BACKGROUND: Carotid intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. To date, large-scale investigations of genetic determinants of cIMT are sparse. METHODS AND RESULTS: To identify cIMT-associated genes and genetic variants, a discovery analysis using the Illumina 200K CardioMetabochip was conducted in 3430 subjects with detailed ultrasonographic determinations of cIMT from the IMPROVE (Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a High Risk European Population) study. Segment-specific IMT measurements of common carotid, bifurcation, and internal carotid arteries, and composite IMT variables considering the whole carotid tree (IMT(mean), IMT(max), and IMT(mean-max)), were analyzed. A replication stage investigating 42 single-nucleotide polymorphisms for association with common carotid IMT was undertaken in 5 independent European cohorts (total n=11,590). A locus on chromosome 16 (lead single-nucleotide polymorphism rs4888378, intronic in CFDP1) was associated with cIMT at significance levels passing multiple testing correction at both stages (array-wide significant discovery P=6.75 × 10(-7) for IMT(max); replication P=7.24×10(-6) for common cIMT; adjustments for sex, age, and population substructure where applicable; minor allele frequency 0.43 and 0.41, respectively). The protective minor allele was associated with lower carotid plaque score in a replication cohort (P=0.04, n=2120) and lower coronary artery disease risk in 2 case-control studies of subjects with European ancestry (odds ratio [95% confidence interval] 0.83 [0.77-0.90], P=6.53 × 10(-6), n=13 591; and 0.95 [0.92-0.98], P=1.83 × 10(-4), n=82 297, respectively). Queries of human biobank data sets revealed associations of rs4888378 with nearby gene expression in vascular tissues (n=126-138). CONCLUSIONS: This study identified rs4888378 in the BCAR1-CFDP1-TMEM170A locus as a novel genetic determinant of cIMT and coronary artery disease risk in individuals of European descent.
BACKGROUND: Carotid intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. To date, large-scale investigations of genetic determinants of cIMT are sparse. METHODS AND RESULTS: To identify cIMT-associated genes and genetic variants, a discovery analysis using the Illumina 200K CardioMetabochip was conducted in 3430 subjects with detailed ultrasonographic determinations of cIMT from the IMPROVE (Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a High Risk European Population) study. Segment-specific IMT measurements of common carotid, bifurcation, and internal carotid arteries, and composite IMT variables considering the whole carotid tree (IMT(mean), IMT(max), and IMT(mean-max)), were analyzed. A replication stage investigating 42 single-nucleotide polymorphisms for association with common carotid IMT was undertaken in 5 independent European cohorts (total n=11,590). A locus on chromosome 16 (lead single-nucleotide polymorphism rs4888378, intronic in CFDP1) was associated with cIMT at significance levels passing multiple testing correction at both stages (array-wide significant discovery P=6.75 × 10(-7) for IMT(max); replication P=7.24×10(-6) for common cIMT; adjustments for sex, age, and population substructure where applicable; minor allele frequency 0.43 and 0.41, respectively). The protective minor allele was associated with lower carotid plaque score in a replication cohort (P=0.04, n=2120) and lower coronary artery disease risk in 2 case-control studies of subjects with European ancestry (odds ratio [95% confidence interval] 0.83 [0.77-0.90], P=6.53 × 10(-6), n=13 591; and 0.95 [0.92-0.98], P=1.83 × 10(-4), n=82 297, respectively). Queries of human biobank data sets revealed associations of rs4888378 with nearby gene expression in vascular tissues (n=126-138). CONCLUSIONS: This study identified rs4888378 in the BCAR1-CFDP1-TMEM170A locus as a novel genetic determinant of cIMT and coronary artery disease risk in individuals of European descent.
