Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events

Abstract

Background: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk. Methods: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD. Results: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUS-CHD odds ratio, 1.02; 95% CI, 0.99–1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18–1.22; P for interaction <0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04–1.09). Conclusions: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.

Analysis of Polymorphism rs1333049 (Located at 9P21.3) in the White Population of Western Siberia and Associations with Clinical and Biochemical Markers

“…Our study revealed an association of the G allele of rs1333049 with TC and LDL-C levels among males. These data contradict some other studies [10,11,33], for example, Ellis et al have demonstrated a correlation of the C/C genotype with higher TG and TC levels in blood [26]. The study by Ellis et al was performed on patients with ischemic heart disease (New Zealand), whereas our study deals with the general population.…”

“…In contrast to studies comparing individuals with CHD to disease-free controls, they found no clear association between genetic variation in chromosomal region 9p21 and the risk of subsequent acute CHD events when all individuals had CHD at baseline. Nonetheless, they uncovered an association with subsequent revascularization, which may support the postulated mechanism of promotion of atheroma development by chromosomal region 9p21 [10]. Data from Russian patients have confirmed the correlation of rs1333049 with myocardial infarction but not with type 2 diabetes; these studies had some limitations because they involved only small groups [11,12].…”

2018 George Lyman Duff Memorial Lecture

“…A recent study by the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium, albeit a survivors’ cohort, reveals that this locus is not associated with recurrent events in patients with established CAD. It does, however, confer an increased risk for revascularization, 12 consistent with a primary role in atherosclerosis.…”

When drug treatments bias genetic studies: Mediation and interaction

“…Genome-wide association studies (GWAS) attempt to discover associations between genetic variants and a particular phenotype (an outcome)[1]. Due to an increased interest in GWAS of subjects who develop disease (see for example the ongoing Genetics of Subsequent Coronary Heart Disease consortium[2–4]) genetic analyses will more frequently be conducted using information about subjects who have received pharmacological (or other kinds of) treatments.…”