Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Skåne University Hospital Malmö, Malmö, SE-214 28, Sweden.
IFB Adiposity Diseases, University of Leipzig, Leipzig, 04103, Germany.
Int J Obes (Lond). 2019 Apr;43(4):808-820. doi: 10.1038/s41366-018-0112-3. Epub 2018 May 24.
Recent analyses in Greenlandic Inuit identified six genetic polymorphisms (rs74771917, rs3168072, rs12577276, rs7115739, rs174602 and rs174570) in the fatty acid desaturase gene cluster (FADS1-FADS2-FADS3) that are associated with multiple metabolic and anthropometric traits. Our objectives were to systematically assess whether dietary polyunsaturated fatty acid (PUFA) intake modifies the associations between genetic variants in the FADS gene cluster and cardiometabolic traits, and to functionally annotate top-ranking candidates to estimate their regulatory potential.
Data analyses consisted of the following: interaction analyses between the 6 candidate genetic variants and dietary PUFA intake; gene-centric joint analyses to detect interaction signals in the FADS region; haplotype-centric joint tests across 30 haplotype blocks in the FADS region to refine interaction signals; and functional annotation of top-ranking loci from the previous steps. These analyses were undertaken in Swedish adults from the GLACIER Study (N = 5,160); data on genetic variation and eight cardiometabolic traits were used.
Interactions were observed between rs174570 and n-6 PUFA intake on fasting glucose (P = 0.005) and between rs174602 and n-3 PUFA intake on total cholesterol (P = 0.001). Gene-centric analyses demonstrated a statistically significant interaction effect for FADS and n-3 PUFA on triglycerides (P = 0.005) considering genetic main effects as random. Haplotype analyses revealed three blocks (P < 0.011) that could drive the interaction between FADS and n-3 PUFA on triglycerides; functional annotation of these regions showed that each block harbours a number of highly functional regulatory variants; FADS2 rs5792235 demonstrated the highest functionality score.
The association between FADS variants and triglycerides may be modified by PUFA intake. The intronic FADS2 rs5792235 variant is a potential causal variant in the region, having the highest regulatory potential. However, our results suggest that multiple haplotypes may harbour functional variants in a region, rather than a single causal variant.
最近在格陵兰因纽特人中进行的分析确定了脂肪酸去饱和酶基因簇（FADS1-FADS2-FADS3）中的六个遗传多态性（rs74771917、rs3168072、rs12577276、rs7115739、rs174602 和 rs174570），这些多态性与多种代谢和人体测量特征有关。我们的目的是系统评估多不饱和脂肪酸（PUFA）饮食摄入是否会改变 FADS 基因簇中遗传变异与心脏代谢特征之间的关联，并对排名靠前的候选基因进行功能注释，以估计其调控潜力。
数据分析包括以下内容：候选的 6 个遗传变异与饮食 PUFA 摄入之间的相互作用分析；FADS 区域的基因中心联合分析，以检测相互作用信号；FADS 区域 30 个单倍型块之间的单倍型中心联合检验，以细化相互作用信号；以及前几步中排名靠前的基因座的功能注释。这些分析是在瑞典 GLACIER 研究（N=5160）中的成年人中进行的；使用了遗传变异和 8 种心脏代谢特征的数据。
rs174570 与 n-6 PUFA 摄入之间存在空腹血糖的相互作用（P=0.005），rs174602 与 n-3 PUFA 摄入之间存在总胆固醇的相互作用（P=0.001）。基因中心分析表明，考虑到遗传主效应为随机，FADS 和 n-3 PUFA 对甘油三酯存在统计学上显著的相互作用效应（P=0.005）。单倍型分析显示三个块（P<0.011）可以驱动 FADS 和 n-3 PUFA 对甘油三酯的相互作用；这些区域的功能注释表明，每个块都包含多个高度功能的调节变异；FADS2 rs5792235 表现出最高的功能评分。
FADS 变异与甘油三酯之间的关联可能受 PUFA 摄入的影响。内含子 FADS2 rs5792235 变异是该区域的一个潜在因果变异，具有最高的调节潜力。然而，我们的结果表明，一个区域可能存在多个单倍型的功能变异，而不是单个因果变异。
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