Cardiovascular diseases (CVD) comprise the global leading cause of morbidity and mortality, and in the United States, CVD account for more than one-third of all deaths, of which ~150,000 deaths per year occurs in individuals younger than 65 years. Over the past decades, hundreds of circulating biomarkers have been associated with CVD, but their relative importance and potential involvement in the actual disease processes have been less investigated. Using a very large cohort study that recently became available to the scientific community, we will deploy Mendelian randomization methods to study the causal role of biomarkers proposed to be associated with CVD. In 2006-2010, the UK Biobank recruited 502,650 participants aged 37-73 years to undergo physical measurements, detailed assessments about risk factors and future disease events, and sampling of blood, urine and saliva. Genome-wide genotyping on the UK Biobank Axiom Array (820,967 genetic markers) and measurement of 36 circulating biomarkers with relevance for CVD will be finished during 2016. We will study the associations of 36 circulating biomarkers representing coagulation and inflammation (fibrinogen, D-dimer, hsCRP, rheumatoid factor), glucose homeostasis (HbA1c, glucose, IGF-1), lipid metabolism (total cholesterol, LDL-C, HDL-C, triglycerides, ApoAI, ApoB, Lp(a)), liver function (ALT, AST, ALP, direct and total bilirubin, GGT, albumin, total protein), kidney function (creatinine, cystatin C, phosphate, urate, urea, urinary sodium, potassium, microalbumin and creatinine), reproductive system (SHBG, testosterone, oestradiol), and mineral metabolism (calcium, vitamin D) with incidence of coronary heart disease, stroke, heart failure, atrial fibrillation and type 2 diabetes in traditional observational multivariable-adjusted analyses. We will then perform genome-wide association studies (GWAS) of all 36 biomarkers to establish common genetic variation associated with respective biomarker. With a sample size of ~390,000 individuals, we will have excellent statistical power to uncover a substantial fraction of common genetic variants associated with the biomarkers. These associations will be used to develop robust instrumental variables. Finally, using instrumental variable analyses, we will study the causal roles of these circulating biomarkers for development of cardiovascular disease. The large sample size of the present study will allow for unprecedented possibilities of Mendelian randomization studies of CVD biomarkers with adequate statistical power and with low risk of pleiotropy. Knowledge about the causal roles of CVD-related biomarkers for development of coronary heart disease, stroke, heart failure, atrial fibrillation and type 2 diabetes will provide important insights regarding the etiological understanding of these diseases and accelerate new prevention strategies, including druggable targets.

Public Health Relevance

Cardiovascular disease comprises the global leading cause of morbidity and mortality, and new approaches for prevention and treatment are urgently needed. We will assess the causal role of 36 biomarkers on the development of coronary heart disease, stroke, heart failure, atrial fibrillation and type 2 diabetes in 502,650 participants of the UK Biobank using Mendelian randomization. Our work is anticipated to give important insights regarding the etiological understanding of these diseases and accelerate development of new prevention strategies, including druggable targets.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL135313-02
Application #
9418533
Study Section
Cancer, Heart, and Sleep Epidemiology B Study Section (CHSB)
Program Officer
Luo, James
Project Start
2017-02-01
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
Tikkanen, Emmi; Gustafsson, Stefan; Ingelsson, Erik (2018) Associations of Fitness, Physical Activity, Strength, and Genetic Risk With Cardiovascular Disease: Longitudinal Analyses in the UK Biobank Study. Circulation 137:2583-2591
Schooling, C Mary; Luo, Shan; Au Yeung, Shiu Lun et al. (2018) Genetic predictors of testosterone and their associations with cardiovascular disease and risk factors: A Mendelian randomization investigation. Int J Cardiol 267:171-176
Zhou, Ang; Taylor, Amy E; Karhunen, Ville et al. (2018) Habitual coffee consumption and cognitive function: a Mendelian randomization meta-analysis in up to 415,530 participants. Sci Rep 8:7526
DeBoever, Christopher; Tanigawa, Yosuke; Lindholm, Malene E et al. (2018) Medical relevance of protein-truncating variants across 337,205 individuals in the UK Biobank study. Nat Commun 9:1612
Lindholm, Daniel; Fukaya, Eri; Leeper, Nicholas J et al. (2018) Bioimpedance and New-Onset Heart Failure: A Longitudinal Study of >500 000 Individuals From the General Population. J Am Heart Assoc 7:
Fall, Tove; Gustafsson, Stefan; Orho-Melander, Marju et al. (2018) Genome-wide association study of coronary artery disease among individuals with diabetes: the UK Biobank. Diabetologia :
Nielsen, Jonas B; Fritsche, Lars G; Zhou, Wei et al. (2018) Genome-wide Study of Atrial Fibrillation Identifies Seven Risk Loci and Highlights Biological Pathways and Regulatory Elements Involved in Cardiac Development. Am J Hum Genet 102:103-115
Rao, Abhiram S; Lindholm, Daniel; Rivas, Manuel A et al. (2018) Large-Scale Phenome-Wide Association Study of PCSK9 Variants Demonstrates Protection Against Ischemic Stroke. Circ Genom Precis Med 11:e002162
Figarska, Sylwia M; Gustafsson, Stefan; Sundström, Johan et al. (2018) Associations of Circulating Protein Levels With Lipid Fractions in the General Population. Arterioscler Thromb Vasc Biol 38:2505-2518
Tikkanen, Emmi; Gustafsson, Stefan; Amar, David et al. (2018) Biological Insights Into Muscular Strength: Genetic Findings in the UK Biobank. Sci Rep 8:6451

Showing the most recent 10 out of 19 publications