Association of a sequence variant in DAB2IP with coronary heart disease

Abstract

AimsA sequence variant, rs7025486[A], in DAB2IP on chromosome 9q33 has recently been associated with coronary heart disease (CHD). We sought to replicate this finding and to investigate associations with a panel of inflammatory and haemostatic biomarkers. We also sought to examine whether this variant, in combination with a chromosome 9p21 CHD variant (rs10757278) and the Framingham risk score (FRS), could improve the prediction of events compared with the FRS alone.Methods and resultsrs7025486 was genotyped in 1386 CHD cases and 3532 controls and was associated with CHD [odds ratio (OR) of 1.16, 95% confidence interval (CI) 1.05–1.29, P= 0.003]. Meta-analysis, using data from the original report and from genome-wide association studies in both the Wellcome Trust Case Control Consortium and the Cardiovascular Health Study, comprising 9968 cases and 20 048 controls, confirmed the association (OR of 1.10, 95% CI 1.06–1.14, P= 3.2 × 10−6). There was no association with a panel of CHD biomarkers, including any lipid, inflammation, or coagulation trait, nor with telomere length. Addition to the FRS of this variant plus rs10757278 on chromosome 9p21 improved the area under the receiver-operating characteristic curve (AROC) from 0.61 to 0.64 (P= 0.03) as well as improving the reclassification (net reclassification index = 11.1%, P= 0.007).ConclusionThis study replicates a previous association of a variant in DAB2IP with CHD. Addition of multiple variants improves the performance of predictive models based upon classical cardiovascular risk factors.

Genome-wide association studies of late-onset cardiovascular disease

“…[39, 40] A genetic variant in the DAB2IP gene associated with aortic aneurysms [41] has also shown suggestive evidence for association with lower limb ischemia and coronary artery disease. [41, 42] Furthermore, there is evidence that a missense variant in the nicotinic acetylcholine receptor gene cluster is associated with both nicotine dependence and lower limb ischemia, potentially corroborating the well-established role for smoking in this disease as for other atherosclerotic disease manifestations. [43] Recently, a polygenic score aggregating the effects of multiple individual genetic variants associated with CAD was also associated with both lower limb ischemia and ischemic stroke.…”

AIP1-Mediated Stress Signaling in Atherosclerosis and Arteriosclerosis

“…In supporting our mouse model studies, a recent genome-wide association study (GWAS) performed on 1,292 individuals with abdominal aortic aneurysm (AAA) and 30,503 controls, has identified a sequence variant in the AIP1 gene (rs7025486[A]) to be strongly associated with several vascular diseases (14, 46). In tests for association with specific vascular diseases, results show that AIP1 is associated with AAA, early-onset myocardial infarction (MI), venous thrombo-embolism, peripheral arterial disease (PAD), but not with intracranial aneurysm or ischemic stroke.…”

“…In tests for association with specific vascular diseases, results show that AIP1 is associated with AAA, early-onset myocardial infarction (MI), venous thrombo-embolism, peripheral arterial disease (PAD), but not with intracranial aneurysm or ischemic stroke. More notably, this association is independent on classical risk factors for arterial and venous diseases - that is, smoking, lipid levels, obesity, type 2 diabetes and hypertension (14, 46). It needs to be determined how this sequence variant in the intron affects the AIP1 gene expression.…”

Genomic Research to Identify Novel Pathways in the Development of Abdominal Aortic Aneurysm

“…We have found the same with regard to risk of CHD; approximately 40% of the population who carry 2 or more risk alleles at these loci have a hazard ratio for myocardial infarction of 1.7 compared to individuals carrying zero risk alleles [41]. This suggests that accumulation of small disturbances in different elements of the VSMC proliferation pathway combines to increase the risk of both atherosclerosis and AAA.…”