BACKGROUND: Several sequence variants are known to have effects on serum levels of non-high-density lipoprotein (HDL) cholesterol that alter the risk of coronary artery disease. METHODS: We sequenced the genomes of 2636 Icelanders and found variants that we then imputed into the genomes of approximately 398,000 Icelanders. We tested for association between these imputed variants and non-HDL cholesterol levels in 119,146 samples. We then performed replication testing in two populations of European descent. We assessed the effects of an implicated loss-of-function variant on the risk of coronary artery disease in 42,524 case patients and 249,414 controls from five European ancestry populations. An augmented set of genomes was screened for additional loss-of-function variants in a target gene. We evaluated the effect of an implicated variant on protein stability. RESULTS: We found a rare noncoding 12-base-pair (bp) deletion (del12) in intron 4 of ASGR1, which encodes a subunit of the asialoglycoprotein receptor, a lectin that plays a role in the homeostasis of circulating glycoproteins. The del12 mutation activates a cryptic splice site, leading to a frameshift mutation and a premature stop codon that renders a truncated protein prone to degradation. Heterozygous carriers of the mutation (1 in 120 persons in our study population) had a lower level of non-HDL cholesterol than noncarriers, a difference of 15.3 mg per deciliter (0.40 mmol per liter) (P=1.0×10(-16)), and a lower risk of coronary artery disease (by 34%; 95% confidence interval, 21 to 45; P=4.0×10(-6)). In a larger set of sequenced samples from Icelanders, we found another loss-of-function ASGR1 variant (p.W158X, carried by 1 in 1850 persons) that was also associated with lower levels of non-HDL cholesterol (P=1.8×10(-3)). CONCLUSIONS: ASGR1 haploinsufficiency was associated with reduced levels of non-HDL cholesterol and a reduced risk of coronary artery disease. (Funded by the National Institutes of Health and others.).
BACKGROUND: Several sequence variants are known to have effects on serum levels of non-high-density lipoprotein (HDL) cholesterol that alter the risk of coronary artery disease. METHODS: We sequenced the genomes of 2636 Icelanders and found variants that we then imputed into the genomes of approximately 398,000 Icelanders. We tested for association between these imputed variants and non-HDL cholesterol levels in 119,146 samples. We then performed replication testing in two populations of European descent. We assessed the effects of an implicated loss-of-function variant on the risk of coronary artery disease in 42,524 case patients and 249,414 controls from five European ancestry populations. An augmented set of genomes was screened for additional loss-of-function variants in a target gene. We evaluated the effect of an implicated variant on protein stability. RESULTS: We found a rare noncoding 12-base-pair (bp) deletion (del12) in intron 4 of ASGR1, which encodes a subunit of the asialoglycoprotein receptor, a lectin that plays a role in the homeostasis of circulating glycoproteins. The del12 mutation activates a cryptic splice site, leading to a frameshift mutation and a premature stop codon that renders a truncated protein prone to degradation. Heterozygous carriers of the mutation (1 in 120 persons in our study population) had a lower level of non-HDL cholesterol than noncarriers, a difference of 15.3 mg per deciliter (0.40 mmol per liter) (P=1.0×10(-16)), and a lower risk of coronary artery disease (by 34%; 95% confidence interval, 21 to 45; P=4.0×10(-6)). In a larger set of sequenced samples from Icelanders, we found another loss-of-function ASGR1 variant (p.W158X, carried by 1 in 1850 persons) that was also associated with lower levels of non-HDL cholesterol (P=1.8×10(-3)). CONCLUSIONS: ASGR1 haploinsufficiency was associated with reduced levels of non-HDL cholesterol and a reduced risk of coronary artery disease. (Funded by the National Institutes of Health and others.).
