@article {5880, title = {Genome-wide association study identifies novel loci associated with concentrations of four plasma phospholipid fatty acids in the de novo lipogenesis pathway: results from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortiu}, journal = {Circ Cardiovasc Genet}, volume = {6}, year = {2013}, month = {2013 Apr}, pages = {171-83}, abstract = {

BACKGROUND- Palmitic acid (16:0), stearic acid (18:0), palmitoleic acid (16:1n-7), and oleic acid (18:1n-9) are major saturated and monounsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis and are the main saturated and monounsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes mellitus and coronary heart disease. METHODS AND RESULTS- Genome-wide association studies were conducted in 5 population-based cohorts comprising 8961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these 4 fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of >=1 of these fatty acids. ALG14 (asparagine-linked glycosylation 14 homolog) polymorphisms were associated with higher 16:0 (P=2.7{\texttimes}10(-11)) and lower 18:0 (P=2.2{\texttimes}10(-18)). FADS1 and FADS2 (desaturases) polymorphisms were associated with higher 16:1n-7 (P=6.6{\texttimes}10(-13)) and 18:1n-9 (P=2.2{\texttimes}10(-32)) and lower 18:0 (P=1.3{\texttimes}10(-20)). LPGAT1 (lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0 (P=2.8{\texttimes}10(-9)). GCKR (glucokinase regulator; P=9.8{\texttimes}10(-10)) and HIF1AN (factor inhibiting hypoxia-inducible factor-1; P=5.7{\texttimes}10(-9)) polymorphisms were associated with higher 16:1n-7, whereas PKD2L1 (polycystic kidney disease 2-like 1; P=5.7{\texttimes}10(-15)) and a locus on chromosome 2 (not near known genes) were associated with lower 16:1n-7 (P=4.1{\texttimes}10(-8)). CONCLUSIONS- Our findings provide novel evidence that common variations in genes with diverse functions, including protein-glycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of 4 fatty acids in the de novo lipogenesis pathway. These results expand our knowledge of genetic factors relevant to de novo lipogenesis and fatty acid biology.

}, keywords = {Adult, Aged, Chromosomes, Human, Pair 2, Cohort Studies, Coronary Disease, Diabetes Mellitus, Type 2, Fatty Acids, Monounsaturated, Female, Genetic Loci, Genome-Wide Association Study, Genotype, Humans, Linkage Disequilibrium, Lipogenesis, Male, Middle Aged, Oleic Acid, Palmitic Acid, Polymorphism, Single Nucleotide, Stearic Acids}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.112.964619}, author = {Wu, Jason H Y and Lemaitre, Rozenn N and Manichaikul, Ani and Guan, Weihua and Tanaka, Toshiko and Foy, Millennia and Kabagambe, Edmond K and Djouss{\'e}, Luc and Siscovick, David and Fretts, Amanda M and Johnson, Catherine and King, Irena B and Psaty, Bruce M and McKnight, Barbara and Rich, Stephen S and Chen, Yii-der I and Nettleton, Jennifer A and Tang, Weihong and Bandinelli, Stefania and Jacobs, David R and Browning, Brian L and Laurie, Cathy C and Gu, Xiangjun and Tsai, Michael Y and Steffen, Lyn M and Ferrucci, Luigi and Fornage, Myriam and Mozaffarian, Dariush} } @article {6567, title = {Genome-wide association study of plasma N6 polyunsaturated fatty acids within the cohorts for heart and aging research in genomic epidemiology consortium.}, journal = {Circ Cardiovasc Genet}, volume = {7}, year = {2014}, month = {2014 Jun}, pages = {321-331}, abstract = {

BACKGROUND: Omega6 (n6) polyunsaturated fatty acids (PUFAs) and their metabolites are involved in cell signaling, inflammation, clot formation, and other crucial biological processes. Genetic components, such as variants of fatty acid desaturase (FADS) genes, determine the composition of n6 PUFAs.

METHODS AND RESULTS: To elucidate undiscovered biological pathways that may influence n6 PUFA composition, we conducted genome-wide association studies and meta-analyses of associations of common genetic variants with 6 plasma n6 PUFAs in 8631 white adults (55\% women) across 5 prospective studies. Plasma phospholipid or total plasma fatty acids were analyzed by similar gas chromatography techniques. The n6 fatty acids linoleic acid (LA), γ-linolenic acid (GLA), dihomo-GLA, arachidonic acid, and adrenic acid were expressed as percentage of total fatty acids. We performed linear regression with robust SEs to test for single-nucleotide polymorphism-fatty acid associations, with pooling using inverse-variance-weighted meta-analysis. Novel regions were identified on chromosome 10 associated with LA (rs10740118; P=8.1{\texttimes}10(-9); near NRBF2), on chromosome 16 with LA, GLA, dihomo-GLA, and arachidonic acid (rs16966952; P=1.2{\texttimes}10(-15), 5.0{\texttimes}10(-11), 7.6{\texttimes}10(-65), and 2.4{\texttimes}10(-10), respectively; NTAN1), and on chromosome 6 with adrenic acid after adjustment for arachidonic acid (rs3134950; P=2.1{\texttimes}10(-10); AGPAT1). We confirmed previous findings of the FADS cluster on chromosome 11 with LA and arachidonic acid, and further observed novel genome-wide significant association of this cluster with GLA, dihomo-GLA, and adrenic acid (P=2.3{\texttimes}10(-72), 2.6{\texttimes}10(-151), and 6.3{\texttimes}10(-140), respectively).

