全基因组关联研究确定了与从头脂肪生成途径中四种血浆磷脂脂肪酸浓度相关的新基因座：基因组流行病学心脏与衰老研究队列（CHARGE）联盟的结果。
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) consortium.
作者信息
Wu Jason H Y, Lemaitre Rozenn N, Manichaikul Ani, Guan Weihua, Tanaka Toshiko, Foy Millennia, Kabagambe Edmond K, Djousse Luc, Siscovick David, Fretts Amanda M, Johnson Catherine, King Irena B, Psaty Bruce M, McKnight Barbara, Rich Stephen S, Chen Yii-Der I, Nettleton Jennifer A, Tang Weihong, Bandinelli Stefania, Jacobs David R, Browning Brian L, Laurie Cathy C, Gu Xiangjun, Tsai Michael Y, Steffen Lyn M, Ferrucci Luigi, Fornage Myriam, Mozaffarian Dariush
机构信息
Department of Epidemiology and Nutrition, Harvard School of Public Health, Boston, MA 02115, USA.
出版信息
Circ Cardiovasc Genet. 2013 Apr;6(2):171-83. doi: 10.1161/CIRCGENETICS.112.964619. Epub 2013 Jan 29.
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=2.7×10(-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)). 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.
背景——棕榈酸（16:0）、硬脂酸（18:0）、棕榈油酸（16:1n - 7）和油酸（18:1n - 9）是影响细胞信号传导和代谢途径的主要饱和脂肪酸和单不饱和脂肪酸。它们通过从头脂肪生成合成，是饮食中的主要饱和脂肪酸和单不饱和脂肪酸。这些脂肪酸的水平与包括2型糖尿病和冠心病在内的疾病有关。
方法和结果——在5个基于人群的队列中进行了全基因组关联研究，这些队列包括8961名欧洲血统的参与者，以研究常见基因变异与这4种脂肪酸血浆水平之间的关联。我们在7个新位点中鉴定出与这些脂肪酸中至少1种的循环水平相关的多态性。ALG14（天冬酰胺连接糖基化14同源物）多态性与较高的16:0水平（P = 2.7×10⁻¹¹）和较低的18:0水平（P = 2.2×10⁻¹⁸）相关。FADS1和FADS2（去饱和酶）多态性与较高的16:1n - 7水平（P = 6.6×10⁻¹³）和18:1n - 9水平（P = 2.2×10⁻³²）以及较低的18:0水平（P = 1.3×10⁻²⁰）相关。LPGAT1（溶血磷脂酰甘油酰基转移酶）多态性与较低的18:0水平（P = 2.8×10⁻⁹）相关。GCKR（葡萄糖激酶调节因子；P = 9.8×10⁻¹⁰）和HIF1AN（缺氧诱导因子 - 1抑制因子；P = 5.7×10⁻⁹）多态性与较高的16:1n - 7水平相关，而PKD2L1（多囊肾病2样1；P = 5.7×10⁻¹⁵）和2号染色体上的一个位点（不在已知基因附近）与较低的16:1n - 7水平（P = 4.1×10⁻⁸）相关。
结论——我们的研究结果提供了新的证据，表明具有多种功能的基因中的常见变异，包括蛋白质糖基化、多不饱和脂肪酸代谢、磷脂建模以及葡萄糖和氧感应途径，与从头脂肪生成途径中4种脂肪酸的循环水平相关。这些结果扩展了我们对与从头脂肪生成和脂肪酸生物学相关的遗传因素的认识。
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