Department of Medicine Solna, Unit of Cardiovascular Medicine (O.P., G.A., M.C., P.E., M.B.), Karolinska Institutet, Stockholm.
Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine (S.C.L.), Karolinska Institutet, Stockholm.
Circ Genom Precis Med. 2020 Jun;13(3):e002710. doi: 10.1161/CIRCGEN.119.002710. Epub 2020 May 12.
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 gene, encoding FADS1 (fatty acid desaturase 1), with risk of several cardiovascular outcomes, including AS. 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.
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. 5 and 6 desaturase activity was assessed by the product-to-precursor ratio.
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 5-desaturase activity and the FADS2 6-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.
The association between the FADS1 genotype and AS may implicate effects on valvular fatty acids.
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不清楚。最近的证据将编码 FADS1（脂肪酸去饱和酶 1）的基因中的单核苷酸多态性 rs174547 与包括 AS 在内的几种心血管结局的风险联系起来。该基因编码ω-3 和 ω-6 脂肪酸代谢的限速酶。本研究旨在破译 rs174547 在 AS 患者三尖瓣主动脉瓣中的局部转录组和脂质组学后果。
使用 Illumina Human610-Quad BeadChip、Infinium Global Screening Arrays 和 Affymetrix Human Transcriptome 2.0 阵列在 58 名 AS 患者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（平均年龄 74.2；SD 5.9）。使用气相色谱法评估 25 名 AS 患者的主动脉瓣中脂肪酸含量。通过产物-前体比评估 5 和 6 去饱和酶活性。
rs174547 的次要 C 等位基因与 AS 的保护基因型相对应，与钙化瓣组织中 FADS2 mRNA 水平升高相关，而单核苷酸多态性附近的 FADS1 mRNA 和其他转录本未改变。相反，FADS1 5-去饱和酶活性和 FADS2 6-去饱和酶活性降低。最后，与非钙化组织相比，钙化组织中二十二碳六烯酸减少，C 等位基因携带者表现出增加的二十二碳六烯酸水平。总体而言，用 ω-3 脂肪酸测量的去饱和酶活性在 C 等位基因携带者中更高。
FADS1 基因型与 AS 之间的关联可能暗示对瓣状脂肪酸的影响。
