Flores Alyssa M, Ruan Yunfeng, Misra Anika, Cho So Mi Jemma, Selvaraj Margaret S, Bellomo Tiffany R, Nakao Tetsushi, Rosenfield Kenneth, Eagleton Matthew, Hornsby Whitney, Patel Aniruddh P, Natarajan Pradeep
Division of Vascular and Endovascular Surgery, Department of Surgery, Massachusetts General Hospital, Boston.
Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
JAMA Cardiol. 2025 May 21. doi: 10.1001/jamacardio.2025.1182.
Peripheral artery disease (PAD) is a heritable atherosclerotic condition associated with functional decline and high risk for limb loss. With growing knowledge of the genetic basis for PAD and related risk factors, there is potential opportunity to identify individuals at high risk using polygenic risk scores (PRSs).
To develop a novel integrated, multiancestry polygenic score for PAD (PRS-PAD) and evaluate its risk estimation for PAD and major adverse limb events in 3 populations.
DESIGN, SETTING, AND PARTICIPANTS: This longitudinal cohort study was conducted among individuals with genotyping and electronic health record data in the UK Biobank (2006-2021), All of Us (AoU, 2018-2022), and the Mass General Brigham Biobank (MGBB, 2010-2023). Data were analyzed from July 2023 to February 2025.
PRS-PAD, previously published PAD polygenic scores, and clinical risk factors.
The primary outcomes were PAD and major adverse limb events, defined as a surrogate of major amputation and acute limb ischemia.
The study populations included 400 533 individuals from the UK Biobank (median [IQR] age, 58.2 [45.0-71.4] years; 216 215 female participants [53.9%]), 218 500 from AoU (median [IQR] age, 53.6 [37.7-65.0] years; 132 647 female participants [60.7%]), and 32 982 from MGBB (median [IQR] age, 56.0 [32.0-80.0] years; 18 277 female participants [55.4%]). In the UK Biobank validation cohort, PRS-PAD was associated with an odds ratio [OR] per SD increase of 1.63 (95% CI, 1.60-1.68; P < .001). After adjusting for clinical risk factors, the OR for the top 20% of PRS-PAD was 1.68 (95% CI, 1.62-1.74; P < .001) compared to the remainder of the population. Among PAD cases without a history of diabetes, smoking, or chronic kidney disease (n = 3645), 1097 individuals (30.1%) had a high PRS-PAD (top 20%). In incident disease analysis, PRS-PAD improved discrimination (C statistic, 0.761), which was nearly equivalent to the performances of diabetes (C statistic, 0.760) and smoking (C statistic, 0.765). Among individuals with prevalent PAD, high PRS-PAD was associated with an increased risk of incident major adverse limb events in the UK Biobank (hazard ratio [HR], 1.75; 95% CI, 1.18-2.57; P = .005), MGBB (HR, 1.56; 95% CI, 1.06-2.30; P = .02), and AoU (HR, 1.57; 95% CI, 1.06-2.33; P = .03).
This cohort study develops a new PRS that stratifies risk of PAD and adverse limb outcomes. Incorporating polygenic risk into PAD care warrants further investigation to guide screening and tailor management to prevent major adverse limb events.
外周动脉疾病（PAD）是一种遗传性动脉粥样硬化疾病，与功能衰退和肢体丧失的高风险相关。随着对PAD遗传基础及相关风险因素的认识不断增加，利用多基因风险评分（PRS）识别高危个体具有潜在机会。
开发一种用于PAD的新型综合多祖先多基因评分（PRS-PAD），并评估其在3个群体中对PAD和主要肢体不良事件的风险估计。
设计、设置和参与者：这项纵向队列研究在英国生物银行（2006 - 2021年）、全民健康研究项目（AoU，2018 - 2022年）以及麻省总医院布莱根生物银行（MGBB，2010 - 2023年）中具有基因分型和电子健康记录数据的个体中进行。数据于2023年7月至2025年2月进行分析。
PRS-PAD、先前发表的PAD多基因评分以及临床风险因素。
主要结局为PAD和主要肢体不良事件，定义为大截肢和急性肢体缺血的替代指标。
研究人群包括来自英国生物银行的400533名个体（年龄中位数[四分位间距]，58.2[45.0 - 71.4]岁；女性参与者216215名[53.9%]），来自AoU的218500名个体（年龄中位数[四分位间距]，53.6[37.7 - 65.0]岁；女性参与者132647名[60.7%]），以及来自MGBB的32982名个体（年龄中位数[四分位间距]，56.0[32.0 - 80.0]岁；女性参与者18277名[55.4%]）。在英国生物银行验证队列中，PRS-PAD每增加1个标准差，优势比（OR）为1.63（95%置信区间，1.60 - 1.68；P <.001）。在调整临床风险因素后，与其余人群相比，PRS-PAD最高的20%人群的OR为1.68（95%置信区间，1.62 - 1.74；P <.001）。在无糖尿病、吸烟或慢性肾病病史的PAD病例中（n = 3645），1097名个体（30.1%）的PRS-PAD较高（最高的20%）。在新发疾病分析中，PRS-PAD改善了鉴别能力（C统计量，0.761），几乎等同于糖尿病（C统计量，0.760）和吸烟（C统计量，0.765）的表现。在患有现患PAD的个体中，在英国生物银行（风险比[HR]，1.75；95%置信区间，1.18 - 2.57；P = 0.005）、MGBB（HR，1.56；95%置信区间，1.06 - 2.30；P = 0.02）和AoU（HR，1.57；95%置信区间，1.06 - 2.33；P = 0.03）中，较高的PRS-PAD与发生主要肢体不良事件的风险增加相关。
这项队列研究开发了一种新的PRS，可对PAD和不良肢体结局的风险进行分层。将多基因风险纳入PAD护理值得进一步研究，以指导筛查并定制管理措施，预防主要肢体不良事件。
