BACKGROUND Lipoprotein(a) [Lp(a)] is a causal risk factor for cardiovascular diseases that has no established therapy. The attribute of Lp(a) that affects cardiovascular risk is not established. Low levels of Lp(a) have been associated with type 2 diabetes (T2D). OBJECTIVES This study investigated whether cardiovascular risk is conferred by Lp(a) molar concentration or apolipoprotein(a) [apo(a)] size, and whether the relationship between Lp(a) and T2D risk is causal. METHODS This was a case-control study of 143,087 Icelanders with genetic information, including 17,715 with coronary artery disease (CAD) and 8,734 with T2D. This study used measured and genetically imputed Lp(a) molar concentration, kringle IV type 2 (KIV-2) repeats (which determine apo(a) size), and a splice variant in LPA associated with small apo(a) but low Lp(a) molar concentration to disentangle the relationship between Lp(a) and cardiovascular risk. Loss-of-function homozygotes and other subjects genetically predicted to have low Lp(a) levels were evaluated to assess the relationship between Lp(a) and T2D. RESULTS Lp(a) molar concentration was associated dose-dependently with CAD risk, peripheral artery disease, aortic valve stenosis, heart failure, and lifespan. Lp(a) molar concentration fully explained the Lp(a) association with CAD, and there was no residual association with apo(a) size. Homozygous carriers of loss-of-function mutations had little or no Lp(a) and increased the risk of T2D. CONCLUSIONS Molar concentration is the attribute of Lp(a) that affects risk of cardiovascular diseases. Low Lp(a) concentration (bottom 10%) increases T2D risk. Pharmacologic reduction of Lp(a) concentration in the 20% of individuals with the greatest concentration down to the population median is predicted to decrease CAD risk without increasing T2D risk.

中文翻译：

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脂蛋白 (a) 浓度和心血管疾病和糖尿病的风险

背景脂蛋白(a) [Lp(a)] 是心血管疾病的致病危险因素，尚无确定的治疗方法。影响心血管风险的 Lp(a) 属性尚未确定。低水平的 Lp(a) 与 2 型糖尿病 (T2D) 相关。目的 本研究调查了心血管风险是否由 Lp(a) 摩尔浓度或载脂蛋白 (a) [apo(a)] 大小决定，以及 Lp(a) 与 T2D 风险之间的关系是否存在因果关系。方法 这是一项病例对照研究，涉及 143,087 名具有遗传信息的冰岛人，其中 17,715 名患有冠状动脉疾病 (CAD)，8,734 名患有 T2D。本研究使用测量和遗传推算的 Lp(a) 摩尔浓度、kringle IV 2 型 (KIV-2) 重复序列（决定 apo(a) 大小）、LPA 中的剪接变体与小 apo(a) 但低 Lp(a) 摩尔浓度相关，以解开 Lp(a) 与心血管风险之间的关系。对功能丧失的纯合子和其他基因预测具有低 Lp(a) 水平的受试者进行评估，以评估 Lp(a) 和 T2D 之间的关系。结果 Lp(a) 摩尔浓度与 CAD 风险、外周动脉疾病、主动脉瓣狭窄、心力衰竭和寿命呈剂量依赖性相关。Lp(a) 摩尔浓度完全解释了 Lp(a) 与 CAD 的关联，并且没有与 apo(a) 大小的残余关联。功能丧失突变的纯合子携带者很少或没有 Lp(a) 并增加了 T2D 的风险。结论 摩尔浓度是影响心血管疾病风险的 Lp(a) 的属性。低 Lp(a) 浓度（底部 10%）会增加 T2D 风险。预计将最大浓度的 20% 个体的 Lp(a) 浓度药理学降低至人群中位数可降低 CAD 风险，而不会增加 T2D 风险。