Our objective is to examine the genetic basis for the high risk of atherosclerosis and cardiovascular (CV) disease in rheumatoid arthritis (RA). Recent discoveries have implicated systemic inflammation in the pathogenesis of atherosclerosis. RA is characterized by both systemic inflammation, and a predisposition to atherosclerosis, raising the possibility that the two could be causally associated. However, the mechanism for such an association is not well understood. Early evidence implicating inflammation genes has been limited by the small number of genes studied. METHODS: We will examine the association between inflammation gene variants (i.e. single nucleotide polymorphisms, SNPs) and atherosclerosis, in patients with RA, and persons from the general population. We will seek SNPs associated with the atherosclerosis phenotype in key inflammation genes. We will define the phenotype using the carotid intima-media thickness (IMT) measured by ultrasound, and the incidence of CV events. We will test four hypotheses: That (1) Inflammation gene SNPs are associated with the atherosclerosis phenotype;(2) The presence of RA interacts with inflammation gene SNPs to modify their association with the atherosclerosis phenotype;(3) Inflammation gene SNPs modify the association between other factors related to CV risk, and the atherosclerosis phenotype;and (4) The association between inflammation gene SNPs and the atherosclerosis phenotype varies between ethnic groups. To test these hypotheses, we will study 1,000 members of SRALE (for Outcome of Rheumatoid Arthritis Longitudinal Evaluation), a cohort of RA patients, of whom 500 are Mexican American (MA) and 500 are non-Hispanic White;and 1,000 age-, sex- and ethnicity-matched participants in MESA (for Multi-Ethnic Study of Atherosclerosis), a study of atherosclerosis in the general population. The atherosclerosis phenotype has been ascertained in these two cohorts using equivalent definitions and techniques. Moreover, both cohorts include a considerable number of MAs, enabling ethnic matching. We will use high throughput techniques to seek an average of 20 carefully chosen and prioritized SNPs in each of 25 key inflammation genes. We will use Bayesian Quantitative Trait Nucleotide (BQTN) analysis, a novel statistical technique to efficiently evaluate the association between genetic variants and phenotypic traits, using Bayes factors.

Public Health Relevance

This research will advance considerably current knowledge about the role of inflammation genes in the atherosclerosis that occurs in RA. This new knowledge will be the basis for future efforts to reduce RA's high CV disease burden. For example, comprehensive characterization of atherosclerosis-associated SNPs could be used to enhance the accuracy of current CV risk stratification schemes. This would improve the prevention and early treatment of atherosclerosis in RA, improving survival. SNPs associated with atherosclerosis may also identify pathogenic mechanisms deserving of further attention as potential targets for novel interventions. People with inflammatory diseases such as rheumatoid arthritis (RA) have a high burden of atherosclerosis. We will examine the association between inflammation gene variants and atherosclerosis in RA patients and normal people of the same age and sex. Gene variants associated with atherosclerosis may identify pathogenic mechanisms that could be novel targets for intervention to reduce RA high cardiovascular (CV) morbidity and mortality, and could be used clinically to enhance current CV risk stratification strategies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular and Sleep Epidemiology (CASE)
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Olson, Jean
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University of Texas Health Science Center San Antonio
Internal Medicine/Medicine
Schools of Medicine
San Antonio
United States
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Arya, Rector; Escalante, Agustin; Farook, Vidya S et al. (2018) A genetic association study of carotid intima-media thickness (CIMT) and plaque in Mexican Americans and European Americans with rheumatoid arthritis. Atherosclerosis 271:92-101
Arya, Rector; Escalante, Agustin; Farook, Vidya S et al. (2018) Data on genetic associations of carotid atherosclerosis markers in Mexican American and European American rheumatoid arthritis subjects. Data Brief 17:820-829
Restrepo, Jose Felix; Del Rincon, Inmaculada; Molina, Emily et al. (2017) Use of Hydroxychloroquine Is Associated With Improved Lipid Profile in Rheumatoid Arthritis Patients. J Clin Rheumatol 23:144-148
Molina, Emily; del Rincon, Inmaculada; Restrepo, Jose Felix et al. (2015) Mortality in Rheumatoid Arthritis (RA): factors associated with recording RA on death certificates. BMC Musculoskelet Disord 16:277
Arya, Rector; Del Rincon, Inmaculada; Farook, Vidya S et al. (2015) Genetic Variants Influencing Joint Damage in Mexican Americans and European Americans With Rheumatoid Arthritis. Genet Epidemiol 39:678-88
Molina, Emily; Del Rincon, Inmaculada; Restrepo, Jose Felix et al. (2015) Association of socioeconomic status with treatment delays, disease activity, joint damage, and disability in rheumatoid arthritis. Arthritis Care Res (Hoboken) 67:940-6
del Rincón, Inmaculada; Polak, Joseph F; O'Leary, Daniel H et al. (2015) Systemic inflammation and cardiovascular risk factors predict rapid progression of atherosclerosis in rheumatoid arthritis. Ann Rheum Dis 74:1118-23
Restrepo, José Félix; del Rincón, Inmaculada; Battafarano, Daniel F et al. (2015) Clinical and laboratory factors associated with interstitial lung disease in rheumatoid arthritis. Clin Rheumatol 34:1529-36
del Rincón, Inmaculada; Battafarano, Daniel F; Restrepo, Jose F et al. (2014) Glucocorticoid dose thresholds associated with all-cause and cardiovascular mortality in rheumatoid arthritis. Arthritis Rheumatol 66:264-72
Molina, Emily; Haas, Roy; del Rincon, Inmaculada et al. (2014) Does the ""Hispanic paradox"" occur in rheumatoid arthritis? Survival data from a multiethnic cohort. Arthritis Care Res (Hoboken) 66:972-9

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