The Coronary Artery Disease–Associated 9p21 Variant and Later Life 20-Year Survival to Cohort Extinction

Abstract

Background Common variation at chromosome 9p21 (marked by rs10757278 or rs1333049) is associated with coronary artery disease (CAD) and peripheral vascular disease. A decreasing effect at older age was suggested, and effects on long-term mortality are unclear. We estimated 9p21 associations with CAD and all-cause mortality in a CAD diagnosis–free older population. We also estimated classification gains on adding the variant to the Framingham Risk Score (FRS) for CAD. Methods and Results DNA was from an Established Populations for Epidemiological Study of the Elderly–Iowa cohort from 1988 (participants >71 years), with death certificates obtained to 2008 for 92% of participants. Cox regression models were adjusted for confounders and CAD risk factors. Of 1095 CAD diagnosis–free participants, 52% were heterozygous (CG) and 22% were homozygous (CC) for the risk C allele rs1333049. Unadjusted CAD-attributed death rates in the CC group were 30 vs 22 per 1000 person-years for the GG group. The C allele was associated with all-cause (hazard ratio, 1.19; 95% CI, 1.08–1.30) and CAD (hazard ratio, 1.29; 95% CI, 1.08–1.56) mortality, independent of CAD risk factors. There was no association with stroke deaths. Variant associations with CAD mortality were attenuated after the age of 80 years (age-interaction term P=0.05). In age group 71 to 80 years, FRS classified as high risk 21% of respondents who died of CAD within 10 years; adding 9p21 identified 27% of respondents. Conclusions In 71- to 80-year-old subjects free of CAD diagnoses, 9p21 is associated with excess mortality, mainly attributed to CAD mortality. Adding 9p21 to the FRS may improve the targeting of CAD prevention in older people, but validation in independent samples is needed for confirmation.

Recent Studies of the Human Chromosome 9p21 Locus, Which Is Associated With Atherosclerosis in Human Populations

“…47 This observation is remarkable, because of the presumed weaker effect of Chr9p21 in older populations (Table 1). 9 A metaanalysis in 6 prospective cohort studies showed that Chr9p21 was also associated with sudden and arrhythmic cardiac death, and controlling for cardiovascular and lifestyle risk factors strengthened this relationship (OR 1.29).…”

Socioeconomic Status Interacts with the Genetic Effect of a Chromosome 9p21.3 Common Variant to Influence Coronary Artery Calcification and Incident Coronary Events in the Heinz Nixdorf Recall Study (Risk Factors, Evaluation of Coronary Calcium, and Lifestyle)

“…9p21xSES Interaction and Coronary Artery Disease genes and the environment contribute to the cause of complex diseases. In case of 9p21.3 genetic variants, little consistent findings exist with reports of interaction by single risk factors such as age, 14,15 blood pressure, 16 smoking, 17 dietary intake, 18,19 glycemic control, 20 and abdominal obesity 21 in some study populations, but lack replication in others. [21][22][23] In most of these studies indicators of socioeconomic status (SES) have not been included although strong associations of SES with CAD and CAC have been reported that are partly being explained by socioeconomic differences in CVRF frequency.…”

Genetic Epidemiology in Circulation and the Circulation Subspecialty Journals

“…Adding 9p21 to the Framingham Risk Score may improve the targeting of CAD prevention in older people, but validation in independent samples is needed for confirmation. 33 …”