Circulating lipoprotein(a) levels and health outcomes: Phenome-wide Mendelian randomization and disease-trajectory analyses

孟德尔随机化 现象 医学 2型糖尿病 共病 糖尿病 内科学 疾病 贫血 脂蛋白(a) 生物信息学 脂蛋白 生物 胆固醇 内分泌学 表型 遗传学 基因型 基因 遗传变异
作者
Susanna C. Larsson,Lijuan Wang,Xue Li,Fangyuan Jiang,Xiangjun Chen,Christos S. Mantzoros
出处
期刊:Metabolism-clinical and Experimental [Elsevier BV]
卷期号:137: 155347-155347 被引量:20
标识
DOI:10.1016/j.metabol.2022.155347
摘要

Background Lipoprotein(a) [Lp(a)] is a risk factor for atherosclerotic and valvular diseases, but its possible role in other diseases has not yet been established. We conducted phenome-wide Mendelian randomization and disease-trajectory analyses to assess any associations of circulating Lp(a) levels with a broad range of diseases. Methods A weighted polygenic risk score was constructed using independent genetic variants in the LPA gene and with an established effect on Lp(a) levels. The PheWAS analysis included 1081 phenotype outcomes ascertained among 385,917 White participants of the UK Biobank. Novel findings were investigated in MR analysis using data from the FinnGen consortium. Disease-trajectory and comorbidity analyses were further conducted to explore the sequential patterns of multiple morbidities related to high circulating Lp(a) levels. Results PheWAS revealed statistically significant associations of higher circulating Lp(a) levels with increased risk of a large number of circulatory system diseases (including various cardiac diseases, peripheral vascular disease, hypertension, and valvular and cerebrovascular diseases) as well as some endocrine/metabolic diseases (including hyperlipidemia, hypercholesterolemia, disorders of lipoid metabolism, and type 2 diabetes), genitourinary system diseases (renal failure), and hematologic diseases (including different types of anemia). Two-sample MR analysis supported the association between Lp(a) and risk of anemia, showed a suggestive association with type 2 diabetes, but found no association with renal failure. Disease-trajectory and comorbidity analyses identified 3 major sequential patterns of multiple morbidities, mainly in the cardiovascular, metabolic, and mental disorders, related to high circulating Lp(a) levels. Conclusions Genetically predicted higher circulating Lp(a) levels were associated with increased risk of many circulatory system diseases and anemia. Additionally, this study identified three major sequential patterns of multiple morbidities related to high Lp(a).
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