Division of Experimental Medicine (M.H., H.Y.C., G.T., J.C.E.), McGill University, Montreal, Quebec.
Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Montreal, Quebec, Canada (M.H., H.Y.C., L.D., G.T., J.C.E.).
Arterioscler Thromb Vasc Biol. 2021 Jan;41(1):458-464. doi: 10.1161/ATVBAHA.120.314965. Epub 2020 Oct 29.
Lp(a) (lipoprotein[a]) is an independent risk factor for cardiovascular diseases and plasma levels are primarily determined by variation at the locus. We performed a genome-wide association study in the UK Biobank to determine whether additional loci influence Lp(a) levels. Approach and Results: We included 293 274 White British individuals in the discovery analysis. Approximately 93 095 623 variants were tested for association with natural log-transformed Lp(a) levels using linear regression models adjusted for age, sex, genotype batch, and 20 principal components of genetic ancestry. After quality control, 131 independent variants were associated at genome-wide significance ≤5×10). In addition to validating previous associations at , , and , we identified a novel variant at the locus, encoding β2GPI (beta2-glycoprotein I). The variant rs8178824 was associated with increased Lp(a) levels (β [95% CI] [ln nmol/L], 0.064 [0.047-0.081]; =2.8×10) and demonstrated a stronger effect after adjustment for variation at the locus (β [95% CI] [ln nmol/L], 0.089 [0.076-0.10]; =3.8×10). This association was replicated in a meta-analysis of 5465 European-ancestry individuals from the Framingham Offspring Study and Multi-Ethnic Study of Atherosclerosis (β [95% CI] [ln mg/dL], 0.16 [0.044-0.28]; =0.0071).
In a large-scale genome-wide association study of Lp(a) levels, we identified as a novel locus for Lp(a) in individuals of European ancestry. Additional studies are needed to determine the precise role of β2GPI in influencing Lp(a) levels as well as its potential as a therapeutic target.
脂蛋白（a）[Lp(a)]是心血管疾病的独立风险因素，其血浆水平主要由 基因座的变异决定。我们在英国生物库中进行了全基因组关联研究，以确定是否有其他基因座影响 Lp(a)水平。
我们在发现分析中纳入了 293274 名白种英国人。使用线性回归模型，根据年龄、性别、基因型批次和 20 个遗传祖先主成分，对大约 93095623 个变体与自然对数转换的 Lp(a)水平进行关联检验。经过质量控制，有 131 个独立的变体在全基因组显著水平≤5×10-8 时与 Lp(a)水平相关。除了验证以前在 、 和 基因座上的关联外，我们还在编码β2GPI（β2-糖蛋白 I）的 基因座上发现了一个新的变体。 变体 rs8178824 与 Lp(a)水平升高相关（β[95%CI] [ln nmol/L]，0.064 [0.047-0.081]；=2.8×10-8），并且在调整 基因座上的变异后，这种关联更强（β[95%CI] [ln nmol/L]，0.089 [0.076-0.10]；=3.8×10-8）。在弗雷明汉后代研究和多民族动脉粥样硬化研究的 5465 名欧洲血统个体的荟萃分析中复制了这种关联（β[95%CI] [ln mg/dL]，0.16 [0.044-0.28]；=0.0071）。
在一项针对 Lp(a)水平的大型全基因组关联研究中，我们确定 为欧洲血统个体中 Lp(a)的一个新基因座。需要进一步的研究来确定β2GPI 在影响 Lp(a)水平方面的确切作用及其作为治疗靶点的潜力。
