The long term objective of this proposal is to increase understanding of the inflammatory component of coronary artery disease (CAD) risk in rheumatoid arthritis (RA) through the study of genetic risk factors. Studies have demonstrated that traditional risk factors (e.g., dyslipidemia) cannot account for the additional 1.5-3.0 fold excess risk of CAD in RA patients compared to the general population. This proposal will be conducted within the infrastructure of the NIH informatics for integrating biology and the bedside (i2b2), a national initiative to harness the electronic medical record (EMR) to enable discovery research. This project directly addresses two long range goals of NIAMS by (1) linking developments in genetics to predict a clinical outcome, CAD in RA, and (2) by employing a multidisciplinary, "cross cutting" approach utilizing bioinformatics and novel analytical techniques to understand an important clinical question in RA. The bioinformatics methodology developed as part of this project can be applied to future research in rheumatoid arthritis.
The aims of this project are to conduct a genetic association study to (1) determine how genetic markers associated with traditional risk factors and CAD risk in the general population relate to CAD risk in RA, (2) study whether genetic risk factors for developing RA, markers of immune dysregulation, also increase risk for CAD in RA, and (3) test whether inflammatory mediators thought to accelerate atherosclerosis in RA, increase risk for CAD. Analyses for aims 1-3 entail single SNP analyses, as well as application of genetic risk scores (GRS) in aims 1 and 2. In each aim a clinical model of risk for CAD in RA will be developed and compared to one incorporating clinical + genetic data. As part of aim 3, the contribution of genetic information to a clinical model will be determined using predictive modeling and reclassification measures. Findings from this study can inform the future management of CAD in RA patients. Dr. Katherine Liao received a Masters of Public Health degree at the Harvard School of Public Health (HSPH) in March 2010, completed her rheumatology fellowship at Brigham and Women's Hospital (BWH) in July 2010, and has stayed on as an Instructor in Medicine in the Division of Rheumatology. Her immediate career goal involves pursuit of her proposal to study genetic risk factors for CAD in RA. Her long term career goal is to become an independent investigator in the field of clinical and genetic epidemiology of the rheumatic diseases with expertise in utilizing EMRs for clinical research. Dr. Liao's mentors, Dr. Elizabeth Karlson, Director of Rheumatic Disease Epidemiology, and Dr. Robert Plenge, Director of Genetics and Genomics in the Division of Rheumatology, will allow her to effectively bridge epidemiology and genetics. Her career development plan entails ongoing training in genetics, advanced biostatistics and epidemiology, through direct experience from her research and didactic coursework. Dr. Liao is situated in the rich research and collaborative environment of BWH, HSPH, and the Broad Institute.

Public Health Relevance

Heart disease has been recognized as a serious complication of RA for at least five decades. However, little is known about whether RA itself, its treatment, or genetic factors lead to heart disease. This study would provide insight into our understanding of these factors in RA patients and can inform future treatment and prevention strategies for heart disease in RA.

Agency
National Institute of Health (NIH)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AR060257-04
Application #
8687593
Study Section
Special Emphasis Panel (ZAR1)
Program Officer
Wang, Yan Z
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
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Ananthakrishnan, Ashwin N; Cagan, Andrew; Cai, Tianxi et al. (2015) Colonoscopy is associated with a reduced risk for colon cancer and mortality in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol 13:322-329.e1
Ananthakrishnan, Ashwin N; Cagan, Andrew; Gainer, Vivian S et al. (2014) Thromboprophylaxis is associated with reduced post-hospitalization venous thromboembolic events in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol 12:1905-10
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Ananthakrishnan, Ashwin N; Cagan, Andrew; Gainer, Vivian S et al. (2014) Mortality and extraintestinal cancers in patients with primary sclerosing cholangitis and inflammatory bowel disease. J Crohns Colitis 8:956-63
Liao, Katherine P; Diogo, Dorothee; Cui, Jing et al. (2014) Association between low density lipoprotein and rheumatoid arthritis genetic factors with low density lipoprotein levels in rheumatoid arthritis and non-rheumatoid arthritis controls. Ann Rheum Dis 73:1170-5
Ananthakrishnan, Ashwin N; Cai, Tianxi; Savova, Guergana et al. (2013) Improving case definition of Crohn's disease and ulcerative colitis in electronic medical records using natural language processing: a novel informatics approach. Inflamm Bowel Dis 19:1411-20
Henderson, Lauren A; Loring, Stephen H; Gill, Ritu R et al. (2013) Shrinking lung syndrome as a manifestation of pleuritis: a new model based on pulmonary physiological studies. J Rheumatol 40:273-81
Ananthakrishnan, Ashwin N; Cagan, Andrew; Gainer, Vivian S et al. (2013) Normalization of plasma 25-hydroxy vitamin D is associated with reduced risk of surgery in Crohn's disease. Inflamm Bowel Dis 19:1921-7

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