatty Acids, Omega-3, Humans, Outcome Assessment, Health Care, Sleep}, issn = {1938-3207}, doi = {10.1093/ajcn/nqab408}, author = {Murphy, Rachel A and Tintle, Nathan and Harris, William S and Darvishian, Maryam and Marklund, Matti and Virtanen, Jyrki K and Hantunen, Sari and de Mello, Vanessa D and Tuomilehto, Jaakko and Lindstr{\"o}m, Jaana and Bolt, Matthew A and Brouwer, Ingeborg A and Wood, Alexis C and Senn, Mackenzie and Redline, Susan and Tsai, Michael Y and Gudnason, Vilmundur and Eiriksdottir, Gudny and Lindberg, Eva and Shadyab, Aladdin H and Liu, Buyun and Carnethon, Mercedes and Uusitupa, Matti and Djouss{\'e}, Luc and Riserus, Ulf and Lind, Lars and van Dam, Rob M and Koh, Woon-Puay and Shi, Peilin and Siscovick, David and Lemaitre, Rozenn N and Mozaffarian, Dariush} } @article {9533, title = {Plasma Ceramides and Sphingomyelins and Sudden Cardiac Death in the Cardiovascular Health Study.}, journal = {JAMA Netw Open}, volume = {6}, year = {2023}, month = {2023 Nov 01}, pages = {e2343854}, abstract = {

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.

}, keywords = {Aged, Ceramides, Cohort Studies, Death, Sudden, Cardiac, Eicosanoic Acids, Fatty Acids, Female, Humans, Male, Sphingolipids, Sphingomyelins}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2023.43854}, author = {Bockus, Lee B and Jensen, Paul N and Fretts, Amanda M and Hoofnagle, Andrew N and McKnight, Barbara and Sitlani, Colleen M and Siscovick, David S and King, Irena B and Psaty, Bruce M and Sotoodehnia, Nona and Lemaitre, Rozenn N} }