CONCLUSIONS: Our findings suggest that along with the FADS gene cluster, additional genes may influence n6 PUFA composition.

}, keywords = {Adult, Aged, Aged, 80 and over, Aging, Chromosomes, Human, Pair 10, Chromosomes, Human, Pair 16, Chromosomes, Human, Pair 6, Fatty Acid Desaturases, Fatty Acids, Omega-6, Female, Genome-Wide Association Study, Genomics, Heart Diseases, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Prospective Studies, Sequence Analysis, DNA}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.113.000208}, author = {Guan, Weihua and Steffen, Brian T and Lemaitre, Rozenn N and Wu, Jason H Y and Tanaka, Toshiko and Manichaikul, Ani and Foy, Millennia and Rich, Stephen S and Wang, Lu and Nettleton, Jennifer A and Tang, Weihong and Gu, Xiangjun and Bandinelli, Stafania and King, Irena B and McKnight, Barbara and Psaty, Bruce M and Siscovick, David and Djouss{\'e}, Luc and Chen, Yii-Der Ida and Ferrucci, Luigi and Fornage, Myriam and Mozafarrian, Dariush and Tsai, Michael Y and Steffen, Lyn M} } @article {9911, title = {Methylome-wide association analyses of lipids and modifying effects of behavioral factors in diverse race and ethnicity participants.}, journal = {Clin Epigenetics}, volume = {17}, year = {2025}, month = {2025 Apr 02}, pages = {54}, abstract = {

Circulating lipid concentrations are clinically associated with cardiometabolic diseases. The phenotypic variance explained by identified genetic variants remains limited, highlighting the importance of searching for additional factors beyond genetic sequence variants. DNA methylation has been linked to lipid concentrations in previous studies, although most of the studies harbored moderate sample sizes and exhibited underrepresentation of non-European ancestry populations. In addition, knowledge of nongenetic factors on lipid profiles is extremely limited. In the Population Architecture Using Genomics and Epidemiology (PAGE) Study, we performed methylome-wide association analysis on 9,561 participants from diverse race and ethnicity backgrounds for HDL-c, LDL-c, TC, and TG levels, and also tested interactions between smoking or alcohol intake and methylation in their association with lipid levels. We identified novel CpG sites at 16 loci (P < 1.18E-7) with successful replication on 3,215 participants. One additional novel locus was identified in the self-reported White participants (P = 4.66E-8). Although no additional CpG sites were identified in the genome-wide interaction analysis, 13 reported CpG sites showed significant heterogeneous association across smoking or alcohol intake strata. By mapping novel and reported CpG sites to genes, we identified enriched pathways directly linked to lipid metabolism as well as ones spanning various biological functions. These findings provide new insights into the regulation of lipid concentrations.

}, keywords = {Adult, Aged, Alcohol Drinking, CpG Islands, DNA Methylation, Ethnicity, Female, Genome-Wide Association Study, Humans, Lipids, Male, Middle Aged, Racial Groups, Smoking, White People}, issn = {1868-7083}, doi = {10.1186/s13148-025-01859-3}, author = {Hu, Yao and Haessler, Jeff and Lundin, Jessica I and Darst, Burcu F and Whitsel, Eric A and Grove, Megan and Guan, Weihua and Xia, Rui and Szeto, Mindy and Raffield, Laura M and Ratliff, Scott and Wang, Yuxuan and Wang, Xuzhi and Fohner, Alison E and Lynch, Megan T and Patel, Yesha M and Lani Park, S and Xu, Huichun and Mitchell, Braxton D and Bis, Joshua C and Sotoodehnia, Nona and Brody, Jennifer A and Psaty, Bruce M and Peloso, Gina M and Tsai, Michael Y and Rich, Stephen S and Rotter, Jerome I and Smith, Jennifer A and Kardia, Sharon L R and Reiner, Alex P and Lange, Leslie and Fornage, Myriam and Pankow, James S and Graff, Mariaelisa and North, Kari E and Kooperberg, Charles and Peters, Ulrike} }