Elsevier

Atherosclerosis

Volume 222, Issue 1, May 2012, Pages 135-137
Atherosclerosis

The 9p21 genetic variant is additive to carotid intima media thickness and plaque in improving coronary heart disease risk prediction in white participants of the Atherosclerosis Risk in Communities (ARIC) Study

https://doi.org/10.1016/j.atherosclerosis.2012.01.028Get rights and content

Abstract

Objective

We evaluated whether the addition of carotid intima media thickness and plaque (CIMT-P), and a single nucleotide polymorphism on chromosome 9p21 (9p21) together improve coronary heart disease (CHD) risk prediction in the ARIC study.

Methods

Ten year CHD risk was estimated using the ARIC coronary risk score (ACRS) alone and in combination with CIMT-P and 9p21 individually and together in White participants (n = 9338). Area under the receiver operating characteristic curve (AUC), model calibration, net reclassification index (NRI), integrated discrimination index (IDI) and number of individuals reclassified were estimated.

Results

The AUC of the ACRS, ACRS + 9p21, ACRS + CIMT-P and ACRS + CIMT-P + 9p21 models were 0.748, 0.751, 0.763 and 0.766 respectively. The percentage of individuals reclassified, model calibration, NRI and IDI improved when CIMT-P and 9p21 were added to the ACRS only model (see manuscript).

Conclusion

Addition of 9p21 allele information to CIMT-P minimally improves CHD risk prediction in whites in the ARIC study.

Highlights

► CIMT/plaque and 9p21 SNP are known to be associated with CHD. ► CIMT/plaque and 9p21 SNP can improve CHD risk prediction. ► We now show that combining CIMT/plaque, 9p21 further marginally improves CHD risk prediction. ► Improvements in CHD risk prediction conferred by adding CIMT/plaque were greater than 9p21.

Introduction

A single nucleotide polymorphism (SNP) in chromosome 9p21 (9p21) has been associated with coronary heart disease (CHD) in whites [1], [2], [3]. Data from the Atherosclerosis Risk in Communities (ARIC) study [4] have suggested that adding 9p21 to traditional risk factors (TRF) and similarly adding information on carotid intima media thickness (CIMT) and presence or absence of plaque to TRF [5] improves CHD risk prediction improves CHD risk prediction. Studies have however suggested that 9p21 is not associated with CIMT [6].

We therefore evaluated whether CIMT/plaque information together with 9p21 further improves CHD risk prediction in the ARIC study.

Section snippets

Materials and methods

The ARIC study is a population based study of cardiovascular disease incidence that recruited 15,792 middle aged individuals aged between 45 and 64 years of age in 1987–1989 in four communities in the United States. A complete description of the study design, objectives and sampling strategy have been previously described [7]. After excluding non-whites [(n = 4314), because 9p21 is associated with CHD only in whites], individuals with prevalent CHD (n = 1050), those missing TRF covariate data (n = 

Experimental results

Over a mean follow up of 14.7 years there were 1231 incident CHD events (74 CHD deaths, 612 myocardial infarctions, and 545 coronary revascularizations). The baseline characteristics of the study cohort are described in supplemental Table 1a and b. The baseline mean CIMT was 0.71 mm and the distribution of genotypes GG, AG, AA, of the rs10757274 variant was 24%, 50% and 26% respectively; 9p21 was associated with a hazards ratio of 1.21 (95% CI 1.12, 1.31) after adjusting for ACRS + C-IMT + plaque (

Discussion

Traditional risk factors form the basis of any CHD risk prediction score used clinically [8]. However, there is significant room for improvement in CHD risk prediction. Several additional markers including biomarkers, imaging markers and genetic markers have been and will continue to be evaluated for their ability to improve CHD risk prediction. Although several efforts have examined the combination of multiple biomarkers [13] or genotypes [14] none have combined these biomarkers/genetic

Limitations

Our data cannot be generalized to all races. Specifically, our results pertain only to whites as 9p21 has been associated with CHD only in whites and not in African Americans (Franceschini et al. submitted). Our risk models used data from the baseline ARIC visit only. Therapies and risk factors will likely have changed during the follow up time period. However, this is true for any risk prediction model/effort.

Conclusion

We used one genetic marker (a SNP in 9p21) and one imaging marker (CIMT + assessment of presence or absence of plaque), both of which have previously been shown to be associated with CHD and improve CHD risk prediction, in combination and now show that the combination of these two markers further marginally improves CHD risk prediction in whites.

Acknowledgments

The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the

References (15)

There are more references available in the full text version of this article.

Cited by (11)

  • Biomarkers and degree of atherosclerosis are independently associated with incident atherosclerotic cardiovascular disease in a primary prevention cohort: The ARIC study

    2016, Atherosclerosis
    Citation Excerpt :

    We used the mean IMT value averaged across the six sites imputing any missing sites from the observed sites. Methods for imputation have been described previously [40,41]. The presence of plaque was determined by trained readers based on the presence or absence of two out of the following three criteria: abnormal wall thickness (defined as CIMT >1.5 mm), abnormal shape (protrusion into the lumen and loss of alignment with adjacent arterial wall boundary), and abnormal wall texture (brighter echoes than adjacent boundaries).

  • A genetic risk score based on direct associations with coronary heart disease improves coronary heart disease risk prediction in the Atherosclerosis Risk in Communities (ARIC), but not in the Rotterdam and Framingham Offspring, Studies

    2012, Atherosclerosis
    Citation Excerpt :

    CIMT was recently shown to improve CHD risk prediction in older adults, with an AUC increase of 0.017 (from 0.728 to 0.745, P = 0.04) and NRI of 13.7% (P < 0.001) [27], which were better than the AUC improvement and NRI in our study. Interestingly, the combination of CIMT and a single SNP in the 9p21 region was shown to improve risk prediction compared with TRFs and CIMT in the ARIC Study [28], suggesting that certain genetic variants and CIMT have an additive effect on CHD risk prediction. The possibility that adding imaging and biomarker variables to the GRS might improve risk prediction is an important question to be addressed in future studies.

  • Genetics of carotid disease

    2017, Stroke Genetics: Second Edition
  • Methods to assess genetic risk prediction

    2017, Methods in Molecular Biology
View all citing articles on Scopus
View full text