JLR:中科院上海生科院林旭研究组发表单不饱和脂肪酸遗传关联研
2017年3月15日，国际脂代谢研究领域知名期刊《Journal of Lipid Research》在线发表了中国科学院上海生命科学研究院林旭研究组题为Discovery and fine-mapping of loci associated with monounsaturated fatty acids through trans-ethnic meta-analysis in Chinese and European populations的研究论文，研究不仅发现了多个影响单不饱和脂肪酸血液水平的基因位点，而且还对潜在的功能性位点进行了精细定位分析。林旭研究组胡瑶博士研究生和黎怀星研究员为论文第一作者，林旭研究员为论文通讯作者。
最新的《美国膳食指南科学报告》建议适当增加单不饱和脂肪酸的摄入，从而达到优化不饱和与饱和脂肪酸的摄入比例，以保持膳食平衡。体内单不饱和脂肪酸水平不仅受膳食摄入水平的影响，而且也受遗传变异的影响。虽然之前的研究在西方人群中发现了几个与血液单不饱和脂肪酸水平相关的基因位点，但是由于中西方人群在遗传背景和膳食结构方面存在着较大差异，阐明在中国人群中否存在与单不饱和脂肪酸相关的特异基因位点，以及在西方人群中发现的基因位点是否在中国人群中也起着相似的作用，并对潜在的功能性位点进行精细定位就具有很重要的科学意义和研究价值。
在本研究中，科研人员以9个队列人群(1个中国队列人群、1个华裔队列人群和7个来自CHARGE联盟的欧美队列人群)共1万5千多人的脂肪酸数据和全基因组基因型数据为基础，通过开展全基因组关联分析、跨种族荟萃分析和功能性基因变异位点的精细定位分析，取得如下重要研究进展：1)首次发现FADS1/2和PKD2L1基因变异将显著影响11-十八碳烯酸(vaccenic acid)的血液水平，而FADS1/2和GCKR基因变异将显著影响20-碳-11-烯酸(gondoic acid)水平(图1);2)与西方人群一样，在中国人群中FADS1/2、PKD2L1、GCKR、HIF1AN和LPCAT3基因的变异也显著影响棕榈油酸和/或油酸水平(图2);3)跨种族精细定位分析结果提示，错义突变位点rs1260326可能是GCKR基因区域真正起作用的功能性位点;4)eQTL分析结果表明，PKD2L1-rs603424位点可能通过影响SCD(硬脂酰辅酶A去饱和酶)基因的表达，进而调控MUFA水平的(图3);5) 通路分析(pathway-based analysis)结果表明，上述单不饱和脂肪酸相关的基因位点分别位于不饱和脂肪酸代谢通路和PPAR信号通路上。
这些研究结果不仅为进一步研究血液脂肪酸水平的遗传学基础和潜在的作用机理奠定了基础，也为今后制定适合中国人群的营养推荐及“精准营养”的开展提供了循证依据。
近年来，林旭研究组致力于脂肪酸与遗传方面的研究，并取得了系列研究进展，包括：发现FADS1基因位点在中国汉族人群中与多个多不饱和脂肪酸水平显著相关;发现2个与饱和脂肪酸14:0和1个与20:0水平相关新位点;并在中国人群中发现4个与多不饱和脂肪酸水平显著相关的位点和验证之前在西方人群中发现的新位点，以及与多不饱和脂肪酸相关的基因在中西方人群中存在显著的异质性(Journal of Lipid Research, 2013; European Journal of Nutrition, 2016; Human molecular Genetics, 2016)。
图1：单不饱和脂肪酸水平的全基因组关联分析曼哈顿图
图2：在中国人群中得到验证的西方人群位点
原文链接：
Discovery and fine-mapping of loci associated with monounsaturated fatty acids through trans-ethnic meta-analysis in Chinese and european populations
原文摘要：
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 atFADS1/2 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.
作者：林旭
