Affiliation:
1. Department of Occupational and Environmental Health, School of Public Health Tongji Medical College, Huazhong University of Science and Technology Wuhan China
2. Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology Harvard T.H. Chan School of Public Health Boston MA USA
3. Division of Preventive Medicine Brigham and Women’s Hospital Boston MA
4. Harvard Medical School Boston MA
5. Department of Statistics and Actuarial Science Soongsil University Seoul Korea
6. Department of Nutrition Harvard T.H. Chan School of Public Health Boston MA
7. Division of Rheumatology, Inflammation and Immunity, Department of Medicine Brigham and Women’s Hospital Boston MA
8. Department of Biostatistics Harvard T.H. Chan School of Public Health Boston MA
Abstract
Background
Patients with rheumatoid arthritis (RA) have a 2‐ to 10‐fold increased risk of cardiovascular disease (CVD), but the biological mechanisms and existence of causality underlying such associations remain to be investigated. We aimed to investigate the genetic associations and underlying mechanisms between RA and CVD by leveraging large‐scale genomic data and genetic cross‐trait analytic approaches.
Methods and Results
Within UK Biobank data, we examined the genetic correlation, shared genetics, and potential causality between RA (N
cases
=6754, N
controls
=452 384) and cardiovascular diseases (CVD, N
cases
=44 238, N
controls
=414 900) using linkage disequilibrium score regression, cross‐trait meta‐analysis, and Mendelian randomization. We observed significant genetic correlations of RA with myocardial infarction (r
g
:0.40 [95% CI, 0.24–0.56), angina (r
g
:0.42 [95% CI, 0.28–0.56]), coronary heart diseases (r
g
:0.41 [95% CI, 0.27–0.55]), and CVD (r
g
:0.43 [95% CI, 0.29–0.57]) after correcting for multiple testing (
P
<0.05/5). When stratified by frequent use of analgesics, we found increased genetic correlation between RA and CVD among participants without aspirin usage (r
g
:0.54 [95% CI, 0.30–0.78] for angina;
P
value
=6.69×10
−6
) and among participants with paracetamol usage (r
g
:0.75 [95% CI, 0.20–1.29] for myocardial infarction;
P
value
=8.90×10
−3
), whereas others remained similar. Cross‐trait meta‐analysis identified 9 independent shared loci between RA and CVD, including
PTPN22
at
chr1p13.2
,
BCL2L11
at
chr2q13
, and
CCR3
at
chr3p21.31
(
P
single trait
<1×10
−3
and
P
meta
<5×10
−8
), highlighting potential shared pathogenesis including accelerating atherosclerosis, upregulating oxidative stress, and vascular permeability. Finally, Mendelian randomization estimates showed limited evidence of causality between RA and CVD.
Conclusions
Our results supported shared genetic pathogenesis rather than causality in explaining the observed association between RA and CVD. The identified shared genetic factors provided insights into potential novel therapeutic target for RA‐CVD comorbidities.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine