Background:Polygenic risk scores (PRS) for coronary heart disease (CHD) may contribute to assess the overall risk of CHD. We evaluated how PRS may influence CHD risk when the distribution of age-at-onset, sex, and family health history differ significantly.Methods:Our study included 3 family-based ascertainments: LLFS (Long Life Family Study, N_Individuals=4572), which represents a low CHD risk, and Family Heart Study, which consists of randomly selected families (FamHS-random, N_Individuals=1806), and high CHD risk families (FamHS-high risk, N_Individuals=2301). We examined the effects of PRS, sex, family ascertainment, PRS interaction with sex (PRS*sex) and with family ascertainment (PRS*LLFS and PRS*FamHS-high risk) on CHD, corrected for traditional cardiovascular risk factors using Cox proportional hazard regression models.Results:Healthy-aging LLFS presented ≈17 years delayed for CHD age-at-onset compared with FamHS-high risk (P<1.0×10⁻⁴). Sex-specific association (P<1.0×10⁻¹⁷) and PRS*sex (P=2.7×10⁻³) predicted prevalent CHD. CHD age-at-onset was associated with PRS (hazard ratio [HR], 1.57; P=1.3×10⁻⁵), LLFS (HR, 0.54; P=2.6×10⁻⁵), and FamHS-high risk (HR, 2.86; P=6.70x10⁻¹⁵) in men, and with PRS (HR, 1.76; P=7.70×10⁻³), FamHS-high risk (HR, 4.88; P=8.70×10⁻¹⁰), and PRS×FamHS-high risk (HR, 0.61; P=3.60×10⁻²) in women. In the PRS extreme quartile distributions, CHD age-at-onset was associated (P<0.05) with PRS, FamHS-high risk, and PRS interactions with both low and high CHD risk families for women. For men, the PRS quartile results remained similar to the whole distribution.Conclusions:Differences in CHD family-based ascertainments show evidence of PRS interacting with sex to predict CHD risk. In women, CHD age-at-onset was associated with PRS, CHD family history, and interactions of PRS with family history. In men, PRS and CHD family history were the major effects on the CHD age-at-onset. Understanding the heterogeneity of risks associated with CHD end points at both the personal and familial levels may shed light on the underlying genetic effects influencing CHD and lead to more personalized risk prediction.

中文翻译：

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三种不同冠心病家族确定中冠心病发病年龄预测多基因风险评分的异质性

背景：冠心病（CHD）的多基因风险评分（PRS）可能有助于评估冠心病的总体风险。当发病年龄、性别和家族健康史的分布显着不同时，我们评估了 PRS 如何影响 CHD 风险。方法：我们的研究包括 3 个基于家庭的确定：LLFS（长寿家庭研究，N_个体=4572） ，代表低 CHD 风险，以及家庭心脏研究，由随机选择的家庭（FamHS-随机，N 个_个体=1806）和高 CHD 风险家庭（FamHS-高风险，N 个_个体=2301)。我们检查了 PRS、性别、家庭确定、PRS 与性别的相互作用 (PRS*sex) 和家庭确定 (PRS*LLFS 和 PRS*FamHS-高风险) 对 CHD 的影响，使用 Cox 比例风险校正传统心血管危险因素回归模型。结果：与 FamHS 高风险相比，健康老龄化 LLFS 的 CHD 发病年龄延迟约 17 年（P< 1.0×10 ^-4）。性别特异性关联 ( P <1.0×10 ^-17 ) 和 PRS*sex ( P =2.7×10 ^-3 ) 预测流行的 CHD。CHD 发病年龄与 PRS（风险比 [HR]，1.57；P =1.3×10 ^-5）、LLFS（HR，0.54；P =2.6×10 ^{-5 ）相关}) 和 FamHS 高风险 (HR, 2.86; P = 6.70x10 ^-15 ) 和 PRS (HR, 1.76; P =7.70×10 ^-3 ), FamHS 高风险 (HR, 4.88; P = 8.70×10 ^-10）和女性 PRS×FamHS 高风险（HR，0.61；P =3.60×10 ^-2）。在 PRS 极端四分位数分布中，CHD 发病年龄与 ( P<0.05) 与 PRS、FamHS 高风险以及 PRS 与女性 CHD 低风险和高风险家庭的相互作用。对于男性，PRS 四分位数结果与整个分布相似。结论：基于 CHD 家庭的确定差异显示 PRS 与性别相互作用以预测 CHD 风险的证据。在女性中，CHD 发病年龄与 PRS、CHD 家族史以及 PRS 与家族史的相互作用有关。在男性中，PRS 和 CHD 家族史是对 CHD 发病年龄的主要影响。在个人和家庭层面了解与 CHD 终点相关的风险的异质性可能会揭示影响 CHD 的潜在遗传效应，并导致更个性化的风险预测。