Inframe insertion and splice site variants in MFGE8 associate with protection against coronary atherosclerosis.
Sanni E Ruotsalainen, Ida Surakka, Nina Mars, Juha Karjalainen, Mitja Kurki, Masahiro Kanai, Kristi Krebs, Sarah Graham, Pashupati P Mishra, Binisha H Mishra, Juha Sinisalo, Priit Palta, Terho Lehtimäki, Olli Raitakari, Estonian Biobank Research Team, Lili Milani, Biobank Japan Project, Yukinori Okada, FinnGen, Aarno Palotie, Elisabeth Widen, Mark J Daly, Samuli Ripatti
Author Information
Sanni E Ruotsalainen: Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland. ORCID
Ida Surakka: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Nina Mars: Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
Juha Karjalainen: The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Mitja Kurki: The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Masahiro Kanai: The Broad Institute of MIT and Harvard, Cambridge, MA, USA. ORCID
Kristi Krebs: Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia. ORCID
Sarah Graham: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Pashupati P Mishra: Department of Clinical Chemistry, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
Binisha H Mishra: Department of Clinical Chemistry, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
Juha Sinisalo: Heart and Lung Center, Helsinki University Hospital and Helsinki University, Helsinki, Finland.
Priit Palta: Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland. ORCID
Terho Lehtimäki: Department of Clinical Chemistry, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
Olli Raitakari: Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
Lili Milani: Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
Yukinori Okada: Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan. ORCID
Aarno Palotie: Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland. ORCID
Elisabeth Widen: Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
Mark J Daly: Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
Samuli Ripatti: Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland. samuli.ripatti@helsinki.fi. ORCID
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.
References
Bioinformatics. 2019 Nov 1;35(22):4862-4865
[PMID: 31116374]
