Abstract 14351: Increased Levels of IgM Autoantibodies to Oxidation-Specific Epitopes are Inversely Associated With Coronary Heart Disease: Analyses of Data From 204,257 Participants
Background: Immunoglobulin M (IgM) autoantibodies to oxidation-specific epitopes (OSE) have been shown to be protective against atherosclerosis in animal models, but the data in human studies is controversial.
Objectives: This study sought to determine the association between IgM autoantibodies to OSE and apolipoprotein B-100-immune complexes (apoB-IC) and risk of coronary heart disease through a Mendelian Randomization study design.
Methods: IgM autoantibodies to malondialdehyde-low density lipoprotein (MDA-LDL), phosphocholine-modified bovine serum albumin (PC-BSA) and IgM apoB-IC were measured in 9,830 participants (4966 first-onset cases with myocardial infarction [MI] and 4864 age and sex-matched controls) in the Pakistan Risk of Myocardial Infarction Study (PROMIS). Analyses in association with MI were conducted using logistic regression models progressively adjusted for age, sex, center, self-reported ethnicity, tobacco use, waist-to-hip ratio, history of diabetes and hypertension and LDL-C levels. Genetic analyses (GWAS and exome-chip) were also conducted using additive models. Variants associated with GWAS levels of significance were further assessed for pleiotropy and used as instruments to assess causality with CHD risk using genetic data on 63,746 CHD cases and 130,681 controls from the CARDIoGRAMplusC4D consortium.
Results: In PROMIS, compared to the bottom quintile, the odds ratio for MI among participants in the top quintiles of IgM MDA-LDL, IgM PC-BSA and IgM apoB-IC were: 0.62 ([95% CI. 0.55-0.70], p<0.001), 0.60 ([95% CI. 0.53-0.68], p<0.001) and 0.64 ([95% CI. 0.56-0.73], p<0.001], respectively. Genetic analyses identified several novel variants associated with circulating IgM MDA-LDL, IgM PC-BSA and IgM apoB-IC at GWAS levels of significance. In CARDIoGRAMplusC4D variants that exclusively increased circulating IgM autoantibodies were causally associated with reduced CHD risk (P<1x10-5).
Conclusions: Increased levels of IgM autoantibodies to MDA-LDL and PC-BSA and IgM apoB-IC are likely causally associated with a protective effect on CHD. This inverse association supports the hypothesis of the atheroprotective role of IgM autoantibodies.
Author Disclosures: A. Taleb: None. W. Zhao: None. A. Shahzada: None. A. Rasheed: None. C.J. Binder: None. J.L. Witztum: None. J. Danesh: None. D.J. Rader: None. S. Tsimikas: Employment; Significant; isis pharma. Research Grant; Significant; NIH. Other; Modest; UCSD patents. D. Saleheen: None.
- © 2015 by American Heart Association, Inc.