Background Palmitic acid(16:0), stearic acid(18:0), palmitoleic acid(16:1n-7), and oleic acid(18:1n-9) are major saturated and mono-unsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis (DNL) and are the main saturated and mono-unsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes and coronary heart disease. Methods and Results Genome-wide association studies were conducted in 5 population-based cohorts comprising 8,961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these four fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of one or more of these fatty acids. ALG14 (asparagine-linked glycosylation 14 homolog) polymorphisms were associated with higher 16:0(P=2.7×10-11) and lower 18:0(P=2.2×10-18). FADS1 and FADS2 (desaturases) polymorphisms were associated with higher 16:1n-7(P=6.6×10-13) and 18:1n-9(P=2.2×10-32), and lower 18:0(P =1.3×10-20). LPGAT1 (lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0(P=2.8×10-9). GCKR(glucokinase regulator, P =9.8×10-10) and HIF1AN(factor inhibiting hypoxia-inducible factor-1, P=5.7×10-9) polymorphisms were associated with higher 16:1n-7, whereas PKD2L1(polycystic kidney disease 2-like 1, P=5.7×10-15) and a locus on chromosome 2(not near known genes) were associated with lower 16:1n-7(P=4.1×10-8). Conclusion 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 four fatty acids in the DNL pathway. These results expand our knowledge of genetic factors relevant to DNL and fatty acid biology.

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Introduction: Activated partial thromboplastin time (aPTT) is commonly used to screen for coagulation factor deficiencies. Shorter aPTT is also a risk marker for incident and recurrent venous thromboembolism (VTE). Genetic factors influencing aPTT are not well understood. aPTT was associated with common genetic variants of coagulation factors V (F5), XI (F11), XII (F12), KNG1, HRG, and ABO in previously reported genome-wide association studies (GWAS) that were conducted in individuals of European ancestry; no data have been reported in other race groups. Hypothesis: The present study aimed to identify aPTT-related gene variants in European Americans (EAs) and African Americans (AAs). Methods: We conducted a large-scale candidate gene study for aPTT in 9,719 EAs and 2,799 AAs from the Atherosclerosis Risk in Communities (ARIC) study. Subjects on anticoagulants were excluded. Nearly 50,000 single nucleotide polymorphisms (SNPs) located in 2,100 candidate genes were genotyped by the Candidate gene Association Resource (CARe) gene chip. The association between each SNP and aPTT was assessed with an additive genetic model using linear regression adjusted for age, sex, and field center. We additionally adjusted for principal components in AAs to account for potential population stratification. P-value for significant threshold was set at 2x10-6 after accounting for multiple testing. Results: In EAs, fifty-five SNPs from F5, HRG, KNG1, F11, F12, and ABO genes exceeded the significant p-value threshold. The signals in HRG, KNG1, F11, F12, and ABO genes replicated the previously reported GWAS findings. The top variant in F5 identified in EAs was only weakly associated with the previously reported GWAS variant (rs2239852, p=1.89x10-08 and r2=0.02 with rs9332701 reported in the previously reported GWAS). In AAs, twenty-seven SNPs from the HRG, KNG1, F12, and ABO genes were significantly associated with aPTT. The top signals from the HRG (rs9898, p=1.19x10-27) and KNG1 genes ( rs710446 , p=8.41x10-42) replicated the previously reported signals in EAs with similar effect size and direction of association, but the top signals in the F12 and ABO genes were weakly associated with the previously reported variants in EAs (rs1801020 in F12: p=1.01x10-84 and r2=0.12 with rs2545801, and rs8176722 in ABO: p=1.62x10-29 and r2=0.26 with rs687621 , respectively). Conclusions: Our study replicated the previously reported associations of aPTT with HRG, KNG1, F11, F12, and ABO genes in EAs and with HRG and KNG1 in AAs. The signals from F5 identified in EAs and from F12 and ABO identified in AAs may represent new genetic variants for aPTT.

Background: Activated partial thromboplastin time (aPTT) is a clinical test used to measure the clotting time between the activation of factor XII and the formation of a fibrin clot. Prolonged aPTT indicates a deficiency in the coagulation pathway while shortened aPTT is associated with prothrombotic risk factors and venus thromboembolism. Despite the high heritability of aPTT (40-80%), previous genome-wide association studies (GWAS) of aPTT have been limited to European descent populations, with only a smaller candidate gene study conducted in African Americans. Methods: We included 13,803 participants of European ancestry (EU) and 2,724 participants of African American ancestry (AA) from the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) consortium. aPTT, in seconds (s), was measured using standard protocols in plasma with the use of automated coagulometers. Genotype data were imputed to the 1000 Genomes Phase 1 reference panel, and associations were examined using linear regression assuming an additive genetic model and adjusting for global ancestry, age, sex, and study design. Study-specific results were combined using a fixed-effects, inverse variance weighted meta-analysis. Results: We identified seven loci associated with aPTT in EU populations ( F5, FRMD5, KNG1, F11, F12, HLA, ABO ) and three loci associated with aPTT in AA populations ( KNG1, F12, ABO ) at genome-wide significant levels ( P < 5x10 -8 ). These results are consistent with previously reported genetic studies in EU and AA populations. Effect sizes were larger in AA populations (1.08 to 1.32 s) than in EU populations (0.40 to 1.00 s). Conclusions: We successfully replicated associations with aPTT at seven loci in EU populations and three loci in AA populations. Our results suggest that genetic determinants of aPTT are consistent across race/ethnicity but that studies in AA populations are currently underpowered relative to EU populations. Future work in aPTT genetics should consider more diverse populations.