Genome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry
Pharmacogenomics J. 2020 Jun;20(3):482-493. doi: 10.1038/s41397-019-0132-y. Epub 2019 Dec 6.
L de Las Fuentes 1 , Y J Sung 2 , C M Sitlani 3 , C L Avery 4 , T M Bartz 5 , C de Keyser 6 , D S Evans 7 , X Li 8 , S K Musani 9 , R Ruiter 6 , A V Smith 10 11 , F Sun 12 , S Trompet 13 14 , H Xu 12 , D K Arnett 15 , J C Bis 3 , U Broeckel 16 , E L Busch 17 18 , Y-D I Chen 8 , A Correa 9 , S R Cummings 7 , J S Floyd 19 , I Ford 20 , X Guo 8 , T B Harris 21 , M A Ikram 6 , L Lange 22 , L J Launer 21 , A P Reiner 23 24 , K Schwander 2 , N L Smith 25 26 , N Sotoodehnia 19 27 , J D Stewart 4 28 , D J Stott 29 , T Stürmer 4 30 , K D Taylor 8 , A Uitterlinden 6 , R S Vasan 31 32 , K L Wiggins 3 , L A Cupples 12 31 , V Gudnason 10 11 , S R Heckbert 25 , J W Jukema 13 33 , Y Liu 34 , B M Psaty 35 36 , D C Rao 2 , J I Rotter 8 , B Stricker 6 , J G Wilson 37 , E A Whitsel 4 38
1 Cardiovascular Division, Department of Medicine, Washington University, St. Louis, MO, USA. lfuentes@wustl.edu.
2 Division of Biostatistics, Washington University, St. Louis, MO, USA.
3 Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
4 Gillings School of Global Public Health, Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
5 Cardiovascular Health Research Unit, Departments of Medicine and Biostatistics, University of Washington, Seattle, WA, USA.
6 Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
7 Research Institute, California Pacific Medical Center, San Francisco, CA, USA.
8 Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
9 Jackson Heart Study, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
10 Icelandic Heart Association, Kopavogur, Iceland.
11 Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
12 Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
13 Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
14 Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
15 Dean's Office, University of Kentucky College of Public Health, Lexington, KY, USA.
16 Section of Genomic Pediatrics, Department of Pediatrics, Medicine and Physiology, Medical College of Wisconsin, Milwaukee, WI, USA.
17 Channing Division of Network Medicine, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.
18 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
19 Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, WA, USA.
20 Robertson Center for biostatistics, University of Glasgow, Glasgow, UK.
21 Laboratory of Epidemiology and Population Sciences, Intramural Research Program, National Institute on Aging, Bethesda, MD, USA.
22 Department of Genetics, University of Colorado, Denver, Denver, CO, USA.
23 Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
24 School of Public Health, Department of Epidemiology, University of Washington, Seattle, WA, USA.
25 Cardiovascular Health Research Unit, Department of Epidemiology, University of Washington, Seattle, WA, USA.
26 Seattle Epidemiologic Research and Information Center (ERIC), VA Cooperative Studies Program, VA Puget Sound Health Care System, Seattle, WA, USA.
27 Cardiology, Department of Medicine, University of Washington, Seattle, WA, USA.
28 Carolina Population Center, University of North Carolina, Chapel Hill, NC, USA.
29 Institute of cardiovascular and medical sciences, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom.
30 Center for Pharmacoepidemiology, University of North Carolina, Chapel Hill, NC, USA.
31 The Framingham Heart Study, Framingham, MA, USA.
32 Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
33 Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
34 Division of Public Health Sciences, Department of Epidemiology and Prevention, Wake Forest University, Winston-, Salem, NC, USA.
35 Cardiovascular Health Research Unit, Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle, WA, USA.
36 Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
37 Biophysics and Physiology, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
38 School of Medicine, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA.
Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p < 5 × 10-8) loci with single nucleotide variant (SNV)-loop diuretic interaction on TG concentrations (including COL11A1). Analysis of AA data identified one genome-wide significant locus adjacent to BMP2 with SNV-loop diuretic interaction on TG concentrations. Trans-ancestry analysis strengthened evidence of association for SNV-loop diuretic interaction at two loci (KIAA1217 and BAALC). There were few significant SNV-thiazide diuretic interaction associations on TG concentrations and for either diuretic on cholesterol concentrations. Several promising loci were identified that may implicate biologic pathways that contribute to adverse metabolic side effects from diuretic therapy.
UL1 TR001079/TR/NCATS NIH HHS/United States
N01HC85086/HL/NHLBI NIH HHS/United States
HHSN268201200036C/HL/NHLBI NIH HHS/United States
R01 HL080295/HL/NHLBI NIH HHS/United States
HHSN268201500003I/HL/NHLBI NIH HHS/United States
N01 HC095163/HC/NHLBI NIH HHS/United States
HHSN268201100001C/WH/WHI NIH HHS/United States
UL1 RR033176/RR/NCRR NIH HHS/United States
U01 HL054471/HL/NHLBI NIH HHS/United States
N01 AG012100/AG/NIA NIH HHS/United States
Z01 EY000401/ImNIH/Intramural NIH HHS/United States
R01 AG015928/AG/NIA NIH HHS/United States
N02 HL64278/HL/NHLBI NIH HHS/United States
K25 HL121091/HL/NHLBI NIH HHS/United States
U01 HG004402/HG/NHGRI NIH HHS/United States
HHSN268200782096C/HG/NHGRI NIH HHS/United States
HHSN271201100004C/AG/NIA NIH HHS/United States