Genome-wide association study of fish oil supplementation on lipid traits in 81,246 individuals reveals new gene-diet interaction loci.
Genome-wide association study of fish oil supplementation on lipid traits in 81,246 individuals reveals new gene-diet interaction loci.
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鱼油补充对81246例个体脂质性状的全基因组关联研究发现了新的基因-饮食相互作用位点。
DOI：
10.1371/journal.pgen.1009431
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发表时间：
2021-03
期刊：
影响因子：
4.5
通讯作者：
Ye K
中科院分区：
文献类型：
--
作者：
Francis M;Li C;Sun Y;Zhou J;Li X;Brenna JT;Ye K
鱼油补充剂被广泛用于降低血清甘油三酯（TAGs），但对其他循环心血管生物标志物的影响好坏参半。许多遗传多态性与血脂有关，包括高、低密度脂蛋白胆固醇（HDL-C、LDL-C）、总胆固醇和标签。在这项研究中，研究人员在多达73962名英国生物银行参与者的发现队列中分析了鱼油补充剂对这些脂质的基因-饮食相互作用效应，使用了相互作用效应的1自由度（1df）检验和2自由度（2df）检验来联合分析相互作用和主要效应。在社区动脉粥样硬化风险（ARIC）研究的7284名参与者中，两项测试中P < 1×10−6的相关性（26,157;18,300个独特变异）被提升到复制。在荟萃分析中，重复关联达到1df P < 0.05（2175； 1763个独特变异）。我们发现13个重复和159个非重复（仅限UK Biobank）基因座具有显著的2df联合试验，主要由主效应驱动，并且先前已报道过。在meta分析中发现了4个新的相互作用位点，其1df P < 5×10−8。GJB6-GJB2-GJA3基因簇的先导变异rs112803755 （A>G，次要等位基因频率= 0.041）仅表现出互作效应。在补充鱼油的个体中，小等位基因与tag降低显著相关，而在未补充鱼油的个体中，小等位基因与tag升高显著相关。该位点与脂肪组织中GJB2连接蛋白26的高表达显著相关；连接蛋白的活性在接触omega-3脂肪酸时会发生变化。SLC12A3 （HDL-C）、ABCA6 （LDL-C）和MLXIPL （LDL-C）基因的其他三个位点也发现了显著的互作效应，但也存在高度显著的主效应。我们的研究发现了四个基因位点的新的基因-饮食相互作用效应，这些基因位点对血脂的影响被鱼油补充剂所改变。这些发现强调了个性化营养的必要性和可能性。我们利用英国生物银行空前庞大的基因型和表型数据集进行了一项全基因组关联研究（GWAS），该研究解释了基因型和饮食摄入量之间的相互作用。我们研究了补充鱼油对血脂水平（LDL-C、HDL-C、tag和总胆固醇）的相互作用。我们的发现在社区动脉粥样硬化风险（ARIC）研究中得到了重复。我们发现，在遗传变异rs112803755 （A b> G）中，小等位基因(G)与补充鱼油的个体中tag的减少有关，但与未补充鱼油的个体中tag的增加有关。换句话说，只有携带次要等位基因的个体才能从补充鱼油中受益，以降低TAG水平。我们进一步利用基因型-组织表达（GTEx）项目的功能基因组学数据分析rs112803755，以确定潜在的靶基因，并发现了一个连接蛋白编码基因，该基因先前已报道与细胞omega-3水平有关。这项研究表明，基因型可以部分解释TAG对鱼油补充反应的个体差异，并且应该研究基于基因型的鱼油剂量调整作为预防心血管疾病风险的一种手段。
Fish oil supplementation is widely used for reducing serum triglycerides (TAGs) but has mixed effects on other circulating cardiovascular biomarkers. Many genetic polymorphisms have been associated with blood lipids, including high- and low-density-lipoprotein cholesterol (HDL-C, LDL-C), total cholesterol, and TAGs. Here, the gene-diet interaction effects of fish oil supplementation on these lipids were analyzed in a discovery cohort of up to 73,962 UK Biobank participants, using a 1-degree-of-freedom (1df) test for interaction effects and a 2-degrees-of-freedom (2df) test to jointly analyze interaction and main effects. Associations with P < 1×10−6 in either test (26,157; 18,300 unique variants) were advanced to replication in up to 7,284 participants from the Atherosclerosis Risk in Communities (ARIC) Study. Replicated associations reaching 1df P < 0.05 (2,175; 1,763 unique variants) were used in meta-analyses. We found 13 replicated and 159 non-replicated (UK Biobank only) loci with significant 2df joint tests that were predominantly driven by main effects and have been previously reported. Four novel interaction loci were identified with 1df P < 5×10−8 in meta-analysis. The lead variant in the GJB6-GJB2-GJA3 gene cluster, rs112803755 (A>G; minor allele frequency = 0.041), shows exclusively interaction effects. The minor allele is significantly associated with decreased TAGs in individuals with fish oil supplementation, but with increased TAGs in those without supplementation. This locus is significantly associated with higher GJB2 expression of connexin 26 in adipose tissue; connexin activity is known to change upon exposure to omega-3 fatty acids. Significant interaction effects were also found in three other loci in the genes SLC12A3 (HDL-C), ABCA6 (LDL-C), and MLXIPL (LDL-C), but highly significant main effects are also present. Our study identifies novel gene-diet interaction effects for four genetic loci, whose effects on blood lipids are modified by fish oil supplementation. These findings highlight the need and possibility for personalized nutrition. We utilized the unprecedentedly large genotype and phenotype dataset in the UK Biobank to perform a genome-wide association study (GWAS) which accounts for the interplay between genotype and dietary intake. We examined the interaction effects of fish oil supplementation on levels of blood lipids (LDL-C, HDL-C, TAGs, and total cholesterol). Our findings were replicated in the Atherosclerosis Risk in Communities (ARIC) Study. We found that at the genetic variant rs112803755 (A>G), the minor allele (G) is associated with a decrease in TAGs among individuals with fish oil supplementation, but is associated with an increase in TAGs among those without supplementation. In other words, only individuals carrying the minor allele benefit from fish oil supplementation in reducing TAG levels. We further analyzed rs112803755 with functional genomics data from the Genotype-Tissue Expression (GTEx) project to identify potential target genes, and found a connexin coding gene which has been previously reported to respond to cellular omega-3 levels. This research suggests that inter-personal variation in TAG response to fish oil supplementation is in part explained by genotype, and that fish oil dose adjustment based on genotype should be investigated as a means to protect against cardiovascular disease risk.
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影响因子：
6.5
作者：
Bokor, Szilvia;Dumont, Julie;Dallongeville, Jean
通讯作者：
Dallongeville, Jean
影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
5.6
作者：
Innes JK;Calder PC
通讯作者：
Calder PC
影响因子：
30.8
作者：
Das, Sayantan;Forer, Lukas;Schoenherr, Sebastian;Sidore, Carlo;Locke, Adam E.;Kwong, Alan;Vrieze, Scott I.;Chew, Emily Y.;Levy, Shawn;McGue, Matt;Schlessinger, David;Stambolian, Dwight;Loh, Po-Ru;Iacono, William G.;Swaroop, Anand;Scott, Laura J.;Cucca, Francesco;Kronenberg, Florian;Boehnke, Michael;Abecasis, Goncalo R.;Fuchsberger, Christian
通讯作者：
Fuchsberger, Christian