Genomic Risk Variants at 1p13.3, 1q41, and 3q22.3 Are Associated With Subsequent Cardiovascular Outcomes in Healthy Controls and in Established Coronary Artery Disease

Abstract

Background— Genome-wide association studies have identified gene variants associated with coronary artery disease risk; however, whether they affect disease progression is largely unknown. This study investigated associations between polymorphisms at 1p13.3 (rs599839), 1q41 (rs17465637), and 3q22.3 (rs9818870) and cardiovascular outcomes in healthy volunteers and in patients with established heart disease. Methods and Results— Canterbury Healthy Volunteer study (HV) (n=1649), Coronary Disease Cohort Study (CDCS) (n=1797), and Post-Myocardial Infarction study (PMI) (n=906) participants (New Zealand), were genotyped for rs599839, rs9818870, and rs17465637. Associations between genotype and anthropometric characteristics, neurohormonal analysis, echocardiography, and clinical outcomes over medium-long-term follow-up (median HV, 5.9 years; CDCS, 3.7 years; PMI, 11.3 years) were tested. At 1p13.3, HV and CDCS participants carrying 1 or more rs599839 G allele had a lower prevalence of dyslipidemia ( P ≤0.005) or lower levels of low-density lipoprotein ( P =0.031) and total ( P =0.004) cholesterol and/or less history of myocardial infarction ( P ≤0.04) compared with AA participants. Moreover, CDCS and PMI AG/GG participants had better cardiac function as indicated by echocardiography ( P ≤0.026), and fewer CDCS AG/GG participants were readmitted for a non-ST-segment elevation MI ( P =0.012) during follow-up. The polymorphism at 1q41 (rs17465637) was associated with better cardiovascular outcomes in the HV ( P =0.028) and PMI ( P =0.008) cohorts, and 3q22.3 (rs9818870) was a predictor of death/admission in the HV cohort ( P =0.045). Conclusions— These data suggest that coronary artery disease genomic risk variants at 1p13.3 and 1q41 are associated with subsequent clinical outcome in heart patients and confirm rs9818870 at 3q22.3 as a predictor of cardiovascular risk in individuals free of overt heart disease.

MRAS gene marker rs9818870 is not associated with acute coronary syndrome in the Czech population and does not predict mortality in males after acute coronary syndrome

“…13,20,[21][22][23] Four studies, with quite different designs, suggested a possible, but weak, association between the rs9818870 polymorphism at the MRAS locus and CVD risk. [8][9][10][11] In comparison with these studies, we failed to detect this polymorphism as a risk for ACS development in the Czech-Slavonic population. Furthermore, no effect was observed regardless of whether patients with a STE-MI or NSTEMI diagnosis were analyzed.…”

“…Three studies have been performed in Western European Caucasians (and the 4 th on Saudi-Arabians), which possibly indicates some differences both in genetic background and/or lifestyle. [8][9][10][11] Furthermore, previous studies have focused on different outcomes, e.g., arterial calcification or angiographically-proven atherosclerosis, which is in contrast to our study, which includes cases with clinically manifested atherosclerosis. The number of analyzed individuals is not an issue, as it is similar in our and other original studies.…”

“…8,9 Further, an association between the same locus and coronary arterial calcification was described, and Ellis et al identified rs9818870 as a CAD risk predictor in individuals without apparent heart disease from the pooled sample of the Coronary Disease Cohort Study (CDCS), Canterbury Healthy Volunteer study (HV) and PostMyocardial Infarction study (PMI). 9,10 Finally, a study of angiographed Saudi individuals suggests an association between the rs9818870 polymorphism and coronary artery disease, defined as narrowing of the coronary vessels by at least 50%. 11 We attempted to determine whether the rs9818870 variant at the MRAS locus would be associated with risk of ACS in the Czech Slavonic population, since, based on previous reports, the rs9818870 variant at the MRAS locus seems to be responsible for enhanced risk of coronary disease.…”

Association between 1p13.3 genomic markers and coronary artery disease: a meta-analysis involving patients and controls

“…These populations were listed as separate data sets; all data were extracted independently by two reviewers according to the inclusion criteria. All the consistent datasets by reviewers were Samani et al, 2007;Huang et al, 2008;Muendlein et al, 2009;MIGen Consortium, 2009;Wang et al, 2011;Xie et al, 2011;Guo et al, 2011;Ellis et al, 2011;Gigante et al, 2012;Esparragón et al, 2012;Lee et al, 2013. Discrepancies were recorded and solved by discussion with a third reviewer.…”

“…The second most replicated region for risk of coronary artery disease (CAD) is located near 1p13.3. A variant within or near the 1p13.3 region is associated with lower risk of both CAD and myocardial infarction (MI) (Wellcome Trust Case Control Consortium, 2007;Samani et al, 2007;Myocardial Infarction Genetics (MIGen) Consortium et al, 2009;Aulchenko et al, 2009;Muendlein et al, 2009;Ellis et al, 2011) primarily through its association with lowdensity lipoprotein (LDL) and cholesterol serum levels (Kathiresan et al, 2008a,b;Samani et al, 2008;Sandhu et al, 2008;Willer et al, 2008;Karvanen et al, 2009); lower levels of LDL, LDL triglycerides, and ApoB; and an increased radius of LDL particles (Aulchenko et al, 2009;Linsel-Nitschke et al, 2010;Kleber et al, 2010). Two leading SNPs mapping at this locus, rs646776T/C and rs599839A/G, explain 1% of the genetic variation in circulating LDL cholesterol (LDL-C) levels and rare alleles are linked to reduced LDL-C levels (Willer et al, 2009).…”