Inframe insertion and splice site variants in MFGE8 associate with protection against coronary atherosclerosis
Authors: Ruotsalainen Sanni E. , Surakka Ida , Mars Nina , Karjalainen Juha , Kurki Mitja , Kanai Masahiro , Krebs Kristi , Graham Sarah , Mishra Pashupati P. , Mishra Binisha H. , Sinisalo Juha , Palta Priit , Lehtimäki Terho , Raitakari Olli ,   Estonian Biobank Research Team, Esko Tõnu , Metspalu Andres , Mägi Reedik , Nelis Mari , Milani Lili ,   The Biobank Japan Project, Matsuda Koichi , Yamanashi Yuji , Furukawa Yoichi , Morisaki Takayuki , Murakami Yoshinori , Kamatani Yoichiro , Muto Kaori , Nagai Akiko , Obara Wataru , Yamaji Ken , Takahashi Kazuhisa , Asai Satoshi , Takahashi Yasuo , Suzuki Takao , Sinozaki Nobuaki , Yamaguchi Hiroki , Minami Shiro , Murayama Shigeo , Yoshimori Kozo , Nagayama Satoshi , Obata Daisuke , Higashiyama Masahiko , Masumoto Akihide , Koretsune Yukihiro , Okada Yukinori ,   FinnGen,   Steering Committee, Palotie Aarno , Daly Mark ,   Pharmaceutical Companies, Riley-Gills Bridget , Jacob Howard , Paul Dirk , Runz Heiko , John Sally , Plenge Robert , McCarthy Mark , Hunkapiller Julie , Ehm Meg , Auro Kirsi , Fox Caroline , Mälarstig Anders , Klinger Katherine , Raipal Deepak , Behrens Tim , Yang Robert , Siegel Richard ,   University of Helsinki & Biobanks, Mäkelä Tomi , Kaprio Jaakko , Virolainen Petri , Hakanen Antti , Kilpi Terhi , Perola Markus , Partanen Jukka , Pitkäranta Anne , Junttila Juhani , Serpi Raisa , Laitinen Tarja , Mäkelä Johanna , Kosma Veli-Matti , Kujala Urho ,   Other Experts/Non-Voting Members, Tuovila Outi , Pakkanen Raimo ,   Scientific Committee,   Pharmaceutical Companies, Waring Jeffrey , Abbasi Ali , Liu Mengzhen , Tachmazidou Ioanna , Chen Chia-Yen , Biswas Shameek , Raghavan Neha , Huertas-Vazquez Adriana , Hu Xinli , Gossel Matthias , Graham Robert , Cummings Beryl , Fleuren Wilco , Waterworth Dawn , Renaud Nicole , Obeidat Ma´en ,   University of Helsinki & Biobanks, Ripatti Samuli , Schleutker Johanna , Arvas Mikko , Carpén Olli , Hinttala Reetta , Kettunen Johannes , Mannermaa Arto , Laukkanen Jari ,   Clinical Groups,   Neurology Group, Kälviäinen Reetta , Julkunen Valtteri , Soininen Hilkka , Remes Anne , Hiltunen Mikko , Peltola Jukka , Tienari Pentti , Rinne Juha , Kallionpää Roosa , Ziemann Adam , Esmaeeli Sahar , Smaoui Nizar , Lehtonen Anne , Eaton Susan , Lahdenperä Sanni , van Adelsberg Janet , Bowers Natalie , Teng Edmond , Pendergrass Sarah , Soylemez Onuralp , Linden Kari , Xu Fanli , Pulford David , Addis Laura , Eicher John , Raivio Minna , Partanen Juulia ,   Gastroenterology Group, Färkkilä Martti , Koskela Jukka , Pikkarainen Sampsa , Jussila Airi , Kaukinen Katri , Blomster Timo , Kiviniemi Mikko , Voutilainen Markku , Heap Graham , Rahimov Fedik , Usiskin Keith , Lu Tim , Oh Danny , Kalpala Kirsi , Miller Melissa , McCarthy Linda ,   Rheumatology Group, Eklund Kari , Palomäki Antti , Isomäki Pia , Pirilä Laura , Kaipiainen-Seppänen Oili , Huhtakangas Johanna , Lertratanakul Apinya , Close David , Hochfeld Marla , Bing Nan , Gordillo Jorge Esparza ,   Pulmonology Group, Laitinen Tarja , Pelkonen Margit , Kauppi Paula , Kankaanranta Hannu , Harju Terttu , Lahesmaa Riitta , Mackay Alex , Lassi Glenda , Greenberg Steven , Chen Hubert , Betts Joanna , Ghosh Soumitra , Mishra Rajashree , Rüeger Sina ,   Cardiometabolic Diseases Group, Niiranen Teemu , Vaura Felix , Salomaa Veikko , Juonala Markus , Metsärinne Kaj , Kähönen Mika , Junttila Juhani , Laakso Markku , Pihlajamäki Jussi , Gordin Daniel , Sinisalo Juha , Taskinen Marja-Riitta , Tuomi Tiinamaija , Laukkanen Jari , Challis Benjamin , Parkkinen Jaakko , Miller Russell , Chu Audrey , Elliott Amanda , Rämö Joel , Reeve Mary Pat , Ruotsalainen Sanni ,   Oncology Group, Meretoja Tuomo , Joensuu Heikki , Carpén Olli , Aaltonen Lauri , Mattson Johanna , Auranen Annika , Karihtala Peeter , Kauppila Saila , Auvinen Päivi , Elenius