Authors: Liyong Wang; Ashley Beecham; Nicole Dueker; Susan H Blanton; Tatjana Rundek; Ralph L Sacco Journal: Hum Genet Date: 2015-08-30 Impact factor: 4.132
Authors: Liyong Wang; Tatjana Rundek; Ashley Beecham; Barry Hudson; Susan H Blanton; Hongyu Zhao; Ralph L Sacco; Chuanhui Dong Journal: Arterioscler Thromb Vasc Biol Date: 2013-11-07 Impact factor: 8.311
Authors: Yun J Sung; Thomas W Winkler; Lisa de Las Fuentes; Amy R Bentley; Michael R Brown; Aldi T Kraja; Karen Schwander; Ioanna Ntalla; Xiuqing Guo; Nora Franceschini; Yingchang Lu; Ching-Yu Cheng; Xueling Sim; Dina Vojinovic; Jonathan Marten; Solomon K Musani; Changwei Li; Mary F Feitosa; Tuomas O Kilpeläinen; Melissa A Richard; Raymond Noordam; Stella Aslibekyan; Hugues Aschard; Traci M Bartz; Rajkumar Dorajoo; Yongmei Liu; Alisa K Manning; Tuomo Rankinen; Albert Vernon Smith; Salman M Tajuddin; Bamidele O Tayo; Helen R Warren; Wei Zhao; Yanhua Zhou; Nana Matoba; Tamar Sofer; Maris Alver; Marzyeh Amini; Mathilde Boissel; Jin Fang Chai; Xu Chen; Jasmin Divers; Ilaria Gandin; Chuan Gao; Franco Giulianini; Anuj Goel; Sarah E Harris; Fernando Pires Hartwig; Andrea R V R Horimoto; Fang-Chi Hsu; Anne U Jackson; Mika Kähönen; Anuradhani Kasturiratne; Brigitte Kühnel; Karin Leander; Wen-Jane Lee; Keng-Hung Lin; Jian 'an Luan; Colin A McKenzie; He Meian; Christopher P Nelson; Rainer Rauramaa; Nicole Schupf; Robert A Scott; Wayne H H Sheu; Alena Stančáková; Fumihiko Takeuchi; Peter J van der Most; Tibor V Varga; Heming Wang; Yajuan Wang; Erin B Ware; Stefan Weiss; Wanqing Wen; Lisa R Yanek; Weihua Zhang; Jing Hua Zhao; Saima Afaq; Tamuno Alfred; Najaf Amin; Dan Arking; Tin Aung; R Graham Barr; Lawrence F Bielak; Eric Boerwinkle; Erwin P Bottinger; Peter S Braund; Jennifer A Brody; Ulrich Broeckel; Claudia P Cabrera; Brian Cade; Yu Caizheng; Archie Campbell; Mickaël Canouil; Aravinda Chakravarti; Ganesh Chauhan; Kaare Christensen; Massimiliano Cocca; Francis S Collins; John M Connell; Renée de Mutsert; H Janaka de Silva; Stephanie Debette; Marcus Dörr; Qing Duan; Charles B Eaton; Georg Ehret; Evangelos Evangelou; Jessica D Faul; Virginia A Fisher; Nita G Forouhi; Oscar H Franco; Yechiel Friedlander; He Gao; Bruna Gigante; Misa Graff; C Charles Gu; Dongfeng Gu; Preeti Gupta; Saskia P Hagenaars; Tamara B Harris; Jiang He; Sami Heikkinen; Chew-Kiat Heng; Makoto Hirata; Albert Hofman; Barbara V Howard; Steven Hunt; Marguerite R Irvin; Yucheng Jia; Roby Joehanes; Anne E Justice; Tomohiro Katsuya; Joel Kaufman; Nicola D Kerrison; Chiea Chuen Khor; Woon-Puay Koh; Heikki A Koistinen; Pirjo Komulainen; Charles Kooperberg; Jose E Krieger; Michiaki Kubo; Johanna Kuusisto; Carl D Langefeld; Claudia Langenberg; Lenore J Launer; Benjamin Lehne; Cora E Lewis; Yize Li; Sing Hui Lim; Shiow Lin; Ching-Ti Liu; Jianjun Liu; Jingmin Liu; Kiang Liu; Yeheng Liu; Marie Loh; Kurt K Lohman; Jirong Long; Tin Louie; Reedik Mägi; Anubha Mahajan; Thomas Meitinger; Andres Metspalu; Lili Milani; Yukihide Momozawa; Andrew P Morris; Thomas H Mosley; Peter Munson; Alison D Murray; Mike A Nalls; Ubaydah Nasri; Jill M Norris; Kari North; Adesola Ogunniyi; Sandosh Padmanabhan; Walter R Palmas; Nicholette D Palmer; James S Pankow; Nancy L Pedersen; Annette Peters; Patricia A Peyser; Ozren Polasek; Olli T Raitakari; Frida Renström; Treva K Rice; Paul M Ridker; Antonietta Robino; Jennifer G Robinson; Lynda M Rose; Igor Rudan; Charumathi Sabanayagam; Babatunde L Salako; Kevin Sandow; Carsten O Schmidt; Pamela J Schreiner; William R Scott; Sudha Seshadri; Peter Sever; Colleen M Sitlani; Jennifer A Smith; Harold Snieder; John M Starr; Konstantin Strauch; Hua Tang; Kent D Taylor; Yik Ying Teo; Yih Chung Tham; André G Uitterlinden; Melanie Waldenberger; Lihua Wang; Ya X Wang; Wen Bin Wei; Christine Williams; Gregory Wilson; Mary K Wojczynski; Jie Yao; Jian-Min Yuan; Alan B