Authors: Kiran Musunuru; Pankaj Arora; John P Cooke; Jane F Ferguson; Ray E Hershberger; Kathleen T Hickey; Jin-Moo Lee; João A C Lima; Joseph Loscalzo; Naveen L Pereira; Mark W Russell; Svati H Shah; Farah Sheikh; Thomas J Wang; Calum A MacRae Journal: Circ Genom Precis Med Date: 2018-06
Authors: Luis Fernández-Vega Cueto; Tin Aung; Mineo Ozaki; Mei Chin Lee; Ursula Schlötzer-Schrehardt; Gudmar Thorleifsson; Takanori Mizoguchi; Robert P Igo; Aravind Haripriya; Susan E Williams; Yury S Astakhov; Andrew C Orr; Kathryn P Burdon; Satoko Nakano; Kazuhiko Mori; Khaled Abu-Amero; Michael Hauser; Zheng Li; Gopalakrishnan Prakadeeswari; Jessica N Cooke Bailey; Alina Popa Cherecheanu; Jae H Kang; Sarah Nelson; Ken Hayashi; Shin-Ichi Manabe; Shigeyasu Kazama; Tomasz Zarnowski; Kenji Inoue; Murat Irkec; Miguel Coca-Prados; Kazuhisa Sugiyama; Irma Järvelä; Patricio Schlottmann; S Fabian Lerner; Hasnaa Lamari; Yildirim Nilgün; Mukharram Bikbov; Ki Ho Park; Soon Cheol Cha; Kenji Yamashiro; Juan C Zenteno; Jost B Jonas; Rajesh S Kumar; Shamira A Perera; Anita S Y Chan; Nino Kobakhidze; Ronnie George; Lingam Vijaya; Tan Do; Deepak P Edward; Lourdes de Juan Marcos; Mohammad Pakravan; Sasan Moghimi; Ryuichi Ideta; Daniella Bach-Holm; Per Kappelgaard; Barbara Wirostko; Samuel Thomas; Daniel Gaston; Karen Bedard; Wenda L Greer; Zhenglin Yang; Xueyi Chen; Lulin Huang; Jinghong Sang; Hongyan Jia; Liyun Jia; Chunyan Qiao; Hui Zhang; Xuyang Liu; Bowen Zhao; Ya-Xing Wang; Liang Xu; Stéphanie Leruez; Pascal Reynier; George Chichua; Sergo Tabagari; Steffen Uebe; Matthias Zenkel; Daniel Berner; Georg Mossböck; Nicole Weisschuh; Ursula Hoja; Ulrich-Christoph Welge-Luessen; Christian Mardin; Panayiota Founti; Anthi Chatzikyriakidou; Theofanis Pappas; Eleftherios Anastasopoulos; Alexandros Lambropoulos; Arkasubhra Ghosh; Rohit Shetty; Natalia Porporato; Vijayan Saravanan; Rengaraj Venkatesh; Chandrashekaran Shivkumar; Narendran Kalpana; Sripriya Sarangapani; Mozhgan R Kanavi; Afsaneh Naderi Beni; Shahin Yazdani; Alireza Lashay; Homa Naderifar; Nassim Khatibi; Antonio Fea; Carlo Lavia; Laura Dallorto; Teresa Rolle; Paolo Frezzotti; Daniela Paoli; Erika Salvi; Paolo Manunta; Yosai Mori; Kazunori Miyata; Tomomi Higashide; Etsuo Chihara; Satoshi Ishiko; Akitoshi Yoshida; Masahide Yanagi; Yoshiaki Kiuchi; Tsutomu Ohashi; Toshiya Sakurai; Takako Sugimoto; Hideki Chuman; Makoto Aihara; Masaru Inatani; Masahiro Miyake; Norimoto Gotoh; Fumihiko Matsuda; Nagahisa Yoshimura; Yoko Ikeda; Morio Ueno; Chie Sotozono; Jin Wook Jeoung; Min Sagong; Kyu Hyung Park; Jeeyun Ahn; Marisa Cruz-Aguilar; Sidi M