Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease

• Published in: Nature genetics Vol. 49; no. 10; pp. 1450 - 1457
• Main Authors: Zhao, Wei, Rasheed, Asif, Tikkanen, Emmi, Lee, Jung-Jin, Butterworth, Adam S, Howson, Joanna M M, Assimes, Themistocles L, Chowdhury, Rajiv, Orho-Melander, Marju, Damrauer, Scott, Small, Aeron, Asma, Senay, Imamura, Minako, Yamauch, Toshimasa, Chambers, John C, Chen, Peng, Sapkota, Bishwa R, Shah, Nabi, Jabeen, Sehrish, Surendran, Praveen, Lu, Yingchang, Zhang, Weihua, Imran, Atif, Abbas, Shahid, Majeed, Faisal, Trindade, Kevin, Qamar, Nadeem, Mallick, Nadeem Hayyat, Yaqoob, Zia, Saghir, Tahir, Rizvi, Syed Nadeem Hasan, Memon, Anis, Rasheed, Syed Zahed, Memon, Fazal-ur-Rehman, Mehmood, Khalid, Ahmed, Naveeduddin, Qureshi, Irshad Hussain, Tanveer-us-Salam, Iqbal, Wasim, Malik, Uzma, Mehra, Narinder, Kuo, Jane Z, Sheu, Wayne H-H, Guo, Xiuqing, Hsiung, Chao A, Juang, Jyh-Ming J, Taylor, Kent D, Hung, Yi-Jen, Lee, Wen-Jane, Quertermous, Thomas, Lee, I-Te, Hsu, Chih-Cheng, Bottinger, Erwin P, Ralhan, Sarju, Teo, Yik Ying, Wang, Tzung-Dau, Alam, Dewan S, Di Angelantonio, Emanuele, Epstein, Steve, Nielsen, Sune F, Nordestgaard, Børge G, Tybjaerg-Hansen, Anne, Young, Robin, Benn, Marianne, Frikke-Schmidt, Ruth, Kamstrup, Pia R, Jukema, J Wouter, Sattar, Naveed, Smit, Roelof, Chung, Ren-Hua, Liang, Kae-Woei, Anand, Sonia, Sanghera, Dharambir K, Ripatti, Samuli, Loos, Ruth J F, Kooner, Jaspal S, Tai, E Shyong, Rotter, Jerome I, Chen, Yii-Der Ida, Frossard, Philippe, Maeda, Shiro, Kadowaki, Takashi, Reilly, Muredach, Pare, Guillaume, Melander, Olle, Salomaa, Veikko, Rader, Daniel J, Danesh, John, Voight, Benjamin F, Saleheen, Danish
• Format: Journal Article
• Language: English
• Published: New York Springer New York 01.10.2017; Nature Publishing Group
• Subjects: 45; 45/43; 631/208; 631/208/212; 692/699/2743/137/773; 692/699/75; Adipocytes; Agriculture; Animal Genetics and Genomics; Asia; Asia - epidemiology; Asian continental ancestry group; Asian People - genetics; Atherosclerosis; Basic Medicine; Bioinformatics; biological marker; Biomarkers; Biomedicine; Cancer Research; Cardiovascular disease; Cardiovascular diseases; Caucasian; CCDC92 gene; Comorbidity; comparative study; controlled study; Coronary artery disease; Coronary Disease; Coronary Disease - epidemiology; Coronary Disease - etiology; Coronary Disease - genetics; Coronary heart disease; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - epidemiology; Diabetes Mellitus, Type 2 - etiology; Diabetes Mellitus, Type 2 - genetics; East Asian; Etiology; Europe; Europe - epidemiology; European; European Continental Ancestry Group; fatty acid binding protein 4; Fatty acids; gene; Gene Function; Gene loci; gene locus; Genetic aspects; Genetic diversity; Genetic Loci; Genetic Loci - genetics; genetic predisposition; Genetic Predisposition to Disease; genetic risk; genetic susceptibility; genetic variability; Genetic variation; genetics; Genome-Wide Association Study; Genomes; Health aspects; Heart diseases; Histocompatibility antigen HLA; HLA DRB5 antigen; HLA DRB5 gene; HLA-DRB5 Chains; HLA-DRB5 Chains - genetics; human; Human Genetics; Humans; icosapentaenoic acid ethyl ester; ischemic heart disease; major clinical study; Medical and Health Sciences; Medical Genetics; Medical Genetics and Genomics (including Gene Therapy); Medicin och hälsovetenskap; Medicinsk genetik; Medicinsk genetik och genomik (Här ingår: Genterapi); Medicinska och farmaceutiska grundvetenskaper; Meta-analysis; Metabolic Networks and Pathways; Metabolic Networks and Pathways - genetics; Metabolic Syndrome - epidemiology; Metabolic Syndrome - genetics; metabolic syndrome X; metabolism; missense mutation; Molecular Targeted Therapy; molecularly targeted therapy; Mutation, Missense; non insulin dependent diabetes mellitus; Polymorphism, Single Nucleotide; priority journal; Proteins; Quantitative trait loci; Risk analysis; risk factor; Risk Factors; single nucleotide polymorphism; South Asian; Triglycerides; Type 2 diabetes; White People - genetics; Asia; Europe
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.3943

Danish Saleheen, Benjamin Voight and colleagues perform genome-wide analysis of multi-ancestry cohorts to identify genetic associations with type 2 diabetes (T2D) and coronary heart disease (CHD). They find novel loci and show that 24% of T2D loci are also associated with CHD and that greater genetic risk of T2D increases risk of CHD. To evaluate the shared genetic etiology of type 2 diabetes (T2D) and coronary heart disease (CHD), we conducted a genome-wide, multi-ancestry study of genetic variation for both diseases in up to 265,678 subjects for T2D and 260,365 subjects for CHD. We identify 16 previously unreported loci for T2D and 1 locus for CHD, including a new T2D association at a missense variant in HLA-DRB5 (odds ratio (OR) = 1.29). We show that genetically mediated increase in T2D risk also confers higher CHD risk. Joint T2D–CHD analysis identified eight variants—two of which are coding—where T2D and CHD associations appear to colocalize, including a new joint T2D–CHD association at the CCDC92 locus that also replicated for T2D. The variants associated with both outcomes implicate new pathways as well as targets of existing drugs, including icosapent ethyl and adipocyte fatty-acid-binding protein.