BACKGROUND Aortic stenosis (AS) contributes to cardiovascular mortality and morbidity but disease mechanisms remain largely unknown. Recent evidence associates a single nucleotide polymorphism rs174547 within the FADS1 gene, encoding FADS1 (fatty acid desaturase 1), with risk of several cardiovascular outcomes, including AS. FADS1 encodes a rate-limiting enzyme for ω-3 and ω-6 fatty acid metabolism. The aim of this study was to decipher the local transcriptomic and lipidomic consequences of rs174547 in tricuspid aortic valves from patients with AS. METHODS Expression quantitative trait loci study was performed using data from Illumina Human610-Quad BeadChip, Infinium Global Screening Arrays, and Affymetrix Human Transcriptome 2.0 arrays in calcified and noncalcified aortic valve tissue from 58 patients with AS (mean age, 74.2; SD, 5.9). Fatty acid content was assessed in aortic valves from 25 patients with AS using gas chromatography. Δ5 and Δ6 desaturase activity was assessed by the product-to-precursor ratio. RESULTS The minor C-allele of rs174547, corresponding to the protective genotype for AS, was associated with higher FADS2 mRNA levels in calcified valve tissue, whereas FADS1 mRNA and other transcripts in proximity of the single nucleotide polymorphism were unaltered. In contrast, the FADS1 Δ5-desaturase activity and the FADS2 Δ6-desaturase activity were decreased. Finally, docosahexaenoic acid was decreased in calcified tissue compared with non-calcified tissue and C-allele carriers exhibited increased docosahexaenoic acid levels. Overall desaturase activity measured with ω-3 fatty acids was higher in C-allele carriers. CONCLUSIONS The association between the FADS1 genotype and AS may implicate effects on valvular fatty acids.

中文翻译：

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FADS1（脂肪酸去饱和酶 1）基因型与主动脉瓣 FADS mRNA 表达、脂肪酸含量和钙化有关。

背景主动脉瓣狭窄（AS）导致心血管死亡率和发病率，但疾病机制在很大程度上仍然未知。最近的证据表明 FADS1 基因内的单核苷酸多态性 rs174547 编码 FADS1（脂肪酸去饱和酶 1）与多种心血管结局的风险有关，包括 AS。FADS1 编码 ω-3 和 ω-6 脂肪酸代谢的限速酶。本研究的目的是解读 rs174547 在 AS 患者三尖瓣主动脉瓣中的局部转录组学和脂质组学后果。方法 使用来自 Illumina Human610-Quad BeadChip、Infinium Global Screening Arrays 和 Affymetrix Human Transcriptome 2.0 阵列的数据在来自 58 名 AS 患者（平均年龄，74.2；SD，5.9）的钙化和非钙化主动脉瓣组织中进行表达数量性状基因座研究. 使用气相色谱法评估了 25 名 AS 患者的主动脉瓣中的脂肪酸含量。Δ5 和 Δ6 去饱和酶活性通过产物与前体的比率进行评估。结果 rs174547 的次要 C 等位基因，对应于 AS 的保护基因型，与钙化瓣膜组织中较高的 FADS2 mRNA 水平相关，而 FADS1 mRNA 和单核苷酸多态性附近的其他转录本未改变。相反，FADS1 Δ5-去饱和酶活性和FADS2 Δ6-去饱和酶活性降低。最后，与非钙化组织相比，钙化组织中的二十二碳六烯酸减少，并且 C 等位基因载体表现出增加的二十二碳六烯酸水平。用 ω-3 脂肪酸测量的总体去饱和酶活性在 C 等位基因载体中更高。