Ezzouhairi; Abderrahman Rafei; Yaan Fun Chong; Xiao Yu Ng; Shuang Ru Goh; Yueming Chen; Victor H K Yong; Muhammad Imran Khan; Olusola O Olawoye; Adeyinka O Ashaye; Idakwo Ugbede; Adeola Onakoya; Nkiru Kizor-Akaraiwe; Chaiwat Teekhasaenee; Yanin Suwan; Wasu Supakontanasan; Suhanya Okeke; Nkechi J Uche; Ifeoma Asimadu; Humaira Ayub; Farah Akhtar; Ewa Kosior-Jarecka; Urszula Lukasik; Ignacio Lischinsky; Vania Castro; Rodolfo Perez Grossmann; Gordana Sunaric Megevand; Sylvain Roy; Edward Dervan; Eoin Silke; Aparna Rao; Priti Sahay; Pablo Fornero; Osvaldo Cuello; Delia Sivori; Tamara Zompa; Richard A Mills; Emmanuelle Souzeau; Paul Mitchell; Jie Jin Wang; Alex W Hewitt; Michael Coote; Jonathan G Crowston; Sergei Y Astakhov; Eugeny L Akopov; Anton Emelyanov; Vera Vysochinskaya; Gyulli Kazakbaeva; Rinat Fayzrakhmanov; Saleh A Al-Obeidan; Ohoud Owaidhah; Leyla Ali Aljasim; Balram Chowbay; Jia Nee Foo; Raphael Q Soh; Kar Seng Sim; Zhicheng Xie; Augustine W O Cheong; Shi Qi Mok; Hui Meng Soo; Xiao Yin Chen; Su Qin Peh; Khai Koon Heng; Rahat Husain; Su-Ling Ho; Axel M Hillmer; Ching-Yu Cheng; Francisco A Escudero-Domínguez; Rogelio González-Sarmiento; Frederico Martinon-Torres; Antonio Salas; Kessara Pathanapitoon; Linda Hansapinyo; Boonsong Wanichwecharugruang; Naris Kitnarong; Anavaj Sakuntabhai; Hip X Nguyn; Giang T T Nguyn; Trình V Nguyn; Werner Zenz; Alexander Binder; Daniela S Klobassa; Martin L Hibberd; Sonia Davila; Stefan Herms; Markus M Nöthen; Susanne Moebus; Robyn M Rautenbach; Ari Ziskind; Trevor R Carmichael; Michele Ramsay; Lydia Álvarez; Montserrat García; Héctor González-Iglesias; Pedro P Rodríguez-Calvo; Çilingir Oguz; Nevbahar Tamcelik; Eray Atalay; Bilge Batu; Dilek Aktas; Burcu Kasım; M Roy Wilson; Anne L Coleman; Yutao Liu; Pratap Challa; Leon Herndon; Rachel W Kuchtey; John Kuchtey; Karen Curtin; Craig J Chaya; Alan Crandall; Linda M Zangwill; Tien Yin Wong; Masakazu Nakano; Shigeru Kinoshita; Anneke I den Hollander; Eija Vesti; John H Fingert; Richard K Lee; Arthur J Sit; Bradford J Shingleton; Ningli Wang; Daniele Cusi; Raheel Qamar; Peter Kraft; Margaret A Pericak-Vance; Soumya Raychaudhuri; Steffen Heegaard; Tero Kivelä; André Reis; Friedrich E Kruse; Robert N Weinreb; Louis R Pasquale; Jonathan L Haines; Unnur Thorsteinsdottir; Fridbert Jonasson; R Rand Allingham; Dan Milea; Robert Ritch; Toshiaki Kubota; Kei Tashiro; Eranga N Vithana; Shazia Micheal; Fotis Topouzis; Jamie E Craig; Michael Dubina; Periasamy Sundaresan; Kari Stefansson; Janey L Wiggs; Francesca Pasutto; Chiea Chuen Khor Journal: Nat Genet Date: 2017-05-29 Impact factor: 38.330