Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Commun Biol. 2022 Aug 17;5(1):802. doi: 10.1038/s42003-022-03552-0.
Cardiovascular diseases are the leading cause of premature death and disability worldwide, with both genetic and environmental determinants. While genome-wide association studies have identified multiple genetic loci associated with cardiovascular diseases, exact genes driving these associations remain mostly uncovered. Due to Finland's population history, many deleterious and high-impact variants are enriched in the Finnish population giving a possibility to find genetic associations for protein-truncating variants that likely tie the association to a gene and that would not be detected elsewhere. In a large Finnish biobank study FinnGen, we identified an association between an inframe insertion rs534125149 in MFGE8 (encoding lactadherin) and protection against coronary atherosclerosis. This variant is highly enriched in Finland, and the protective association was replicated in meta-analysis of BioBank Japan and Estonian biobank. Additionally, we identified a protective association between splice acceptor variant rs201988637 in MFGE8 and coronary atherosclerosis, independent of the rs534125149, with no significant risk-increasing associations. This variant was also associated with lower pulse pressure, pointing towards a function of MFGE8 in arterial aging also in humans in addition to previous evidence in mice. In conclusion, our results suggest that inhibiting the production of lactadherin could lower the risk for coronary heart disease substantially.
心血管疾病是全球范围内导致过早死亡和残疾的主要原因，其涉及遗传和环境决定因素。虽然全基因组关联研究已经确定了多个与心血管疾病相关的遗传位点，但确切的基因驱动这些关联仍然大多未被发现。由于芬兰的人口历史，许多有害和高影响的变体在芬兰人群中丰富，这使得有可能发现与蛋白质截断变体相关的遗传关联，这些变体可能与一个基因有关，而在其他地方则无法检测到。在一项大型芬兰生物库研究 FinnGen 中，我们在 MFGE8（编码乳贴蛋白）中的内含子插入 rs534125149 与冠状动脉粥样硬化的保护之间发现了关联。这种变体在芬兰高度丰富，并且在对 BioBank Japan 和爱沙尼亚生物库的荟萃分析中复制了这种保护关联。此外，我们在 MFGE8 中的剪接受体变体 rs201988637 与冠状动脉粥样硬化之间发现了一种保护关联，与 rs534125149 无关，且没有显著的风险增加关联。这种变体还与较低的脉搏压相关，这表明 MFGE8 在人类动脉老化中的作用除了先前在小鼠中的证据外，还有进一步的证据。总之，我们的结果表明，抑制乳贴蛋白的产生可能会大大降低患冠心病的风险。
