A functionally significant polymorphism in ID3 is associated with human coronary pathology

Abstract

Aims: We previously identified association between the ID3 SNP rs11574 and carotid intima-media thickness in the Diabetes Heart Study, a predominantly White diabetic population. The nonsynonymous SNP rs11574 results in an amino acid substitution in the C-terminal region of ID3, attenuating the dominant negative function of ID3 as an inhibitor of basic HLH factor E12-mediated transcription. In the current investigation, we characterize the association between the functionally significant polymorphism in ID3, rs11574, with human coronary pathology.

Methods and results: The Multi-Ethnic Study of Atherosclerosis (MESA) is a longitudinal study of subclinical cardiovascular disease, including non-Hispanic White (n = 2,588), African American (n = 2,560) and Hispanic (n = 2,130) participants with data on coronary artery calcium (CAC). The Coronary Assessment in Virginia cohort (CAVA) included 71 patients aged 30-80 years, undergoing a medically necessary cardiac catheterization and intravascular ultrasound (IVUS) at the University of Virginia. ID3 SNP rs11574 risk allele was associated with the presence of CAC in MESA Whites (P = 0.017). In addition, the risk allele was associated with greater atheroma burden and stenosis in the CAVA cohort (P = 0.003, P = 0.04 respectively). The risk allele remained predictive of atheroma burden in multivariate analysis (Model 1: covariates age, gender, and LDL, regression coefficient = 9.578, SE = 3.657, p = 0.0110; Model 2: covariates Model 1, presence of hypertension, presence of diabetes, regression coefficient = 8.389, SE = 4.788, p = 0.0163).

Conclusions: We present additional cohorts that demonstrate association of ID3 SNP rs11574 directly with human coronary artery pathology as measured by CAC and IVUS: one a multiethnic, relatively healthy population with low levels of diabetes and the second a predominantly White population with a higher incidence of T2DM referred for cardiac catheterization.

Figure 1. (top panel) Representative IVUS frame from a patient with the ancestral allele (left) and a patient with the risk allele (right).

Light green represents fibrofatty plaque, dark green fibrous plaque, red necrotic core, and white calcium. (bottom panel) Representative QCA from a patient with the ancestral allele with a 28% stenosis (left) and a patient with the risk allele and stenosis of 73% (right). Automated edge detection is used to determine stenosis severity.

Figure 2. Effect of the risk allele on burden and stenosis as measured by IVUS.

Burden differed significantly between groups with greater burden in the presence of the risk allele. Stenosis was marginally significant. Vertical line represents complete spread of the data. Burden represents the percent of the vessel wall occupied by plaque. Stenosis represents percent luminal stenosis.