Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Montreal, Quebec, Canada.
JAMA Cardiol. 2020 Jun 1;5(6):694-702. doi: 10.1001/jamacardio.2020.0246.
Aortic stenosis (AS) has no approved medical treatment. Identifying etiological pathways for AS could identify pharmacological targets.
To identify novel genetic loci and pathways associated with AS.
DESIGN, SETTING, AND PARTICIPANTS: This genome-wide association study used a case-control design to evaluate 44 703 participants (3469 cases of AS) of self-reported European ancestry from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort (from January 1, 1996, to December 31, 2015). Replication was performed in 7 other cohorts totaling 256 926 participants (5926 cases of AS), with additional analyses performed in 6942 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Follow-up biomarker analyses with aortic valve calcium (AVC) were also performed. Data were analyzed from May 1, 2017, to December 5, 2019.
Genetic variants (615 643 variants) and polyunsaturated fatty acids (ω-6 and ω-3) measured in blood samples.
Aortic stenosis and aortic valve replacement defined by electronic health records, surgical records, or echocardiography and the presence of AVC measured by computed tomography.
The mean (SD) age of the 44 703 GERA participants was 69.7 (8.4) years, and 22 019 (49.3%) were men. The rs174547 variant at the FADS1/2 locus was associated with AS (odds ratio [OR] per C allele, 0.88; 95% CI, 0.83-0.93; P = 3.0 × 10-6), with genome-wide significance after meta-analysis with 7 replication cohorts totaling 312 118 individuals (9395 cases of AS) (OR, 0.91; 95% CI, 0.88-0.94; P = 2.5 × 10-8). A consistent association with AVC was also observed (OR, 0.91; 95% CI, 0.83-0.99; P = .03). A higher ratio of arachidonic acid to linoleic acid was associated with AVC (OR per SD of the natural logarithm, 1.19; 95% CI, 1.09-1.30; P = 6.6 × 10-5). In mendelian randomization, increased FADS1 liver expression and arachidonic acid were associated with AS (OR per unit of normalized expression, 1.31 [95% CI, 1.17-1.48; P = 7.4 × 10-6]; OR per 5-percentage point increase in arachidonic acid for AVC, 1.23 [95% CI, 1.01-1.49; P = .04]; OR per 5-percentage point increase in arachidonic acid for AS, 1.08 [95% CI, 1.04-1.13; P = 4.1 × 10-4]).
Variation at the FADS1/2 locus was associated with AS and AVC. Findings from biomarker measurements and mendelian randomization appear to link ω-6 fatty acid biosynthesis to AS, which may represent a therapeutic target.
主动脉瓣狭窄（AS）目前尚无有效的治疗方法。确定 AS 的病因途径可能有助于发现药理学靶点。
确定与 AS 相关的新的遗传位点和途径。
设计、地点和参与者：本全基因组关联研究采用病例对照设计，纳入了来自遗传流行病学成人健康与衰老研究（GERA）队列的 44703 名自报欧洲血统的参与者（3469 例 AS）（从 1996 年 1 月 1 日至 2015 年 12 月 31 日）。在另外 7 个队列中进行了验证，共纳入 256926 名参与者（5926 例 AS），并在基因组流行病学心脏与衰老研究（CHARGE）联盟的 6942 名参与者中进行了进一步分析。还进行了后续的生物标志物分析，包括主动脉瓣钙（AVC）。数据分析时间为 2017 年 5 月 1 日至 2019 年 12 月 5 日。
基因变异（615643 个）和血液样本中测量的多不饱和脂肪酸（ω-6 和 ω-3）。
通过电子健康记录、手术记录或超声心动图定义的主动脉瓣狭窄和主动脉瓣置换，以及通过计算机断层扫描测量的 AVC。
44703 名 GERA 参与者的平均（SD）年龄为 69.7（8.4）岁，22019 名（49.3%）为男性。FADS1/2 基因座的 rs174547 变异与 AS 相关（每个 C 等位基因的比值比 [OR]，0.88；95%CI，0.83-0.93；P = 3.0×10-6），与 7 个复制队列的汇总分析具有全基因组显著性，共纳入 312118 名个体（312118 名个体中有 9395 例 AS）（OR，0.91；95%CI，0.88-0.94；P = 2.5×10-8）。也观察到与 AVC 的一致性关联（OR，0.91；95%CI，0.83-0.99；P = .03）。花生四烯酸与亚油酸的比值与 AVC 相关（自然对数标准差的 OR，1.19；95%CI，1.09-1.30；P = 6.6×10-5）。在孟德尔随机化中，FADS1 肝脏表达增加和花生四烯酸与 AS 相关（单位标准化表达的 OR，1.31；95%CI，1.17-1.48；P = 7.4×10-6）；AVC 中花生四烯酸增加 5%的 OR，1.23；95%CI，1.01-1.49；P = .04）；AS 中花生四烯酸增加 5%的 OR，1.08；95%CI，1.04-1.13；P = 4.1×10-4）。
FADS1/2 基因座的变异与 AS 和 AVC 相关。生物标志物测量和孟德尔随机化的结果似乎将 ω-6 脂肪酸生物合成与 AS 联系起来，这可能代表一个治疗靶点。