Zonderman; Diane M Becker; Michael Boehnke; Donald W Bowden; John C Chambers; Yii-Der Ida Chen; Ulf de Faire; Ian J Deary; Tõnu Esko; Martin Farrall; Terrence Forrester; Paul W Franks; Barry I Freedman; Philippe Froguel; Paolo Gasparini; Christian Gieger; Bernardo Lessa Horta; Yi-Jen Hung; Jost B Jonas; Norihiro Kato; Jaspal S Kooner; Markku Laakso; Terho Lehtimäki; Kae-Woei Liang; Patrik K E Magnusson; Anne B Newman; Albertine J Oldehinkel; Alexandre C Pereira; Susan Redline; Rainer Rettig; Nilesh J Samani; James Scott; Xiao-Ou Shu; Pim van der Harst; Lynne E Wagenknecht; Nicholas J Wareham; Hugh Watkins; David R Weir; Ananda R Wickremasinghe; Tangchun Wu; Wei Zheng; Yoichiro Kamatani; Cathy C Laurie; Claude Bouchard; Richard S Cooper; Michele K Evans; Vilmundur Gudnason; Sharon L R Kardia; Stephen B Kritchevsky; Daniel Levy; Jeff R O'Connell; Bruce M Psaty; Rob M van Dam; Mario Sims; Donna K Arnett; Dennis O Mook-Kanamori; Tanika N Kelly; Ervin R Fox; Caroline Hayward; Myriam Fornage; Charles N Rotimi; Michael A Province; Cornelia M van Duijn; E Shyong Tai; Tien Yin Wong; Ruth J F Loos; Alex P Reiner; Jerome I Rotter; Xiaofeng Zhu; Laura J Bierut; W James Gauderman; Mark J Caulfield; Paul Elliott; Kenneth Rice; Patricia B Munroe; Alanna C Morrison; L Adrienne Cupples; Dabeeru C Rao; Daniel I Chasman Journal: Am J Hum Genet Date: 2018-02-15 Impact factor: 11.025
Authors: Philipp S Wild; Janine F Felix; Arne Schillert; Alexander Teumer; Ming-Huei Chen; Maarten J G Leening; Uwe Völker; Vera Großmann; Jennifer A Brody; Marguerite R Irvin; Sanjiv J Shah; Setia Pramana; Wolfgang Lieb; Reinhold Schmidt; Alice V Stanton; Dörthe Malzahn; Albert Vernon Smith; Johan Sundström; Cosetta Minelli; Daniela Ruggiero; Leo-Pekka Lyytikäinen; Daniel Tiller; J Gustav Smith; Claire Monnereau; Marco R Di Tullio; Solomon K Musani; Alanna C Morrison; Tune H Pers; Michael Morley; Marcus E Kleber; Jayashri Aragam; Emelia J Benjamin; Joshua C Bis; Egbert Bisping; Ulrich Broeckel; Susan Cheng; Jaap W Deckers; Fabiola Del Greco M; Frank Edelmann; Myriam Fornage; Lude Franke; Nele Friedrich; Tamara B Harris; Edith Hofer; Albert Hofman; Jie Huang; Alun D Hughes; Mika Kähönen; Knhi Investigators; Jochen Kruppa; Karl J Lackner; Lars Lannfelt; Rafael Laskowski; Lenore J Launer; Margrét Leosdottir; Honghuang Lin; Cecilia M Lindgren; Christina Loley; Calum A MacRae; Deborah Mascalzoni; Jamil Mayet; Daniel Medenwald; Andrew P Morris; Christian Müller; Martina Müller-Nurasyid; Stefania Nappo; Peter M Nilsson; Sebastian Nuding; Teresa Nutile; Annette Peters; Arne Pfeufer; Diana Pietzner; Peter P Pramstaller; Olli T Raitakari; Kenneth M Rice; Fernando Rivadeneira; Jerome I Rotter; Saku T Ruohonen; Ralph L Sacco; Tandaw E Samdarshi; Helena Schmidt; Andrew S P Sharp; Denis C Shields; Rossella Sorice; Nona Sotoodehnia; Bruno H Stricker; Praveen Surendran; Simon Thom; Anna M Töglhofer; André G Uitterlinden; Rolf Wachter; Henry Völzke; Andreas Ziegler; Thomas Münzel; Winfried März; Thomas P Cappola; Joel N Hirschhorn; Gary F Mitchell; Nicholas L Smith; Ervin R Fox; Nicole D Dueker; Vincent W V Jaddoe; Olle Melander; Martin Russ; Terho Lehtimäki; Marina Ciullo; Andrew A Hicks; Lars Lind; Vilmundur Gudnason; Burkert Pieske; Anthony J Barron; Robert Zweiker; Heribert Schunkert; Erik Ingelsson; Kiang Liu; Donna K Arnett; Bruce M Psaty; Stefan Blankenberg; Martin G Larson; Stephan B Felix; Oscar H Franco; Tanja Zeller; Ramachandran S Vasan; Marcus Dörr Journal: J Clin Invest Date: 2017-04-10 Impact factor: 19.456
Authors: Leif Å Söderström; Karl Gertow; Lasse Folkersen; Maria Sabater-Lleal; Eva Sundman; Yuri Sheikine; Anuj Goel; Damiano Baldassarre; Steve E Humphries; Ulf de Faire; Hugh Watkins; Elena Tremoli; Fabrizio Veglia; Anders Hamsten; Göran K Hansson; Peder S Olofsson Journal: Mol Med Date: 2014-10-14 Impact factor: 6.354