Circulation: Cardiovascular Genetics HCG Candidate Pathway-Based GWAS Identifies Novel Associations of Genomic Variants in the Complement System Associated with Coronary Artery Disease Association of complement SNPs and CAD CIRCCVG/2014/000738-T CIRCCVG/2014/000738-T 10.1161/CIRCGENETICS.114.000738 7 12/16/14 6 Sine Kristina 617-542-5100 617-542-6539 Vasan, Ramachandran Boston University School of Medicine Prof. Qing Wang qkwang@mail.hust.edu.cn Prof. Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science 1037 Luoyu Road Wuhan N/A 430072 CHINA 86-27-87793502 27-87793502 8990 Chengqi Xu Huazhong University of Science and Technology xcq1127@gmail.com 205928 Qin Yang Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science yangqin200954@163.com 143416 Hongbo Xiong Huazhong University of Science and Technology 371721341@qq.com 205929 Longfei Wang Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science 455206286@qq.com 143431 Jianping Cai Beijing Hospital caijp61@vip.sina.com 30531 Fan Wang Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science hgrcoffice@gmail.com 143409 Sisi Li Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science lisisi2002@163.com 145359 Jing Chen Huazhong University of Science and Technology 182052509@qq.com 205930 Chuchu Wang Key Laboratory of Molecular Biophysics of the Ministry of Education, Center for Human Genome Research and Cardio-X Institute xiaochuchu1984@qq.com 203708 Dan Wang Huazhong University of Science and Technology 4995665@qq.com 221239 Xin Xiong Huazhong University of Science and Technology 65248669@qq.com 221312 Pengyun Wang Huazhong University of Science and Technology wpy0110@126.com 205933 Yuanyuan Zhao Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science 494730998@qq.com 143423 Xiaojing Wang Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science wxj0516101109@163.com 143420 Yufeng Huang Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science hyf08@126.com 143428 Shanshan Chen Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science nnnhg122@126.com 143422 Dan Yin Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science 340035989@qq.com 143427 Xiuchun Li Huazhong University of Science and Technology lxchhust@gmail.com 205937 Ying Liu First Affiliated Hospital of Dalian Medical University liuying_8686@sina.com 205941 Jinqiu Liu First Affiliated Hospital of Dalian Medical University liujq_818@sina.com 205942 Jingjing Wang Huazhong University of Science and Technology wangjing.123@126.com 205939 Hui Li Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science huili0930@163.com 143435 Tie Ke Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science ket@mail.hust.edu.cn 143440 Xiang Ren Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science renxiang@mail.hust.edu.cn 143441 Yanxia Wu The First Hospital of Wuhan City spring_w@126.com 205947 Gang Wu Renmin Hospital of Wuhan University 116793341@qq.com 205945 Jing Wan Zhongnan Hospital of Wuhan University wanjing110@sohu.com 205946 Rongfeng Zhang First Affiliated Hospital of Dalian Medical University zrf0088@126.com 143443 Tangchun Wu MOE key , HUST wut@mails.tjmu.edu.cn 6386 Junhan Wang Huazhong University of Science and Technology cqxu@mail.hust.edu.cn 205943 Yunlong Xia First Affiliated Hospital of Dalian Medical University yunlong.xia@gmail.com 60976 Yanzong Yang First Affiliated Hospital of Dalian Medical University yangyanzong123@126.com 205944 Xiang Cheng Union Hospital, Tongji Medical College, Huazhong University of Science and Technology nathancx@hotmail.com 179880 Yuhua Liao Union Hospital, Tongji Medical College, Huazhong University of Science and Technology liaoyh27@yeah.net 205948 Qiuyun Chen Cleveland Clinic & Case Western Reserve University, Cleveland, OH chenq3@ccf.org 11019 Yanhong Zhou Huazhong University of Science and Technology 346843733@qq.com 221787 Qing He Beijing Hospital of the Ministry of Health heqingli2001@yahoo.com 205949 Xin Tu Huazhong University of Science and Technology xtu@mail.hust.edu.cn 59833 Qing Wang Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science qkwang@mail.hust.edu.cn 8990 03/27/2014 03/27/2014 08/16/2014 08/21/2014 10/05/2014 12/16/2014 Original Article complement system coronary artery disease genome-wide association study (GWAS) single nucleotide polymorphisms variants CIRCCVG/2014/000909 Editorial based on "Candidate Pathway-Based GWAS Identifies Novel Associations of Genomic Variants in the Complement System Associated with Coronary Artery Disease" by Xu et al. (CIRCCVG/2014/000738) <P><B><I>Background</I></B>—Genomic variants identified by genome-wide association studies (GWAS) explain <20% of heritability of coronary artery disease (CAD), thus many risk variants remain missing for CAD. Identification of new variants may unravel new biological pathways and genetic mechanisms for CAD. To identify new variants associated with CAD, we developed a candidate pathway-based GWAS by integrating expression quantitative loci (eQTL) analysis and mining of GWAS data with variants in a candidate pathway. </P><P><B><I>Methods and Results</I></B>—Mining of GWAS data was performed to analyze variants in 32 complement system genes for positive association with CAD. Functional variants in genes showing positive association were then identified by searching existing expression quantitative loci databases and validated by RT-PCR. A follow-up case control design was then used to determine whether the functional variants are associated with CAD in two independent GeneID Chinese populations. Candidate pathway-based GWAS identified positive association between variants in <I>C3AR1</I> and <I>C6</I> and CAD. Two functional variants, rs7842 in <I>C3AR1</I> and rs4400166 in <I>C6</I>, were found to be associated with expression levels of <I>C3AR1</I> and <I>C6</I>, respectively. Significant association was identified between rs7842 and CAD (<I>P</I>=3.99×10<sup>-6</sup>, OR=1.47) and between rs4400166 and CAD (<I>P</I>=9.30×10<sup>-3</sup>, OR=1.24) in the validation cohort. The significant findings were confirmed in the replication cohort (<I>P</I>=1.53×10<sup>-5</sup>, OR=1.37 for rs7842; <I>P</I>=8.41×10<sup>-3</sup>, OR=1.21 for rs4400166. </P><P><B><I>Conclusions</I></B>—Integration of GWAS with biological pathways and eQTL is effective in identifying new risk variants for CAD. Functional variants increasing <I>C3AR1</I> and <I>C6</I> expression were shown to confer significant risk of CAD for the first time.</P> 4 1 0 1 2 yes CircGenetics_CIRCCVG-2014-000738-T.xml 000738_clinical perspective.docx CircGenetics_CIRCCVG-2014-000738-T_file1.docx
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Article has supplemental material (1 PDF) and a clinical perspective. Dr. Chengqi Xu and Ms Qin Yang contributed equally to this work. Article will have editorial #000909 (D. Herrington) Rec'd 3/27/14 Please set the flag 'exportcadmusahafundingtypecodes' with the funding type code of the sources you wish to list. Subject Codes: [135] Risk factors [146] Genomics ksine