Abstract
BackgroundThe 9p21.3 locus is strongly associated with the risk of coronary artery disease (CAD) and with type 2 diabetes (T2D). We investigated the association of 9p21.3 variants with severity of CAD (defined by the number of vessel diseased [VD]) in the presence and absence of T2D.MethodsWe tested 11 9p21.3-variants for association in a white Italian study (N = 2,908), and carried out replication in 2 independent white populations, a German study (N = 2,028) and a Canadian Study (N=950). SNP association and permutation analyses were conducted.ResultsWe identified two 9p21.3-variants, rs4977574 (P < 4×10-4) and rs2383207 (P < 1.5×10-3) that were associated with severity of CAD in subjects without T2D. Association of rs4977574 with severity of CAD was confirmed in the Canadian Study. Results from subgroup analysis among patients with T2D showed an interaction between rs10738610 and T2D with P = 4.82×10-2. Further investigation showed that rs10738610 (P < 1.99×10-2) was found to be significantly associated with severity of CAD in subjects with T2D.ConclusionsThe 9p21.3 locus is significantly associated with severity of CAD. The number of associations of 9p21.3 variants with severity of CAD is variable to the presence and absence of T2D. In a CAD-susceptible region of 115 kb, there is only one variant associated with the severity of coronary vessel disease in the presence of type 2 diabetes.
Highlights
The 9p21.3 locus is strongly associated with the risk of coronary artery disease (CAD) and with type 2 diabetes (T2D)
Baseline characteristics by 9p21.3 genotypes for severity of CAD are shown in Additional file 1: Table S2
Results (Table 1) of the association analysis performed on the 11 Single nucleotide polymorphism (SNP) in the 2,908 Italian subjects showed that two SNPs in high Linkage disequilibrium (LD) (r2 > 0.93) were significantly (Pemp < 0.05) associated with severity of CAD after correcting for multiple testing
Summary
The 9p21.3 locus is strongly associated with the risk of coronary artery disease (CAD) and with type 2 diabetes (T2D). We investigated the association of 9p21.3 variants with severity of CAD (defined by the number of vessel diseased [VD]) in the presence and absence of T2D. Coronary artery disease (CAD) concomitant with type 2 diabetes (T2D) is the leading cause of cardiovascular (CV) morbidity and mortality. Severity of CAD is higher in diabetics than in non-diabetics, often presenting itself as a 3-vessel disease with a more diffuse coronary artery involvement. The combination of genetics, intermediate phenotypes, and environmental factors (such life-style) play a major role in the pathogenesis of CAD and T2D, including determining the conditions and stability of these diseases. The genetic architectures of CAD and T2D are dependent on multiple genetic and environmental triggers that may overlap or may be specific to each disease. The estimated heritability of CAD ranges from 30 to 60% [2,3], whereas of T2D is from 40 to 90% [4,5]
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