# The Effect of Human Leukocyte Antigen Type on Associations between Antibodies to Citrullinated Protein Antigens (ACPA) and Myocardial Structure and Function

> **NIH NIH R03** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $78,500

## Abstract

PROJECT SUMMARY
 Rheumatoid arthritis (RA) has been considered an independent risk factor for coronary heart disease
(CHD), and mortality from CHD in RA is double what it is in the general population. Mechanisms of CHD in the
general population are not fully known, but it is proposed that in addition to its inflammatory features, CHD may
have autoimmune features as well. Using RA and RA-related autoimmunity as model to understand the
contributions of autoantibodies, changes in autoantibodies, and genetic predisposition to the development of
these autoimmune features could provide new insights into CHD and myocardial disease in the general
population, thus providing new ways to monitor, prevent, and potentially intervene.
 In the setting of rheumatologic diseases, antibodies to citrullinated protein antigens (ACPA) have been
linked to cardiovascular disease (CVD), and these findings have been extended to other select patient
populations without RA. Citrullination of proteins occurs in several normal cellular processes, including
inflammation, apoptosis, and cellular differentiation. While citrullination is normal, autoantibodies to these
citrullinated proteins are abnormal, and elicit a self-directed immune response. Citrullinated proteins have been
located in the myocardial interstitium among diverse disease states, including RA, and antibodies against
these citrullinated myocardial proteins may induce myocardial remodeling.
 RA-related autoantibodies, including ACPA, occur in individuals at least 15 years prior to onset of RA, and
in individuals who may never develop RA. My preliminary data from my K01-supported study of 1232 MESA
participants found significant associations between the number of positive ACPA and lower left ventricular
ejection fraction as well as with incident angina and myocardial infarction. It is unknown, however, whether
changes in ACPA levels over time are associated with worse CVD outcomes. This proposal aims to further
investigate relationships of longitudinal changes in ACPA with myocardial structure and function.
 The major histocompatibility complex (MHC) is a well-recognized immune response gene that controls the
magnitude and specificity of antibody production. In humans, the MHC HLA-DRB1 shared epitope alleles
predisposes for ACPA development, and have been associated with vascular injury markers in a population of
RA-free first-degree relatives of RA patients. In individuals possessing the HLA-DRB1 alleles, the associations
with cardiac abnormalities may be stronger, and thus offer an opportunity for screening and earlier surveillance
of cardiac structure and function should an individual possess these alleles. Thus, the goal of this proposal is
to fully characterize whether ACPA are associated with markers of myocardial disease, and whether
possessing the HLA-DRB1 alleles modifies these associations.

## Key facts

- **NIH application ID:** 9881340
- **Project number:** 5R03HL146875-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Jan Marie Hughes-Austin
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $78,500
- **Award type:** 5
- **Project period:** 2019-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9881340

## Citation

> US National Institutes of Health, RePORTER application 9881340, The Effect of Human Leukocyte Antigen Type on Associations between Antibodies to Citrullinated Protein Antigens (ACPA) and Myocardial Structure and Function (5R03HL146875-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9881340. Licensed CC0.

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