Klaus , Schleutker Johanna , Popovic Relja , Riley-Gillis Bridget , Schutzman Jennifer , Loboda Andrey , Chhibber Aparna , Lehtonen Heli , McDonough Stefan , Crohns Marika , Vuoti Sauli , Kulkarni Diptee , Pitkänen Esa ,   Opthalmology Group, Kaarniranta Kai , Turunen Joni A. , Ollila Terhi , Seitsonen Sanna , Uusitalo Hannu , Aaltonen Vesa , Uusitalo-Järvinen Hannele , Luodonpää Marja , Hautala Nina , Loomis Stephanie , Strauss Erich , Chen Hao , Podgornaia Anna , Karjalainen Juha ,   Dermatology Group, Tasanen Kaisa , Huilaja Laura , Hannula-Jouppi Katariina , Salmi Teea , Peltonen Sirkku , Koulu Leena , Wu Ying , Choy David ,   Odontology Group, Pussinen Pirkko , Salminen Aino , Salo Tuula , Rice David , Nieminen Pekka , Palotie Ulla , Siponen Maria , Suominen Liisa , Mäntylä Päivi , Gursoy Ulvi , Anttonen Vuokko , Sipilä Kirsi ,   Women’s Health and Reproduction Group, Laivuori Hannele , Kurra Venla , Heikinheimo Oskari , Kalliala Ilkka , Kotaniemi-Talonen Laura , Nieminen Kari , Polo Päivi , Mäkikallio Kaarin , Ekholm Eeva , Vääräsmäki Marja , Uimari Outi , Morin-Papunen Laure , Tuppurainen Marjo , Kivinen Katja , Tukiainen Taru , Aoxing Liu , Laakkonen Eija , Välimäki Niko , Kettunen Johannes , Arvas Mikko , Kumar Janet , Ganna Andrea ,   FinnGen Analysis Working Group, Davis Justin Wade , Quarless Danjuma , Petrovski Slavé , Wigmore Eleonor , Mitchell Adele , Sun Benjamin , Tsai Ellen , Baird Denis , Bronson Paola , Tian Ruoyu , Huang Yunfeng , Maranville Joseph , Mohammed Elmutaz , Wadhawan Samir , Kvikstad Erika , Caliskan Minal , Chang Diana , Bhangale Tushar , Shkura Kirill , Neduva Victor , Chen Xing , Hedman Åsa , King Karen S. , Gormley Padhraig , Liu Jimmy , Wang Clarence , Xu Ethan , Auge Franck , Chatelain Clement , Rajpal Deepak , Liu Dongyu , Call Katherine , Xia Tai-He , Brauer Matt , Xu Huilei , Cole Amy , Chung Jonathan , Jacob Jaison , de Lange Katrina , Zierer Jonas , Kurki Mitja , Havulinna Aki , Mehtonen Juha , Palta Priit , Hassan Shabbeer , Della Briotta Parolo Pietro , Zhou Wei , Maasha Mutaamba , Lemmelä Susanna , Rivas Manuel , Lehisto Arto , Llorens Vincent , Niemi Mari E. , Heyne Henrike , Palin Kimmo , Garcia-Tabuenca Javier , Siirtola Harri , Kiiskinen Tuomo , Lee Jiwoo , Tsuo Kristin , Kristiansson Kati , Hyvärinen Kati , Ritari Jarmo , Koskinen Miika , Pylkäs Katri , Kalaoja Marita , Karjalainen Minna , Mantere Tuomo , Kangasniemi Eeva , Heikkinen Sami , Heron Samuel , Jambulingam Dhanaprakash , Rathinakannan Venkat Subramaniam , Pitkänen Nina ,   Biobank Directors, Kallio Lila , Soini Sirpa , Punkka Eero , Kuopio Teijo ,   FinnGen Teams,   Administration, Jalanko Anu , Shen Huei-Yi , Kajanne Risto , Aavikko Mervi ,   Analysis, Kanai Masahiro ,   Clinical Endpoint Development, Lahtela L. Elisa ,   Communication, Kaunisto Mari ,   E-Science, Kilpeläinen Elina , Sipilä Timo P. , Brein Georg , Dada Oluwaseun Alexander , Ghazal Awaisa , Shcherban Anastasia ,   Genotyping, Donner Kati ,   Sample Collection Coordination, Loukola Anu ,   Sample Logistics, Laiho Päivi , Sistonen Tuuli , Kaiharju Essi , Laukkanen Markku , Järvensivu Elina , Lähteenmäki Sini , Männikkö Lotta , Wong Regis ,   Registry Data Operations, Mattsson Hannele , Koskelainen Sami , Hiekkalinna Tero , Paajanen Teemu ,   Sequencing Informatics, Pärn Kalle , Luo Shuang , Sinha Vishal ,   Trajectory, Gracia-Tabuenca Javier , Helminen Mika , Luukkaala Tiina , Vähätalo Iida ,   Data Protection Officer, Jyrhämä Tero ,   FinBB—Finnish Biobank Cooperative, Hautalahti Marco , Mustaniemi Laura , Koivusalo Mirkka , Smith Sarah , Southerington Tom , Palotie Aarno , Widen Elisabeth , Daly Mark J. , Ripatti Samuli 
Published: August 2022

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 inMFGE8(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 inMFGE8and 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 ofMFGE8in 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.